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CHAPTER 117 THROMBOCYTOPENIA

CHAPTER 117 THROMBOCYTOPENIA
Williams Hematology

CHAPTER 117 THROMBOCYTOPENIA

JAMES N. GEORGE
MUJAHID A. RIZVI

Platelet Kinetics

Platelet Distribution in the Body

Platelet Survival and Senescence

Platelet Heterogeneity
Spurious Thrombocytopenia (Pseudothrombocytopenia)
Thrombocytopenia due to Splenic Pooling (Sequestration)

Etiology and Pathogenesis

Clinical Features

Laboratory Features

Treatment and Prognosis
Thrombocytopenia Associated with Massive Transfusion
Hereditary and Congenital Thrombocytopenias

Fanconi Anemia

Thrombocytopenia with Absent Radius (TAR) Syndrome
Miscellaneous Thrombocytopenias Inherited as Autosomal Recessive Traits

May-Hegglin Anomaly

Alport Syndrome and its Variants
Miscellaneous Thrombocytopenias Inherited as Autosomal Dominant Traits

Wiskott-Aldrich Syndrome

Miscellaneous Thrombocytopenias Inherited as X-Linked Traits

Kasabach-Merritt Syndrome
Acquired Thrombocytopenias due to Decreased Platelet Production

Megakaryocytic Aplasia

Infection

Thrombocytopenia Associated with HIV Infection

Nutritional Deficiencies and Alcohol-Induced Thrombocytopenia
Acquired Thrombocytopenia due Primarily to Shortened Platelet Survival

Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndromes

Thrombocytopenia in Pregnancy

Idiopathic Thrombocytopenic Purpura

Cyclic Thrombocytopenia

Drug-Induced Thrombocytopenia

Neonatal Alloimmune Thrombocytopenia
Chapter References

This chapter describes the pathogenesis, clinical features, and management of patients with thrombocytopenia, defined as a platelet count less than 150,000/µl (150 × 109/liter). Since a number of different artifacts can produce pseudothrombocytopenia, the initial step in evaluating patients is to establish that the patient truly has thrombocytopenia. Thereafter, the thrombocytopenia can be categorized according to inheritance and whether there are defects in platelet production, platelet removal from the circulation, and/or platelet sequestration in the spleen. Platelet kinetic studies have provided useful information on determining the mechanism(s) of thrombocytopenia, but they remain research tools. It is important to construct a broad differential diagnosis for thrombocytopenia, since relatively rare, inherited disorders may be mistaken for autoimmune thrombocytopenia and result in inappropriate therapy.
Hereditary thrombocytopenias include a variety of disorders such as Fanconi anemia, thrombocytopenia with absent radii, May-Hegglin anomaly, Alport syndrome, and Wiskott-Aldrich syndrome. Thrombocytopenia can also be due to a variety of viral, bacterial, and parasitic infections; HIV infection commonly results in thrombocytopenia through multiple mechanisms. Nutritional deficiencies and alcohol ingestion can also cause thrombocytopenia.
TTP-HUS causes thrombocytopenia and ischemic vascular damage as a result of microvascular platelet-mediated thrombosis. The precise mechanism remains unknown, but abnormalities in von Willebrand factor proteolytic processing appear to contribute to some forms of the disorder. TTP-HUS has been associated with Shiga-toxin-producing Escherichia coli infection, especially in children, as well as other infections (including HIV), drugs, marrow transplantation, cancer, autoimmune disease, and pregnancy. Plasma exchange has dramatically improved the outcome of TTP-HUS and is the mainstay of therapy.
A number of different disorders may result in thrombocytopenia in pregnancy, including gestational thrombocytopenia, preeclampsia, and the HELLP syndrome. ITP is usually an acute, self-limited disorder in children. In adults, it is more often a chronic disorder commonly associated with other autoimmune phenomena. Glucocorticoids, IVIg, anti-Rh(D) globulin, and splenectomy are usually effective in securing hemostatically adequate platelet counts in patients with ITP.
Many different drugs can cause thrombocytopenia, and, even though the mechanisms remain obscure, most patients respond well to discontinuing the drug. Heparin-induced thrombocytopenia, which appears to be due to antibodies directed against the heparin-platelet factor 4 complex in most cases, can be associated with both venous and arterial thrombosis, as well as disseminated intravascular coagulation.
Neonatal alloimmune thrombocytopenia, caused by the transplacental passage of maternal antibodies to fetal platelet protein polymorphisms inherited from the father, can cause profound thrombocytopenia and severe hemorrhage both in utero and in the neonatal period. Posttransfusion purpura, in which the platelet count decreases dramatically 5 to 15 days after a blood transfusion, also involves an immune response to platelet protein polymorphisms, but it is complicated by a poorly understood mechanism that results in clearance of the patient’s own platelets.
A systematic evaluation of patients with thrombocytopenia almost always reveals the etiology, thus laying the groundwork for instituting appropriate therapy.
Thrombocytopenia is defined as a platelet count less than 150,000/µl (150 × 109/liter). Multiple mechanisms can cause, or contribute to, the development of thrombocytopenia, including decreased platelet production, increased platelet removal from the circulation, and abnormal sequestration of platelets in the spleen. In many cases of thrombocytopenia, more than one mechanism may be operative. In addition, a number of phenomena can result in a spuriously low platelet count (pseudothrombocytopenia) as measured by automated platelet counters. Disorders causing thrombocytopenia may be due to inherited and/or acquired abnormalities. This chapter first discusses platelet kinetic measurements, the major method for determining the mechanism of thrombocytopenia, and then discusses the disorders that can cause thrombocytopenia based on a combination of whether the disorder is inherited or acquired and the dominant mechanism of thrombocytopenia.

Acronyms and abbreviations that appear in this chapter include: DIC, disseminated intravascular coagulation; EDTA, ethylenediaminetetraacetic acid; ELISA, enzyme-linked immunosorbent assay; HELLP, microangiopathic hemolysis (H), elevated liver enzymes (EL), and low platelet (LP) counts; HIV, human immunodeficiency virus; ITP, idiopathic thrombocytopenic purpura; IVIg, intravenous immunoglobulin;M-CSF, macrophage colony stimulating factor; MAIPA, monoclonal antibody-immobilized platelet protein assays; NATP, neonatal alloimmune thrombocytopenia;PF4, platelet factor 4; PTP, posttransfusion purpura; SLE, systemic lupus erythema-tosus; SPRCA, solid-phase red cell adherence assays; TTP, thrombotic thrombocytopenic purpura; TTP-HUS, thrombotic thrombocytopenic purpura-hemolytic uremic syndrome; vWf, von Willebrand factor.

PLATELET KINETICS
There are three fundamental mechanisms of thrombocytopenia: decreased platelet production, increased platelet destruction, and pooling of a larger than normal fraction of platelets within the spleen. Platelet kinetic studies help to define the mechanism responsible for thrombocytopenia.
Studies employing an acidified citrate anticoagulant and 51Cr-chromate to label platelets yield platelet survival patterns that are nearly linear, indicating that senescence is the major mechanism of platelet removal from the circulation. However, the slight deviation from a linear equation supports the current view that while the majority of platelets survive to senescence, some are randomly removed from the circulation, presumably in the support of vascular endothelium.1 During the 1970s, 51Cr was replaced by 111In-oxine as the radiolabel of choice for platelet kinetic studies because of the latter’s greater labeling efficiency, greater isotope energy, and shorter half-life, and it remains the current standard for measurement of platelet recovery and survival.2,3 Current methods still require platelet isolation from whole blood, a centrifugation process that usually results in the loss of approximately one-third of the platelets,4 and the recovered platelets may be activated by the labeling procedure. These variables are difficult to standardize and may profoundly affect platelet recovery and survival. Therefore platelet kinetic measurements remain investigational and are not used for clinical evaluation of thrombocytopenic patients.
PLATELET DISTRIBUTION IN THE BODY
In normal subjects, about one-third of radiolabeled, reinfused platelets are sequestered in the spleen,5 indicating that at any time about one-third of the total body platelet mass is in the spleen. In contrast, approximately 100 percent of infused platelets remain in the circulation in splenectomized subjects (Fig. 117-1).5,6 Platelets within the spleen are in equilibrium with the peripheral circulation,7 as demonstrated by both the transience of the sequestration of radiolabeled platelets upon reinfusion8 and the shift of platelets from the splenic pool following removal of peripheral blood platelets by apheresis.5,7,9,10 The normal spleen receives about 5 percent of the total blood flow; some passes directly through capillaries to splenic veins, but most is diverted into the sluggish circulation of the splenic sinusoids in the red pulp before returning to the venous system.11 Based on the initial time required for equilibration of radiolabeled platelets, the time required for platelets to pass through the normal spleen has been estimated as 10 to 12 min.8,12,13 This slow transport may simply be a function of the platelets’ smaller size, or it may reflect a specific interaction between platelets and the splenic architecture. Epinephrine infusion can increase the platelet count by 30 to 40 percent in normal subjects by a-adrenergic stimulation that diminishes splenic blood flow.5,11 In contrast, b-adrenergic stimulation by isoprenaline causes a slight decrease in the platelet count.14 After splenectomy, a transient thrombocytosis is common, but the steady-state platelet count in splenectomized subjects is not usually dramatically elevated unless anemia persists.15

FIGURE 117-1 Platelet recovery and survival in patients with splenomegaly and hypersplenism. Left: recovery of 51Cr-labeled platelets in the circulation 2 h after injection of autologous radiolabeled platelets. Among the 15 patients with splenomegaly, 11 had liver cirrhosis; others had chronic lymphocytic leukemia, infectious mononucleosis, and polycythemia vera. Right: survival pattern of autologous 51Cr-labeled platelets in a normal subject, a patient with ITP, and a patient with hypersplenism due to congestive splenomegaly. (From Aster5 and Ginsberg AD, Aster RH: Disease-a-Month, September, 1970.)

PLATELET SURVIVAL AND SENESCENCE
The most commonly utilized method for analyzing platelet survival curves is the “multiple-hit model,”1 implying that the platelet is subject to multiple environmental events before it is removed from the circulation. The combined effects of intrinsic senescence and random platelet removal can be appreciated from clinical observations. During the acute thrombocytopenic phase of quinidine-induced thrombocytopenia, platelet disappearance is rapid and not linear, consistent with immune injury and destruction.16 Immediately after clearance of the quinidine, the newly produced platelets survive for about 7 days and then are cleared in a short period of time (Fig. 117-2).16 This observation on a cohort of young platelets is consistent with aging as the major factor in platelet disappearance. Platelet survival after normalization of the platelet count demonstrated the typical, nearly linear disappearance pattern. On the other hand, the contribution of random removal of platelets in the process of hemostasis is emphasized in patients who are thrombocytopenic due to marrow failure. Figure 117-3 demonstrates that among patients with aplastic anemia, platelet survival is nearly normal when platelet counts are nearly normal, but that with increasingly severe thrombocytopenia platelet survival is progressively decreased. These data suggest a fixed requirement of approximately 7000 platelets/µl per day (7 × 109/liter per day) for support of vascular integrity and provide an explanation for observations of decreased platelet survival in thrombocytopenic patients whose primary disorder is failure of platelet production.17,18 As the total number of platelets diminishes with thrombocytopenia of any cause, the number that are removed to maintain vascular integrity represents a greater fraction of the total, resulting in a nonlinear disappearance in labeling studies. In a normal individual with a platelet count of 300,000/µl (300 × 109/liter), the fixed consumption of 7000/µl (7 × 109/liter) per day of platelets is only a small fraction of the daily turnover ascribable to senescence, approximately 40,000/µl (40 × 109/liter) per day. In contrast, when the platelet count drops below about 80,000/µl, the fixed consumption of 7000 platelets per µl actually exceeds the number of platelets that would be removed by a mechanism exclusively based on senescence.

FIGURE 117-2 Platelet survival studies in patients with quinidine-induced thrombocytopenia. A patient with a quinidine-associated antibody was observed for survival of 51Cr-labeled platelets on three separate occasions. The open circles demonstrate the survival of platelets immediately after quinidine administration, with dramatically shortened life span. The closed circles demonstrate the survival after recovery from drug-induced thrombocytopenia, when most of the circulating platelets will have been recently produced, and indicates the survival of a young cohort. The triangles show the platelet survival in the patient after recovery, which is a normal, linear survival curve. (Reprinted from Harker16 with permission.)

FIGURE 117-3 The relationship between the survival time of 111In-oxine-labeled autologous platelets and the circulating platelet count. The closed circles are data from patients with megakaryocytic hypoplasia; the open circles are data from patients with ITP. Platelet survival strongly correlates with platelet count in patients with megakaryocytic hypoplasia but not in patients with ITP. Analysis of the data is consistent with a fixed requirement of platelets for support of vascular integrity. (Reproduced from Tomer et al.17)

PLATELET HETEROGENEITY
An indirect measure of platelet production, analogous to the reticulocyte count to assess red cell production, is the flow cytometric assay for platelet RNA content.19,20 This assay assumes that platelets are similar to reticulocytes, in that only the youngest cells still have detectable intracellular RNA. Increased concentrations of a-granule IgG (as well as albumin and other plasma proteins) may also correlate with younger mean platelet age, and this may be an explanation for the consistent observation of high total platelet IgG concentrations in patients with thrombocytopenia due to increased platelet destruction by either immunologic or nonimmunologic mechanisms.21
Clinical evidence suggests that young platelets are more hemostatically effective than old platelets. For example, a patient with ITP and severe thrombocytopenia often will not have serious bleeding, suggesting that the young platelets present in these patients are more hemostatically capable than the mixed-aged population found in normal individuals. These clinical observations are supported by experimental evidence in dogs that aged platelets are less responsive to thrombin than younger platelets.41
SPURIOUS THROMBOCYTOPENIA (PSEUDOTHROMBOCYTOPENIA)
The initial observation of thrombocytopenia, based on a platelet count reported by an automated particle counter, must be confirmed by microscopic examination of the blood film. False diagnoses of thrombocytopenia have led to serious problems: postponed surgery, discontinued medications, and even unnecessary glucocorticoid therapy and splenectomy.22 Pseudothrombocytopenia occurs in both healthy subjects and patients, and it need not be associated with any particular disorder or medication.23
The most common artifact causing pseudothrombocytopenia is in vitro clumping of platelets in blood samples collected into EDTA anticoagulant. Alternatively, instead of clumping one to another, platelets may attach to leukocytes (platelet-leukocyte rosettes, platelet satellitism, or platelet-leukocyte adherence phenomenon). Platelet satellitism is not truly distinct from simple platelet agglutination, as some patients incorporate neutrophils within EDTA-dependent platelet clumps, and the adherence to leukocytes usually requires EDTA anticoagulant and low temperatures.24,25 Typically platelets bind around the periphery of neutrophils (rosette), but they may also form rosettes with monocytes.26
Table 117-1 presents data from six surveys that reported a consistent incidence of pseudothrombocytopenia of 0.09 to 0.21 percent.27,28,29,30,31 and 32 Platelet clumping is detected by examination of the blood film made from the EDTA-anticoagulated sample, demonstrating more platelets than expected from the reported count, with many in large clumps (Fig. 117-4). Cell counters merely define platelets as particles between 2 and 20 fl. Platelet clumps often appear in the leukocyte size histogram as particles less than 35 fl, the size of the smallest lymphocytes, but they may be large enough to be counted as leukocytes and thus may cause a false elevation of the white cell count.30 Similar blood count abnormalities occur in patients with giant platelets (Fig. 117-4). As the anticoagulated blood sample stands for a longer time, platelet clumping increases; this may make the artifact more recognizable or the leukocyte histogram artifact may disappear as the clumps become too large to be recorded.28

TABLE 117-1 FREQUENCY OF PSEUDOTHROMBOCYTOPENIA CAUSED BY EDTA-DEPENDENT PLATELET AGGLUTININS

FIGURE 117-4 Blood films of platelet abnormalities associated with pseudothrombocytopenia. Left: clumped platelets from EDTA-anticoagulated blood with an EDTA-dependent platelet agglutinin. Right: giant platelets from a patient with Bernard-Soulier syndrome. (Reproduced with permission from Hoffbrand AV, Pettit JE: Sandoz Slide Atlas of Clinical Hematology, Sandoz Pharmaceutical Corp, 1990.)

Correct platelet counts may be obtained by collecting the blood sample in citrate, a weaker chelator of calcium, but some platelet agglutinins are active in any anticoagulant.23 Therefore in some patients an accurate count can only be obtained by sampling blood directly into ammonium oxalate diluting fluid and manually counting the platelets by phase microscopy.
Typically the artifact is most prominent in the presence of EDTA, whether the abnormality is platelet clumping or platelet satellitism.24,25 In most series, some patients also demonstrate some platelet clumping in other anticoagulants, such as citrate, acid-citrate dextrose, oxalate, and heparin.23,28,30 In most patients, the clumping activity is greater at temperatures less than 37°C, with maximum activity at 22°C or 4°C.23,25 Platelet clumping occurs within a few minutes and increases over 60 to 90 min in most patients, but one report described three patients in whom no platelet clumping occurred until after 90 min.29 Patients whose platelet-clumping activity is more pronounced at lower temperatures are often described as having “platelet cold agglutinins,” although temperature dependence is also a property of many agglutinins described only as EDTA-dependent.
Platelet clumping is caused by an immunoglobulin, presumably an antibody recognizing an epitope exposed on platelets by the in vitro conditions in anticoagulated blood. The antibodies are usually IgG, though both IgA and IgM antibodies have been described.22,23,33 The antibody titers are typically low, but in one patient12 a monoclonal IgM protein agglutinated platelets at a titer of 1:16,384.33 Direct interaction with platelet antigen is demonstrated by the activity of F(ab’)2 fragments.22 The platelet epitope appears to be on GPIIb/IIIa in many, if not all, patients, as demonstrated by the absence of clumping with platelets from patients with Glanzmann thrombasthenia24,34 and by immunochemical techniques.35 These observations are consistent with the ability of EDTA to remove calcium from the GPIIb/IIIa complex36 and expose neoepitopes on GPIIb.37 It is unlikely that the EDTA needs to dissociate the GPIIb/IIIa complex, since the GPIIb/IIIa complex is more stable in EDTA at lower temperatures, whereas clumping is facilitated at low temperatures.36 In one series of 88 patients with EDTA-dependent pseudothrombocytopenia, 56 also had anticardiolipin antibodies; adsorption of these sera on cardiolipin removed the EDTA-dependent platelet clumping activity, suggesting that there may be additional epitopes on platelets.38 Antibodies mediating platelet-neutrophil satellitism appear to be able to react with both an epitope on platelet GPIIb/IIIa and the neutrophil FcgIII receptor, presumably via the Fab and Fc regions of the molecule, respectively.24
Platelet agglutinins appear to have no clinical importance; no abnormalities of hemostasis or thrombosis have been reported.23 There are no complications when platelet agglutinins are discovered during pregnancy.39 Neonatal pseudothrombocytopenia due to an EDTA-dependent agglutinin was observed in one infant born to a mother with pseudothrombocytopenia, while two other infants born to other women with pseudothrombocytopenia had normal platelet counts in EDTA.39 Although some reports have suggested that the occurrence of these agglutinins is more frequent in ill, hospitalized patients, or in patients with autoimmune disorders,27,28,40 others have found no correlation with any illness or even with the presence or absence of illness.23,29,30 Sex and age incidences probably merely reflect the populations studied. Serial observations have usually demonstrated persistence of the platelet clumping.23,28,29,40
THROMBOCYTOPENIA DUE TO SPLENIC POOLING (SEQUESTRATION)
ETIOLOGY AND PATHOGENESIS
Platelet kinetic studies have demonstrated the reversible pooling of a large fraction, up to 90 percent, of the total body platelets within the spleen as contributory to the thrombocytopenia in patients with splenomegaly.5,8 This process may be described as an exaggeration of the normal splenic pooling of approximately one-third of the platelet mass. Splenic pooling is demonstrated by the disappearance of radiolabeled platelets from the circulation during the first minutes after injection and their accumulation by the spleen.5 Following equilibration within the splenic circulation, platelet survival is often normal (Fig. 117-1) or may be moderately reduced.42 Even though the peripheral blood platelet count may be only 20 percent of normal, the total number of platelets in the circulation, counting those pooled in the spleen, is normal (Table 117-2). Platelet production, estimated by dividing the total body platelet mass by the platelet life span, is usually normal.5 Therefore the thrombocytopenia of hypersplenism can be described as the displacement of a majority of platelets from the peripheral circulation into a slowly exchangeable splenic pool. Splenic pooling must be distinguished from increased removal of platelets in the spleen, as occurs in idiopathic thrombocytopenic purpura. Selective transient sequestration of platelets, in contrast to red cells, may result from a sieving effect that causes platelets, because of their small size, to take a more tortuous course through the splenic sinusoids, or platelets may transiently and reversibly adhere to splenic macrophages.8,43

TABLE 117-2 TOTAL BODY PLATELET MASS IN NORMAL SUBJECTS AND PATIENTS WITH THROMBOCYTOPENIA DUE TO SPLENIC POOLING*

Evidence supporting splenic pooling as a mechanism of thrombocytopenia is compelling. (1) The fraction of radiolabeled platelets that can be recovered from the circulation after infusion into patients with hypersplenism is very small, from 10 to 30 percent, in contrast to values of 60 to 80 percent in normal subjects and 90 to 100 percent in asplenic patients (Fig. 117-1).5,4 (2) Intravenous epinephrine causes constriction of the splenic artery, with a fivefold decrease in splenic blood flow and passive emptying of the spleen. This results in an immediate increase in platelet count in patients with hypersplenism that is proportionately greater than the 30 to 40 percent increase seen in normal subjects.5,11,15 Epinephrine causes a significant but minimal increase in platelet counts in asplenic subjects.15 The epinephrine effect appears to be mediated by a-adrenergic receptors. Stimulation of b-receptors with isoprenaline infusion causes a slight decrease in the platelet count that is inhibited by b-adrenergic blockade with metoprolol or propranolol; b blockade itself causes a slight increase in the platelet count.14 (3) Large quantities of platelets, three to seven times the number present in the peripheral circulation, can be flushed from enlarged spleens after surgical removal.5 Removal of large numbers of platelets from the peripheral circulation by apheresis is rapidly and effectively followed by replenishment from the splenic pool, without resulting in thrombocytopenia.8,10
The lack of an increase in platelet production in response to the thrombocytopenia associated with increased splenic pooling indicates that the feedback mechanisms controlling platelet production do not respond to the peripheral platelet count. This is consistent with a mechanism involving clearance of the major growth factor controlling platelet production, thrombopoietin, by platelet binding and internalization, in which case the total platelet mass (which is normal in states associated with splenic pooling) is the controlling factor (see Chap. 110).
Transient thrombocytopenia occurs during hypothermia, at body temperatures below 25°C, in both animals and humans.45 Thus, there is less severe thrombocytopenia in cardiac surgery patients supported by normothermic systemic perfusion (35° to 37°C) compared to moderately hypothermic systemic perfusion (25° to 29°C).46 In hypothermic dogs, radiolabeled platelets are sequestered in the spleen, liver, and other organs; the platelets return to the circulation when normal body temperature is restored.45,47 Pooling of platelets in splenic sinusoids occurs in hibernating, hypothermic ground squirrels.48 The clinical relevance of these observations is illustrated by reports of patients, often elderly, who are hypothermic after periods of unconsciousness in inadequately heated rooms. In one report, a 69-year-old woman had 13 admissions over an 8-year period with repeated hypothermia, 31° to 34°C, and she was thrombocytopenic (platelet counts of 7000/µl to 39,000/µl) on each admission; with no therapy other than rewarming, platelet counts returned to normal in 4 to 10 days.49 However, a review of 75 patients admitted with a diagnosis of hypothermia and temperatures of 26° to 35°C demonstrated that only three patients were thrombocytopenic.49
CLINICAL FEATURES
Thrombocytopenia associated with hypersplenism is often of no clinical importance; signs and symptoms are related to the primary disorder, and bleeding manifestations are usually primarily the result of coagulation abnormalities caused by the primary liver disease. This is consistent with the relatively moderate degree of thrombocytopenia, the near-normal total body content of platelets (Table 117-2),5 and the ability to mobilize platelets from the spleen to replenish losses.10
The most common disorder causing thrombocytopenia due to splenic pooling is chronic liver disease with portal hypertension and congestive splenomegaly (see Chap. 125). In patients with cirrhosis and portal hypertension, moderate thrombocytopenia is the rule. Any other disease associated with an enlarged, congested spleen can similarly be associated with mild or moderate thrombocytopenia, such as in homozygous sickle cell disease in young children (before splenic atrophy occurs as a result of repeated infarctions); hemoglobin C and SC diseases; thalassemia major; chronic infections; Gaucher disease; myelofibrosis; and lymphoma. The degree of thrombocytopenia is usually correlated with the size of the spleen,5,50,51 and the spleen is usually palpable. However, in some patients an enlarged spleen may not be palpable, and some experts believe that thrombocytopenia may be attributed to hypersplenism even in the absence of an enlarged spleen. In some of these disorders, relative failure of platelet production may contribute to the thrombocytopenia, either due to marrow involvement or due to severe liver disease with decreased thrombopoietin synthesis.52
LABORATORY FEATURES
The platelet count is rarely less than 40,000/µl. In patients with very large spleens and more severe thrombocytopenia, a marrow infiltrative process or severe liver disease may be present, contributing an additional component of decreased platelet production. More severe thrombocytopenia should also trigger a search for additional etiologies, such as sepsis.
TREATMENT AND PROGNOSIS
Since thrombocytopenia due to splenic pooling is rarely of clinical importance, no treatment is indicated. When splenectomy is performed for another purpose, however, the platelet count predictably returns to normal and thrombocytosis may even occur.5 Platelet counts may also return to normal in patients following surgical correction of portal hypertension by portal-systemic shunting.53 Platelet transfusions are usually not needed and rarely produce significant increases in the peripheral platelet count since as many as 90 percent of the transfused platelets may be sequestered in the spleen.
THROMBOCYTOPENIA ASSOCIATED WITH MASSIVE TRANSFUSION
In the era before routine platelet transfusion, thrombocytopenia often accompanied severe hemorrhage with transfusion of stored blood.54 The severity of thrombocytopenia is related to the number of red cell transfusions but is not simply a function of the dilution factor of massive transfusion. Platelet counts may be higher than predicted, possibly by release of platelets from the splenic pool, or they may be less than predicted, because of consumption in microvascular lesions.55 A deficiency of fibrinogen develops earlier than thrombocytopenia when major loss is replaced by red cell concentrates and plasma substitutes.56 A study of patients requiring massive transfusion, defined as 10 or more red cell units within 24 h, demonstrated that mild throm-bocytopenia (47,000/µl to 100,000/µl) occurred in all after transfusion of 15 red cell units, and more severe thrombocytopenia (25,000µl to 61,000/µl) developed after 20 red cell units.56,57 Disseminated intravascular coagulation, triggered by the disease responsible for the blood loss or the hypotension that commonly occurs with massive blood loss, may also contribute to the thrombocytopenia. Management of the thrombocytopenia depends on the clinical condition and the severity of the thrombocytopenia. It does not appear to be desirable to routinely transfuse platelets in a fixed ratio to packed red blood cells.
HEREDITARY AND CONGENITAL THROMBOCYTOPENIAS
Thrombocytopenia at birth or during infancy may be caused by acquired disorders (e.g., congenital syphilis); developmental abnormalities that affect platelet survival (e.g., the Kasabach-Merritt syndrome); or inherited disorders of platelet production, structure, and/or function. Table 117-3 lists the recognized disorders in the latter two categories. Thrombocytopenia may be the only abnormality or it may be associated with other abnormalities. In the Bernard-Soulier syndrome, the thrombocytopenia is associated with a well-characterized abnormality in the membrane glycoprotein Ib/IX complex, resulting in abnormal platelet functions (see Chap. 119). The descriptions of platelet function abnormalities in the other disorders are less well defined and of uncertain clinical importance. In some patients, thrombocytopenia is discovered in infancy; in others it may not be discovered until a later age, even adulthood. In these older patients a mistaken diagnosis of ITP is often made, resulting in inappropriate glucocorticoid treatment and splenectomy. Hereditary thrombocytopenia should be particularly suspected in children with moderate thrombocytopenia in whom the initial impression is chronic refractory ITP.58 Family studies can be particularly helpful in establishing the diagnosis.

TABLE 117-3 HEREDITARY AND CONGENITAL THROMBOCYTOPENIAS

FANCONI ANEMIA
ETIOLOGY AND PATHOGENESIS
Fanconi anemia is an autosomal recessive disorder characterized by severe aplastic anemia in more than 90 percent of homozygotes, usually beginning at age 8 to 9 years.59,60 Cells from homozygous patients demonstrate increased sensitivity to the induction of chromosomal breakage by DNA cross-linking agents such as diepoxybutane and mitomycin C. Diverse congenital abnormalities may occur, including short stature, skin hyperpigmentation, skeletal anomalies including hypoplasia of the thumb and radius (similar to the thrombocytopenia with absent radius syndrome described below), and anomalies of the genitourinary, cardiac, and central nervous systems.59 In patients over 16 years of age, the most common anomalies are short stature and skin hyperpigmentation, but these may not be initially recognized in patients presenting with hypoplastic thrombocytopenia or pancytopenia. For example, three siblings with Fanconi anemia diagnosed at ages 22 to 36 years had no physical anomalies.61 Patients with Fanconi anemia are at increased risk of developing leukemia and other malignancies.62 The disorder is generally fatal unless corrected by allogeneic marrow transplantation.63
THROMBOCYTOPENIA WITH ABSENT RADIUS (TAR) SYNDROME
The syndrome of thrombocytopenia with absent radius (often referred to by its acronym, TAR) is usually noted at birth because of the skeletal anomalies; the thrombocytopenia may not be severe and thus may be overlooked until adulthood.64
ETIOLOGY AND PATHOGENESIS
Family members may be affected in a pattern suggesting an autosomal recessive trait, but the lack of consanguinity and occasional reports of affected persons in consecutive generations65 implies a more complex pattern of inheritance, such as double heterozygosity.66,67 and 68 The syndrome is two to three times as common as Fanconi syndrome,67 suggesting that the gene frequency may be sufficiently high in the population as to occur often without consanguinity. Thrombopoietin production is normal, and the thrombopoietin receptor is present on platelets, but signal transduction in response to thrombopoietin is defective.69
CLINICAL FEATURES
The syndrome is defined by the absence of both radii, but other skeletal anomalies are common: Ulnas are absent or abnormal in most patients, and the humeri, bones of the shoulder girdle, and bones of the feet are abnormal in many patients.68,70 One-third of patients will have congenital heart anomalies, most commonly tetralogy of Fallot and atrial septal defects.70 Allergy to cow’s milk is common, with resulting gastrointestinal symptoms.67
LABORATORY FEATURES
Platelet counts are variable. The most severe thrombocytopenia occurs during infancy, and most babies have purpura at birth.70 In the initial review describing 40 patients, only 2 were older than age 4 months at diagnosis (these patients were 2 and 21 years old). During the first year of life, platelet counts are typically 15,000 to 30,000/µl, but they may decrease during periods of stress, such as surgery and infection. It is during these periods of more severe thrombocytopenia that leukemoid responses, white cell counts over 35,000/µl, with immature granulocytes, occur in more than half of infants.67 Eosinophilia is also common, probably related to the milk allergy.67 Marrow examination demonstrates diminished or absent megakaryocytes, and erythroid hypoplasia may also be present.70
TREATMENT, COURSE, AND PROGNOSIS
Treatment with glucocorticoids, splenectomy, or intravenous IgG usually has no effect.70 Among the 15 deaths reported in the initial review of 40 patients, 10 occurred before age 4 months and 4 others occurred between ages 4 and 14 months; 13 of these deaths were due to hemorrhage, 8 from intracranial hemorrhage. One death occurred later from sepsis in a splenectomized patient.70 If patients can be sustained during the first year or two of life, the platelet count usually recovers and survival is normal.67 In a review of 77 patients, only one death related to thrombocytopenia occurred after the age of 14 months.68 Platelet counts may vary during adulthood, but symptoms other than menorrhagia are unusual.67,70 Rare patients may present as adults, with significant numbers of marrow megakaryocytes; splenectomy may be effective.71
MISCELLANEOUS THROMBOCYTOPENIAS INHERITED AS AUTOSOMAL RECESSIVE TRAITS
The Bernard-Soulier and gray platelet syndromes are primarily characterized by their abnormalities of platelet structure and function and are discussed in Chap. 119 (Fig. 117-4). Many isolated kindreds with hereditary or congenital thrombocytopenia have been reported. In this latter group, marrow megakaryocytes were either reduced72 or increased,73 and platelet survival was either decreased73 or normal.74 Splenectomy was effective in one family.73
MAY-HEGGLIN ANOMALY
ETIOLOGY AND PATHOGENESIS
The May-Hegglin anomaly is defined by autosomal dominant inheritance of giant platelets and characteristic leukocyte inclusion bodies; thrombocytopenia is common but may be absent. Thus, in an early comprehensive review, only 10 of 25 patients were thrombocytopenic. Since the disorder is commonly asymptomatic, the diagnosis may not be made until adulthood, as in 4 of the 25 patients in the early review.75 A later report of 15 patients found that thrombocytopenia was rarely severe, most patients had no symptoms and were discovered incidentally, and no patients died as a result of this disorder.76 In these and other patients with giant platelets, the total platelet mass (estimated by the product of platelet number and platelet volume) is more normal than the platelet count, and total platelet mass may more accurately predict hemostatic competence. Coexpression of May-Hegglin anomaly with hereditary nephritis in one family77 suggests an overlap with variants of Alport syndrome, described in “Alport Syndrome and Its Variants,” below. With the current use of automated cell counters, it is likely that more patients will be discovered, primarily by falsely low platelet counts and abnormal platelet histograms resulting from the presence of giant platelets (Fig. 117-4).
LABORATORY FEATURES
Since automated platelet counters may not identify giant platelets as platelets, patients may have true thrombocytopenia, pseudothrombocytopenia, neither, or both. Platelet ultrastructure is normal. In one analysis of platelet volume, most were between 30 and 80 fl, with about 25 percent even larger than red cells78; therefore the mean platelet volume reported by routine clinical laboratory analysis will be inaccurate. Platelet membrane proteins are normal78; marrow megakaryocytes are normal in number and appearance75; and bleeding times are normal or prolonged.76 The defining abnormality is the unique inclusion body found in most neutrophils and eosinophils, and some monocytes, which is similar in appearance on routine blood smears to toxic Döhle bodies that occur during acute infections. However, in contrast to Döhle bodies, which contain segments of rough endoplasmic reticulum arranged in parallel stacks, the May-Hegglin inclusions are composed of parallel 7- to 10-nm filaments oriented as spindle-shaped bodies.76,79
TREATMENT, COURSE, AND PROGNOSIS
Usually no treatment is needed, and surgery, pregnancies, and deliveries are uncomplicated, though platelet transfusions are commonly given.75,76 Glucocorticoids, IVIg, and splenectomy have all been tried, usually because of an initial mistaken diagnosis of ITP, without effect.76
ALPORT SYNDROME AND ITS VARIANTS
Alport syndrome is the association of hereditary nephritis and deafness.80 In a number of families, this syndrome has been associated with thrombocytopenia and giant platelets.81 In one family, nephritis, deafness, and macrothrombocytopenia were accompanied by congenital cataracts (another potential feature of Alport syndrome) and leukocyte inclusions resembling Döhle bodies and the May-Hegglin inclusions.79
Severe thrombocytopenia is common. Platelets are large, with mean diameters of 4 to 12 µm and mean volumes of 20 to 27 fl,79,81,82 but their ultrastructure is normal.81,82 Marrow megakaryocytes are normal.81,82 Bleeding times are normal or slightly prolonged; the latter may be caused by uremia rather than thrombocytopenia.81 Platelet aggregation was abnormal in one report81 and normal in another.79
Treatment with glucocorticoids and splenectomy has no effect on platelet counts. In all patients, the major cause of morbidity and mortality is progressive renal failure.81,82
MISCELLANEOUS THROMBOCYTOPENIAS INHERITED AS AUTOSOMAL DOMINANT TRAITS
Many families have been reported with the autosomal dominant inheritance of isolated thrombocytopenia, some with as many as 22 affected family members spanning five generations83 and 18 family members spanning six generations.84 The clinical data are heterogeneous, but most patients have only moderate thrombocytopenia with minimal symptoms, normal platelet morphology, and normal bone marrow megakaryocytes.83,85,86 In some families large platelets have been observed,86,87 and some patients have abnormal platelet function studies.83,87 One report described a family with Wiskott-Aldrich syndrome inherited in an autosomal dominant manner.88 In most patients platelet function is normal,83 platelet survival is normal, and the thrombocytopenia is caused by ineffective platelet production.83,87,89 Most patients are discovered as adults and have minimal or no bleeding symptoms, though some have severe hemorrhagic episodes.84 A benign syndrome of uncertain inheritance with mild thrombocytopenia, large platelets, and no clinical symptoms has been described in persons of Mediterranean ethnic origin.90
Patients with inherited thrombocytopenia may not be rare. One report describes 83 patients who were typically referred with the diagnosis of refractory ITP, but in whom family studies demonstrated autosomal dominant thrombocytopenia.58 All patients had large platelets, normal marrow megakaryocytes, and normal platelet survival; none had Döhle bodies. Sixty-three of the 83 patients were initially discovered to be thrombocytopenic when they were over 15 years old. Bleeding symptoms were minimal, platelet counts were greater than 50,000/µl in 59 patients, and treatment with glucocorticoids (28 patients), splenectomy (10 patients), and other modalities for the presumed diagnosis of ITP had no effect.
WISKOTT-ALDRICH SYNDROME
Wiskott-Aldrich syndrome is an X-linked immunodeficiency syndrome originally described with thrombocytopenia, eczema, and immunodeficiency.91 However, only a minority of identified cases have the classic clinical triad of thrombocytopenia with small platelets, recurrent otitis media, and eczema. Since the platelets of patients with Wiskott-Aldrich syndrome have qualitative abnormalities, this entity is discussed in Chap. 119.
MISCELLANEOUS THROMBOCYTOPENIAS INHERITED AS X-LINKED TRAITS
Other families with X chromosome–linked thrombocytopenia have been reported, but all may be variants of the Wiskott-Aldrich syndrome.92 In most patients, the thrombocytopenia is mild and has been discovered incidentally during family studies.
KASABACH-MERRITT SYNDROME
Thrombocytopenia associated with giant cavernous angiomas is most often described in infants with congenital lesions,93,94 but thrombocytopenia may first become apparent in adults.95,96 and 97
ETIOLOGY AND PATHOGENESIS
The principal lesion in Kasabach-Merritt syndrome is not a true capillary hemangioma, which typically regresses during childhood, but rather a distinctive vascular tumor, described as a tufted angioma or kaposiform hemangioendothelioma with lymphaticlike vessels.98 This distinction is important because the lesion can infiltrate aggressively and require intensive therapy.98 Hypofibrinogenemia is common in association with thrombocytopenia, consistent with the etiology of platelet consumption within the tumor being due to intravascular coagulation.96,97 and 98
CLINICAL AND LABORATORY FEATURES
The hemangiomas are usually present at birth, and neonatal thrombocytopenia may be present.98 The angiomas may be initially small and inapparent, but many grow suddenly and become painful.98 Angiomas are usually solitary and superficial but may involve any internal organ site. Cardiac failure may occur as a result of high-volume arteriovenous shunting through the hemangioma; a bruit over the lesion may support this diagnosis.
Thrombocytopenia may be severe, red cell fragmentation may be marked,97 and laboratory parameters typical of disseminated intravascular coagulation are usually present93,95,96 and 97 (see Chap. 126).
TREATMENT, COURSE, AND PROGNOSIS
Treatment is often necessary because of severe bleeding or growth of the tumor.98 Surgical resection can eliminate accessible lesions, but many angiomas are unresectable.93,95,96 and 97 Radiation therapy may be effective.94 Correction of the hemostatic abnormalities has been achieved by thrombosis of the lesion using aminocaproic acid and intraarterial embolization,95,96 and 97 but these may also be ineffective.98 Ticlopidine plus aspirin98 and high doses of glucocorticoid93 have been effective in correcting thrombocytopenia in isolated cases.
ACQUIRED THROMBOCYTOPENIAS DUE TO DECREASED PLATELET PRODUCTION
MEGAKARYOCYTIC APLASIA
Thrombocytopenia due to pure aplasia or hypoplasia of megakaryocytes is a rare disorder. Patients with amegakaryocytic thrombocytopenia associated with subtle abnormalities of other lineages, such as macrocytosis or dyserythropoiesis, are less rare, and these abnormalities are more likely to be a prodrome for myelodysplasia or aplastic anemia.99,100 and 101 In patients with acquired pure megakaryocytic aplasia, the etiology appears to be autoimmune suppression of megakaryocyte development. The mechanism of thrombocytopenia is probably analogous to that in acquired pure red cell aplasia and in some patients with aplastic anemia,102 namely, the development of autoantibodies to thrombopoietin103 or to megakaryocytes.104 Patients in whom an autoimmune mechanism is operative may respond to treatment with cyclosporine and antithymocyte globulin, achieving durable remissions.105
INFECTION
Possibly the most common cause of thrombocytopenia is infection. Thrombocytopenia occurs during the course of many diverse viral infections, such as cytomegalovirus,106 Epstein-Barr virus,107 and hantavirus108; it also occurs predictably in children receiving the measles virus vaccine (Fig. 117-5).109 Thrombocytopenia also occurs with many other infectious diseases, such as mycoplasma,110 myco-bacteria,111 Ehrlichiosis,112 and malaria.113 In most cases the etiology appears to be decreased platelet production,109,114 although immune-mediated platelet destruction has been postulated in some patients.115 Thrombocytopenia is common in critically ill patients with sepsis, in whom the dominant cause is platelet phagocytosis mediated by increased M-CSF.116,117 and 118

FIGURE 117-5 Thrombocytopenia caused by live measles vaccine: (A) Course of platelet counts in five infants after immunization. (B) Repeated decreases in platelet counts after three immunizations in one infant. (C) Changes in marrow megakaryocyte number in three infants after immunization. (Reproduced from Oski and Naiman.109)

THROMBOCYTOPENIA ASSOCIATED WITH HIV INFECTION
Thrombocytopenia is common in patients with HIV infection. Among 738 HIV-positive patients with hemophilia, the cumulative frequency of thrombocytopenia at 6 years after seroconversion was 16 percent for children and 18 percent for adults; at 10 years the frequency increased to 27 percent in children and 43 percent in adults.117 In another study the frequency of thrombocytopenia was 16 percent among 103 homosexual men and 37 percent among 182 intravenous drug users with a new diagnosis of HIV infection.120 Thrombocytopenia was also common among the HIV-negative homosexual men (3%) and intravenous drug users (9%) in this last study, possibly related to the common occurrence of hepatitis.120 HIV-infected, thrombocytopenic patients (except those with hemophilia) rarely have clinically important bleeding; platelet counts are rarely less than 50,000/µl; the mild thrombocytopenia often spontaneously resolves; and the presence of thrombocytopenia does not increase the risk of progression of AIDS.119,121,122 Although many HIV-infected patients do not have symptoms related to their immunodeficiency when the thrombocytopenia is discovered, the occurrence of thrombocytopenia correlates with plasma viral load and CD4 cell depletion.122,123
ETIOLOGY AND PATHOGENESIS
The principal cause of thrombocytopenia is ineffective platelet production caused by HIV infection of the auxiliary cells of the marrow that facilitate hematopoiesis, such as macrophages and microvascular endothelial cells, resulting in diminished hematopoietic support by the marrow stroma. Direct HIV infection of hematopoietic progenitor cells is probably not responsible for the thrombocytopenia.124,125 and 126 In addition to decreased platelet production, platelet survival is decreased, but the decease is less than in patients with chronic ITP (Table 117-4).125,127,128 Patients with HIV-associated thrombocytopenia also have lower-than-normal initial intravascular recoveries of injected radiolabeled autologous platelets but no increased spleen or liver sequestration. This contrasts with the results in ITP patients who have normal initial platelet recoveries but subsequently demonstrate increased splenic sequestration.125,127 The increased platelet destruction may be a result of immune platelet injury. Patients may have true autoantibodies to the specific platelet membrane glycoprotein complexes Ib/IX and IIb/IIIa, but some anti-HIV antibodies appear to cross-react nonspecifically with unidentified sites on normal platelets.125,129,130 HIV-infected patients also may have circulating immune complexes that contain antiplatelet GPIIIa antibodies.131

TABLE 117-4 PLATELET PRODUCTION, SURVIVAL, AND CLEARANCE IN ADULT ITP AND HIV-ASSOCIATED THROMBOCYTOPENIA*

CLINICAL AND LABORATORY FEATURES
The thrombocytopenia is typically mild and is often discovered as a result of routine blood testing.121,132 The marrow demonstrates normal or increased numbers of megakaryocytes in spite of the kinetic studies demonstrating decreased platelet production (Table 117-4).125 Bone marrow aspiration may be required to assess whether a granulomatous infection or lymphoma is contributing to, or causing, the thrombocytopenia.
THERAPY, COURSE, AND PROGNOSIS
The principal treatment for thrombocytopenia is antiretroviral therapy. This was previously accomplished with zidovudine,122 but current combination antiretroviral regimens will likely be more effective in increasing platelet counts, as well as enhancing CD4 cell counts and reducing HIV viral loads.133 Management of patients with severe and symptomatic thrombocytopenia is similar to that for patients with severe ITP: Prednisone (1 mg/kg per day) is effective122; short courses of dexamethasone are also effective.134 IVIg may be effective in low weekly doses (0.04 g/kg per week),135 and anti-D has been used extensively for these patients.136 As in ITP, splenectomy may be the most effective therapy and appears to have no adverse effect on the progression of the immunodeficiency.137 Splenectomy may be considered sooner119 in patients with hemophilia because of their greater risk of severe bleeding. Of note, thrombocytopenia does not commonly occur at birth in infants born to mothers with HIV infection, at least not with the frequency reported for thrombocytopenia in infants born to mothers with ITP.138 A report of 28 infants with neonatal platelet counts demonstrated thrombocytopenia in one, and that infant had acquired HIV infection.139 These data, although limited, are consistent with the hypothesis that HIV-associated thrombocytopenia is principally due to decreased platelet production rather than immune destruction by antiplatelet antibodies (which can cross the placenta), as in ITP.
NUTRITIONAL DEFICIENCIES AND ALCOHOL-INDUCED THROMBOCYTOPENIA
Mild thrombocytopenia occurs in about 20 percent of patients with megaloblastic anemia due to vitamin B12 deficiency140; the frequency may be higher in patients with folic acid deficiency because of the common accompanying alcoholism. Occasionally thrombocytopenia can be severe in the megaloblastic anemias, and when this coincides with fever and splenomegaly,141 the presenting features may suggest acute leukemia. The primary mechanism for thrombocytopenia is ineffective platelet production142; bone marrow megakaryocytes are normal or increased in number. Abnormalities of megakaryocyte morphology are much less distinctive than the characteristic erythroid and myeloid defects, but larger size and dispersed nuclear segments, rather than polyploid single nuclei, may be seen.143
Thrombocytopenia in alcoholic patients is almost always due to liver cirrhosis with congestive splenomegaly or to folic acid deficiency, but in some patients acute thrombocytopenia may occur in the absence of nutritional deficiency or splenomegaly, apparently as a result of direct marrow suppression of platelet production.144 Ingestion of large amounts of alcohol for 5 to 10 days is required to produce sustained thrombocytopenia, which is associated with decreased numbers of marrow megakaryocytes; following withdrawal of alcohol, platelet counts return to normal in 5 to 21 days and transient thrombocytosis often occurs.144
Iron deficiency typically causes thrombocytosis, but it has also been reported to cause severe thrombocytopenia.145
ACQUIRED THROMBOCYTOPENIA DUE PRIMARILY TO SHORTENED PLATELET SURVIVAL
THROMBOTIC THROMBOCYTOPENIC PURPURA-HEMOLYTIC UREMIC SYNDROMES
IDIOPATHIC THROMBOTIC THROMBOCYTOPENIC PURPURA-HEMOLYTIC UREMIC SYNDROME
TTP146,147 and HUS148,149 were described initially as distinct disorders. Although some reports continue to distinguish them, they will be discussed here as a single clinical syndrome. Many diverse clinical features may be present in patients with TTP-HUS, but the minimum criteria are thrombocytopenia and microangiopathic hemolytic anemia without another clinically apparent cause.150,151 Thrombi consisting primarily of platelets (hyaline thrombi) in terminal arterioles and capillaries152 are consistently present, but these pathologic features are not specific for TTP-HUS, being also present in patients with malignant hypertension and nephrosclerosis, scleroderma, acute renal allograft rejection, and preeclampsia.152 Since some clinical features of these other conditions may be similar to TTP-HUS, the distinction may be difficult.
Furthermore, the types of patients currently diagnosed as having TTP-HUS may differ from the patients who made up earlier reports, as the definition of TTP-HUS has changed since the original descriptions146,148 and the classic review in 1966153 which defined the pentad of clinical features: (1) microangiopathic hemolytic anemia, (2) thrombocytopenia, (3) neurologic symptoms and signs, (4) renal function abnormalities, and (5) fever. In that review,153 the diagnosis of TTP was supported by pathologic demonstration of hyaline thrombi in 93 percent of patients and 90 percent of the patients died. In the past 20 years, the availability of curative plasma exchange treatment has created an urgency for the diagnosis, which in turn has resulted in less stringent diagnostic criteria, leading inevitably to a broader spectrum of disorders diagnosed as TTP-HUS. The availability of effective treatment has also revealed new features of the long-term clinical course.
A current classification of presenting clinical features and disease associations is presented in Table 117-5. Epidemic HUS in young children appears to be distinct from the adult syndromes, but this disorder also is different from the original description of HUS in 1955.148 Descriptions of the childhood syndrome most commonly encountered today only began in 1982 with the appearance of Shiga-toxin-producing E. coli (typically E. coli 0157:H7).154,155,156 and 157 Though children infected with this organism who have HUS all have, by definition, microangiopathic hemolytic anemia and thrombocytopenia, their predominant clinical problems are acute renal failure following hemorrhagic colitis. Most recover with only supportive care. In contrast, most adults are treated with plasma exchange upon diagnosis, regardless of presenting features or possible etiology, because of a presumption of a very high mortality based on extrapolations from the era prior to plasma exchange treatment.153

TABLE 117-5 THROMBOTIC THROMBOCYTOPENIC PURPURA-HEMOLYTIC UREMIC SYNDROME (TTP-HUS): A CLASSIFICATION OF CLINICAL PRESENTATIONS AND DISEASE ASSOCIATIONS

This presentation will initially focus on the classic idiopathic adult syndrome. Specific characteristics of TTP-HUS syndromes associated with other conditions and apparent etiologies will be discussed in separate sections below.
Etiology and Pathogenesis The common pathologic features of all TTP-HUS syndromes suggest a common underlying mechanism of disease. This postulate is consistent with the hypothesis that vWf abnormalities are central to the formation of the platelet thrombi158; vWf is a multimeric glycoprotein synthesized in endothelial cells and megakaryocytes.159 Endothelial vWf is secreted both into the plasma and abluminally, and the latter becomes a component of the subendothelial matrix along with other proteins such as collagen and fibronectin. Subendothelial vWf is important for platelet adhesion at sites of endothelial injury mediated by the platelet GPIb/IX receptor, and vWf secreted into the plasma is processed into smaller multimers that do not interact with unstimulated circulating platelets. The platelet cofactor activity of vWf correlates with multimer size, with larger multimers more effective in supporting platelet-platelet interactions. In 1982 Moake and colleagues observed unusually large vWf multimers in the plasma of patients with chronic relapsing TTP160 which were comparable in size to the unprocessed vWf found in endothelial cells and platelets. These unusually large vWf multimers could directly agglutinate platelets, especially when the mixtures were subjected to high shear stress, which can unfold vWf.161 Regions of high shear stress may well occur in the vasculature of patients with TTP-HUS due to partial arteriolar obstruction and could augment platelet reactivity with vWF.162 Additional evidence for a role for vWf is that increased amounts of vWf are found on circulating platelets, as well as circulating aggregated platelets, in patients with TTP-HUS,163 and immunohistochemical studies of platelet thrombi in TTP-HUS demonstrate that they are enriched in vWf and contain less fibrin, distinct from the fibrin-rich thrombi of disseminated intravascular coagulation.158 These observations provide an explanation for the disseminated platelet agglutination, which appears to be the primary pathogenetic mechanism of TTP-HUS. Red cell fragmentation, the other cardinal clinical manifestation of TTP-HUS, is then due to passage of erythrocytes through partially obstructed blood vessels in the microcirculation under conditions of high shear stress.
Enzymatic processing of plasma vWf following endothelial synthesis and secretion may be the result of both reduction of the disulfide bonds that link the vWf monomers and specific proteolysis of vWf monomers themselves by a metalloprotease present in normal plasma.164 Proteolysis of vWf is enhanced by shear stress; therefore the same forces that can modify plasma vWf structure and induce platelet reactivity also make the vWf molecule vulnerable to proteolysis.164
The importance of these observations for the etiology of TTP-HUS has been supported by the demonstration of deficient activity of the vWf-cleaving protease activity in patients with TTP-HUS. The deficiency may be inherited, as appears to be common in patients with familial or chronic, relapsing TTP-HUS,165,166 or may be caused by autoantibody inhibition of protease activity in patients with acquired, sporadic TTP-HUS.164,166,167 Although these reports distinguish TTP from HUS, the clinical and laboratory data presented were indistinguishable. Therefore the conclusion that the vWf-cleaving protease activity is deficient in patients diagnosed with TTP but not deficient in patients diagnosed with HUS remains unclear. Two separate reports on a total of 67 patients documented deficient vWf-cleaving protease activity.164,166 In most patients with nonfamilial TTP, a serum inhibitor of the vWf-cleaving protease (presumably an autoantiantibody) was demonstrated164,166; no patients with familial TTP had a demonstrable inhibitor.166 vWf-cleaving protease activity returned to normal in these patients when they were in clinical remission.164,166 Plasma vWf-cleaving protease activity was normal in patients with a variety of other hematologic disorders.164
The deficiency of vWf-cleaving protease is assumed to result in the accumulation of the unusually large vWf multimers, which then cause platelet agglutination and microvascular thrombi.159,161 However, in another study of 30 patients (in whom TTP and HUS were considered as a single syndrome), unusually large vWf multimers were demonstrated in 8 of 10 patients with recurrent idiopathic TTP-HUS (both during the acute episode and during remission) but in none of 15 patients with familial TTP-HUS and none of 5 patients with acute, single episodes of TTP-HUS.168 In sharp contrast to the other studies, in this study, all patients demonstrated enhanced proteolysis of vWf, with accumulation of abnormal low-molecular-weight forms that persisted throughout remission in patients with familial TTP-HUS but corrected to normal during remission in patients with non-familial TTP-HUS.168 These observations suggest that multiple abnormalities of vWf may occur in patients with TTP-HUS.
Other abnormal protease activities have been demonstrated in these patients. Cysteine protease activity, not normally present in plasma, has been demonstrated in sera from TTP patients and can cause platelet aggregation and secretion.169,170 Plasma from TTP patients can also cause neutrophil-platelet aggregates,171 and activated neutrophils may be a source of increased plasma protease activity. It has been postulated that one mechanism by which the Shiga toxin of E. coli 0157:H7 can cause diffuse endothelial damage and result in HUS is by mediating neutrophil adhesion to endothelial cells with resulting neutrophil activation and secretion.172
Endothelial cell damage appears to be a central phenomenon in the pathogenesis of TTP-HUS. Direct evidence for this is the demonstration that plasma from patients with both TTP and sporadic HUS (distinguished from childhood epidemic diarrhea-associated HUS) can cause apoptosis of microvascular endothelial cells.173 Apoptosis occurred in endothelial cell cultures from organs typically affected by TTP-HUS (kidney, brain) but not in endothelial cells from organs not commonly affected (lung, liver).173 Apoptosis was also demonstrated in microvascular endothelial cells from spleens removed from TTP patients but not from spleens removed from patients with ITP or trauma.174 Complement regulation abnormalities have also been observed in patients with TTP and HUS, which may cause increased susceptibility for the development of postinfectious HUS or may enhance endothelial injury after initiation of a microangiopathic process.175 TTP-HUS has also occurred with bee sting176 and after cardiovascular surgery,177,178 conditions that may also affect complement.
Thus, TTP-HUS remains a clinical syndrome that can be triggered by multiple distinct events and may be associated with multiple other disorders. The presence of the characteristic pathologic lesions of thrombotic microangiopathy in other disorders152,180 that have distinct etiologies and outcomes, and the observation of unusually large vWf multimers in other clinically distinct disorders, such as Henoch-Schönlein purpura,181 emphasize the inherent heterogeneity of TTP-HUS.
Clinical Features Before the era of effective treatment, TTP was diagnosed by the defining classic pentad of symptoms and physical findings documented in the review of Amorosi and Ultmann.153 Few patients did not have all five criteria at presentation or during the unrelenting, fatal course of the disease. However, because of the urgent need to initiate plasma exchange treatment, recent studies have required only the presence of microangiopathic hemolytic anemia and thrombocytopenia, without another clinically apparent cause, to establish the diagnosis.150,151,182,183 The drift from the classic pentad to the current dyad is illustrated in Table 117-6 by the clinical findings at diagnosis in three consecutive large series of patients spanning 64 years.150,153,184 The most common presenting symptoms are neurologic abnormalities, hemorrhage, fatigue (probably related to severe anemia), and abdominal pain. The duration of disease prior to initiating therapy was 1 day to 2 weeks in two series185,186 and a median of 3 days in another study.187

TABLE 117-6 EVOLUTION OF DIAGNOSTIC CRITERIA FOR TTP-HUS

Among neurologic abnormalities, headache and confusion are the most common findings, followed by visual symptoms, seizures, dysphasia, and paresis.153,184 Coma was present some time during the illness in 31 percent of patients reported in 1964153 and in 20 percent of patients reported from 1964 to 1980,184 but it is much less common now. Brain CT and MRI scans are often normal even in the presence of severe abnormalities such as hemiparesis, seizures, and coma, consistent with global ischemia due to microvascular obstruction and the frequency of complete recovery.188,189 and 190 New neurologic abnormalities may occur during the course of TTP-HUS.152 Fluctuating neurologic signs may be caused by nonconvulsive status epilepticus and respond to anticonvulsant therapy.190 Hemorrhagic symptoms are those expected from thrombocytopenia: epistaxis, hematuria, gastrointestinal bleeding, and menorrhagia.151
The cause of severe abdominal pain as a major presenting symptom is less obvious, but this is prominent in many series. It presumably reflects bowel ischemia due to microvascular obstruction. Amorosi and Ultmann noted nausea, vomiting, diarrhea, and abdominal pain as chief complaints in 35 percent of their patients, nearly as frequent as chief complaints of the classic presentations of neurologic abnormalities (60 percent) and purpura or hemorrhage (44 percent).153 These three presenting complaints were noted in an identical frequency in a subsequent review,184 and another series noted that abdominal or flank pain was the most common presenting symptom.185 These symptoms have not been explained by pancreatitis except in isolated cases.191 Adults may present with severe abdominal pain and bloody diarrhea, similar to the typical presentation of epidemic childhood HUS, that may initially be mistaken for ischemic colitis.
Case series of patients with TTP-HUS consistently report a female predominance of 60 to 70 percent.150,153,192,193 The significance of this is unknown. This female predominance may be consistent with an autoimmune etiology, but other disorders have a female predominance without immunologic involvement (e.g., cholecystitis).
Even after patients recover from the active, life-threatening phase of TTP-HUS, mild thrombocytopenia and other subtle abnormalities may persist. The risk of relapse exists for all patients, but it is uncertain whether those with chronic thrombocytopenia are at higher risk of relapse.194
Laboratory Features The defining features of TTP are usually apparent from the initial blood counts and examination of the blood film; however, earlier diagnosis, especially in patients with recurrent episodes, has caused a change in the presenting laboratory features. In one series,185 9 of 26 patients had normal hematocrits, although anemia rapidly developed in all. Another series of 17 patients186 included two who were not anemic at diagnosis but whose hematocrits dropped to 20 percent within several days. Similarly, red cell fragmentation may be minimal or inapparent initially.195,196 Thrombocytopenia is an essential component of the diagnosis, and, if absent at presentation, it usually develops rapidly.197 Consistent with the severe hemolysis, the serum indirect bilirubin and LDH levels are increased. LDH levels are often very high, with mean values of over 1000 units per liter in most series150,151,186,192 and values up to 6000 units per liter in some cases.197 Isoenzyme analysis has demonstrated that the increased LDH reflects not only hemolysis but also ischemic injury to multiple organs.198 Most patients will have microscopic hematuria and proteinuria; some may have acute, oliguric renal failure.
In contrast to the era before plasma exchange treatment, tissue biopsy is not required to establish the diagnosis. Biopsies are performed only when different diagnoses are considered that require different management, such as lupus erythematosus. The characteristic lesions of TTP-HUS are arteriolar and capillary thrombi composed primarily of platelets, but also with vWf and some fibrin (Fig. 117-6).152,158 Subendothelial hyaline deposits and periarteriolar concentric fibrosis are also common features. Renal biopsies demonstrate platelet thrombi that may occlude the lumens of glomerular capillaries and interlobular and afferent arterioles. The glomerular endothelial cells may be swollen, possibly even to the extent of occluding the capillary lumen in a pattern indistinguishable from preeclampsia. Fibrin and red cells may permeate the arterial wall and be associated with a process of mucoid intimal hyperplasia.152 These changes are characteristic of TTP-HUS but also may be identical to the pathology of some patients with preeclampsia, malignant hypertension, acute scleroderma, and renal allograft rejection.152 Electron microscopy of renal biopsies consistently demonstrates widening of the subendothelial space, which is pale and contains “fluffy” electron-dense material. Renal biopsies may be especially important to distinguish TTP-HUS from other forms of rapidly progressive glomerulonephritis.152

FIGURE 117-6 Pathology of TTP-HUS. (A) Renal biopsy demonstrating hyaline thrombi obstructing most capillary lumens and thrombosis occluding a preglomerular arteriole. No significant inflammatory changes are seen in the glomerulus. [Reproduced with permission from Habib R in Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura, Kaplan B, Trompeter R, Moake J (eds), Marcel Dekker, New York, 1992, p 324.] (B) Pulmonary arteriole from autopsy of a patient with gastric adenocarcinoma. The lumen is nearly obstructed by a tumor embolus. Tumor cells have also penetrated between layers of intimal proliferation. No fibrin or platelets are present. (Reproduced with permission from Antman KH et al, Medicine 58:377, 1979.)

Differential Diagnosis The spectrum of TTP-HUS has become wider and differential diagnosis more challenging as making the diagnosis with fewer criteria has become accepted. With plasma exchange treatment so effective, appropriate management is to err on the side of initiating plasma exchange rather than delaying treatment in an attempt to establish the diagnosis with greater certainty. Other disorders that can cause similar clinical and laboratory findings include sepsis, autoimmune disorders, pregnancy-related conditions (preeclampsia, HELLP syndrome), malignant hypertension, and unrecognized metastatic carcinoma. Sepsis (bacterial, fungal, viral, or rickettsial) should be considered in an acutely ill patient with chills, fever, and dysfunction of multiple organs. DIC is typically present in sepsis and should raise concern for diagnoses other than TTP-HUS. Evidence of DIC may be present in patients with TTP-HUS, resulting from tissue ischemia, but coagulation abnormalities are not usually severe199 (see Chap. 126). An example of infection mimicking TTP-HUS is bacterial endocarditis, which can present with anemia, thrombocytopenia, fever, and neurologic and renal abnormalities. TTP-HUS can share both clinical and pathological features with systemic lupus erythematosus, catastrophic antiphospholipid syndrome, and scleroderma.152,200,201,202,203,204 and 205 Moreover, TTP-HUS may occur in association with an underlying autoimmune disorder. Evan’s syndrome, the concomitant presence of autoimmune hemolytic anemia and ITP, may initially be indistinguishable from TTP-HUS, but microangiopathic erythrocyte changes are uncommon in Evan’s syndrome. The demonstration of a positive direct antiglobulin test is the distinguishing feature, but it may be negative in autoimmune hemolysis.206 TTP-HUS may be initially confused with megaloblastic anemia or myelodysplasia thrombocytopenia because red cell poikilocytosis and high serum LDH may be present in all three entities.
Treatment During the past 20 years plasma exchange has become the primary treatment for TTP-HUS. This has profoundly affected the prognosis; the mortality rate has decreased from >90% before 1964153 to <20% in current series. Ironically, effective treatment has revealed a new spectrum of chronic relapsing disease among many of the survivors. Less intensive therapies such as prednisone alone192 or plasma infusion alone185 have been used for some patients with minimal disease, but the unpredictability of TTP-HUS and the continued presence of patients with unrelenting and fatal disease in every case series support the prompt initiation of plasma exchange treatment.207 Although some reports suggest that patients defined as having HUS respond to plasma exchange treatment less well than patients with TTP, most reports describe no difference.182
Plasma Exchange With the wide availability of portable equipment, plasma exchange can be performed in almost any place at any time. Rapid initial therapy with plasma exchange is essential since anemia, thrombocytopenia, and neurologic complications may worsen in the initial days after diagnosis,150 and about half of the deaths in patients with TTP-HUS occur in the first week of illness. Why plasma exchange is effective remains unknown. Theories of the pathogenesis of TTP-HUS could support either the removal of a harmful plasma component (such as the unusually large vWf multimers or antibodies that inhibit the vWf-cleaving metalloproteinase) or the replacement of a deficient component (such as the vWf-cleaving protease or low-molecular-weight vWf multimers). The latter idea is supported by the efficacy in some patients of merely infusing plasma.208 A randomized, controlled trial documented that plasma infusions are less effective than plasma exchange, but this may simply have been because the patients treated with plasma exchange received threefold as much plasma.150 The risks of plasma exchange are real and include complications associated with inserting a large central venous catheter; infectious and thrombotic complications of the indwelling catheter; allergic reactions to the plasma; infectious complications from the plasma; and alkalosis symptoms due to the infused citrate. One prospective study of 65 courses of plasma exchange in 59 patients with TTP-HUS documented that 40 percent of courses were free of complications, 30 percent had minor complications, and 30 percent had major complications, including two deaths and eight episodes of bacteremia.209 Each procedure requires several hours and costs about $2000.
Plasma exchange is performed once daily until a response is achieved, defined by resolution of the neurologic abnormalities, a normal platelet count, and a normal or nearly normal LDH concentration.183 Thrombocytopenia and high LDH levels usually resolve within 1 or 2 weeks; neurologic abnormalities, such as headache, confusion, and seizures, usually resolve earlier.151 Deep coma may be completely reversible with plasma exchange.189 One plasma volume (40 ml/kg) is the recommended volume of plasma to exchange. Larger volumes have lower efficiency as more of the infused plasma is promptly removed. An increased “dose” of plasma is one parameter to adjust if the patient does not promptly respond, and this is best achieved by increasing the frequency of plasma exchange to twice daily.
Patient plasma is routinely replaced with fresh frozen plasma, but some reports recommend “cryoprecipitate-poor” or “cryosupernatant” plasma, the fraction recovered after removal of the cryoprecipitate, which contains a significant amount of vWf, factor VIII, and fibrinogen. Theories that unusually large vWf multimers are involved in the pathogenesis of TTP-HUS suggest that infusion of vWf may retard recovery,161 and it has been suggested that use of cryosupernatant plasma improved the response of patients who were initially refractory to plasma exchange.209,210 However, the only data from a controlled randomized comparison of whole plasma versus cryosupernatant plasma demonstrated equivalent responses.211 The deficiencies of factor VIII and fibrinogen in cryosupernatant plasma may necessitate the use of some whole plasma.
The optimal duration of plasma exchange treatment is unknown and the range in published series is great.212,213 The earliest signs of recovery are improvement of neurologic abnormalities, decreased serum LDH concentration, and increased platelet count.151 The rate of these responses may predict the clinical outcome and duration of required treatment.212,214 An initial response may occur within minutes after beginning the first exchange or may not be observed for over 1 month.192 Typically an initial response is seen during the first week, and recovery is nearly complete within 3 weeks.213 Nearly all case series have some patients, however, who require more than a month of plasma exchange to achieve a successful, durable response. A prompt correction of the LDH concentration and thrombocytopenia is a good prognostic sign.214 In one series, the serum creatinine level became normal only after a median of 90 days197; in another series, 26 percent of patients had creatinine clearances less than 40 ml/min 1 year after diagnosis.215 It is unknown if continued plasma exchange after neurologic and hematologic recovery affects recovery of renal function.
Plasma exchange is continued daily until neurologic signs resolve and the platelet count is normal; then plasma exchange is often continued at increasing time intervals for another week or two.213 The rationale for such a “tapering” regimen is that it may prevent an exacerbation of active TTP-HUS. Recurrence of the signs of TTP-HUS occurred in 58 of 70 patients in one series when plasma exchange was discontinued.192 In other series, exacerbations occurred in 24 to 39 percent of patients151,212,213,215,216 and required resumed daily plasma exchange before achieving a durable remission. The frequency of exacerbations supports a more prolonged initial course of plasma exchange. Substitution of plasma infusion for plasma exchange has been tried in patients who required prolonged treatment, but in one study exacerbations occurred in 22 of 36 patients treated with plasma infusion.192
No other treatment modality approaches the efficacy of plasma exchange, and so the role of other treatments is uncertain217; therefore, there is risk in discontinuing plasma exchange in favor of another treatment. Remissions may occur after as long as 8 months of plasma exchange treatment.185 Twice-daily plasma exchange185,192,218 and the use of cryosupernatant plasma as the replacement product209 should be tried before plasma exchange is considered ineffective. In practice, the issue of prolonged plasma exchange in unresponsive patients is uncommon as these patients usually die early in the course of their disease.213 Most prolonged courses of plasma exchange, some lasting for months, are required for patients who experience repeated exacerbations when plasma exchange is tapered or stopped.
Glucocorticoids. The mechanism of glucocorticoid benefit may be immunosuppression of autoantibodies to the vWf-cleaving protease.164,166,167 Before the era of plasma exchange, response to glucocorticoid therapy alone was observed only in about 10 percent of patients.219 In one series, prednisone (200 mg/d) was used alone in patients who had minimal symptoms and no neurologic abnormalities.192 Half of the 108 patients in this series fulfilled these criteria, but 24 of these 54 patients worsened on prednisone therapy and then required plasma exchange. The other 30 patients responded, and prednisone was tapered over 11 to 16 weeks. Two of these 30 patients relapsed suddenly after an initial excellent response and died before other therapy could be instituted.192 In contrast to this report, another group did not use glucocorticoids in any patients and achieved comparable success.150,182 Since there are usually no contraindications for glucocorticoid therapy, and because glucocorticoids alone can be effective in selected patients,192 they are commonly used. However the duration of glucocorticoid treatment should be minimized to decrease steroid toxicity.
Antiplatelet Agents. The rationale for antiplatelet agents is their ability to inhibit platelet aggregation and thus potentially prevent microvascular thrombi. Intravenous infusion of dextran, 1 g per day, has been used as an antiplatelet agent in combination with high doses of prednisone and splenectomy.151 A risk for these agents is increased bleeding, as most patients with TTP-HUS are severely thrombocytopenic at diagnosis, many patients present with bleeding and purpura as major problems, and life-threatening hemorrhage can develop during the course of treatment.151 As with glucocorticoids, some case series150 used antiplatelet agents, such as aspirin and dipyridamole, in all patients, while others with comparable clinical success192 used these agents rarely. In patients who have had a stroke or transient cerebral ischemic event, aspirin therapy is appropriate when severe thrombocytopenia resolves.
Splenectomy. Before the era of plasma exchange, splenectomy and glucocorticoids were the principal therapeutic options, and splenectomy was often performed soon after diagnosis in spite of the risk of operative complications in critically ill patients.220 By 1982, at the beginning of the plasma exchange era, splenectomy in combination with high doses of glucocorticoids and dextran infusion was reported to achieve responses in most patients.220 The mechanism of benefit of splenectomy is unknown. Splenectomy may have a role in the management of refractory TTP-HUS.151,220,221
Other Treatments. There are anecdotal reports of success with multiple other treatments, all of which are impossible to evaluate because the clinical course of TTP-HUS is unpredictable. Reports with IVIg describe both success and failure.222 A concern for IVIg is the risk for exacerbation of renal failure.223 Several reports suggest a beneficial effect of vincristine.222,224 Successful treatment with azathioprine,225 cyclophosphamide,226 cyclosporine,227 and extracorporeal immunoabsorption228 has been reported.
Platelet Transfusion. Platelet transfusions have been reported to exacerbate TTP-HUS, which is consistent with disseminated platelet aggregation as the principal pathogenesis of TTP-HUS. Cases have been reported with acute deterioration and death following platelet transfusion192,229; others have associated platelet transfusions with increased mortality.230 However, most case series do not mention platelet transfusions or do not comment on adverse reactions. Thus, the risks, if any, of platelet transfusions remain unknown. The requirement for an invasive procedure in a patient with severe thrombocytopenia and risk for major bleeding is an appropriate indication for platelet transfusion, but the patient should be carefully monitored for signs and symptoms of clinical deterioration. Severe thrombocytopenia in the absence of clinically important bleeding is not an indication for platelet transfusion.
Treatment Summary. Plasma exchange is the most important treatment modality and should be continued until a durable remission is achieved. For patients who do not respond or deteriorate during the first week of daily plasma exchange, twice-daily plasma exchange may provide dramatic benefit. Both whole plasma and cryosupernatant plasma are effective. Although other treatments are commonly used, especially in patients with prolonged courses, their efficacy is uncertain.
Course and Prognosis Improved survival is the most striking feature of TTP-HUS compared to three decades ago. Of 271 patients diagnosed before 1964, only 27 (10 percent) survived.153 Current survival is about 80 percent. Although plasma exchange has revolutionized the management and prognosis of TTP-HUS, some patients continue to have severe, refractory disease; most deaths occur early in the course of the illness or before treatment can be initiated.
With effective treatment, a new spectrum of TTP has been revealed. Acute exacerbations occur when initial daily plasma exchange is decreased in frequency in many if not most patients.150,192,212,213,215,216 Relapses, defined as occurring after a complete hematologic remission on treatment for over 1 month, occur in approximately one-third of patients within 10 years.230,231 Clinical features of the initial episode may predict which patients are at risk for relapse. For example, TTP-HUS occurring as an adverse reaction to quinine or ticlopidine appears to be unlikely to recur without reexposure to the drug. TTP-HUS occurring after hemorrhagic colitis does not appear to recur,193 in accord with the lack of relapses in children following recovery from epidemic HUS caused by E. coli 0157:H7. No maintenance therapy appears to prevent relapses. Patients who recover from TTP-HUS and then have a late relapse predictably recover if treated,212 though rare deaths have occurred.230,231 Asymptomatic patients with moderate thrombocytopenia and/or poikilocytosis present difficult management dilemmas; careful observation alone, glucocorticoid treatment, or plasma exchange may each be appropriate.
The frequency of long-term sequelae after TTP-HUS is unknown but may be significant. Permanent neurologic deficits are not commonly reported. One report documented renal failure in 26 percent of patients 1 year after diagnosis,215 comparable to the 23 to 66 percent frequency of abnormalities of renal function and blood pressure in children 10 years after an episode of epidemic HUS.232,233,234,235,236,237 and 238
EPIDEMIC HEMOLYTIC UREMIC SYNDROME IN CHILDREN CAUSED BY SHIGA-TOXIN-PRODUCING E. coli
Epidemic HUS of young children is a distinct disorder from the other syndromes described as TTP-HUS (Table 117-5) with regard to etiology, treatment, and prognosis. It is commonly referred to as epidemic, enteropathic, or simply D+ HUS, designating the prodrome of diarrhea.154,155,239 This disorder follows acute enteric infection caused by E. coli or Shigella dysenteriae serotypes that produce Shiga toxin. Although this disorder typically occurs in young children, it can also occur in adults; in adults the course and prognosis may be more severe, similar to the other adult TTP-HUS syndromes.239 In children, 85 to 90 percent of HUS is preceded by diarrhea; the disease in the other 10 to 15 percent of children is similar to the typical idiopathic TTP-HUS of adults, exhibiting no seasonal incidence variation, more neurologic symptoms, and a greater risk for relapse.240 These children, in contrast to children with diarrhea-associated HUS, may require plasma exchange treatment.241
Epidemiology In 1982 enterohemorrhagic strains of E. coli (predominantly E. coli 0157:H7) that acquired a plasmid containing the Shiga toxin were first recognized as human pathogens,154,155,239 and 1 year later the association between Shiga-toxin-producing E. coli 0157:H7 and HUS was documented.154 This appeared to be a new disease, since retrospective analysis of over 3000 E. coli cultures from 1973 to 1982 found only one isolate with serotype 0157:H7, from a woman with bloody diarrhea in 1975.239 Serologic evidence suggests that all E. coli 0157 isolates from patients with colitis are derived from one particularly adaptive clone of E. coli that has spread throughout the world.242 The occurrence of gastrointestinal infections caused by E. coli 0157:H7 is increasing dramatically,155 but HUS can also follow diarrhea caused by Shiga-toxin-producing E. coli serotypes other than 0157:H7239 and may even follow infections other than colitis.243,244
Epidemiologic studies have defined the features of E. coli 0157:H7 infections and childhood HUS.154,156,239,245 The occurrence of colitis in persons consuming infected food is estimated to be 4 to 8 percent in community outbreaks but was 33 percent in a nursing home epidemic, which also included person-to-person transmission.239 Progression of E. coli 0157:H7 infection to HUS is estimated to occur in 2 to 7 percent of sporadic cases but up to 30 percent in some epidemics.154,239,246 E. coli 0157:H7 is present in the intestines of about 1 percent of healthy cattle,155 and most outbreaks are traced to undercooked beef. However, contamination of unpasteurized milk, juices, fruits, vegetables, and water have all been implicated in outbreaks of colitis.154,155,239,245 Person-to-person transmission is a particular problem in day-care and chronic-care facilities.154 The peak age of infection is 6 months to 5 years, reflecting the period after weaning and maximum exposure to enteric pathogens and further suggests that older children and adults may acquire immunity to the Shiga toxin.154,155,239 In contrast to the female predominance in adults with TTP-HUS, boys and girls are equally affected.239 Consistent with the association with enteric pathogens, over 80 percent of cases occur between April and September.154,155, 245
Etiology In addition to the Shiga toxin, E. coli 0157:H7 contains factors that promote mucosal attachment and colitis.154 The toxic effects of the released Shiga toxin are focused on glomerular endothelial cells because of their rich display of glycosphingolipid receptors for the toxins.157 Once bound, the toxin can initiate production of endothelin-1, which can induce vasoconstriction and provoke acute renal failure.247
Clinical and Laboratory Features The clinical presentation is dominated by diarrhea, which is bloody in most patients. The average duration of symptoms before diagnosis of HUS is 6 days; antimicrobial treatment of the initial diarrhea does not appear to influence the clinical course.154,155,239 The symptoms may be severe enough to mimic ischemic colitis and require colectomy. Most patients are oliguric at the time of admission and require dialysis support.154,237,244,247 Fever and hypertension are common. Extrarenal involvement, including pancreatitis (20 percent) and seizures (20 percent) may be prominent.248 The most prominent laboratory features are abnormalities of acute renal failure, microangiopathic hemolytic anemia, and thrombocytopenia.
Treatment, Course, and Prognosis Plasma exchange, the cornerstone of treatment for adult TTP-HUS, appears to have minimal or no benefit.154 Treatment is supportive; dialysis is necessary in about half of children.154 In contrast to TTP-HUS in adults before the era of plasma exchange, epidemic childhood HUS is an acute and severe illness, but the mortality is only 3 to 10 percent.154,239 However, HUS occurring during outbreaks of E. coli 0157:H7 colitis among elderly subjects may have up to 88 percent mortality.245 Relapses are not mentioned in studies with long-term follow-up, but 23 to 66 percent of patients have abnormal renal function at evaluations many years after their acute childhood HUS.232,233,234,235,236,237 and 238 Children who had more severe renal disease with their initial HUS232,237 or atypical HUS had a greater risk for developing renal failure.
THROMBOTIC THROMBOCYTOPENIC PURPURA-HEMOLYTIC UREMIC SYNDROME ASSOCIATED WITH INFECTIONS OTHER THAN SHIGA-TOXIN-PRODUCING E. coli
Anecdotal reports have described TTP-HUS associated with infections caused by bacteria, rickettsiae, and viruses. Some of these infectious agents are thought to cause TTP-HUS, others may merely mimic TTP-HUS, and still others may exacerbate established TTP-HUS.249 Distinguishing among these possibilities may be difficult. With the exception of Shigella dysenteriae type I, which carries the same Shiga toxin as E. coli 0157:H7, none of these infections is as clearly associated with the cause of TTP-HUS as the enterohemorrhagic E. coli. Misdiagnosis of TTP-HUS may cause a delay in the treatment of an infectious disease, and so it is important to have a high index of suspicion for infection.
Enteric Bacterial Infections TTP-HUS following infection with Shigella dysenteriae type I has been described in children and in adults with TTP-HUS.250 Shigella dysenteriae is uncommon among Shigella species causing gastroenteritis. Other reported associations with TTP-HUS include Yersinia enterocolitica,251 Campylobacter species,252 and Clostridium difficile.253 Shiga-toxin-producing E. coli other than 0157:H7 strain may also be responsible for causing TTP-HUS, and these are not so easily distinguished from nonpathogenic E. coli.245
Other Bacterial Infections TTP-HUS has been reported following Streptococcus pneumoniae pneumonia, bacteremia, and meningitis in children254 and adults.255 In one patient TTP-HUS occurred simultaneously with Borrelia burgdorferi infection,256 and another had meningococcemia.153 Five adult patients were reported with TTP-HUS and Bartonella-like red cell inclusions; treatment with doxycycline appeared to be effective.257
Rickettsial Infections A patient with ehrlichiosis was described who was initially misdiagnosed with TTP-HUS because of acute, critical illness with coma, renal failure, and severe thrombocytopenia.258
Viral Infections Over 100 patients have been reported with a TTP-HUS-like syndrome during the course of infection with HIV.180 These patients have been identified both by the observation of unanticipated positive tests for anti-HIV antibodies in patients with a primary diagnosis of TTP-HUS259,260 and by evaluating patients with HIV infection for signs of TTP-HUS.261 In one series, 11 of 50 serum samples from TTP-HUS patients demonstrated anti-HIV antibodies, suggesting an epidemiologic relationship.260 A role for HIV infection in the pathogenesis of TTP-HUS has been postulated to be related to HIV infection of endothelial cells.262 The clinical features of patients with TTP-HUS associated with HIV infection are distinct from the features characteristic of patients with idiopathic TTP-HUS: Patients usually have a gradual onset of the disorder, survive for weeks to months without plasma exchange, have many concurrent medical problems that could account for abnormalities attributed to TTP-HUS, and have a less predictable response to plasma exchange.180 These clinical features are similar to the reports of TTP-HUS in patients following bone marrow transplantation (described below). In these immunocompromised patients, a superimposed systemic infection, such as cytomegalovirus,263,264 could mimic TTP-HUS.
DRUG-INDUCED THROMBOTIC THROMBOCYTOPENIC PURPURA-HEMOLYTIC UREMIC SYNDROME
TTP-HUS can be an idiosyncratic, acute adverse reaction to a drug, mediated by drug-dependent antibodies to platelets and other cells. Quinine is the best described example.265 TTP-HUS associated with mitomycin C appears to be dose-dependent. Recognition of drug-induced TTP-HUS is critical because withdrawal of the offending drug is essential for both recovery and avoidance of recurrence.
Quinine Acute, severe TTP-HUS has been reported following quinine ingestion,265 and quinine ingestion was associated with 5 percent of all patients diagnosed with TTP-HUS in one recent series.227 These patients may have quinine-dependent antiplatelet antibodies, and some may also have quinine-dependent antineutrophil antibodies, causing severe neutropenia.265,266 Abdominal pain with nausea and vomiting are prominent presenting features, as is common in TTP-HUS.265 Most patients require hemodialysis in addition to plasma exchange, but the prognosis is good for recovery of normal renal function. Repeated ingestion of quinine or even quinine water (“tonic”)267 can cause an immediate recurrence of TTP-HUS.
Ticlopidine Acute, severe TTP-HUS following a short course of ticlopidine, usually less than 4 weeks, has been reported in 60 patients.268 The frequency of TTP-HUS due to ticlopidine following coronary artery stent placement has been estimated to be approximately 1 in 1600 patients269 in one study and somewhat lower in another.270 Since ticlopidine is now routinely used in the estimated 400,000 patients per year in the United States who undergo coronary intervention involving a stent,270 the above estimate corresponds to about 250 cases of TTP-HUS in the United States each year. Whether TTP-HUS is associated with clopidogrel, an analog of ticlopidine, remains to be assessed.269
Mitomycin C and Other Cancer Chemotherapeutic Agents Data from a registry of cancer-associated HUS established in the 1980s identified an association between mitomycin C and TTP-HUS,233 and a review in 1987 documented 128 cases of mitomycin-C-associated TTP-HUS.272 Mitomycin C, an alkylating agent, is most commonly used in combination with 5-fluorouracil and doxorubicin for gastric and pancreatic carcinoma.273,274 In this regimen, mitomycin C is administered at a dose of 10 mg/m2 on the first day of each 8-week cycle, and the cycles are continued as long as a response occurs, which may last for more than a year.274 Most episodes of TTP-HUS occur in patients with gastric carcinoma, but they may also occur in patients receiving adjuvant chemotherapy who have no evidence of carcinoma at autopsy.275,276,277 and 278 TTP-HUS, like renal toxicity,279 appears to be a dose-related toxicity of mitomycin C. In one review, 75 of 84 patients with TTP-HUS had received at least 60 mg271; in another study, all of 24 patients had received at least 1.2 mg/kg275; and another review reported that all patients had received at least 30 mg/m2, equivalent to about 0.75 mg/kg.280 Even at these total doses, however, fewer than 10 percent of patients develop the clinical features of TTP-HUS.280,281 Renal pathology is identical to that of other TTP-HUS syndromes (Fig. 117-6).278 Most patients who develop TTP-HUS following mitomycin C therapy die from their cancer or of renal failure.271,272,276 The efficacy of plasma exchange treatment is uncertain.276 The occurrence of TTP-HUS following cancer treatment with chemotherapy regimens not containing mitomycin C is uncommon; TTP-HUS associated with treatment with cisplatin, bleomycin, or pentostatin has been reported.271,277
Cyclosporine A The major toxicity of cyclosporine is dose-related renal toxicity; seizures and other neurotoxic effects also occur.282,283 A syndrome of severe renal failure, microangiopathic hemolytic anemia, and thrombocytopenia associated with cyclosporine were first reported in patients following allogeneic marrow transplantation.284 Allogeneic marrow transplantation itself has been reported to cause a syndrome resembling TTP-HUS (see “Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndrome Associated with Marrow Transplants”), and thus a specific association with cyclosporine administration is difficult to establish. For example, in one report the occurrence of microangiopathy correlated with the severity of acute graft-versus-host disease, which alone can cause many clinical features similar to those of TTP-HUS.285 Although the early reports suggested that TTP-HUS may be a common complication of cyclosporine,285,286 and 287 the diagnosis is now much less common in spite of the wide use of cyclosporine in patients receiving marrow and solid organ allografts. This may simply be related to better regulation of cyclosporine doses and less toxicity. Tacrolimus has also been reported to cause TTP-HUS,288 but the interpretation of these reports is difficult because the patients usually have complicated illnesses. Cyclosporine-induced TTP-HUS is almost always reversible when cyclosporine is discontinued, and in some patients cyclosporine is restarted without toxicity.286 The efficacy of plasma exchange treatment is uncertain.
Other Drugs Other drugs that have been associated with TTP-HUS include metronidazole,289 cocaine,290 simvastatin,291 pentostatin,292 and ecstasy (3,4-methylenedroxy methamphetamine).293
THROMBOTIC THROMBOCYTOPENIC PURPURA-HEMOLYTIC UREMIC SYNDROME ASSOCIATED WITH MARROW TRANSPLANTS
Although TTP-HUS has been diagnosed following autologous marrow or peripheral blood stem cell transplantation, most reported patients have undergone allogeneic marrow transplantation.282,283,294,295 The diagnosis of TTP-HUS has been principally based on the unexpected appearance of microangiopathic hemolytic anemia, characterized by prominent red cell fragmentation and a persistent increase in serum LDH.282,294 The diagnosis is supported when other features of TTP-HUS, thrombocytopenia, neurologic abnormalities, and renal failure seem unexplained by other complications of marrow transplantation.283 However, since patients following bone marrow transplantation are frequently critically ill with multiorgan dysfunction, it may be difficult to establish the diagnosis of TTP-HUS. This diagnostic uncertainty has probably led to the extreme variations in the reported frequencies of TTP-HUS (2 to 76 percent among patients with allografts; 0 to 27 percent among patients with autografts) and in reported mortality (0 to 87 percent).282 All features of TTP-HUS could be caused by more predictable complications of marrow transplantation: graft-versus-host disease, radiation toxicity, and systemic infections. Nephrotoxicity and neurotoxicity of cyclosporine may also be complicating factors.282 Therefore it is understandable that TTP-HUS is most often diagnosed in the most complicated patients, who are at greatest risk for developing graft-versus-host disease: patients who have received transplants from matched, unrelated donors, and patients who had an HLA antigen mismatched donor.294,296,297 Also, total body irradiation as part of the preparative regimen is correlated with the subsequent diagnosis of TTP-HUS.294,297
The immediate and critical decision is whether a patient may benefit from plasma exchange treatment. In contrast to patients with idiopathic TTP-HUS, delay in initiating plasma exchange treatment while alternative etiologies are assessed may be an appropriate decision. Some patients demonstrate hematologic improvement following plasma exchange,297,298 and 299 sometimes apparently requiring the use of cryosupernatant plasma or immunoabsorption by protein A columns, but most patients do not respond.297,299 Even in responsive patients, plasma exchange may not affect the clinical outcome.300
THROMBOTIC THROMBOCYTOPENIC PURPURA-HEMOLYTIC UREMIC SYNDROME ASSOCIATED WITH CANCER
Patients with extensive metastatic carcinoma who developed syndromes indistinguishable from TTP-HUS have been reported.272,301,302 Although the full syndrome of TTP-HUS is rare, red cell poikilocytosis occurs in about 5 percent of patients with metastatic cancer,301,303 and prospective analyses suggest that metastatic carcinoma accounts for the majority of patients (excluding patients with renal failure) who are noted to have red cell poikilocytosis.303 The occurrence of TTP-HUS has been associated with a variety of carcinomas, but over half of the patients have had gastric carcinoma.272,301,302 In fact, microangiopathic hemolytic anemia may be the sign that initiates the discovery of occult metastatic carcinoma.301 In addition to red cell fragmentation and thrombocytopenia, a leukoerythroblastic reaction indicating marrow involvement by tumor is frequently observed.272,301 DIC may be triggered by mucin-producing adenocarcinomas,304 but laboratory evidence of DIC is present in only a minority of patients with metastatic carcinoma who have microangiopathic hemolysis and thrombocytopenia.301,302 The characteristic pathological feature is widespread occurrence of microvascular tumor emboli with associated proliferation of the vascular intima, most commonly in the pulmonary circulation (Fig. 117-6).272,301,302,305 In a retrospective search, diffuse involvement of pulmonary arterioles with tumor emboli was found in only 7 of 800 autopsies performed on patients with carcinoma.302 Therapy, course, and prognosis are determined by the metastatic carcinoma; in patients responsive to chemotherapy, the syndrome resolves.302 There appears to be no role for plasma exchange treatment.
THROMBOTIC THROMBOCYTOPENIC PURPURA-HEMOLYTIC UREMIC SYNDROME ASSOCIATED WITH AUTOIMMUNE DISORDERS
An association of TTP-HUS with autoimmune disorders such as SLE has been described,153 but the diagnosis of TTP-HUS may be difficult to establish, since the signs and symptoms of SLE can mimic those of TTP-HUS.212,213 and 214 Further complicating this association is the presence in some SLE patients of opportunistic central nervous system infections (aspergillus, candida, cytomegalovirus) and cerebral emboli from verrucous endocarditis.212 Patients with TTP-HUS have been found to have antiphospholipid antibodies,306 and the clinical features of catastrophic antiphospholipid syndrome may be identical to those of TTP-HUS.215 Acute scleroderma can also be clinically216,217 and pathologically152,217 indistinguishable from TTP-HUS. The differential diagnosis between TTP-HUS and autoimmune disorders may be irrelevant, as all of these acute, severe autoimmune disorders have been reported to respond to plasma exchange treatment.215,216,307 However, patients with SLE and TTP-HUS appear to have a higher mortality than patients with idiopathic TTP-HUS.183,205
THROMBOTIC THROMBOCYTOPENIC PURPURA-HEMOLYTIC UREMIC SYNDROME ASSOCIATED WITH PREGNANCY
In many case series of TTP-HUS, 10 to 25 percent of patients are pregnant or in the postpartum period.153,183,308 The incidence of TTP-HUS among all pregnancies, however, is only 1 in 25,000.309 Several case series and reviews focus on the specific issues related to the diagnosis and management of TTP-HUS during pregnancy.309,310,311 and 312 The clinical and pathologic similarity to preeclampsia309,310,312 suggests a relationship between these disorders. The recognized risk for stroke as a complication of preeclampsia further blurs its distinction from TTP-HUS.313 Recurrent TTP-HUS has developed during successive pregnancies, and TTP-HUS that initially occurred in nonpregnant women has relapsed during a subsequent pregnancy.308,309,311 If the disease is severe and the fetus is viable, delivery should be induced, since this will resolve preeclampsia and may151,311,314 or may not312 cause resolution of TTP-HUS. The possible therapeutic response to termination of the pregnancy further blurs the distinction between TTP-HUS and preeclampsia. However, termination of the pregnancy may not be necessary. In one series of 108 patients, 9 women were in their third trimester at the time of initial presentation of TTP-HUS, and all nine successfully completed their pregnancies, with delivery of 10 infants who remained healthy throughout 2 months of observation.204 Others have reported successful completion of pregnancies with delivery of healthy infants.153,308,310,311 There has been no report of transmission of TTP to the infant,204,308,309 and 310 although intrauterine fetal death may occur due to placental infarction caused by thrombosis of the decidual arterioles.315 Five of the nine women described above subsequently had a normal pregnancy and delivery,204 and in another study most subsequent deliveries were successful.311 Nevertheless, after recovery from TTP-HUS, subsequent pregnancies must be considered to carry a risk for recurrence.
THROMBOCYTOPENIA IN PREGNANCY
Thrombocytopenia is a common diagnostic and management issue during pregnancy. Asymptomatic thrombocytopenia occurs near term or in the peripartum period in about 5 percent of normal pregnancies, and thrombocytopenia, sometimes severe, occurs in about 15 percent of women with preeclampsia, which itself occurs in about 9 percent of all pregnancies (Table 117-7). Platelet counts during pregnancy are normal in most women,316 but the mean may be slightly lower than in healthy nonpregnant women.317 Serial platelet counts during pregnancy may318 or may not319 demonstrate a significant decrease during pregnancy, but the mean values of groups may not reflect both increases as well as decreases that occur in individual, otherwise normal patients.320 This discussion focuses on two issues: (1) thrombocytopenia discovered incidentally during a normal pregnancy and its distinction from ITP, and (2) thrombocytopenia associated with preeclampsia and its distinction from TTP-HUS.

TABLE 117-7 INCIDENCE OF MATERNAL AND FETAL THROMBOCYTOPENIA IN 15,471 CONSECUTIVE WOMEN ADMITTED FOR LABOR AND DELIVERY, 1986–1992A

GESTATIONAL THROMBOCYTOPENIA
Incidental thrombocytopenia of pregnancy, also termed gestational thrombocytopenia, is defined by the following five criteria: (1) the presence of mild and asymptomatic thrombocytopenia, (2) lack of a past history of thrombocytopenia (except possibly during a previous pregnancy), (3) occurrence during late gestation, (4) lack of association with fetal thrombocytopenia, and (5) spontaneous resolution after delivery.321 Platelet counts are typically greater than 70,000/µl, with about two-thirds being between 130,000 and 150,000/µl.322,323 The frequency of gestational thrombocytopenia in the largest series of consecutive women admitted for labor and delivery is 5 percent (Table 117-7).322 In this series neonatal thrombocytopenia did not occur in infants born to mothers with gestational thrombocytopenia (except in one infant with congenital myelodysplasia); therefore, it is considered to be benign, and any change from routine obstetrical care is discouraged.324,325 and 326
Etiology The cause of gestational thrombocytopenia is unknown. Many, if not all, of its features are similar to those of mild ITP. Therefore an immunologic etiology for gestational thrombocytopenia, as part of a spectrum including ITP, has been suspected. Supporting this hypothesis was the unexpected observation that 160 women with gestational thrombocytopenia (defined by the criteria stated above) could not be distinguished from 90 women with ITP by assays for antiplatelet antibodies; both groups had higher than normal values.327 Another study of 50 women with thrombocytopenia during pregnancy also reported that 21 had positive results for one or more antiplatelet autoantibodies,328 although some of these women could have had a clinical diagnosis of ITP. Patients with ITP not uncommonly have more severe thrombocytopenia during pregnancy, with improvement after delivery.329 The lack of thrombocytopenia in infants born to women with gestational thrombocytopenia, in contrast to the 5 to 10 percent occurrence of neonatal thrombocytopenia in ITP (Table 117-7),138 may simply reflect absence of neonatal thrombocytopenia in infants born to mothers with mild ITP compared to more severe ITP.330,331 Therefore whether gestational thrombocytopenia is truly distinct from ITP remains unknown.
Differential Diagnosis In women with mild thrombocytopenia, the distinction from ITP is impossible, except possibly in retrospect. If the infant’s platelet count is normal and the mother’s platelet count returns to normal following delivery, gestational thrombocytopenia is considered the appropriate diagnosis. When thrombocytopenia is initially encountered during pregnancy, ITP is the more likely diagnosis if thrombocytopenia occurs early during pregnancy or if the platelet count is very low (<50,000/µl) during the third trimester or at term.321
Treatment For both mother and infant, normal obstetric management is appropriate.321,326,332 Epidural anesthesia is considered to be safe in women with gestational thrombocytopenia and platelet counts >50,000/µl.333 Many women at delivery safely have epidural anesthesia with no platelet count performed, and some are likely to be mildly thrombocytopenic,334 prompting the interesting, but controversial, suggestion that platelet counts should be avoided in asymptomatic pregnant women.335 Delivery should be managed according to routine obstetrical practice.332
Course and Prognosis The immediate concern is for fetal thrombocytopenia and the resulting risk for intracranial hemorrhage at delivery. The large case series summarized in Table 117-7 suggests that there is no risk.322 However, other reports of selected women who had more severe thrombocytopenia than the women reported in Table 117-7 (and therefore may have had a clinical diagnosis of ITP) described severe neonatal thrombocytopenia. One report of 41 pregnancies described two infants with mild thrombocytopenia (platelet counts, 75,000 and 80,000/µl) and one with severe thrombocytopenia (12,000/µl); none had clinically important bleeding.336 However, most of the mothers had platelet counts less than 100,000/µl, different from the women described in Table 117-7. Another study of 50 women referred for thrombocytopenia discovered during pregnancy described 63 pregnancies; 24 (38 percent) infants were thrombocytopenic either at birth or during the first two weeks of life.328 Only one infant had clinically important bleeding, a scalp hematoma. These observations contrast not only with the data in Table 117-7 but also with the frequency of neonatal thrombocytopenia in infants born to mothers with documented ITP.138,321,330,331 But the women in this study actually had more severe and persistent thrombocytopenia than the women described in Table 117-7, with half having platelet counts less than 70,000/µl and half having persistent thrombocytopenia after delivery.328 Therefore, many of these women probably had ITP; these data are consistent with observations that the risk of neonatal thrombocytopenia correlates with the severity of maternal ITP.330,331
Although the large study of consecutive women at delivery (Table 117-7)322 defined the frequency of thrombocytopenia, no follow-up of these women was performed, and no comparable study has defined long-term outcomes. Smaller studies of selected patients have demonstrated that thrombocytopenia in some women does not resolve for many months.325,328,336 For those women whose platelet counts recover, and who therefore fulfill the current definition of gestational thrombocytopenia, recurrent thrombocytopenia with a subsequent pregnancy may be expected.325
PREECLAMPSIA
Definition Pregnancy-induced hypertension and preeclampsia are common syndromes, especially among nulliparous women, and are a major cause of maternal and fetal morbidity and mortality.337 Prevalence is variable in different parts of the world, but an estimate of 5 to 10 percent of all pregnancies is generally accepted (Table 117-7).322,337 Pregnancy-induced hypertension appears after 20 weeks’ gestation and disappears following delivery; preeclampsia is the presence of hypertension plus significant proteinuria and/or edema. Eclampsia is defined by the occurrence of acute neurologic abnormalities in a preeclamptic woman in the peripartum period337,338 and 339; its incidence is about 0.05 percent in developed countries but as high as 1 percent in underdeveloped countries.337,339 Headache, hyperflexia, and visual disturbances can occur in patients who do not progress beyond preeclampsia, whereas seizures are the diagnostic hallmark of eclampsia; aphasia, paresis, and coma may then occur.337,339 The additional renal pathologic features usually seen in preeclampsia are indistinguishable from TTP-HUS: thrombi and mucoid intimal hyperplasia of the afferent arterioles, glomerular capillary thrombi, and subendothelial “fluffy” deposits seen with electron microscopy.152
Platelet counts are lower in preeclamptic women than in women with uncomplicated pregnancies,319 with the incidence of thrombocytopenia estimated to be approximately 15 percent (Table 117-7).322,337 Severe thrombocytopenia, with platelet counts less than 50,000/µl, probably occurs in less than 5 percent of preeclamptic women, though the frequency and severity of thrombocytopenia increase with the severity of preeclampsia. The frequency and severity of thrombocytopenia are greater with eclampsia. If 9 percent of women have preeclampsia and 15 percent of them become thrombocytopenic (Table 117-7), thrombocytopenia due to preeclampsia will occur in about 14 of 1000 deliveries.
Etiology, Laboratory Features, and Differential Diagnosis Preeclampsia is caused by a disorder of placental cytotrophoblast invasion of the uterine wall, resulting in shallow placental anchoring, circulatory abnormalities, and ischemia.337 Placental ischemia triggers a systemic response causing vasoconstriction and endothelial abnormalities.337 Vasoconstriction may also be caused by stimulatory autoantibodies to the angiotensin receptor (AT1).340 Typically, the systemic signs resolve within hours to days following delivery. In severe preeclampsia and eclampsia, thrombocytopenia and microangiopathic hemolytic anemia combined with seizures and other organ dysfunction to produce a disorder clinically indistinguishable from TTP-HUS.
The combination of thrombocytopenia and microangiopathic hemolysis, the current diagnostic dyad of TTP-HUS (Table 117-6), is characteristic of patients with severe preeclampsia, particularly patients with the HELLP syndrome, an acronym for microangiopathic hemolysis (H), elevated liver enzymes (EL), and low platelet (LP) counts.341 HELLP occurs in 5 to 20 percent of women with severe preeclampsia, but it may also become manifest near term without preceding hypertension.337 Symptoms and signs of liver disease may predominate in the HELLP syndrome, representing the spectrum of acute fatty liver of pregnancy, which itself is part of the preeclampsia syndrome.342 Thrombocytopenia and hemolysis can be severe, and serum LDH levels can be extremely high.341 The distinction between preeclampsia/HELLP syndrome and TTP-HUS is further obscured by: (1) the oliguric acute renal failure that can occur in preeclampsia and can be exacerbated by hemorrhage and DIC resulting from placental abruption337,341 (see Chap. 126), and (2) the occurrence of stroke during pregnancy, which is associated with pregnancy-related hypertension.313
Therapy, Course, and Prognosis Delivering the fetus is the most effective method of treating preeclampsia, eclampsia, and the HELLP syndrome; advances in the care of premature neonates allow this to be performed at increasingly early time points. The platelet count nadir and the peak serum LDH may occur postpartum, during the first postpartum day in most patients, but as late as 5 to 7 days in some. For patients with severe thrombocytopenia and microangiopathic hemolytic anemia, plasma exchange is indicated if the fetus cannot be delivered or if improvement does not follow delivery. The third postpartum day is often considered the limit for only supportive therapy in anticipation of a spontaneous recovery.341 If thrombocytopenia and hemolysis (as assessed by serum LDH levels) continue to worsen beyond this time, intervention with plasma exchange is appropriate for the presumed diagnosis of TTP-HUS. At this point TTP-HUS cannot be distinguished from atypical preeclampsia/eclampsia/HELLP syndrome, for which plasma exchange treatment may also be beneficial.341 Earlier intervention with plasma exchange is indicated for more severe clinical problems, such as neurologic abnormalities or acute, anuric renal failure.
Infants born to mothers with preeclampsia are not at increased risk for thrombocytopenia, except for the risks related to prematurity (Table 117-7). Management of the delivery is guided by obstetrical, not hematologic, considerations.329
As with TTP-HUS, recurrence of HELLP syndrome in subsequent pregnancies is a concern. In the absence of persistent hypertension between pregnancies, HELLP syndrome is uncommon in subsequent pregnancies (3%), but less severe complications are more common in subsequent pregnancies: preeclampsia (19%) and preterm delivery (21%).343
IDIOPATHIC THROMBOCYTOPENIC PURPURA
Idiopathic thrombocytopenic purpura (ITP, also known as primary immune thrombocytopenic purpura) is an acquired disease of children and adults defined as isolated thrombocytopenia with no clinically apparent associated conditions or other causes of thrombocytopenia.321 No specific criteria establish the diagnosis of ITP; the diagnosis relies on the exclusion of other causes of thrombocytopenia.321
The clinical syndromes of ITP are distinct between children and adults: Childhood ITP characteristically is acute in onset and resolves spontaneously in most cases within 6 months, whereas adult ITP typically has an insidious onset and rarely resolves spontaneously (Table 117-8). The incidence of ITP appears to be greater in children than in adults, and in children both sexes are equally affected344,345 in contrast to the female predominance in adults. However, among older adults, the sex incidence may be equivalent.346 With the expanding practice of routinely reporting platelet counts with all requests for blood counts, the apparent incidence of ITP has increased.346 Currently 30 to 40 percent of adult patients with ITP are asymptomatic and diagnosed only incidentally.346,347 and 348 The incidence of ITP in children is estimated to be approximately 46 new cases per million population per year,349 and in adults it is estimated to be approximately 38 new cases per million population per year.346

TABLE 117-8 CLINICAL FEATURES OF ITP IN CHILDREN AND ADULTS

ADULT IDIOPATHIC THROMBOCYTOPENIC PURPURA
Adult ITP may be more common in young women,350 a group in which other autoimmune disorders are also relatively common, but recognition of ITP in older patients is increasing.346 Because of greater risks for bleeding, the clinical manifestations and management of ITP in older adults deserve special consideration.347,351
Etiology and Pathogenesis Harrington and coworkers demonstrated in 1951 that infusion of whole blood or plasma from patients with ITP into normal volunteers caused thrombocytopenia, and subsequent studies identified the active principal in ITP plasma as gamma globulin.352,353 When ITP patients’ plasmas were infused into normal subjects, the ability to induce thrombocytopenia was greatest in the plasmas of patients with severe thrombocytopenia refractory to splenectomy; it was substantially less in the plasmas of patients whose thrombocytopenia responded to therapy.354 Increasing doses of ITP plasma infused into a normal recipient caused progressively more severe thrombocytopenia, while much higher doses were required to cause thrombocytopenia in a splenectomized recipient, suggesting that splenic removal, rather than intravascular destruction, was the major mechanism of platelet loss from the circulation354 (Fig. 117-7). Infusion of ITP plasma into patients with hereditary spherocytosis resulted in less thrombocytopenia despite their larger spleens and accelerated red cell destruction, suggesting that platelet removal is reduced when reticuloendothelial clearance is saturated—an observation relevant to the use of intravenous gamma globulin (IVIg) and anti-Rh(D) globulin therapy 20 years later (see “Therapy, Course and Prognosis,” below). Administration of prednisone to normal subjects also diminished thrombocytopenia following infusion of ITP plasma but was less effective than splenectomy354 (Fig. 117-7). Therefore, splenectomy not only removes a major source of antiplatelet antibody production, probably important for long-term remissions, but also removes a major site of platelet destruction, providing the commonly observed immediate response. The normal spleen contains one-third of the body’s platelets, and altered microcirculation associated with lymphoid hyperplasia in ITP may allow greater platelet phagocytosis.355 Macrophage-mediated platelet destruction may be influenced by plasma levels of M-CSF, which are significantly higher than normal in patients with ITP.356 The positive response to splenectomy in the majority of patients with ITP further supports a central role for the spleen in the pathogenesis of ITP (Table 117-8).
Platelet Production and Destruction. Platelet kinetic studies using radiolabeled autologous platelets have demonstrated shortened intravascular survival, consistent with peripheral platelet destruction as the primary mechanism of thrombocytopenia (Table 117-4). This is consistent with the marrow finding of normal or increased megakaryocytes.357,358 Body surface imaging with 111In-oxine–labeled platelets has demonstrated splenic sequestration as the major site of platelet clearance in ITP.357,358 and 359 These studies have also demonstrated the common occurrence of inappropriate marrow response to thrombocytopenia, with most patients having either normal or diminished platelet production36,127,357,358 in spite of the presence of normal or increased numbers of megakaryocyte progenitors with increased cell cycle activity.357 In several studies, the platelet production rate in patients with ITP varied from decreased to increased, with the average being approximately normal (Table 117-4). Earlier platelet survival studies found shorter platelet survival in ITP patients, suggesting greater platelet turnover and production,357 but these studies are now considered less accurate because they employed homologous rather than autologous platelets. Ineffective thrombocytopoiesis may be due to the effect of antiplatelet antibodies on megakaryocytes or their progenitors.360 The marrow contains normal or increased numbers of megakaryocytes.363,364

FIGURE 117-7 Response to infusions of plasma from ITP patients into normal subjects. The left two panels illustrate the occurrence of thrombocytopenia in a normal subject following different doses of plasma from a patient with ITP, and the results of infusion of the same ITP plasma into a splenectomized subject. Note that the ITP plasma dose that did not produce thrombocytopenia in the splenectomized subject was greater than the dose that produced marked thrombocytopenia in the normal subject. The right panel illustrates the effect of prednisone on the response to ITP plasma. Plasma from one ITP patient was infused into three normal subjects without and with treatment with prednisone, 60–80 mg per day. Prednisone was begun 3 h, 1 day, or 3 days before the plasma infusion and continued for a minimum of 7 days. The control infusions were given 1 and 2 months prior to, and 3 weeks after, the infusion with prednisone. (Adapted from Shulman et al,354 with permission.)

Antiplatelet Antibodies. The initial tests used in studies of ITP were designed to measure the effect of patient plasma on the function of normal platelets, such as induction of platelet aggregation or secretion, similar to the tests currently used in studies of heparin-induced thrombocytopenia (see “Heparin-Induced Thrombocytopenia”). These assays were relatively insensitive to the abnormalities in ITP. When quantitative measurements of platelet IgG were developed, high values were noted in patients with ITP.361 It was assumed that all platelet IgG was antiplatelet antibody and was located on the platelet surface. These assumptions, both of which were inaccurate, caused many difficulties in the interpretation of platelet-associated IgG measurements over the next 25 years. Normal platelets contain two distinct pools of IgG: only about 100 molecules of IgG are normally on the surface, while a granules contain about 20,000 IgG molecules.21
Total platelet IgG is increased in patients with ITP, and the magnitude of increase is greater in patients with more severe thrombocytopenia.21,362 Many patients with nonimmune thrombocytopenia, however, also have high platelet concentrations of IgG.21,362 The concentrations of the plasma proteins, IgG, IgA, and albumin in normal platelet a granules mirror the plasma concentrations of these proteins,363 supporting the hypothesis that these proteins are taken up by pinocytosis. In patients with ITP, platelets contain more IgG, IgA, IgM, and albumin than do normal platelets,363 but this can be largely accounted for by increased thrombopoietic stimulation and increased platelet volume.364,365 Thus, total platelet IgG measurements in thrombocytopenic patients may reflect only platelet size, which is known to be increased in response to thrombopoietic stress.365 This is consistent with the observation of an increased number of younger platelets produced by thrombopoietic stress and defined by their RNA content in patients with ITP.366 Patients with nonimmune thrombocytopenia due to increased peripheral platelet removal have increased total platelet IgG, whereas patients with thrombocytopenia due to marrow failure have normal values.40 Exceptions to this interpretation are patients who have disorders with increased plasma IgG concentrations, such as those with IgG myeloma, liver disease, or chronic inflammatory or infectious diseases. In these patients, increased total platelet IgG content merely reflects their increased plasma IgG.363
Recent techniques to measure antibodies that bind to platelets or to specific platelet membrane glycoproteins detect antibodies in most patients with ITP, primarily with specificity for GPIIb/IIIa and/or GPIb/IX.357,367,368 Titers vary inversely with the degree of thrombocytopenia during the course of the disease.374 In one study, antibody concentrations decreased with improved platelet counts following treatment with glucocorticoid, splenectomy, cyclophosphamide, or combination chemotherapy; antibody concentrations did not change with improved platelet counts following vincristine and danazol.369 These data suggest that the former modalities act primarily by decreasing antibody production, while the latter agents act primarily by decreasing platelet sequestration.
The clinical value of tests for antiplatelet antibodies remains uncertain. Some methods are not readily adaptable to routine clinical laboratories, and there are inconsistencies in results among reference laboratories.370 Few studies have addressed the correlation between antiplatelet antibody tests results and clinical diagnosis. In one such study, ITP could not be distinguished from gestational thrombocytopenia327; in another, ITP could not be distinguished from thrombocytopenias with a demonstrable alternative etiology.371 A third study reported that 6 of 18 patients with thrombocytopenia of apparent nonimmune etiology had serum antibodies to GPIIb/IIIa,372 perhaps because neoepitopes can be exposed on membrane proteins during accelerated platelet destruction by any mechanism. Indeed, many plasma antibodies to GPIIb/IIIa in patients with ITP react with normally concealed cytoplasmic epitopes.373
In spite of problems with their measurement and interpretation, autoantibodies certainly appear to be involved in the pathogenesis of ITP. However, laboratory assays for antiplatelet antibodies in ITP remain investigational; they have not yet been demonstrated to be important for either diagnosis or management.321
Platelet Function. The bleeding times of patients with ITP are usually shorter than expected for the degree of thrombocytopenia,374 suggesting that the circulating platelets, which tend to be larger and younger than normal, have enhanced hemostatic activity. However, some patients appear to have impaired platelet function. Autoantibodies to GPIIb/IIIa and GPIb/IX can cause functional platelet disorders indistinguishable from Glanzmann thrombasthenia375 and Bernard-Soulier syndrome,376 but these are rare complications. Antiplatelet antibodies may also impair the aggregation of normal platelets in a manner similar to that of aspirin,377 or inhibit platelet adhesion to subendothelial matrix.378 Whether these observations are clinically important is unknown.
Association with Autoimmune Diseases and Other Disorders. ITP is associated with a variety of immunologic disorders. Patients in whom the thrombocytopenia is part of a clinically overt autoimmune disease are considered distinct from ITP, because the course of the illness is primarily determined by the primary disease.321 For example, thrombocytopenia is common in patients with SLE,379 and management is directed principally at treating the systemic manifestations. Similarly, several case series have described the association of autoimmune thyroid disorders and thrombocytopenia380,381; in these patients the thrombocytopenia often resolves with effective treatment of the hyperthyroidism.380,382 However, patients with abnormal serologic tests (e.g., antinuclear or antiphospholipid antibodies), but without a clinically evident disease such as SLE, are included within the definition of ITP because these positive serologic tests are frequently encountered in patients with typical ITP.383,384 and 385
Clinical Features Most adults present with long-standing histories of purpura, which differs from the more acute presentation typical in children. An increasing number of patients are being diagnosed incidentally as a result of routine platelet counting.346 One-third of patients in a recent case series had platelet counts greater than 30,000/µl at diagnosis; they were not treated and had no significant bleeding symptoms during 30 months of observation.347
The history and physical examination are normal except for the symptoms and signs of bleeding. Petechiae are not palpable and occur most commonly in dependent regions. The distribution of petechiae is also influenced by the tissue turgor, with none on the palms and soles and more in mucous membranes where hemorrhagic bullae may occur when severe thrombocytopenia is present. Symptoms and signs are predictable from the known pattern of bleeding associated with congenital platelet function disorders: purpura, menorrhagia, epistaxis, and gingival bleeding are common; gastrointestinal bleeding and hematuria are less common.386 Intracerebral hemorrhage is uncommon, but it is the most common cause of death and may occur at any time during a prolonged course.387,388 Older patients may be at greater risk for intracerebral hemorrhage.347,351 Bleeding symptoms are rare unless the thrombocytopenia is severe, i.e., less than 10,000/µl (10 × 109/liter), and even at this level most patients do not experience major bleeding episodes (Fig. 117-8).389

FIGURE 117-8 Bleeding manifestations in relation to the platelet count in patients with ITP. Bleeding criteria are designated: 0, no bleeding; 1, minimal bleeding after trauma; 2, spontaneous but self-limited bleeding; 3, spontaneous bleeding requiring special attention, such as nasal packs for epistaxis; and 4, severe, life-threatening bleeding. (Reproduced from Lacy and Penner389 with permission.)

A palpable spleen strongly suggests that ITP is not the etiology for the thrombocytopenia. One large study found that fewer than 3 percent of patients had an enlarged spleen, both by physical examination and by weight at splenectomy.390
Laboratory Features Isolated thrombocytopenia is the essential abnormality. Platelet counts may be higher than in acute childhood ITP. The hemoglobin concentration is normal unless significant hemorrhage due to the thrombocytopenia has resulted in anemia. The white blood cell count is usually normal. Although increased platelet volume appears to correlate with the presence of accelerated platelet production,364 the observation of truly giant platelets, approaching the size of red cells, is not consistent with the diagnosis of ITP and suggests the presence of congenital thrombocytopenia.58 Measurements of plasma levels of glycocalicin, a soluble proteolytic product of GPIb, has been useful in differentiating ITP from thrombocytopenias due to impaired platelet production.391 Coagulation studies are normal, and the bleeding time does not provide useful information.392 Marrow aspiration is appropriate for patients over 60 years old because of concern for myelodysplasia.321 Increased marrow megakaryocytes with a shift to younger, less polyploid megakaryocytes and fewer mature, platelet-producing megakaryocytes has been commonly reported, but assessment of megakaryocyte number and morphology is not quantitative. Erythropoiesis and myelopoiesis are normal.
Differential Diagnosis The diagnosis of ITP is made by excluding other causes of thrombocytopenia. First, true thrombocytopenia must be distinguished from pseudothrombocytopenia caused by innocent antibodies such as EDTA-dependent agglutinins [see “Spurious Thrombocytopenia (pseudothrombocytopenia),” above]. Patients have been inappropriately treated with glucocorticoids and have even been subjected to splenectomy even though true thrombocytopenia never existed.1,393 Other conditions that can mimic ITP at presentation are acute infectious illness, chronic liver disease with hypersplenism, myelodysplastic syndromes,394,395 and chronic DIC.396 The distinction from inherited thrombocytopenia is especially important, and recent observations suggest that inherited thrombocytopenias are not rare among patients with presumed chronic refractory ITP.58 Drug-induced thrombocytopenia may account for some of the acute thrombocytopenias that appear to resolve spontaneously.397,398
Therapy, Course, and Prognosis The clinical data on adult ITP can be estimated from 12 published series, representing 1761 patients.321 The responses to therapy and the percentages of patients who had a complete remission at the time of the latest follow-up are remarkably consistent. Since glucocorticoids were not available until 1950, reports including patients before that time can provide information on the natural history of untreated patients. Of the ten patients with symptoms suggestive of chronic ITP, only one had a remission, and that was after 3 years; in contrast, of the 16 patients with symptoms suggestive of acute ITP, 12 had complete recovery within 3 months. Spontaneous remissions were uncommon in patients with thrombocytopenia lasting more than 100 days.399 These observations suggest that patients at any age who have an abrupt, acute onset are more likely to have a spontaneous remission, and it may be these patients who have complete responses to glucocorticoid therapy in current practice.
More than one-third of adults with ITP fail to achieve a remission with steroids and splenectomy. Table 117-8 provides data on the frequency of spontaneous remissions and mortality in these patients, but these data are imprecise because long-term follow-up was not an objective of most reports. The mortality of patients with chronic, refractory ITP due to hemorrhage or the complications of therapy is approximately 5 percent over the lifetime of the patient. In another report of 312 patients with chronic ITP (ages 7 to 91 years), seven deaths occurred, five due to intracranial hemorrhage and two due to gastrointestinal hemorrhage.400 Thus, the mortality in these patients is low, spontaneous remissions occur, and the reported success of many modalities does not differ greatly from the estimated frequency of spontaneous remissions.
At equivalent platelet counts, major hemorrhagic complications are more common in patients with ITP who are over 60 years of age.347 In one study, all three hemorrhagic deaths occurred in patients 75 to 85 years old.401 A review of 40 patients, ages 45 to 93, demonstrated more complications, greater mortality, and fewer responses to treatment in older patients.351 Ten patients presented with life-threatening hemorrhage, and 14 others had significant gastrointestinal bleeding. Only 12 patients had a complete response to therapy, and 14 patients (35%) died of bleeding or of complications of treatment.351
Emergency Treatment of Acute Bleeding Due to Severe Thrombocytopenia. In patients with severe bleeding, in addition to conventional critical care measures, appropriate treatment includes platelet transfusions, high-dose parenteral glucocorticoids, and IVIg.321 Despite presumably having short platelet survival, some patients have substantial increments in their platelet counts for many hours or even days following platelet transfusion.402 Even if the increment is negligible, hemostasis may be achieved, at least temporarily. There are no adverse effects of platelet transfusion in patients with ITP beyond those associated with platelet transfusions in general. High doses of glucocorticoids, such as 1 g of methylprednisolone given by intravenous infusion daily for 3 days, may also cause a rapid increase of the platelet count and may ameliorate bleeding even if platelet counts remain low due to an effect on the vasculature. IVIg alone, given as 1 g/kg per day for 2 days, will increase the platelet count in most patients within 3 days.321 A single infusion of IVIg, 0.4 to 1.0 g/kg, may increase the response to platelet transfusion and prolong the duration of response.403 Finally, aminocaproic acid (5 g initially, then 1 g every 4 h, given orally or intravenously) has been reported to be effective in controlling acute, severe bleeding in ITP after failure of oral prednisone and platelet transfusions.404
Initial Management. Observation: Most patients who are incidentally discovered to have asymptomatic mild or moderate thrombocytopenia can safely be followed with no treatment. The risk that more severe thrombocytopenia will subsequently develop is estimated by one case series to be 15 percent; in this series another 15 percent of patients with asymptomatic, incidentally discovered ITP recovered spontaneously; the remaining 70 percent of patients had persistent asymptomatic thrombocytopenia.348 Patients with platelet counts over 50,000/µl (50 × 109/liter) usually do not have spontaneous, clinically important bleeding389 and may undergo invasive procedures.405 Patients with platelet counts over 30,000/µl (30 × 109/liter) may also be observed without treatment and without significant risk from hemorrhage.347
Glucocorticoids. The proposed mechanisms of therapeutic effect of glucocorticoids in ITP are diverse. Severe thrombocytopenia may cause thinning and fenestrations of the microvascular endothelium, and glucocorticoids appear to reverse this abnormality.406 This may explain why symptomatic purpura often improves before the platelet count increases or even without an increase in platelet count. The increased platelet count appears to reflect increased platelet production407 as well as diminished platelet sequestration and destruction of antibody-sensitized platelets (Fig. 117-7).354
Prednisone, typically given in a dose of 1 mg/kg per day as a single dose, is indicated for all patients with symptomatic thrombocytopenia and probably for all patients with platelet counts below 30,000 to 50,000/µl (30 to 50 × 109/liter) who may be at increased risk for hemorrhagic complications.321 Approximately 60 percent of patients will increase their platelet count to over 50,000/µl. However, in most patients, thrombocytopenia will recur when prednisone is tapered or discontinued. The goal of prednisone therapy is to promptly lower the risk for acute hemorrhagic complications and to allow time for a spontaneous remission to occur. About one-fourth of patients will achieve a complete recovery from their ITP coincident with prednisone therapy.321 How long to continue prednisone therapy before considering splenectomy in refractory patients depends upon the severity of the bleeding symptoms, the dose of prednisone required to maintain an adequate response, and the risks of surgery in the individual patient. The insidious onset of osteoporosis, often within 3 months of beginning treatment, is a serious side effect of glucocorticoids.408,409 Patients should be considered promptly for splenectomy if severe bleeding complications due to thrombocytopenia do not respond to prednisone. A common practice is to consider splenectomy in patients with persistent severe thrombocytopenia despite 4 to 6 weeks of optimal therapy.321 Initial treatment with IVIg has no advantage over prednisone.410
IVIg. Following the observed disappearance of thrombocytopenia in two children with ITP who were treated with IVIg for congenital agammaglobulinemia, intravenous immunoglobulin preparations have become a standard therapy for ITP.411 In adults, IVIg is used primarily when clinical situations require a transient increase of the platelet count or when the use of glucocorticoids is contraindicated.412 The mechanism of action is postulated to be saturation of phagocytic Fc receptors or perhaps neutralization of antiplatelet autoantibodies by anti-idiotypic antibodies present in the IVIg.413 The initial dose is 2 g/kg given over 2 to 5 days, and a typical response is for the platelet count to increase several days after the infusions are initiated and to return to the pretreatment level within several weeks. Comparable responses may occur with half this dose or a single dose of 0.8 g per kg.414 In adult patients who were maintained on intermittent infusions of IVIg when platelet counts fell below 20,000/µl (20 × 109/liter), a single infusion of 60 g seemed adequate.412 The principal side effects are fever, headache, nausea, and vomiting, which occur in 16 to 34 percent of patients,414,415 with aseptic meningitis in 10 percent.416 These symptoms can mimic intracerebral hemorrhage in severely thrombocytopenic patients, and often a CT scan of the head is required to determine the diagnosis. Other side effects include acute renal failure, which may be caused by the hypertonic sucrose in the IVIg preparation,235 and hemolysis caused by alloantibodies.417
Anti-Rh(D) Immune Globulin. Infusion of anti-Rh(D) antiserum was tried because it was postulated that IVIg may contain red cell alloantibodies and that the mechanism of its therapeutic effect was the induction of mild hemolysis, diverting macrophages from destruction of antibody-coated platelets. Clinical trials have demonstrated that platelet counts above 50,000/µl (50 × 109/liter) could be sustained with intermittent treatment of Rh(D)+ children to defer splenectomy.418 A large experience with anti-Rh(D) has demonstrated that children with ITP respond better than adults, but that 70 percent of patients respond with an increase in platelet count of greater than 20,000/µl, with half having an increase in platelet count of >50,000/µl.136 In most patients, the response lasts more than 3 weeks.136 These data and a retrospective study of treated children417 suggest that the efficacy of anti-Rh(D) may be equivalent to IVIg, except that anti-Rh(D) is not effective in Rh(D)– patients (about 15 percent of the population) and is ineffective following splenectomy.136 The only clinically important side effect of anti-Rh(D) is the predictable alloimmune hemolysis. At a dose of 50 µg/kg, few patients will have a hemoglobin decrease greater than 2 g/dl, which is not greater than the hemolysis associated with IVIg.136,417 Other side effects, such as headache, nausea, chills, and fever, are rare (3%136), compared to IVIg (16 to 34 percent of patients414,415). Anti-Rh(D) immune globulin can be administered more rapidly than IVIg (5 to 10 min versus several hours) and is considerably less expensive.
Splenectomy. Splenectomy was a well-recognized treatment for adults with ITP for over 30 years before the introduction of glucocorticoids in 1950.390 The success of splenectomy in achieving complete and apparently permanent responses in two-thirds of patients is reported in many case series,321 but with longer follow-up thrombocytopenia recurs in many patients.419 Case series that reported greater success rates may have been biased by the inclusion of children and the performance of splenectomy soon after diagnosis.185,390 The major effects of splenectomy are twofold: (1) removal of the major site of destruction of antibody-sensitized platelets (Fig. 117-7),354 which accounts for the frequent prompt recovery of thrombocytopenia,390 and (2) removal of a major site of antibody synthesis.
The timing of splenectomy in adults requires judgment about the course and severity of the disease as well as the risks of glucocorticoid side effects. Surgical complications may be greater in patients who have had prolonged glucocorticoid therapy.390 Some studies have suggested that an initial response to glucocorticoid therapy predicts a good response to splenectomy,420 but other studies have found no relationship with the response to glucocorticoid therapy.390,421,422 One report suggested that response to IVIg correlates with subsequent response to splenectomy,423 but other studies have not found a correlation.424 Attempts to predict the response to splenectomy by measuring the pattern of splenic versus hepatic sequestration with radiolabeled platelets have suggested a correlation in some studies425 but not in others.354,358,407,426 The overall experience with splenectomy indicates that no clinical parameters are helpful in predicting response, except that younger patients respond better.422,426,427 and 428
Although the immediate risks of operative and postoperative hemorrhage with splenectomy are remarkably small, even in the face of severe thrombocytopenia, it is prudent to have platelet preparations available for transfusion if bleeding is excessive during surgery. IVIg can induce a transient remission of thrombocytopenia within several days in most patients, so it can be used for preoperative preparation of patients with severe thrombocytopenia. Laparoscopic splenectomy has the disadvantage of less effective visualization to provide hemostasis in severely thrombocytopenic patients, but it offers less morbidity for patients with adequate platelet counts.429,430
Splenectomy is associated with a small but significantly increased risk for severe infectious complications431; therefore the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention recommends that all patients should be immunized with polyvalent pneumococcal vaccine, Haemophilus influenzae b vaccine and quadrivalent meningococcal polysaccharide vaccine at least 2 weeks before splenectomy.432 In addition, children are routinely placed on penicillin prophylaxis433; this is not routine care for adults.
Most patients who will respond to splenectomy do so within several days; responses after 10 days are unusual.390,427 The rapidity and extent of platelet recovery appears to correlate with the durability of the response.422,426,427 Of patients who initially respond to splenectomy and subsequently have recurrent thrombocytopenia, half will relapse within 6 months.427 Some patients develop dramatic thrombocytosis, with platelet counts over 1,000,000/µl (1000 × 109/liter), but there appears to be a low risk for thrombosis.434
Removal of Accessory Spleens. Accessory spleens are found and removed at the time of splenectomy in 15 to 20 percent of patients.435,436 and 437 Additional accessory spleens may be found in as many as 10 percent of patients who are refractory to splenectomy or who relapse after splenectomy.438 In spite of frequent reports of the efficacy of surgical removal of accessory spleens in patients with refractory or recurrent ITP, complete and durable remissions have not been documented in adults.438 Children may have a higher frequency of partial transient responses.438
Splenic Irradiation and Embolization. For patients who are poor surgical candidates, a short course (1 to 6 weeks) of radiation therapy to the spleen (total dose, 75 to 1370 cGy) may be a safe alternative treatment. In two studies, 13 of 19 patients who had platelet counts of less than 50,000/µl (<50 × 109/liter) responded with an increase in platelet count; in only one patient, however, was the platelet count sustained for 6 months at a normal level.439,440 Another alternative to splenectomy may be splenic artery embolization.441
Chronic Refractory ITP. The proper management of adult patients who have not responded to glucocorticoids and splenectomy is a dilemma. Many different treatment modalities have been published, each with reports of success. However, in contrast to the results of splenectomy, results with these modalities have been inconsistent. Further, many of these additional treatments have significant risks.
Observation. The goal of treatment is to achieve a platelet count that ensures hemostasis, not necessarily a normal platelet count. Therefore, it is appropriate to withhold treatment in patients with platelet counts greater than 30,000/µl who have no bleeding symptoms.321 Patients who are asymptomatic with platelet counts less than 30,000/µl389,442,443 may also be safely observed. Treatment decisions must include assessment of lifestyle and other medical conditions that may influence the relative risks of bleeding and of immunosuppressive treatment.
Glucocorticoids. In some patients a safe platelet count can be maintained with very low doses of prednisone or intermittent doses of glucocorticoids. However, even daily prednisone doses that are equivalent to or even less than physiologic cortisol secretion (e.g., 2.5 to 5 mg per day) can cause osteoporosis by impairing normal diurnal cortisol secretion.408,409 One report described success in 10 selected patients treated with a regimen adapted from management of multiple myeloma: dexamethasone, 40 mg per day for 4 days, repeated every 4 weeks.444 Six of these 10 patients had failed splenectomy, and all apparently had a complete response. However, others have been unable to duplicate this success rate, and serious adverse events have been reported with this regimen.445,446
Azathioprine. Azathioprine was the first agent reported to be effective in patients refractory to glucocorticoid treatment and splenectomy.447,448 Approximately 20 percent of patients may have a complete response, defined as a normal platelet count sustained on no therapy. An additional 40 percent of patients may have a partial response, defined as an increased platelet count but only with continued treatment. The typical initial dose of azathioprine is 150 mg, or 1 to 2 mg/kg daily. Although complete responses have been seen after as many as 26 months of treatment, all responding patients increased their platelet count within 4 months.447
Azathioprine is relatively free of side effects, but a major concern, particularly in young patients who may require prolonged treatment, is the risk for developing a malignancy. Acute leukemia and myelodysplastic syndromes have been reported in 30 patients treated with azathioprine for nonneoplastic diseases.449 Two patients developed leukemia and lymphoma, respectively, after prolonged treatment of ITP with azathioprine.450,451 Risks for fetal malformations when azathioprine is taken during early pregnancy are suspected but undocumented.452
Cyclophosphamide. The response to cyclophosphamide is similar to the response to azathioprine. Approximately 20 percent of patients have a complete response and 30 percent have a partial response.448,453 A daily oral dose of 1 to 2 mg/kg per day, adjusted for leukopenia, may be given; complete responses have occurred after 1 to 6 months of treatment.448,453 Alternatively, cyclophosphamide can be administered in larger, intermittent intravenous doses. One case series of 20 selected patients used a regimen of 1000 mg/m2, repeated at 4-week intervals for one to five doses, and reported complete responses in 8 patients.454 This regimen is similar to the use of cyclophosphamide in other severe autoimmune disorders.455
Cyclophosphamide has greater risks than azathioprine. Dose-related marrow suppression, infertility456,457 and teratogenicity,458 have been reported; alopecia is common; hemorrhagic cystitis occurs in about 10 percent of patients; and bladder fibrosis may occur in 25 percent.458 The incidence of bladder cancer also appears to be increased.449 Of greatest concern is the increased incidence of acute myelocytic leukemia and myelodysplastic syndromes. Alkylating agents are associated with a greater risk of causing malignancies than antimetabolites such as azathioprine, and daily oral doses of alkylating agents have higher risks than intermittent parenteral therapy.449 The risk for development of acute leukemia appears to have a threshold at a total dose of 20 g.459 Four patients have been reported who developed acute myelocytic leukemia 23 to 44 months after treatment with cyclophosphamide for chronic ITP.451,460
Vinca Alkaloids (Vincristine, Vinblastine). The rationale for the use of vinca alkaloids in ITP was based on their efficacy in lymphopro-liferative disorders461 and observations that vinblastine and vincristine can cause thrombocytosis in humans and experimental animals.462,463 Vinca alkaloids have been administered either by intravenous bolus injection or intravenous infusion over several hours. Results of treatment are similar with both agents by both methods of administration. The most common regimen is vincristine, 2 mg per week by intravenous bolus, for 3 to 6 weeks. The typical platelet count response is an increase within several days and then a return to the pretreatment level within a few days to weeks. Case series vary greatly in their reports of success, with complete remissions achieved in as few as 3 percent or as many as 30 percent of patients.464,465 and 466
The major side effect of vincristine is dose-related peripheral neuropathy; paralytic ileus may also be a severe problem. The major side effect of vinblastine is dose-related marrow suppression. An increased frequency of second malignancies after vinca alkaloid therapy has not been reported. Vincristine causes alopecia in about 20 percent of patients; this occurs less often with vinblastine.
Danazol. In 1980, it was reported that patients treated with danazol for endometriosis had increased platelet counts.468 Three years later, danazol was reported to increase the platelet count in patients with ITP.467 Doses used in patients with ITP vary between 50 mg per day469 to 800 mg per day467; it is unknown if there are any therapeutic differences between these regimens. When patients respond to danazol, the response is slow, occurring over a period of weeks to months. Typically, responses endure only while danazol is administered. Its major therapeutic benefit is to sustain partial remissions from symptomatic thrombocytopenia. Many patients appear to have no response.470,471
Side effects include headache, nausea, breast tenderness,472 maculopapular rash,473 and liver function abnormalities.474 Hepatic adenomas and carcinomas have been reported in patients treated with danazol, and thus periodic ultrasound evaluations may be appropriate. Seborrhea (30 percent) and acne (20 percent) are common, and hirsutism and voice changes occur in about 7 percent of women.471 Amenorrhea or oligomenorrhea are common and may be beneficial in symptomatic women.471 Acute thrombocytopenia has been reported in five patients given danazol for endometriosis or to stimulate erythropoiesis; in two of these patients acute thrombocytopenia recurred with readministration of danazol.475,476 One patient has been reported in whom thrombocytopenia worsened during treatment for ITP.477 Acute pulmonary fibrosis has also been reported.478
Plasma Exchange. Plasma exchange has been used in patients who are unresponsive to other regimens with reports of limited, transient success.479,480
Colchicine. Colchicine treatment was tried because it has pharmacologic similarity to the vinca alkaloids, but without the latter’s severe toxicities. One case series reported on 14 patients treated with colchicine,481 12 of whom had chronic refractory ITP. Colchicine was given in doses of 0.6 to 1.2 mg/day, adjusted from higher initial doses to avoid diarrhea. No patients had a complete response, and three had partial responses.
Vitamin C. Vitamin C was studied following a serendipitous observation of an increased platelet count in a patient who initiated taking vitamin C supplements.482 This initial report was followed by multiple case series reporting a few patients with limited responses.321
Combination Chemotherapy. One report described the use of various regimens adapted from the treatment of patients with malignant lymphoma in 10 patients; 5 had a complete response.483 Recent reports describe 4 patients treated with even more intensive chemotherapy, either with484,485 or without486 peripheral blood stem cell support. Of these 4 patients, 2 had complete sustained remissions,484 1 had no response,485 and 1 died.486
Other Modalities. Seventy-two patients were treated with immunoadsorption by ex vivo perfusion of plasma through a protein A column; 16 patients (22 percent) responded with a platelet count of greater than 100,000/µl for more than 2 months.487 However, others have reported much less favorable results and significantly greater toxicity, including severe vasculitis.488,489 Seven patients treated with 2-chlorodeoxyadenosine had no response.490 Reports describing patients treated with interferon-a-2b have described some success, but higher platelet counts were not sustained after interferon was discontinued.491,492 Interferon therapy may also exacerbate thrombocytopenia.493 Other reports have suggested benefit from treatment with cyclosporine494 and dapsone.495
Treatment of ITP during Pregnancy and Delivery. The first decision is to estimate the likelihood that thrombocytopenia is due to ITP rather than gestational thrombocytopenia (Table 117-7). Tests for antiplatelet antibodies do not distinguish these presumably distinct disorders (see “Antiplatelet Antibodies”).327 ITP may worsen during pregnancy and improve after delivery.329
Early in pregnancy the management of ITP is the same as if the patient were not pregnant, using prednisone as initial therapy to treat patients whose platelet counts are less than 30,000 to 50,000/µl (30 to 50 × 109/liter), depending on symptoms.321 Splenectomy should be deferred if possible, because the severity of thrombocytopenia may spontaneously improve after delivery. Splenectomy may increase the risk of fetal death and premature labor in early pregnancy, and uterine enlargement presents technical problems in performing a splenectomy later during pregnancy. IVIg is an alternative therapy that may help to delay splenectomy, although splenectomy remains the most effective treatment for severe, symptomatic, ITP.
The greatest concern for ITP during pregnancy is the risk of thrombocytopenia in the newborn infant. Although published data vary widely on the risk of thrombocytopenia in infants born to mothers with ITP,321 a summary of published case series suggests that there is a 10 percent risk of having a platelet count of less than 50,000/µl and a 4 percent chance of having a platelet count of less than 20,000/µl.144 The severity of ITP in the mother appears to correlate with the risk for thrombocytopenia in the infant. Neonatal thrombocytopenia is more frequent when the mother has had a splenectomy and when her platelet count has been less than 50,000/µl at some time during the pregnancy.330,331 The occurrence of neonatal thrombocytopenia is similar among siblings.331 Despite reports to the contrary, prednisone given for several weeks before delivery or IVIg closer to term do not seem to affect the fetal platelet count; treatment should be given only as indicated for management of the mother’s thrombocytopenia.329 Some authors recommend percutaneous umbilical blood sampling at 38 weeks’ gestation to determine the fetal platelet count and recommend cesarean section delivery if the platelet count is less than 50,000/µl (50 × 109/liter).324 However, this procedure has risks for fetal hemorrhage and death.326,330,496 Direct determination of the fetal platelet count from a scalp vein when the cervix is dilated and the fetal head engaged has also been recommended, but this procedure is subject to artifacts causing either falsely low or falsely high platelet counts.326 Current recommendations are to manage the delivery in a conventional manner, with cesarean delivery only for obstetrical indications.321,326,332
Neonatal intracerebral hemorrhage at birth is very rare and has not been reported among case series describing 10 or more patients with platelet counts performed at birth.138,330,331 However, it is critical to carefully monitor the infant’s platelet counts through the first several days of life, as severe thrombocytopenia and major hemorrhage can develop after delivery.321,328,330,331,497
CHILDHOOD ITP
Clinical Features The peak incidence of childhood ITP occurs between ages 2 and 4 with equal incidence in boys and girls.344,345,498 After age 10, the female predominance characteristic of adult ITP begins; therefore, ITP in adolescents, particularly adolescent girls, may be similar to the more chronic disease typically found in adults.344
The characteristic clinical features of childhood ITP are presented in Table 117-8 and in a summary of 12 case series reported on 1693 children.321 Since these reports are from referral children’s hospitals, they are probably biased to more severely affected patients. Children typically present with a short history of acute purpura, most often with symptoms of less than 1 or 2 weeks’ duration. Bruises and petechiae are the nearly universal presenting clinical symptom. Other bleeding manifestations characteristic of thrombocytopenia, epistaxis, gingival bleeding, and gastrointestinal bleeding are uncommon.345 A palpable spleen is present in 12 percent of patients. This difference from adults is probably related to the greater frequency of a palpable spleen in normal children, estimated to be about 10 percent.321
Laboratory Features Most children present with platelet counts below 20,000/µl (20 × 109/liter).321,345 Marrow aspiration has been recommended before beginning glucocorticoid treatment to exclude the possibility of acute lymphocytic leukemia, which may partially respond to glucocorticoids and thereby be masked, but this may not be necessary if the presenting clinical features are compatible with ITP and do not include atypical findings.321 A study of 332 children with typical presentations of ITP found none to have leukemia.499 Most U.S. pediatric hematologists perform a bone marrow aspiration before beginning glucocorticoid treatment500; most British pediatric hematologists do not.345
Course and Prognosis Eighty-three percent of patients have a complete response within 6 months without steroid treatment or splenectomy.321 This figure is higher than the overall response at 6 months because patients are often selected for no specific treatment based on good prognostic features: a short duration of disease with an abrupt onset and mild symptoms.349 Most of the patients who will eventually respond develop no new purpuric symptoms after the first week. The time until the platelet count becomes normal is typically 2 to 8 weeks; approximately half of all patients who spontaneously recover do so within 4 weeks. A history of purpura longer than 2 to 4 weeks before diagnosis is the best predictor of a chronic course. Other risk factors are female sex, age over 10 years, and a higher platelet count at presentation.498 The fate of children with chronic ITP is uncertain, but most children have a spontaneous remission when follow-up is carried on for over 15 years.349
Very few children with ITP have critical complications, and even fewer die or have residual disability. Among the 1693 patients in 12 case series, only 16 (1 percent) had intracerebral hemorrhage, and the risk is probably even lower with current practice.321 Of 29 reported cases of intracerebral hemorrhage in children,321,387 12 occurred within the first 12 days of diagnosis, and two of these patients had a history of head trauma. The intracerebral hemorrhages in the other 17 patients occurred between 1 month and 5 years after diagnosis, typically after failure of steroids and splenectomy to induce a remission.
Most series emphasize the benign nature of childhood ITP, even for patients with chronic, symptomatic thrombocytopenia for many years.349
Treatment Initial treatment is appropriate for children with platelet counts less than 10,000/µl and symptoms of minor purpura, but opinions among pediatric hematologists are sharply divided.321 For children presenting with only bruising, without mucosal or more severe bleeding, no specific treatment is reasonable regardless of the severity of thrombocytopenia.501 In practice, most children receive treatment, and IVIg is more widely used than glucocorticoids500; IVIg (0.8 g/kg as a single dose, or 2 g/kg in divided doses) can increase the platelet count slightly more rapidly than glucocorticoids, and more rapidly by several days than no treatment.414,502 The importance of these differences is, however, uncertain, since treatment has not been shown to decrease the risk of bleeding or death.503
Because most children will recover completely and permanently without splenectomy and because splenectomy in children, particularly those less than 4 years of age, is associated with an increased risk of severe infection,431,433 splenectomy is deferred for at least 6 to 12 months following the diagnosis of ITP. Even then, splenectomy is recommended only for children who have severe thrombocytopenia with significant bleeding symptoms. Splenectomy is clearly efficacious for these patients. Among the 1693 patients, only 178 underwent a splenectomy, and 126 (71 percent) had a continuous complete remission for the duration of the follow-up.321 In a later series, only 3 of 427 children with ITP had a splenectomy.345 In addition to all routine immunizations, polyvalent pneumococcal vaccine, Haemophilus influenzae b, and quadrivalent meningococcal polysaccharide vaccines should be given at least 2 weeks prior to splenectomy to achieve a maximal antibody response. The effect of these immunizations is unpredictable in children less than 2 years old. Penicillin is routinely given as prophylaxis until age 5 years.433 Even with these precautions, splenectomized children and their parents need to be aware of the potential seriousness of febrile illnesses so that they rapidly seek medical attention.
Fewer than 10 percent of children have ITP refractory to splenectomy.321 The efficacy of any measure beyond splenectomy is uncertain. Since the mortality for ITP in children is very low and spontaneous remissions occur even after many years,349 potentially harmful agents must be used only in children who have symptomatic bleeding and substantial risk for death or morbidity from hemorrhage. Specific issues for the management of chronic refractory ITP are discussed above with the adult disease.
CYCLIC THROMBOCYTOPENIA
The etiology of cyclic thrombocytopenias is unknown, but many of the features suggest that these rare syndromes are unusual presentations of idiopathic (autoimmune) thrombocytopenic purpura: They occur predominantly in young women; platelet survival is shortened at the time of decreasing platelet counts; antibodies to platelet membrane glycoproteins are commonly present; cyclic thrombocytopenia can develop during the course of ITP494,504; and, while spontaneous remissions may occur, the cyclic occurrences of thrombocytopenia are chronic in most patients. In other patients, cyclic thrombocytopenia may be a prodrome for marrow failure.505
Oscillations of platelet counts within the normal range may occur in normal subjects; in some normal women oscillations appear to correlate with the menstrual cycle, with lower platelet counts preceding menstruation.506 These observations correlate with the rare occurrence of symptomatic cyclic thrombocytopenia, which was first described in 1936 in three young women, ages 26 to 40, who had repeated episodes of severe thrombocytopenia at the onset of menses.507 In these patients, platelet counts recovered to normal by midcycle, and the disorder spontaneously remitted after three to seven episodes. This pattern of menstrual cyclic thrombocytopenia continues to be reported,504,508,509 and 510 though in some women the platelet cycle does not correlate with the menstrual cycle.504,511 Less commonly, cyclic thrombocytopenia occurs in postmenopausal women and men.505,512,513 and 514 In some patients, there are parallel cycles of neutrophils,512 eosinophils, and lymphocytes.507 The pathogenesis of these syndromes is varied; in some patients autoimmune platelet destruction is predominant510,511; in other patients, cyclic decreases in platelet production are responsible,504,505 which may be mediated by cyclic decreases of thrombopoi-etin.513,514 Another mechanism may be increased platelet phagocytosis mediated by cyclic increases of M-CSF.513
Management of these patients has been difficult. Prednisone often fails to correct the defect but in some patients provides a temporary remission; IVIg and splenectomy have not been effective.505,508,511,515 Danazol induces a temporary remission in some patients with cessation of menses,508 but oophorectomy has been ineffective.504 Some women with menstrual cyclic thrombocytopenia have responded to birth control pills.509
DRUG-INDUCED THROMBOCYTOPENIA
HEPARIN-INDUCED THROMBOCYTOPENIA
Definition and History Heparin-induced thrombocytopenia deserves particular attention because of its frequency and the variability of its clinical manifestations, which include minor and transient decreases in platelet count to severe thrombocytopenia that may be accompanied by severe thrombosis and DIC.536,537,538 and 539 These complications are particularly important because of the clinical settings in which they typically occur; thus, thrombocytopenia can increase the risk of bleeding from heparin anticoagulation, and thrombosis may exacerbate the underlying thromboembolic disease for which heparin was prescribed.
Heparin was in wide clinical use for many years before thrombocytopenia was first established as an adverse reaction by the initial prospective study which documented thrombocytopenia in 16 of 52 treated patients.540 This remarkable observation stimulated many more prospective analyses, but the 31 percent incidence of heparin-induced thrombocytopenia in the initial survey540 has never been duplicated, and, despite multiple case reports, heparin-induced thrombosis has not been documented among more than 2000 patients in prospective studies.541 Complicating the interpretation of the occasional occurrence of severe thrombocytopenia is the much more common occurrence of mild transient thrombocytopenia, which often resolves even with continued heparin treatment.541 Studies of normal subjects receiving either subcutaneous542 or intravenous543 heparin demonstrate that platelet counts fall predictably and progressively during the first 10 days of treatment, with prompt recovery when heparin is discontinued. The heterogeneity among heparin preparations may have contributed to the inconsistency in clinical observations over the past 30 years. For example, heparin derived from beef lung probably causes more thrombocytopenia than heparin derived from porcine intestinal mucosa,541 and differences in the occurrence of heparin-induced thrombocytopenia may even occur among different lots of heparin from the same manufacturer.544
Etiology and Pathogenesis The observation that heparin predictably decreases the platelet count in normal subjects suggests a direct interaction of heparin with platelets, and this has been demonstrated in many ways. Heparin can bind to a single class of saturable sites on platelets with an apparent dissociation constant similar to the therapeutic level in plasma (0.1 to 0.4 U/ml).545 Higher-molecular-weight fractions of heparin bind with higher affinity, probably because of their increased total negative charge.546 Similarly, higher-molecular-weight fractions of heparin, at therapeutic concentrations, are more active in causing platelet aggregation in plasma and enhancing aggregation and secretion induced by physiologic agonists. The platelet response varies widely, however, among normal subjects.547,548 and 549 With higher concentrations of heparin, platelet aggregates form in blood samples in some (but not all) normal individuals. Platelet counts measured with automated counters decrease soon after heparin administration in most patients.550,551 These observations offer a mechanism for the common observation of diminished platelet counts with heparin therapy and raise the possibility that development of antibodies to heparin may be a ubiquitous event.
Assays for heparin-dependent antiplatelet antibodies are well described but not yet immediately available in most clinical settings. In part, this is due to the complexity and unpredictability of the principal components of platelet-based assays: patient serum, normal donor platelets, and heparin. Platelets from different normal donors may or may not aggregate in the presence of patient serum and heparin552,553; platelets from some normal donors are aggregated by heparin without patient sera, and some patient sera can aggregate normal platelets without heparin552; heparin can be replaced by subaggregating concentrations of agonists such as epinephrine552; and the interactions are dependent on the heparin concentration, with higher concentrations inhibiting some platelet responses554 but also causing nonspecific platelet responses in other studies.555 In spite of these complexities, assays based on platelet secretion (14C-serotonin release) have been standardized in experienced laboratories and have increased our understanding of the pathogenesis of heparin-induced thrombocytopenia.537,539,556
Heparin-induced thrombocytopenia appears to be due to the presence of an IgG antibody specific for complexes of heparin and the heparin-binding cationic protein, platelet factor 4 (PF4),557,558 which is secreted from platelet a-granules and is then bound to platelet559 and endothelial cell560 surfaces. Antibodies may bind to heparin complexed with PF4 on platelets or endothelial cells,561 or bind to heparin-PF4 complexes in plasma with the resulting trimolecular complex then binding to platelet surface FcgIIa receptor (FcgRIIa).562 An attractive feature of the latter hypothesis is that these immune complexes have the ability to activate platelets and generate procoagulant membrane microparticles,563,564 which may contribute to the thrombotic complications of heparin-induced thrombocytopenia. It is the thrombotic risk that distinguishes heparin-induced thrombocytopenia from other drug-induced thrombocytopenias.
Immune complexes activate platelets by cross-linking the FcgRIIa molecules on the platelet surface. A His/Arg polymorphism at amino acid 131 in the FcgRIIa molecule affects the binding affinity for IgG and has therefore been investigated as a possible predisposing factor for developing heparin-induced thrombocytopenia and thrombosis.565 Thus, platelets from individuals with the His/His and His/Arg genotypes respond more to sera from patients with heparin-induced thrombocytopenia than do platelets from patients with Arg/Arg.566,567 However, the results from five clinical studies designed to test whether this polymorphism is of clinical importance have yielded conflicting results: Three studies found that the FcgRIIa His/His genotype was overrepresented among patients with heparin-induced thrombocytopenia, consistent with the in vitro data567,568 and 569; one study found the opposite, an overrepresentation of the FcgRIIa Arg/Arg genotype565; one study found no difference.570 The difficulty of precisely defining criteria for the diagnosis of heparin-induced thrombocytopenia and thrombosis may be responsible, at least in part, for these inconsistencies.
In addition to, or as an alternative to, the development of circulating immune complexes composed of antibody, heparin, and PF4, it has been proposed that antibodies can bind to heparin that is already bound to PF4 on the platelet surface.561 This could enhance platelet aggregation by activating platelets and initiating the release reaction, which is consistent with data from studies demonstrating that patient sera induce release of serotonin from dense granules and initiate microparticle formation. ADP appears to be involved in this process, presumably because it is released from platelets and augments platelet aggregation.571 The final mechanism of platelet aggregation appears to require the GPIIb/IIIa receptor, since antagonists of this receptor can inhibit platelet aggregation induced by the sera.
Clinical Features Thrombocytopenia can occur with any heparin preparation537: unfractionated heparin, low-molecular-weight heparins,572 chondroitin sulfatelike glycosaminoglycan agents,573 and heparinlike compounds such as pentosan574 and danaparoid.575,576 and 577 In vitro studies of the effects of these agents on platelet activation and aggregation suggest that the higher-molecular-weight fractions of heparin interact more readily with platelets and thereby cause more thrombocytopenia,546,547 and this has been confirmed with the demonstration of a lower incidence of thrombocytopenia in patients treated with low-molecular-weight heparin.578 But also consistent with in vitro data, any polyanionic molecule can mimic the heparin and cause thrombocytopenia.573 Thrombocytopenia has been reported with all routes of administration, including heparin flushes of indwelling intravenous catheters,579 but most patients have received therapeutic doses of intravenous heparin579 or prophylactic doses of subcutaneously administered heparin.536
Heparin-induced thrombocytopenia is commonly described as two syndromes, although the clinical distinction is often un-clear.537 Minimal thrombocytopenia, with platelet counts not less than 50,000/µl, may begin soon after heparin therapy is initiated; it is usually associated with large intravenous doses of heparin and may resolve even while heparin is continued. This could represent the common, possibly ubiquitous occurrence of diminished platelet counts seen in studies of normal subjects,542,543 probably caused by the direct agglutinating effect of heparin on platelets. Tests for heparin-dependent antiplatelet antibodies are negative in these patients with mild transient thrombocytopenia.537 Severe thrombocytopenia caused by heparin is much less common. It typically occurs after 5 to 8 days of heparin therapy, unless the patient has previously been treated with heparin, in which case it can occur immediately on administration. It may be accompanied by thrombosis or disseminated intravascular coagulation, is associated with heparin-dependent antibodies, and may recur upon readministration of heparin. Even in patients with the more severe, immunologic form of heparin-induced thrombocytopenia, platelet counts are not as low as in reports of other drug-induced thrombocytopenias; nadir platelet counts averaged 46,000 to 62,000/µl in one study.579 Bleeding is rarely an issue; the major clinical problem is thrombosis.536,579 The mechanism for the thrombosis is platelet activation by heparin-dependent antibodies, as described above.
Thrombosis with potentially severe and fatal complications is the most serious adverse reaction to heparin,536,579 but the frequency of this complication is unknown. Among over 2000 patients in a group of prospective studies, only 2 had thrombotic complications, and their relation to heparin therapy was uncertain541; a later prospective study of 358 patients demonstrated only one patient (0.3%) with heparin-induced thrombocytopenia who also had thrombosis, and that was at the site of a femoral venous catheter used for hemodialysis.531 A review of 23,520 consecutive patients hospitalized on an internal medicine service over 9 years, 8261 (35%) of whom were treated with heparin, demonstrated 13 (0.16%) with possible heparin-induced thrombocytopenia; the thrombocytopenia was severe in 2 patients, one of whom probably had heparin-induced arterial thrombosis (0.01%).538 In spite of the low frequency recorded in these studies, retrospective reviews describe many patients with heparin-induced thrombocytopenia with thrombosis: 127 patients in 14 years in a single community536 and 32 patients in 4 years at a single hospital.579
Venous thrombosis is more common than arterial thrombosis in patients with heparin-induced thrombocytopenia.536,579 In the two retrospective reviews, 29 percent and 53 percent of patients with heparin-induced thrombocytopenia developed thrombotic complications.536,579 Deep venous thrombosis and pulmonary embolism were the most common events. Arterial thrombotic events included limb ischemia, myocardial infarction, and stroke.536,579 Most thrombotic events occurred within the first week after diagnosis of heparin-induced thrombocytopenia.536 Patients who developed thrombosis had a high mortality and morbidity: In a review of 32 such patients, 5 died and 3 additional patients required limb amputation.579
Warfarin treatment after heparin has been stopped has been reported to cause venous limb gangrene, presumably as a result of protein C depletion.580 However, these complications may have been related to excessive warfarin doses that caused rapid declines in protein C before producing anticoagulation by reducing the plasma levels of the longer-lived procoagulants prothrombin and factor X.581 Heparin-induced thrombocytopenia with thormbosis is probably best avoided by beginning warfarin and heparin simultaneously at the initiation of anticoagulant treatment. This allows therapeutic warfarin anticoagulation to become established in about 5 days, which is before heparin-induced thrombocytopenia is likely to occur.581
Rare occurrences have been reported of other allergic responses occurring simultaneously with the onset of heparin-induced thrombocytopenia, such as severe anaphylaxis with cardiopulmonary arrest.582
Laboratory Features Two general types of laboratory assays have been described: (1) functional assays, based on end points of platelet aggregation or secretion, and (2) antigen assays based on ELISA using heparin-PF4 as the target antigen.537 The principle of the functional assays is straightforward. Patient serum plus heparin are incubated with normal platelets, and an aggregation or secretion response of the platelets is measured. However, the execution of the assays may be difficult, since platelet responsiveness varies among different normal donors, with platelets from some normal donors being completely unresponsive.537,547,548 and 549 Apparent spontaneous platelet aggregation or secretion in these assays may be caused by the presence of trace amounts of residual thrombin in the sera.
The most widely described tests are functional assays using as end points aggregation or the secretion of 14C-serotonin from normal platelets preincubated with 14C-serotonin.537 Two concentrations of heparin are used in these assays: 0.1 to 0.3 U/ml, to stimulate platelet activation in the presence of platelet-dependent antibodies, and 10 to 100 U/ml, which should not cause platelet activation with sera from patients with heparin-induced thrombocytopenia, because the high heparin concentration decreases the number of heparin molecules that have more than one PF4 molecule attached and thus decreases the ability to form complexes that can cluster receptors on the platelet surface. The higher concentration is thus a control for nonspecific direct heparin activation of the normal donor platelets.537 Although these assays can support a clinical diagnosis of heparin-induced thrombocytopenia, they may also be positive in patients with no thrombocytopenia, even patients with no history of heparin exposure.530,532 These assays have not been adapted to routine clinical laboratories.
ELISA assays are easily adaptable to routine clinical laboratories, but their clinical value is uncertain. Direct comparison of the ELISA assay with functional assays, 14C-serotonin secretion556 or aggregation,583,584 demonstrated general agreement, and, in each study, the ELISA identified more patients as positive, suggesting greater sensitivity. However, multiple studies have reported these antibodies in patients with no thrombocytopenia, even patients with no history of heparin exposure.529,530,532,556,585 Thus, at present, the positive and negative predictive values of these tests remains unknown. In the few patients who had positive functional tests but negative ELISA tests, their antibodies may have been formed against heparin complexed to one or more heparin-binding chemokines (interleukin-8, neutrophil-activating peptide-2) rather than PF4 itself.586
Other laboratory assays are being developed to demonstrate heparin-dependent antiplatelet antibodies,587,588 but the role of laboratory testing in clinical decision making remains unclear. When heparin-induced thrombocytopenia is suspected, heparin must be stopped. No laboratory test has been validated by demonstrating the safety of continuing heparin when a negative result is reported. Similarly, a positive ELISA assay does not necessarily confer a high risk of developing thrombocytopenia. For example, in three studies, 5 to 22 percent of patients tested before cardiac surgery were found to have positive or indeterminate results, and yet none developed the syndrome of heparin-induced thrombocytopenia.529,532,585
Prevention, Diagnosis, and Therapy Awareness of the potential for thrombocytopenia with heparin use, with frequent performance of platelet counts, is the most important preventive measure. The occurrence of heparin-associated thrombocytopenia may be decreasing because of the current use of shorter courses of heparin therapy with concurrent initiation of warfarin and the increasing use of low-molecular-weight heparin.537,581 The diagnosis of heparin-induced thrombocytopenia should be made on the basis of a platelet count less than 100,000/µl, a platelet count decrease by greater than 50 percent that is not explained by other causes, or a new thromboembolic event in the absence of other etiologies.537 If the platelet count drops below 50,000/µl or there is any evidence of thrombosis, heparin should be discontinued. Since there are many reports of asymptomatic patients with platelet counts of 50,000 to 100,000/µl who spontaneously recovered while continuing heparin,541 the decision as to when to stop heparin in asymptomatic patients is complex and needs to weigh the indication for heparin and the patient’s comorbidities. Evidence for disseminated intravascular coagulation should be assessed, which may itself be caused by the heparin.540 All heparin-associated platelet and coagulation changes should reverse within several days of stopping heparin. If laboratory assays for heparin-dependent antibodies are available, they may provide supportive information, but they are unlikely to alter clinical decisions.
In most patients, the thrombocytopenia will be mild and self-limited and will be discovered at a time in the course of therapy when heparin can be safely discontinued. In the uncommon patients when alternative antithrombotic therapy is required, available options include danaparoid and recombinant hirudin539; investigational agents available for clinical trials or compassionate use include ancrod and argatroban.539 Warfarin can be continued and may be sufficient. Warfarin should not be initiated with high loading doses in a patient with heparin-induced thrombocytopenia in whom heparin has been stopped, since a rapid decrease in protein C may exacerbate thrombosis.580 Treatment for severe thrombocytopenia with thrombosis may include the use of plasma exchange.589 There are no reports of adverse reactions to platelet transfusions, but their use in the presence of an antibody that may aggregate platelets could theoretically result in thrombosis, as has been described in thrombotic thrombocytopenic purpura.192,229
A difficult problem is the management of patients with a history of heparin-induced thrombocytopenia who require a procedure that routinely involves heparin anticoagulation.590 Hemodialysis can successfully be performed without heparin.591 Patients have undergone uncomplicated cardiac surgery with limited heparin exposure even in the presence of preoperative positive results for heparin-dependent antibodies,529,531,585 though none of these patients had a documented clinical diagnosis of previous heparin-induced thrombocytopenia. When heparin must be avoided during cardiac surgery, successful anticoagulation has been achieved with danaparoid,592,593 recombinant hirudin,594 and ancrod590,595; however, danaparoid dosing is difficult, and heparin-dependent antibodies may cross-react with danaparoid, resulting in thrombocytopenia and thrombosis.575,576
OTHER DRUG-INDUCED THROMBOCYTOPENIAS
The assessment of isolated thrombocytopenia in a patient taking several medications needs to be systematic, with drug-induced thrombocytopenia considered before establishing a diagnosis of ITP.321 This section will discuss drugs, other than heparin and its analogs, that cause isolated thrombocytopenia by immune platelet destruction; heparin is discussed in the preceding section. Drug-induced TTP-HUS is discussed previously in this chapter; drug-induced aplastic anemia with thrombocytopenia is discussed in Chap. 31.
Etiology and Pathogenesis Reviews of drug-induced thrombocytopenia often contain such extensive lists of implicated drugs, many of which are commonly used, that they are not helpful for decisions of which therapy to interrupt first. To address the issue of which drugs are most likely to cause thrombocytopenia, a systematic review of all published case reports defined levels of evidence to document the causal relation between the drug and the thrombocytopenia.398 This review distinguished drugs with definite or probable causal relationships from those for which the evidence is weaker.398 Table 117-9 presents a list of the drugs for which there is definite evidence of a causal role in producing thrombocytopenia (which includes recurrent thrombocytopenia with rechallenge in the same patient) and drugs for which the causal relation to thrombocytopenia has been validated by at least two reports with probable evidence (thus meeting all of the criteria for definite evidence except for the lack of rechallenge). Quinidine is by far the most commonly cited drug; other commonly cited drugs are similar to drugs documented in a case-control study.397 A remarkable observation from the systematic review was how many case reports did not provide sufficient clinical information to allow a determination of even a probable causal relation.398

TABLE 117-9 DRUGS CAUSING THROMBOCYTOPENIA SUPPORTED BY ONE OR MORE PATIENT CASE REPORTS WITH LEVEL I (DEFINITE) EVIDENCE OR LEVEL II (PROBABLE) CLINICAL EVIDENCE*

Thrombocytopenia is assumed to be the result of immune platelet destruction by drug-dependent antiplatelet antibodies. Initial experimental observations suggested that drug-antibody complexes bound to platelets via the platelet Fc-gamma receptor. This mechanism has been confirmed for heparin-induced thrombocytopenia (see below), but for other drugs, the drug-dependent antibodies appear to bind to platelets via their Fab regions.516 The antigen on the platelet surface is formed by drug binding to a membrane glycoprotein receptor, creating a structural change that initiates antibody formation in susceptible subjects. The new antigen may be a newly revealed sequence of a surface glycoprotein or may be a complex composed of the drug and a platelet surface protein. Most experimental studies have used drug-dependent antibodies isolated from patients with quinidine or quinine-induced thrombocytopenia (Table 117-9). The antigen targets are the major platelet surface glycoproteins (GPIb/IX and GPIIb/IIIa). Different drugs may provoke drug-dependent antibodies that preferentially react with one of these glycoproteins, or drug-dependent antibodies from a single patient may react with multiple epitopes on both glycoproteins. For example, a study of sera from 15 patients with quinine-induced thrombocytopenia demonstrated that in the presence of quinine, the antibodies bound to two distinct domains on GPIb/IX, one on GPIba and one on GPIX.517 Some patients had only one of the antibodies; some had both. The same domains on GPIb/IX also appear to be the antigenic targets for quinidine518,519 and ranitidine-dependent520 antiplatelet antibodies. Definition of the specific epitope involved in patient reactions with drug-dependent antibodies may not only elucidate the mechanism of drug-induced thrombocytopenia but also identify polymorphisms in GPIb/IX that cause sensitivity for producing drug-dependent antiplatelet antibodies. Sulfonamides, along with quinidine and quinine, are frequent causes of drug-induced thrombocytopenia (Table 117-9). Studies of sera from 15 patients with thrombocytopenia caused by sulfamethoxazole or sulfisoxazole demonstrated that the antigenic epitope was not on GPIb/IX but on GPIIb/IIa.521 Some antibodies from patients with quinidine and quinine-dependent antiplatelet antibodies also react with GPIIb/IIIa.522
In addition to specificity for discrete epitopes on platelet surface glycoproteins, drug-dependent antibodies are highly specific for the structure of the drug; for example, no cross-reactivity occurs between quinidine and quinine-dependent antibodies (Fig. 117-9) or between sulfamethoxazole and sulfisoxazole-dependent antibodies, even though both pairs of drugs have similar structures.521 Therefore the neoantigens produced by drug binding to platelets create discrete epitopes that are sensitive to minor changes in drug structure.

FIGURE 117-9 Induction of thrombocytopenia by infusion of a total of 1.3 mg of quinidine over a 24-min period in a patient with quinidine-dependent antibody. A lower dose of quinidine administered earlier was without effect. (From Shulman NR: J Exp Med 107:711, 1958.)

The implications of this mechanism for platelet destruction are apparent. A patient with prior sensitivity to the drug will have preformed antibodies that immediately react with the altered platelets upon repeat drug exposure, as demonstrated in Fig. 117-9. An exception to this is the immediate acute thrombocytopenia that may occur with the initial administration of the new class of antithrombotic agents that block the platelet fibrinogen receptor, GPIIb/IIIa.523,524 It has been postulated that these patients have preformed antibodies to epitopes exposed on GPIIb/IIIa by drug binding; these could be the same antibodies that cause in vitro EDTA-dependent platelet agglutination and pseudothrombocytopenia.34,35,525
Diagnosis The diagnosis can only be made by recovery from thrombocytopenia and can only be confirmed by recurrent thrombocytopenia with rechallenge of the drug. Prompt recovery is predictable, within 5 to 7 days.398 Gold-induced thrombocytopenia is an exception, as gold salts are retained for a long time within the body and thrombocytopenia can persist for months, becoming indistinguishable from ITP.526 Rechallenge with a suspected drug may be considered but can be dangerous, as severe thrombocytopenia can rapidly develop with even very small doses (Fig. 117-9). However, when any one of multiple drugs may be involved and all are important for management, it may be appropriate to reintroduce them individually, followed by several days of close observation. For common drugs, especially those that can be purchased without a prescription, it may be safer to supervise a rechallenge and unequivocally document risk rather than risk future, unintentional use.
Laboratory assays can detect drug-dependent antibodies, and positive results can support a clinical diagnosis. However, the laboratory role remains largely investigational, since results are not promptly available when a clinical decision must be made about discontinuing a drug. Furthermore, no laboratory test has been validated by continuing a suspected drug with no adverse effects following a negative laboratory test.
Drug-dependent antibodies can be detected by flow cytometry techniques,521 MAIPA,527 and SPRCA.528 Strongly positive tests are apparent, but distinction of positive from negative tests is arbitrary and not yet clinically validated. Positive tests for heparin-dependent antibodies have been reported in patients without thrombocytope-nia,529,530,531 and 532 and patients with clinical evidence for drug-induced thrombocytopenia may have negative tests using multiple techniques.520,521
Clinical and Laboratory Features In patients with newly discovered thrombocytopenia, all medications should be identified. It is important to document not only prescription medications but also nonprescription drugs, such as products with acetaminophen (Table 117-9),398 and drinks that may include quinine (“tonic water”).533,534
Drug-induced thrombocytopenia typically produces profoundly low platelet counts. Among the 247 patient case reports with evidence for a definite or probable causal relation of the drug to thrombocytopenia, 23 patients (9%) had major bleeding, including two patients who died from bleeding,398 and 68 patients (28%) had overt but minor bleeding; 96 patients (39%) had only purpura or trivial bleeding, and the remainder had no bleeding.398 The time from beginning the drug to the initial occurrence of thrombocytopenia varies from 1 day to 3 years, but the median time is only 14 days.398 With rechallenge, acute thrombocytopenia may occur within minutes but almost always within 3 days (Fig. 117-9).398 Patients may also have other signs and symptoms of drug sensitivity: nausea and vomiting, rash, fever, and abnormal liver function tests.535 Laboratory data may also demonstrate leukopenia, indicating multiple cell targets of the drug-dependent antibodies.535 Patients who have systemic adverse reactions manifesting TTP-HUS are described in the above section on TTP-HUS.
Treatment Withdrawal of the offending drug is the most important therapeutic measure. Prednisone is commonly given, as the distinction from ITP is never initially clear; however, it does not appear to influence recovery.535 In patients with major bleeding, emergent treatment should be the same as for ITP: platelet transfusions, high doses of parenteral methylprednisolone, and possibly also IVIg.321
NEONATAL ALLOIMMUNE THROMBOCYTOPENIA
ETIOLOGY AND PATHOGENESIS
Approximately 0.14 percent of all newborns have platelet counts less than 50,000/µl (Table 117-7),322,596,597 and alloimmunization is responsible for about one-half of these cases. These data are consistent with the risk for fetal-maternal incompatibility of platelet alloantigens, the risk for maternal antibody formation in response to incompatible fetal platelets, and the risk for neonatal thrombocytopenia when maternal alloantibodies are present. In NATP, fetal platelets are destroyed by transplacentally acquired maternal antibodies against fetal platelet alloantigens inherited from the father. NATP is comparable to neonatal alloimmune hemolytic anemia due to maternal immunization by Rh(D)+ fetal red cells (see Chap. 58), except that NATP frequently occurs during the first pregnancy, indicating that maternal immunization with fetal platelets can occur during pregnancy, not only at delivery, when red cell immunization occurs.
In NATP the dominant alloantigen is HPA-1a (PlA1). In an analysis of 348 infants with suspected NATP, the diagnosis was confirmed by demonstration of antibodies to platelet-specific alloantigens in 117 (34%) of the mothers; 78 percent of the alloantibodies were anti-HPA-1a, 19 percent were anti-HPA-5b (Bra), and 3 percent were other alloantigens, including anti-HPA-1b (PlA2) and anti-HPA-3a (Baka).598 Only 2.5 percent of the Caucasian population is HPA-1a-negative, but in this study598 144 (41%) of the mothers of newborns with NAPT were HPA-1a-negative. Since the frequency of NATP due to HPA-1a incompatibility (about 0.05%) is much lower than the frequency of HPA-1a negativity in the Caucasian maternal population (2.5%), it is clear that not all mothers who are at risk routinely develop antibodies. An association between HLA-DRB3*0101 (DR52a) in the mother and NATP suggests that this HLA determinant is important in permitting an immune response to be mounted. The frequency of this allele in the population is 32 percent.599 In a prospective study of 24,417 consecutive pregnant women (essentially all Caucasian, 55% multiparous, but only one with a previously thrombocytopenic child), 678 (2.8%) were HPA-1a-negative, of whom 385 were observed throughout pregnancy.599 Antibodies to HPA-1a were detected in 46 of the 385 women (12%), all but one of whom was HLA-DRB3*0101 (DR52a)-positive, yielding an odds ratio of 140. Twenty-six of the 46 women had persistent antenatal antibodies and HPA-1a-positive infants; of these infants, 9 had severe thrombocytopenia (platelet count <50,000/µl).599 Severe NATP was significantly associated with a third-trimester anti-HPA-1a titer of greater than 1:32; severe NATP did not occur in infants of women with either transient or postnatal-only antibodies.599 These data are consistent with the observations of NATP in other case series (Table 117-7)322,596,597: HPA-1a alloimmunization complicates 1/350 unselected pregnancies, resulting in severe thrombocytopenia in 1/1200 (0.08%).599 Since only 0.5 percent of Americans of African descent are HPA-1a-negative, their incidence of NATP is less than that of the Caucasian population.600
Among other platelet alloantibodies identified in NATP, most are anti-HPA-5b (Br), and these infants are less severely affected.598,601 Other alloantibodies may cause NATP but are rarely important.326 Since allelic gene frequencies vary among different racial and ethnic groups, the etiology of NATP will also vary. For example, among Japanese the gene frequency for HPA-1b is much lower than in Caucasian populations (0.02 vs. 0.15), and the gene frequency of HPA-4b is much higher (0.0083 vs. <0.001).602 As expected, therefore, anti-HPA-1a has not been shown to cause NATP in the Japanese population, while antibodies to HPA-4b are the most common.603
CLINICAL AND LABORATORY FEATURES
In contrast to neonatal alloimmune hemolytic anemia, about half of infants with NATP are born to primiparous mothers.326,598 The risk for NATP in a subsequent fetus of alloimmunized mothers is 85 to 90 percent,604 and generally the second neonate’s thrombocytopenia is similar to, or more severe, than that found in the first neonate.326 In a case series of 88 infants with NATP due to anti-HPA-1a antibodies, 90 percent of infants had purpura, 66 percent had hematomas, 30 percent had gastrointestinal bleeding, and 14 percent had intracerebral hemorrhages.598 Five of the intracerebral hemorrhages occurred in utero.598 Bleeding may also occur following birth as the platelet count usually falls further during the first several days of life.598 Death or neurologic impairment may occur in up to 25 percent of infants.605 Platelet counts recover to normal in 1 to 2 weeks.598
In every respect, NATP is more severe than thrombocytopenia in infants born to mothers with ITP.138 As a result, determination that the mother’s platelets are HPA-1a-negative provides sufficient presumptive evidence for the diagnosis of NATP to support the institution of therapy.
PREVENTION AND MANAGEMENT
Because NATP can occur during a first pregnancy, a strategy involving antenatal screening of pregnant women for the HPA-1a antigen, and then screening HPA-1a-negative women for HLA-DRB3*0101, has been studied.601,606 However, since the risk of having a severely thrombocytopenic infant is relatively low even among HPA-1a-negative, HLA-DRB3*0101-positive women, the cost-effectiveness of such screening programs needs to be established.
Management of thrombocytopenia in the newborn infant requires platelet transfusions, glucocorticoids, and IVIg.326 The mother is the ideal source for the transfused platelets since her HPA-1a-negative platelets will survive longer than random platelets, which are likely to be HPA-1a-positive. However, it may be technically difficult to arrange for the mother to donate. If the mother’s platelets are used, they should be washed to remove her plasma (which contains the anti-HPA-1a antibodies), irradiated to prevent graft-versus-host disease, and tested for infectious agents.607 Random donor platelets plus IVIg are an appropriate alternative if facilities are not available for collecting and preparing maternal platelets.
The management of subsequent pregnancies presents several interesting challenges. A prospective study of 107 fetuses whose older siblings had NATP found that at the initial in utero sampling (which took place before 24 weeks of gestation in almost 50 percent of the pregnancies), only 4 percent had normal platelet counts, 70 percent had platelet counts less than 50,000/µl, and 50 percent had platelet counts less than 20,000/µl.604 The median initial platelet count was 18,000/µl in the 97 fetuses with HPA-1a incompatibility compared with 60,000/µl in the 10 fetuses with other antigen incompatibilities. Determination of fetal platelet counts by percutaneous blood sampling from the umbilical cord (cordocentesis) has significant risks, including hemorrhage and death of the fetus.496 Treatment of NATP includes administration of IVIg and glucocorticoids to the mother,608 which appears to reduce the frequency of in utero fetal intracerebral hemorrhage604,608 but is not effective in all patients.605 In some infants, serial in utero platelet transfusions are required.26 Delivery by scheduled cesarean section, without labor, may reduce the risk for neonatal intracerebral hemorrhage.609
POSTTRANSFUSION PURPURA
Acute, severe thrombocytopenia occurring about 5 to 15 days after a blood transfusion and associated with a high titer of platelet-specific alloantibodies is a rare but well-recognized disorder defined as posttransfusion purpura (PTP).600 Patients have been described who also have alloantibodies against red cells and granulocytes.610
Etiology and Pathogenesis Although the sequence of events leading to PTP is clear, the etiology and pathogenesis remain obscure. Platelet destruction is caused by an alloantibody to a platelet-specific antigen; as with NATP, anti-HPA-1a (PlA1) is implicated in about 80 percent of cases, but PTP due to alloimmunization to most other platelet-specific antigens has been reported.600 Therefore, PTP occurs predominantly among HPA-1a-negative individuals who constitute 2.5 percent of Caucasians and 0.5 percent of Americans of African descent. Most patients are women, and most women are multiparous.600
The initial alloantibody formation to transfused HPA-1a-positive platelets is well-documented though uncommon and possibly dependent on linkage to the HLA-DRB3*0101 genotype, as in NATP.599 What remains obscure is how the alloantibodies destroy the patient’s own (HPA-1a-negative) platelets. Several hypotheses have been proposed, with varying degrees of experimental support. Soluble HPA-1a antigen on platelet membrane microparticles is present in blood products611 and may adsorb to the patient’s platelets, providing the target antigen.612,613 This hypothesis also provides a potential explanation for the protracted persistence of PTP for 4 to 6 weeks in some patients, since recycling of soluble antigen from platelet to platelet may occur. A second hypothesis is that immune complexes of soluble HPA-1a antigen and anti-HPA-1a alloantibodies mediate autologous platelet destruction.600 A third hypothesis is that an autoantibody forms in parallel with the alloantibody, recognizing a conserved structural determinant adjacent to the specific antigen polymorphic site, and this antibody then destroys autologous platelets.604
Clinical and Laboratory Features Case reports of PTP describe severe thrombocytopenia (platelet counts <5,000/µl) with major bleeding. Often a febrile reaction accompanies the initial presentation, inciting transfusion and subsequent transfusions.600 Deaths from intracerebral hemorrhage have been reported.600 Since PTP, by definition, follows transfusion of a blood product (usually packed red cells), patients are typically hospitalized and often acutely ill; therefore sepsis and drug-induced thrombocytopenia are always included in the differential diagnosis. Excluding other causes of thrombocytopenia in patients following marrow transplantation can be particularly difficult.615
Antibodies to a platelet-specific alloantigen, which can be distinguished from antibodies to HLA antigens, can be detected by a number of different available assays. The patient’s own platelet type will only be evaluable after recovery; then documentation that the patient is HPA-1a-negative further supports the diagnosis of PTP.
Treatment, Course, and Prognosis Because of the severity of the thrombocytopenia, treatment often needs to be initiated without having a firm diagnosis. Platelet transfusions are usually ineffective in achieving a platelet count increment and may cause severe systemic reactions600; nevertheless, if the patient has severe, active bleeding, platelet transfusion support is essential. Even HPA-1a-negative platelets may be rapidly destroyed, though some reports describe satisfactory responses.615 Glucocorticoids and IVIg are usually effective. Plasma exchange is reported to be effective in 80 percent of patients.600 Thrombocytopenia begins to resolve in several days following treatment in most patients, though it may be persistent and severe in some.600 Anti-HPA-1a antibodies may persist in some patients following recovery,616 but interestingly PTP may not recur with subsequent transfusion of HPA-1a-positive blood products.617
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Books@Ovid
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology

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