Williams Hematology



Systemic Disorders Associated with Abnormal Platelet Function


Antiplatelet Antibodies

Cardiopulmonary Bypass

Miscellaneous Disorders
Hematologic Disorders Associated with Abnormal Platelet Function

Chronic Myeloproliferative Disorders

Leukemias and Myelodysplastic Syndromes


Acquired Von Willebrand Disease
Drugs that Affect Platelet Function

Aspirin and Other Nonsteroidaldanti-Inflammatory Drugs




Drugs that affect Platelet Cyclic Nucleotide Levels or Function

Anticoagulants, Fibrinolytic Agents, and Antifibrinolytic Agents

Cardiovascular Drugs

Volume Expanders

Psychotropic Drugs, Anesthetics, and Cocaine

Oncologic Drugs

Miscellaneous Agents

Foods and Food Additives
Chapter References

Acquired qualitative platelet disorders are frequent causes of abnormal platelet function in vitro, prolonged bleeding times, and occasionally mild bleeding diatheses. However, their clinical importance increases in the presence of thrombocytopenia or additional disorders of hemostasis. Acquired disorders of platelet function can be conveniently classified into those that result from systemic diseases, hematologic diseases, and the effect of drugs. Of the systemic diseases, renal failure is most prominently associated with abnormal platelet function due to the retention of platelet inhibitory compounds. Platelet function may also be abnormal in the presence of antiplatelet antibodies, following cardiopulmonary bypass, and in association with liver disease or disseminated intravascular coagulation. Hematologic diseases associated with abnormal platelet function include marrow processes in which platelets may be intrinsically abnormal, such as the myeloproliferative disorders, acute and chronic leukemias, and myelodysplastic syndromes; dysproteinemias in which abnormal plasma proteins can impair platelet function; and acquired forms of von Willebrand disease. Drugs are the most frequent cause of acquired qualitative platelet dysfunction. Aspirin is the most notable drug in this regard because of its frequent use, its irreversible effect on platelet prostaglandin synthesis, and its documented effect on hemostatic competency, although this effect is minimal in normal individuals. Other nonsteroidal anti-inflammatory drugs reversibly inhibit platelet prostaglandin synthesis and usually have little effect on hemostasis. The antiplatelet effect of a number of drugs has proven useful in preventing arterial thrombosis, but, as would be anticipated, excessive bleeding can be a complication of their use. In addition to aspirin, these drugs include the thienopyridines ticlopidine and clopidogrel, which primarily antagonize ADP-stimulated platelet aggregation, and drugs that specifically inhibit the platelet glycoprotein (GP) IIb/IIIa receptor. Other drugs used to treat thrombosis, such as heparin and fibrinolytic agents, can also impair platelet function in vitro and ex vivo, but the clinical significance of these observations is uncertain. High doses of the b-lactam antibiotics can impair platelet function in vitro and prolong the bleeding time, while clinically significant bleeding is unusual in the absence of a coexisting hemostatic defect. Similarly, a number of miscellaneous drugs, including a variety of psychotropic, chemotherapeutic, and anesthetic agents, as well as a number of foods and food additives, have been reported to affect platelet function in vitro, but these effects do not appear to be of clinical significance.

Acronyms and abbreviations that appear in this chapter include: BCNU, carmustine; cGMP, cyclic guanosine monophosphate; DDAVP, 1-desamino-8-D-arginine vasopressin; DIC, disseminated intravascular coagulation; EPIC, evaluation of 7E3 for the prevention of ischemic complications; EPILOG, evaluation of PTCA to improve long-term outcome by c7E3 GPIIb/IIIa receptor blockade; GP, glycoprotein; Ig, immunoglobulin; ITP, idiopathic thrombocytopenic purpura; PG, prostaglandin; PKC, protein kinase C; PGHS-1, PG endoperoxide H synthase-1; SLE, systemic lupus erythematosus; t-PA, tissue plasminogen activator; vWf, von Willebrand factor.

Platelet function may be adversely affected by drugs and by hematologic and nonhematologic disorders. Because the use of aspirin and other nonsteroidal anti-inflammatory agents is pervasive in our society, acquired platelet dysfunction is much more frequent than inherited platelet dysfunction. Acquired disorders of platelet function can be classified according to the underlying clinical condition with which they are associated (Table 120-1).


It is important to have a balanced view of the clinical significance of these disorders. On the one hand, their severity is usually mild. On the other hand, there are important exceptions to this rule, particularly when platelet dysfunction is associated with other hemostatic defects. If the patient does not present with a history of bleeding, it may be difficult to predict the risk of future bleeding. This is not surprising, since even patients with thrombocytopenia may experience little or no spontaneous bleeding until their platelet count is less than 10,000/µl. Furthermore, clinical assessment of these disorders is made problematic by difficulties in standardization and interpretation of the two most frequently used laboratory tests of platelet function: the bleeding time and platelet aggregometry. These tests appear more useful in diagnosing platelet dysfunction than in predicting the risk of bleeding.1,2
Bleeding may be a serious complication of acute and chronic renal failure.3 In the predialysis era, hemorrhage was a cause of morbidity in approximately 50 percent of uremic patients and a cause of death in approximately 30 percent.4 Spontaneous bleeding in patients with renal failure can involve the skin and the gastrointestinal and genitourinary tracts.5 Bleeding into the central nervous system (e.g., subdural hematoma or subarachnoid hemorrhage), pericardial and pleural spaces, anterior chamber of the eye, retroperitoneum, or internal organs is less common. Gastrointestinal hemorrhage is common in patients with acute renal failure, and patients with chronic renal failure account for a significant proportion of patients requiring endoscopy for upper gastrointestinal bleeding.6 It is noteworthy, however, that 90 percent of patients with renal failure and gastrointestinal bleeding have an anatomic diagnosis at endoscopy, most commonly angiodysplasia or peptic ulceration. Rectal ulcers in uremic individuals can cause sudden and massive lower gastrointestinal hemorrhage.
With the advent of dialysis, the frequency of severe, spontaneous hemorrhage has decreased. Experience with percutaneous renal biopsy in several thousand patients with renal disease supports the notion that the hemostatic defect in patients with renal disease is usually mild. Although the incidence of small perirenal hematomas following biopsy may be as high as 85 percent when patients are examined by computed tomography, gross hematuria is observed in only 5 to 10 percent of cases and is usually transient.7,8 Severe bleeding following biopsy requiring surgical intervention is even less common and usually can be attributed to factors other than a uremic hemostatic defect, such as needle lacerations of the kidney or spleen, anomalous vessels, heparin anticoagulation, or the presence of amyloid in the kidney.
The hemostatic defect in uremia has been attributed to abnormal platelet function.5 Defects in every phase of platelet function—adhesion, aggregation, and procoagulant activity—have been reported in uremia. Adhesion of platelets to subendothelial tissues is defective in uremia.9,10 and 11 In theory, an adhesion defect might be caused by factors in the circulating blood, by defects intrinsic to the platelet, or by abnormalities of the vessel wall. One major factor is anemia. In patients with renal disease, the severity of anemia correlates with the severity of renal failure.12 In an ex vivo perfusion system, a lowered hematocrit causes a platelet adhesion defect that can be corrected by increasing the hematocrit to ³30 percent.9 Furthermore, in uremic patients, successful treatment of anemia with red blood cell transfusion or recombinant human erythropoietin results in partial or complete correction of the bleeding time.13 This “beneficial” effect is seen when the hematocrit is corrected to the level of 27 to 32 percent.5,14,15,16 and 17 The influence of red blood cells on primary hemostasis is not unique to uremia. In normal individuals, the bleeding time correlates with the hematocrit even though both sets of values are in the normal range.18 Furthermore, bleeding times can be prolonged in patients with severe anemia of any etiology.18,19 This effect of red cells may be explained, in part, on rheological grounds, inasmuch as they displace platelets to the periphery of a column of circulating blood.20 In addition, red cells have been found to enhance the reactivity of platelets in vitro.21 Thus, anemia appears to play a significant role in the platelet adhesion defect and in the prolonged bleeding times of uremic individuals.
Since correction of anemia does not return the bleeding time to normal in all uremic individuals, there are likely other factors that impair platelet adhesion.9 Normal platelet adhesion requires initial platelet contact followed by platelet spreading upon the subendothelial matrix. At high shear rates, such as those found in the capillary circulation, contact is dependent on the binding of von Willebrand factor (vWf) to the platelet GPIb-IX complex.22,23 This interaction is also necessary for ristocetin-induced platelet aggregation in vitro. Since the latter may be decreased in uremia, it has been suggested that uremia is associated with a quantitative or qualitative abnormality of vWf or GPIb-IX. However, vWf levels in plasma, measured either immunologically or functionally by ristocetin cofactor activity, are normal or elevated in renal failure,24 and qualitative abnormalities of vWf have not been uniformly observed.10,25,26 Moreover, studies in which uremic platelets were mixed with normal plasma or normal platelets were mixed with uremic plasma have failed to demonstrate consistent quantitative or qualitative abnormalities in GPIb-IX.10,26,27
On the other hand, uremic plasma can inhibit platelet adhesion to everted, de-endothelialized human umbilical artery segments, while uremic platelets adhere normally in the presence of normal plasma. High levels of vWf present in uremic plasma could compensate for this relative adhesion defect.10 The component of uremic plasma responsible for this defect remains to be identified. In another perfusion system using rabbit vessels, uremic platelets exhibited markedly reduced spreading on the subendothelium, attributed to impaired interaction of vWf with platelet GPIIb/IIIa.28 Since vWf can bind to GPIIb/IIIa only after platelet activation, this suggests that platelet activation may be defective in uremia.
A number of observations support the existence of a “platelet activation defect” in uremia. For example, uremic platelets exhibit reduced fibrinogen binding, aggregation, and secretion in response to a variety of agonists. This abnormality may be retained by platelets after their separation from uremic plasma, and in some cases uremic plasma has been shown to impart the defect to normal platelets.29 The ability of activated platelets to provide a procoagulant surface for the generation of activated factor X and thrombin (referred to in the past as platelet factor 3) is consistently reduced in uremia.30 Uremic platelets may also exhibit a reduction in several of the biochemical responses necessary for aggregation, secretion, and procoagulant activity, including a rise in cytoplasmic free calcium levels,31 release of arachidonic acid from platelet phospholipids,4 and conversion of arachidonic acid to prostaglandin endoperoxides and thromboxane A2.32,33 and 34 A decrease in the dense-granule content of ADP and serotonin has been observed in uremia,35 as has an increase in the level of cyclic AMP.36 Since ADP and serotonin are platelet agonists and cyclic AMP is an inhibitor of platelet function, decreased platelet ADP and serotonin stores could contribute to an activation defect.
The cause of the platelet activation defects in uremia remains to be defined. Both dialyzable and nondialyzable substances in uremic plasma may be responsible. For example, platelet aggregation in vitro can be inhibited by small dialyzable substances, such as guanidinosuccinic acid and phenolic acids, and by poorly characterized “middle molecules” at concentrations found in uremic plasma.37 Reduced ex vivo aggregation responses may improve after the patient is placed on dialysis.38,39 However, venous and arterial segments from uremic patients produce more prostacyclin than their normal counterparts, and this is not corrected by dialysis.40,41 Moreover, in a rat model of uremia, prolonged bleeding times were normalized by treatment with an inhibitor of nitric oxide formation,42 suggesting that this inhibitor of platelet function, which is produced and released from endothelial cells, is responsible, at least in part, for the defect in uremic platelets.43 Some substances found in high concentrations in uremic plasma, such as urea and parathyroid hormone, appear to play no role in the platelet dysfunction.
Two additional factors should be considered when a patient with renal failure exhibits a bleeding tendency: concurrent medications and thrombocytopenia. Aspirin can prolong the bleeding time inordinately in uremia. It is surprising to note that, unlike the effect of aspirin on cyclooxygenase, this effect is transient and correlates with blood levels of aspirin.44,45 Bleeding in uremia may be potentiated by the administration of heparin during hemodialysis. In these cases, the use of an ethylene–vinyl alcohol copolymer hollow-fiber dialyzer or intermittent saline infusion and high blood flow rates may eliminate the need for heparin.3 Beta-lactam antibiotics that prolong the bleeding time may have a greater effect in uremic patients and increase the occurrence of bleeding, particularly if renal clearance of the antibiotic is reduced.46
Mild thrombocytopenia has been reported in chronic renal failure due to both diminished marrow production and platelet survival.47 Although a slight reduction in the number of normal platelets would not be expected to prolong the bleeding time, the mean platelet volume may also be decreased in uremia. This decreases the “circulating platelet mass” (platelet count × mean platelet volume). It is of interest, therefore, that the circulating platelet mass is inversely related to the bleeding time in uremic individuals.48 A platelet count below 100 × 105/µl should alert the physician that the renal failure may be due to a systemic disease or medication that can also cause thrombocytopenia, such as multiple myeloma, systemic vasculitis, hemolytic-uremic syndrome, eclampsia, renal allograft rejection, or heparin.
Although a lesser problem than in the past, abnormal platelet function in uremic patients remains a clinical issue for several reasons. First, it may contribute to serious bleeding in some patients with renal failure, particularly following surgical procedures or trauma or in conjunction with anatomic lesions of the gastrointestinal tract. Second, it is often associated with a prolongation of the bleeding time. This test measures the adhesion and aggregation of platelets in a skin wound, usually on the volar surface of the forearm. The bleeding time is subject to a number of technical variables that affect its sensitivity. When a sensitive version of the test is performed in uremic individuals, most patients exhibit a prolonged bleeding time.3,40,49 Because the bleeding time is the only readily available in vivo test of platelet function, reliance has been placed on it as an indicator of hemorrhagic risk in uremia. However, recent critical reviews of the published literature indicate that insufficient data are available for the bleeding time to be used for this purpose.1,2,50 Although a less sensitive “thigh” bleeding time has been introduced in the hopes of better correlating with clinical bleeding in uremia,51 it has yet to be evaluated sufficiently to recommend its routine use. Finally, in specific circumstances where therapy for a uremic bleeding diathesis is necessary, the uremic platelet defect can usually be successfully treated.
The first principle of management is to determine, by a careful history and examination of the patient, if an increased risk for clinically significant bleeding is present. Abnormal platelet aggregation and a prolonged bleeding time are common in uremic patients, but they are not, by themselves, indications for therapeutic intervention. The frequency of excessive bleeding after biopsies or other surgical procedures in uremic patients who have not received specific treatment is not known, but it may be uncommon. If bleeding does complicate a procedure, a rapid but thorough search for causes of bleeding should be initiated without assuming that uremia is the etiology. Several therapeutic maneuvers can either partially or completely correct an abnormal bleeding time in uremic patients (see below), and anecdotal observations indicate that they may also improve hemostasis. Apart from inducing remission of the renal disease or successful renal transplantation, these maneuvers are not uniformly effective. Because prospective studies comparing various treatment regimens have not been performed, the choice of therapy should be based on considerations such as the severity of the bleeding, the anticipated severity of the hemostatic stress imposed by surgery or trauma, the predicted duration of the therapeutic effect, and the risks of therapy.
Dialysis Intensive dialysis can correct the bleeding time and bleeding diathesis in many patients, but is only partially effective in others.39,52 Peritoneal dialysis and hemodialysis are equally effective.53,54 If a patient undergoing dialysis bleeds, it may be worthwhile to increase the intensity of the dialysis.
Desmopressin Desmopressin (1-desamino-8-D-arginine vasopressin, DDAVP) is a vasopressin analog whose pressor effects (on V1 vasopressin receptors) are substantially less than its antidiuretic effects (on V2 vasopressin receptors). DDAVP causes the release of vWf from tissue stores, predominantly endothelial cells, and it has been reported to shorten the bleeding time in 50 to 75 percent of patients with uremia. In many cases, surgery has been carried out safely after administration of this drug, although no controlled trial has been performed.55 DDAVP is usually administered intravenously in saline solution in a dose of 0.3 µg/kg over 15 to 30 min (maximum dose 20 µg), but it is also effective at this dose when given subcutaneously.55 The drug can also be given as an intranasal spray.56 Improvement in the bleeding time is seen within 30 to 60 min of administration, lasts for approximately 4 h, and roughly correlates with the rise in the plasma levels of vWf and the appearance in the circulation of high-molecular-weight vWf multimers.57 However, DDAVP is also efficacious in patients whose plasma contains normal or increased amounts of vWf, suggesting that mechanisms in addition to changes in the quantity or quality of circulating vWf may be involved in the DDAVP effect.58 In some patients, the drug has been given repeatedly at 12- to 24-h intervals, although tachyphylaxis can occur.59
At the recommended dose, side effects of DDAVP have been mild and uncommon and have included a 10 to 15 percent decrease in mean arterial pressure, a 20 to 30 percent increase in pulse rate, facial flushing, water retention, and hyponatremia leading to seizures, the latter more common after repeated administration and when fluids are given freely.55,60 Water retention and hyponatremia have not been observed in patients whose kidneys cannot respond to the hormone. Several uremic and nonuremic individuals with atherosclerosis have been reported to develop stroke or myocardial infarction after DDAVP administration, although such complications appear to be rare.61,62 and 63 If dialysis is not effective, DDAVP is the treatment of choice for uremic bleeding, particularly if only a short-term effect is required.57
Transfusion of Red Blood Cells Increasing the hematocrit, either through red blood cell transfusion or treatment with recombinant human erythropoietin, is associated with correction of the bleeding time and a suggestion of diminished clinical bleeding in uremic individuals. Improvement or normalization of the bleeding time is observed at hematocrits ³ 32 percent.5,14,15,16 and 17 The beneficial effects of red cells and DDAVP may be additive.64 Correction of the bleeding time by increasing the red cell mass would be expected to be more durable than correction with DDAVP. The widespread use of recombinant erythropoietin in patients with chronic renal failure should eliminate the contribution of anemia to the hemorrhagic diathesis in these patients.13 Moreover, a number of reports suggest that erythropoietin has an effect on platelets that is independent of an increase in hematocrit,13 perhaps the result of an increase in the number of young platelets in the circulation.65 In addition, except in emergencies, any potential hemostatic advantage to be gained by transfusion of red blood cells is likely be outweighed by the inherent risks of transfusion.
Conjugated Estrogens Conjugated estrogens have been reported to shorten the bleeding time in most, but not all, uremic individuals, both in uncontrolled studies and in randomized, double-blind studies.25,66,67 and 68 In addition, estrogen therapy appears to be useful in some patients with uremia who bleed from gastrointestinal telangiectasia.69 The drug is usually administered in a dose of 0.6 mg/kg intravenously for 5 days. Shortening of the bleeding time may be seen within 72 h of the first dose; the maximal effect occurs within 5 to 7 days, and it can persist for up to 14 days. Lower doses have not been effective.67 One report suggests that oral conjugated estrogens are effective at a dose of 50 mg/day, but this regimen has not been compared with the parenteral regimen in a controlled study.70 Conjugated estrogens have been well tolerated. No changes in the plasma levels or multimer distribution of vWf have been noted with this treatment. It has been postulated that the active component in conjugated estrogens is 17b-estradiol and that it works through an estrogen receptor mechanism.71 While endothelial cells contain such receptors, platelets do not. Thus, the mechanism by which estrogens affect hemostasis remains obscure. Since the reported response to conjugated estrogens is more durable than the response to DDAVP, this therapy may have a role in certain clinical situations.
Cryoprecipitate In uncontrolled studies of uremic patients, the infusion of cryoprecipitate has been reported to correct the bleeding time and to ameliorate bleeding.72,73 However, others have reported inconsistent results.74 It is conceivable that hemostasis is promoted by either the vWf or the platelet microparticles found within cryoprecipitate preparations.75 The uncertain efficacy of this blood product coupled with the risks inherent in its administration argue against its routine use for uremic bleeding.
The a-granules of normal platelets contain approximately 20,000 molecules of IgG, but only about 100 IgG molecules are present on the platelet surface.76 Until recently, measurements of increased IgG on the platelet surface have included IgG that is not necessarily pathogenic or even specific for platelet antigens, making it difficult to assess from the older literature the potential adverse effect of antiplatelet antibodies on platelet function and survival. This should be kept in mind when considering studies that report that increased antibody binding to the platelet surface (with or without complement binding) has been detected in several pathologic conditions, including idiopathic thrombocytopenic purpura (ITP), systemic lupus erythematosus (SLE), and platelet alloimmunization, and can result in platelet destruction (see Chap. 117). In most instances, the surviving platelets function normally. In some cases of ITP, however, bleeding times may be shorter than expected for the degree of thrombocytopenia,77 although some individuals with circulating antiplatelet antibodies have impaired platelet function. Accordingly, while a platelet count above 50,000/µl is generally regarded as “safe,”78 this cannot always be assumed to be the case in patients with immune thrombocytopenia.
While the mechanism by which autoantibodies or alloantibodies impair platelet function is usually not apparent, antibody binding to specific structures on the platelet membrane has been shown to be responsible in a number of cases. Most antibodies are directed against the GPIIb/IIIa complex, but antibodies directed against GPIb/IX/V, GPIa/IIa (integrin a2b1), and GPIV have been detected as well.79 In most cases, the in vivo consequences of antibody-mediated platelet dysfunction are obscured by the presence of thrombocytopenia (see Chap. 117). In some cases, the antibody has actually been demonstrated to have no effect on platelet function in vitro.80 However, in several patients with normal platelet counts and autoantibodies against GPIIb/IIIa, there was absent platelet aggregation and a bleeding diathesis reminiscent of Glanzmann thrombasthenia.81,82,83 and 84 Similarly, two IgG autoantibodies against GPIb have been reported that selectively inhibited ristocetin-induced platelet aggregation. In one patient, lymphadenopathy and polyclonal hypergammaglobulinemia were associated with a prolonged bleeding time and clinical bleeding.85 In the second case, the clinical significance of the antibody’s selective effect on GPIb function was obscured by severe thrombocytopenia.86 In two other patients, impaired collagen-induced platelet aggregation was associated with autoantibodies directed against one of the platelet collagen receptors GPIa/IIa.87,88 Finally, a human monoclonal antibody derived from a patient with SLE was shown to react with a 32-kDa antigen on the surface of activated platelets and inhibit the second wave of platelet aggregation induced by ADP or a thromboxane A2 analog.89
Besides interfering with the function of membrane components, some antibodies can activate platelets and induce aggregation and secretion. In vitro, antibodies can activate platelets through immune complex binding to platelet Fc receptors, by depositing sublytic quantities of the membrane attack complex of complement (C5b-9) on the cell surface90 or by binding to a specific membrane antigen.91 If antibodies are able to activate platelets in vivo in a similar fashion, the platelets might be expected to be refractory to agonists and to exhibit storage pool deficiency. While the activation of platelets in vivo is a possible explanation for the acquired storage pool disease seen in ITP or SLE, alternative mechanisms must also be considered. For example, some antibodies might affect the uptake of substances into platelet granules during megakaryocytopoiesis.92
Platelet dysfunction should be suspected in any patient with ITP or SLE who has mucocutaneous bleeding with a platelet count that is not ordinarily associated with this complication (e.g., ³50,000/µl). In such cases, the bleeding time may be longer than expected for the platelet count.93,94 The clinical spectrum of autoimmune platelet dysfunction may also include some individuals, usually women, with “easy bruising” and a normal platelet count. These patients may have ITP with “compensated thrombocytolysis,” since a substantial proportion of them have circulating antiplatelet antibodies and megathrombocytes.95
Patients with antiplatelet antibodies may exhibit defective platelet function in vitro even if they do not manifest a prolonged bleeding time or excessive bleeding. In two series, 13 of 19 patients with ITP demonstrated impaired platelet aggregation to ADP, epinephrine, or collagen.96,97 Similarly, 22 of 35 patients with SLE were found to have reduced platelet aggregation in response to these agonists.98,99 The functional abnormalities appeared to be antibody mediated, because IgG purified from the plasma or eluted from the platelets of some of the patients inhibited the aggregation of normal platelets.
Several aspects of platelet function may be impaired by antiplatelet antibodies. Some antiplatelet antibodies may inhibit the adhesion of platelets to the subendothelial matrix.100 However, the most frequently reported abnormality is absence of platelet aggregation in response to low concentrations of collagen and absence of the second wave of aggregation in response to ADP or epinephrine. This pattern of abnormalities is identical to that seen in individuals with congenital storage pool disease. In fact, both ITP and SLE may be associated with an acquired form of storage pool disease manifested by a reduced platelet content of dense and a-granule components.93,101 In one report, platelets in ITP also exhibited an activation defect manifested by impaired conversion of arachidonic acid to thromboxane A2.94
Antibody-mediated platelet dysfunction and bleeding almost always occur in the setting of immune thrombocytopenia. The treatment for ITP is discussed in Chap. 117.
Circulation of blood through an extracorporeal bypass circuit during cardiac surgery elicits a variety of hemostatic defects. The most significant challenges to the hemostatic system result from thrombocytopenia, defects in platelet function, and hyperfibrinolysis.102,103 At its extreme, this can lead to significant postoperative bleeding that can last hours to days after bypass. It is estimated that excessive postoperative bleeding occurs in 5 percent of patients after extracorporeal bypass; roughly half of this due to surgical causes, and most of the remainder is attibutable to qualitative platelet defects and hyperfibrinolysis.
Thrombocytopenia is a consistent feature of bypass surgery.103,104 Typically, platelet counts decrease to 50 percent of presurgical levels approximately 25 min after initiation of bypass, but thrombocytopenia may occur within 5 min and can persist for as long as several days.102,105,106 Although the thrombocytopenia is mostly attributable to hemodilution from priming the pump with colloid or crystalloid solutions, it is often more profound than can be accounted for by hemodilution alone.105,106 and 107 Platelet adhesion to artificial surfaces in the circuit has been demonstrated by scanning electron micrographs.108 The mechanism of this interaction is uncertain but probably involves the deposition of fibrinogen onto the bypass circuit and platelet adhesion mediated by the fibrinogen receptor GPIIb/IIIa.109,110 Less common causes of thrombocytopenia during bypass are disseminated intravascular coagulation, sequestration of damaged platelets in the liver, and heparin-induced thrombocytopenia.111
Qualitative platelet defects are the primary nonstructural hemostatic defects induced by the bypass circuit112,113 and manifest as prolonged bleeding times, abnormal ex vivo platelet aggregation in response to several agonists, decreased platelet agglutination in response to ristocetin, deficiency of both a and dense granules, and the generation of platelet microparticles.102,105,106,110,114,115 and 116 The severity of these abnormalities correlates with the duration of extracorporeal bypass, and they generally resolve within 2 to 24 h.112
The bypass-induced defects in platelet function likely result from platelet activation and fragmentation116,117 due to hypothermia, contact with fibrinogen-coated synthetic surfaces, contact with the blood-air interface, damage caused by blood suctioning, and exposure to traces of thrombin, plasmin, ADP, or complement.110,118,119 and 120 Exposure to thrombin during bypass has been reported to reduce subsequent platelet response to the thrombin-activating peptide TRAP and to be associated with increased postoperative blood loss.121 Drugs such as heparin, protamine, and aspirin, as well as the production of fibrin degradation products, can also impair platelet function.103,122,123 Controversy exists about the significance of these defects in vivo. At one extreme, some investigators have suggested that the entire qualitative platelet defect is due to the use of heparin during bypass surgery and its inhibitory effect on thrombin activity122; however, this would not account for the bleeding diathesis that can exist hours after reversal of heparin.
Hyperfibrinolysis may also contribute to the bleeding diathesis associated with cardiopulmonary bypass.124,125 This is likely due to thrombus formation in the pericardial cavity followed by local, and subsequently systemic, fibrinolysis.125 The relevance of hyperfibrinolysis to postbypass bleeding is bolstered by the efficacy of antifibrinolytic therapy in minimizing cardiopulmonary bypass surgery blood loss, as discussed below.
A preoperative evaluation of cardiac surgical candidates should include a history of bleeding in either the patient or a family member. Some authors recommend a screening prothrombin time, partial thromboplastin time, and bleeding time, even in individuals with no history of bleeding.126 However, the validity of this approach is controversial.127 Regardless, prophylactic transfusion of allogeneic blood components, be they platelets, whole blood, red cells, fresh-frozen plasma, or cryoprecipitate, is not indicated.112,128,129 Studies of the preoperative use of recombinant human erythropoietin in anemic, or erythropoietin plus autologous blood donation in nonanemic, patients suggest that these approaches are reasonable.130,131 and 132 Cell savers are now often used during bypass surgery, and the collected washed autologous red blood cells are reinfused after completion of the cardiopulmonary bypass. In addition, blood collected from chest tube drainage has been reinfused to minimize allogeneic transfusion.133 The safety of transfusing large quantities of blood by this technique has not fully been established.134
Several pharmacologic maneuvers have been tried to assist in the management of postoperative bleeding. Postoperative patients with a prolonged bleeding time and excessive blood loss may respond to DDAVP, as evidenced by a shortening of the bleeding time. However, results of trials using this agent have been contradictory, some studies showing a reduced blood loss and others showing no benefit.135,136 These differences may be attributable to the observation that vWf is frequently elevated in postoperative patients.135,136 Based on the assumption that platelet activation during bypass surgery could be a major cause of postoperative platelet dysfunction, infusion of platelet activation inhibitors such as prostaglandin E1 (PGE1), prostacyclin, or stable prostacyclin analogs has been carried out in animal models and in humans. By increasing platelet cyclic AMP and reducing platelet responsiveness, these agents prevent bypass-induced thrombocytopenia and platelet dysfunction. However, randomized trials using prostacyclin and its analog, Iloprost, did not show a clear overall benefit, in part due to significant toxicity, including hypotension.137,138
Evidence suggests that the protease inhibitor aprotinin can reduce mediastinal blood loss and transfusion requirements.139,140 Although some studies suggest that aprotinin exerts a protective effect on platelets,139,141 others do not support this hypothesis.142,143 Aprotinin does inhibit hyperfibrinolysis, and this may be its sole beneficial activity at low dosage.142,144 Treatment with aprotinin is usually started preoperatively and continued for the duration of surgery, with reported reductions of blood loss of 50 percent.141,145 There is little evidence to support the concern that aprotinin causes a postoperative hypercoagulable state leading to coronary graft occlusion.146 Its major toxicities include allergic reactions, particularly in patients who have received the drug within the past 6 months, and pancreatitis.147,148 Other antifibrinolytic agents that may have a role in minimizing postoperative blood loss include e-aminocaproic acid and tranexamic acid.149,150
The most important determinant of blood loss following cardiopulmonary surgery is the surgical procedure itself (i.e., minimal time on the bypass apparatus and rigorous hemostatic technique). If excessive nonsurgical postoperative bleeding occurs, one should verify that the patient is no longer hypothermic and that heparin has been fully reversed. At this point, the administration of pharmacologic agents, along with judicious transfusions of platelets, cryoprecipitate, fresh-frozen plasma, and red blood cells, is appropriate.
Chronic liver disease of various etiologies has been reported to cause a prolonged bleeding time and reduced platelet aggregation and procoagulant activity.151,152 The prolonged bleeding time in such patients may respond to infusion of DDAVP.153 However, the existence of a platelet function defect specific to liver disease was placed in doubt by a study of 60 patients with cirrhosis in whom aggregation studies and bleeding times were compatible with the degree of thrombocytopenia.154 The etiology of the bleeding diathesis associated with fulminant or end-stage liver disease is multifactorial and includes decreased coagulation factor production, fibrinolysis, dysfibrinogenemia, thrombocytopenia due to hypersplenism, and occasionally disseminated intravascular coagulation (DIC; see Chap. 125 and Chap. 126). Thus, the prolonged bleeding time reported in some patients with severe liver disease may be due to multiple factors, including thrombocytopenia, hypofibrinogenemia, and anemia, none of which imply an intrinsic defect in platelet function.155
Patients with DIC may exhibit reduced platelet aggregation and acquired storage pool deficiency (see Chap. 126).156,157 These result from platelet activation in vivo by thrombin or other agonists. Alternatively, elevated levels of fibrin(ogen) degradation products and low fibrinogen levels that accompany DIC may also contribute to the platelet defect. Although purified low-molecular-weight fibrinogen degradation products can impair platelet aggregation, this effect requires concentrations of degradation products unlikely to occur in vivo.158 Furthermore, hypofibrinogenemia would contribute to a defect in aggregation only in extreme cases because the fibrinogen concentration in normal plasma is at least 15-fold greater than that required to saturate platelet fibrinogen receptors.159 Finally, it is difficult to assess the significance of platelet dysfunction in most patients with DIC due to the simultaneous presence of thrombocytopenia and other hemostatic defects.
A prolonged bleeding time and decreased platelet aggregation and secretion in response to epinephrine or ADP has been reported in Bartter syndrome. It has been suggested that the platelet abnormalities are due to an inhibitory plasma factor, possibly a prostaglandin.160 The paradoxical ability of aspirin to correct the prolonged bleeding time supports this contention.
There are isolated reports of a slight prolongation of the bleeding time and/or ex vivo platelet function defects in a number of other clinical conditions. These include nonthrombocytopenic purpura with eosinophilia,161,162 atopic asthma and hay fever,163 acute respiratory failure,164 and Wilms tumor elaborating hyaluronic acid.165 The clinical significance of these associations is not clear.
Bleeding and thrombosis are significant causes of morbidity and mortality in the chronic myeloproliferative disorders: essential thrombocythemia, polycythemia rubra vera, myelofibrosis with myeloid metaplasia, and chronic myelogenous leukemia.166 Thrombocytosis is a constant finding in essential thrombocythemia (see Chap. 118) and may be seen in each of the other disorders.
Several factors contribute to the hemostatic abnormalities in the myeloproliferative disorders. These include:

Increased whole-blood viscosity in polycythemia vera. The engorgement of blood vessels associated with polycythemia is a risk factor for bleeding, particularly in postoperative situations.167,168

Intrinsic defects in platelet function. A number of intrinsic platelet defects have been reported in the myeloproliferative disorders. However, the bleeding time is prolonged in only a minority of patients, and bleeding can occur in individuals with normal bleeding times.169

Elevated platelet counts. The contribution of an elevated platelet count, by itself, to the risk of hemorrhage and thrombosis is controversial.170,171,172,173 and 174 A number of retrospective studies indicate that the risk of abnormal hemostasis cannot be confidently predicted from the degree of thrombocytosis.169
Under the light or electron microscope, platelets in these disorders may be larger or smaller than normal, may be abnormally shaped, and may exhibit a reduction in the number of storage granules.175 In essential thrombocythemia, platelet survival may be modestly reduced.176 A number of functional and biochemical abnormalities have been described in platelets from patients with myeloproliferative disorders. The most frequently encountered functional abnormality is a decrease in platelet aggregation and secretion in response to epinephrine, ADP, or collagen.169 The defect in epinephrine-induced aggregation often includes absence of the primary wave of aggregation, which is unusual in other conditions. This is not simply due to an elevated platelet count, because it is not encountered in reactive thrombocytosis.177 Thus, loss of platelet responsiveness to epinephrine may have utility in confirming the presence of a myeloproliferative disorder. Reduced aggregation and secretion has been associated with one or more of the following: decreased agonist-induced release of arachidonic acid from membrane phospholipids178,179; reduced conversion of arachidonic acid to prostaglandin endoperoxides or lipoxygenase products180; reduced platelet responsiveness to thromboxane A2181,182; deficiency of dense or a-granules183,184; deficiency of GPIa/IIa (a2b1), resulting in platelet unresponsiveness to collagen185; and decreased numbers of a2-adrenergic receptors, leading to reduced or absent platelet responses to epinephrine.186,187 On the other hand, spontaneous platelet aggregation in a patient with essential thrombocythemia188 and thrombosis has been reported, as has increased thromboxane biosynthesis by platelets from patients with essential thrombocythemia189 and polycythemia vera.190
Reduction in platelet procoagulant activity has also been reported in some patients with myeloproliferative disorders and thrombocytosis,191 as have specific platelet membrane abnormalities, including decreased amounts of the GPIb-IX complex, resulting in an acquired form of Bernard-Soulier syndrome192; decreased numbers of receptors for PGD2193; increased numbers of receptors for the Fc portion of IgG194; an increase in GPIV (CD36) with195,196 or without197 a corresponding decrease in GPIb; and impaired expression of thrombopoietin receptors.198 An acquired form of von Willebrand disease has been observed in several individuals with chronic myelogenous leukemia and other myeloproliferative syndromes.199 In these cases, there was a reduction in the plasma level of the high-molecular-weight vWf multimers200; in some, the vWf abnormality was corrected transiently by infusion of DDAVP.196,201 In others, the abnormalities were partially or completely corrected by cytoreductive therapy.199,202
Bleeding occurs in about one-third of patients with myeloproliferative disorders and contributes to mortality in 10 percent. Thrombosis also occurs in one-third of cases, contributing to mortality in 15 to 40 percent.203 Most symptomatic patients experience either bleeding or thrombosis; however, some develop both complications during the course of their disease. Bleeding usually involves the skin or mucous membranes but may also occur after surgery or trauma. Thrombosis may involve arteries or veins and may occur in unusual locations, such as the hepatic, portal, and mesenteric circulations.203,204 and 205 Indeed, full-blown or latent myeloproliferative disorders account for a substantial proportion of patients with the Budd-Chiari syndrome.205,206 Individuals with essential thrombocythemia may experience ischemia and necrosis of the fingers and toes due to digital artery thrombosis, microvascular occlusion in the coronary circulation, and transient neurologic symptoms due to cerebrovascular occlusion.207 A syndrome of redness and burning pain in the extremities, termed erythromelalgia, is strongly associated with essential thrombocythemia and polycythemia vera and is thought to be due to arteriolar platelet thrombi.208 It has been difficult to predict the risk of bleeding or thrombosis in asymptomatic patients,209 but an increased number of reticulated platelets in patients with thrombocytosis, thought to reflect an increase in platelet turnover, has been associated with an increased risk for thrombosis.210 Vascular complications are also more likely to occur in patients older than 60 and in patients with other risk factors for vascular disease.211
Several features of these platelet functional defects require emphasis. First, none is unique to a particular myeloproliferative disorder. Second, their relative frequency has varied widely in reported series. Third, none has been predictive of bleeding or thrombosis. Fourth, although the myeloproliferative disorders comprise several distinct clinicopathologic entities, they represent clonal abnormalities of hematopoiesis. Therefore, platelets may acquire structural and biochemical abnormalities as they develop from a clone of abnormal megakaryocytes.
Therapy should be considered for the symptomatic patient and for the patient about to undergo surgery. Treatment includes correction of polycythemia and maintenance of the hematocrit below 45 percent212 as well as treatment of the underlying disorder. Platelet count reduction in patients with thrombocytosis, either by plateletpheresis or cytoreductive agents, has generally been associated with clinical improvement.203 Effective cytoreductive agents include the ribonuclease reductase inhibitor hydroxyurea213 and anagrelide.214 Anagrelide, an imidazoquinazolin derivative, is thought to decrease platelet counts by specifically impairing megakaryocyte maturation.215 Anagrelide has essentially no effect on red and white cell counts and is not known to be leukemogenic. Nevertheless, 10 to 20 percent of patients experience neurologic, gastrointestinal, and cardiac side effects, in particular, fluid retention, necessitating discontinuation of the drug. During an episode of acute bleeding, DDAVP infusion may temporarily improve hemostasis if the patient has an acquired storage pool defect or acquired von Willebrand disease.184,201 Aspirin (300–600 mg/day) may be useful in patients with thrombosis, particularly those with erythromelalgia or with digital or cerebrovascular ischemia.216,217 However, aspirin can exacerbate a bleeding tendency in patients with myeloproliferative disorders.218
The most frequent cause of bleeding in these disorders is thrombocytopenia. However, abnormal platelet function in vitro has been described in acute myelogenous leukemia, and in some patients this may be clinically significant. In acute myelogenous leukemia and its variants, platelets may be larger than normal, abnormally shaped, and exhibit a marked variation in the number of granules. There may be decreased aggregation and serotonin release in response to ADP, epinephrine, or collagen, as well as decreased platelet procoagulant activity. The functional abnormalities may be due to either acquired storage pool deficiency or a defect in the process of platelet activation.219,220 and 221 These defects are intrinsic to the platelet and are probably related to the fact that the megakaryocytes from which platelets are derived have originated from a leukemic stem cell. Bleeding in the acute leukemias usually responds to platelet transfusions and to treatment of the underlying disease. Identical platelet abnormalities may be seen in the myelodysplastic syndromes (preleukemias).219,222 In these syndromes platelets appear to be less uniformly affected, perhaps because there is a residual population of normal platelets admixed with those from the malignant clone.
Reduced platelet aggregation has been reported in children with acute lymphocytic leukemia.220 Unless the leukemia is biphenotypic, it is difficult to ascribe the platelet defect to the leukemic process itself. Platelets are normal in children with lymphoblastic leukemia in complete remission.223 Hairy-cell leukemia is a lymphoproliferative disease in which platelet dysfunction may rarely complicate the clinical picture. Bleeding is responsible for death in 8 percent of patients, but it is usually due to thrombocytopenia rather than platelet dysfunction.224 Some patients may exhibit storage pool deficiency or a defect in the process of platelet activation, and these abnormalities have been reported to disappear following splenectomy.225,226,227,228 and 229 However, this should be interpreted with caution because splenectomy usually corrects the thrombocytopenia as well. A single case of acquired von Willebrand disease in association with hairy-cell leukemia has been reported.230
Platelet dysfunction is observed in approximately one-third of patients with IgA myeloma or Waldenström macroglobulinemia, 15 percent of patients with IgG multiple myeloma, and occasionally in patients with monoclonal gammopathy of undetermined significance.231 In addition to platelet dysfunction, other causes of bleeding should be considered in these patients, including the hyperviscosity syndrome,232 thrombocytopenia, complications of amyloidosis (e.g., amyloid angiopathy233 or acquired factor X deficiency234,235), and, rarely, a circulating heparin-like anticoagulant236,237 or systemic fibrin(ogen)olysis.238,239 The myeloma protein may also affect in vitro coagulation tests by interfering with fibrin polymerization and with the function of other coagulation proteins.231
The bleeding time may be prolonged in patients with dysproteinemias, even in the absence of clinical bleeding. The platelet defect is caused by the monoclonal protein. It has been suggested that some monoclonal immunoglobulins interact with the platelet surface to interfere nonspecifically with platelet adhesion or stimulus-response coupling. This concept is supported by the observations that platelet dysfunction is more common when the concentration of the paraprotein in plasma or on the platelet membrane is very high240; that platelet aggregation, secretion, clot retraction, and platelet procoagulant activity may all be affected; and that normal platelets acquire these defects when incubated with the purified monoclonal immunoglobulin.241
In some cases, specific interactions of the monoclonal protein with platelets have been described. One IgA myeloma protein inhibited the ability of a suspension of aortic connective tissue to aggregate normal platelets.242 The bleeding time and bleeding diathesis of the patient from whom this myeloma protein was obtained were corrected by removal of the protein by plasmapheresis. In another patient, an IgG myeloma protein bound specifically to platelet GPIIIa. Both the intact immunoglobulin and its F(ab’)2 fragment inhibited the binding of fibrinogen to activated platelets, thus inducing a thrombasthenic-like state.243 Several patients with myeloma, benign monoclonal gammopathy, or chronic lymphocytic leukemia have been reported to have an acquired form of von Willebrand disease in which the plasma level of vWf is reduced or the high-molecular-weight multimers of vWf are lacking (see below).244,245 and 246
When clinically significant platelet dysfunction occurs in a patient with a dysproteinemia, cytoreductive therapy should be considered as a means to reduce the production and plasma level of the monoclonal immunoglobulin.231 Plasmapheresis can also control bleeding by reducing the level of the abnormal protein, and it can be lifesaving during acute bleeds.247,248 Cryoprecipitate, DDAVP, intravenous gamma globulin, and/or plasmapheresis may be transiently effective in patients with acquired von Willebrand disease (see below).244,245,249,250
Although inherited von Willebrand disease is common (1–3% worldwide), acquired von Willebrand disease is a relatively rare disorder that typically occurs in the setting of an autoimmune or clonal hematologic disease. The latter include multiple myeloma,251,252 Waldenström’s macroglobulinemia,253 low-grade non-Hodgkin’s lymphoma,254,255 chronic lymphocytic leukemia,256 and myeloproliferative disorders.257 In many hematologic disorders, a specific anti-vWf antibody is present,249,251,252,258 while in autoimmune disorders, anti-vWf antibodies are part of a generalized autoimmune response.259 When acquired von Willebrand disease occurs in other clinical situations, such as cancer or hypothyroidism, it may result from the nonspecific direct absorption of vWf onto tumor cells230,260,261 or decreased vWf production.262,263
Mucocutaneous bleeding and a prolonged bleeding time should raise the suspicion of acquired von Willebrand disease in patients without a prior personal or family history of bleeding. This is especially important in patients with known autoimmune disease or lymphoproliferative or myeloproliferative disorders.264 Diagnostic evaluation includes measurements of factor VIII coagulant activity, vWf antigen, and ristocetin cofactor activity. The presence of an in vitro inhibitor may or may not be detected, depending on whether the antibody binds to vWf and neutralizes its function or merely leads to accelerated vWf clearance by the reticuloendothelial system.264 Patient management includes infusions of desmopressin,252,256,259 vWf-containing factor VIII concentrates,265 or high-dose intravenous immunoglobulin.266,267 The latter has been efficacious in patients when acquired von Willebrand disease is associated with a lymphoproliferative disorder or monoclonal paraprotein and most likely acts by delaying vWf clearance via reticuloendothelial cell blockade, although other mechanisms have been postulated.268,269 and 270 Treatment of the underlying associated disease is only sometimes helpful.264
Drugs represent the most common cause of platelet dysfunction (Table 120-2).271 For example, in an analysis of 72 hospitalized patients with a prolonged bleeding time, 54 percent were receiving large doses of antibiotics known to prolong the bleeding time and 10 percent were taking aspirin or other nonsteroidal anti-inflammatory drugs.272 Some drugs can prolong the bleeding time and either cause or exacerbate a bleeding diathesis. Other drugs may prolong the bleeding time but not cause bleeding, while others may only affect platelet function ex vivo or when added to platelets in vitro. It is important for the hematologist to understand the clinical significance of these distinctions.


Aspirin inhibits platelets by acetylating and irreversibly inactivating the enzyme PG endoperoxide H synthase-1 (PGHS-1, cyclooxygenase-1; see Chap. 131 for the use of aspirin as an antithrombotic agent).273 Inactivation of PGHS-1 prevents platelet synthesis of PG endoperoxides and the subsequent synthesis of thromboxane A2 by thromboxane synthase, thereby inhibiting platelet responses that require these substances. Thus, platelet responses to ADP, epinephrine, arachidonic acid, and low doses of collagen and thrombin are affected, while responses to higher doses of collagen or thrombin are not.274,275 Platelet prostaglandin synthesis in an adult is nearly completely inhibited by a single 100-mg dose of aspirin or by 30 mg taken daily for 7 to 10 days.276 Although small doses of aspirin inhibit both platelet and endothelial cell cyclooxygenase irreversibly,277 they have no lasting effect on prostacyclin production by endothelial cells.278 This is likely due to the ability of endothelial cells to synthesize additional cyclooxygenase unaffected by aspirin.279 In vitro studies also suggest that the presence of erythrocytes contributes to agonist-stimulated platelet reactivity,21 an effect that can be inhibited by aspirin at doses greater than those required to inhibit platelet PGHS-1.280
Aspirin is one of the few drugs that prolong the bleeding time in humans and appear to act by blocking aggregation rather than adhesion. In normal individuals, the effect on the bleeding time is slight (generally no more than 1.2 to 2.0 times the preaspirin bleeding time),281,282 observed in both males and females, and requires that almost all the cyclooxygenase in the circulating platelets be inhibited.281 The sensitivity of the bleeding time to aspirin is dependent on such technical variables as the direction of the incision on the forearm and the degree of hydrostatic pressure applied to the arm.283 The bleeding time may remain prolonged for 1 to 4 days after the aspirin has been discontinued, and platelet aggregation test results may remain abnormal for up to a week until the affected platelets are replaced by newly formed ones.284
The significance of aspirin ingestion for the hemostatic competency of normal individuals appears to be minimal. Nevertheless, patients chronically taking aspirin report a significant increase in bruising, epistaxis, and gastrointesinal blood loss.285 The latter appears to be due to a direct effect of the drug on the gastric mucosa.286,287 Moreover, there was a slight, but not statistically significant, increase in hemorrhagic strokes in a group of otherwise healthy physicians who took aspirin chronically as primary prophylaxis against myocardial infarction.285 Aspirin may also increase bleeding in the mother and the neonate during parturition.288 In addition, some, but not all, studies have shown that aspirin taken preoperatively increases the amount of blood loss following cardiothoracic surgery (see Chap. 131).289,290 On the other hand, a retrospective analysis has documented the safety of performing epidural and spinal anesthesia in patients who had ingested aspirin.291 While aspirin may increase the amount of blood loss following general surgery,292 the significance of aspirin ingestion in this clinical setting has never been tested in a prospective, randomized, double-blind study with objective end points. Many surgeons ask their patients to avoid aspirin, particularly prior to cardiothoracic, plastic, or neurosurgical procedures, in which the limits of tolerable bleeding are narrow.293 Aspirin causes a marked prolongation of the bleeding time and precipitates hemorrhage in individuals with preexistent hemostatic defects such as von Willebrand disease, hemophilia A, warfarin ingestion, uremia, or other disorders of platelet function.44,45,294 While ingestion of ethanol has no direct effect on the bleeding time, it can potentiate the effect of aspirin.295,296 Infusion of DDAVP has been effective in correcting a prolonged bleeding time due to aspirin.297,298
Nonsteroidal anti-inflammatory drugs such as indomethacin, ibuprofen, naproxen, phenylbutazone, and sulfinpyrazone also inhibit platelet cyclooxygenase.299 In contrast to aspirin, their effect is reversible and generally short-lasting (<4 h). An exception is piroxicam, whose effect may last for days due to its prolonged half-life.300 These drugs may cause a transient prolongation of the bleeding time when given in therapeutic doses; however, this is usually not clinically significant.301,302 and 303 Indeed, ibuprofen has been given safely to patients with hemophilia A.304,305 However, care must be taken when ibuprofen is given to patients with hemophilia and HIV infection receiving zidovudine, since increased bleeding has been reported in this circumstance.306 Analgesics such as acetaminophen, sodium or choline salicylate, and narcotics neither inhibit cyclooxygenase nor prolong the bleeding time.304,307,308 Drugs that inhibit thromboxane synthetase (e.g., OKY-1581) may impair platelet secretion and second-wave aggregation in response to ADP; however, these effects have not been observed in every subject.309,310
Various penicillins contain a b-lactam ring and a unique side chain. Most penicillins cause a dose-dependent prolongation of the bleeding time in normal volunteers.311 Because they reduce platelet aggregation and secretion as well as ristocetin-induced platelet agglutination, they may affect both platelet adhesion and platelet activation. Results of tests of platelet aggregation are abnormal in at least 50 to 75 percent of individuals receiving large doses (at least several grams per day) of carbenicillin, penicillin G, ticarcillin, ampicillin, nafcillin, and azlocillin and in 25 to 50 percent of patients taking piperacillin, azlocillin, apalcillin, or mezlocillin.311,312 and 313 Differences in the antiplatelet effects of these antibiotics probably relate to differences in blood levels and drug potency. Their effect on platelets is maximal after 1 to 3 days of administration and may remain for several days after the antibiotic has been stopped, suggesting that the effect of these antibiotics on platelets in vivo is irreversible.
Penicillins may impair the interaction of agonists and vWf with the platelet membrane.314 Indeed, when many penicillins are incubated with washed platelets, albeit at concentrations higher than those attained in vivo, they inhibit the interaction of vWf and agonists, such as ADP and epinephrine, with their platelet receptors.315 The relative in vitro antiplatelet potency of the penicillins correlates well with their lipid solubility and with the inhibitory potency of the isolated side chains.316,317 Moreover, the inhibitory effect of penicillin G on platelet function in vitro is potentiated by the presence of probenecid.318 When platelet function was tested after intravenous administration of penicillin, oxacillin, or mezlocillin for 3 to 17 days to patients or normal volunteers, irreversible inhibition of agonist-induced aggregation was noted, along with a 40 percent reduction in low-affinity thromboxane A2 receptors.319 Thus, penicillins probably inhibit platelet function by binding to one or more membrane components necessary for adhesive interactions with the vessel wall or for stimulus-response coupling.
Although clinically significant bleeding has been associated with the use of carbenicillin, penicillin G, ticarcillin, and nafcillin, it is far less common than prolongation of the bleeding time.311,320 Patients with coexisting hemostatic defects (e.g., thrombocytopenia, vitamin K deficiency, or uremia) may be particularly prone to this complication. On the other hand, high doses of penicillin G did not increase gastrointestinal blood loss in a thrombocytopenic rabbit model.321 In our experience, bleeding due to antibiotic-induced platelet dysfunction is uncommon and unpredictable. Since b-lactam–induced platelet dysfunction resolves with time following cessation of the drug, this class of drugs should be considered as a potential cause of bleeding in the appropriate clinical setting. A similar pattern of platelet dysfunction has been reported with some cephalosporins or related antibiotics but not with others.311,322,323 Broad-spectrum antibiotics can also cause a bleeding diathesis attributable to vitamin K deficiency. Nitrofurantoin, a structurally unrelated antibiotic, may cause a mild prolongation of the bleeding time and impair platelet aggregation when blood levels of the drug are higher than 20 µM.324 Miconazole, an antifungal agent, has been shown to inhibit human and rabbit platelet cyclooxygenase in vitro and rabbit platelet cyclooxygenase after intravenous infusion.325
The thienopyridines ticlopidine and clopidogrel are used as antithrombotic agents in arterial diseases (see Chap. 131). They may be more effective than aspirin in the secondary prevention of cerebrovascular and cardiovascular events.326,327,327a,328,329 and 330 The antithrombotic effects of thienopyridines and aspirin may be additive, especially in preventing thrombotic complications after coronary artery stent placement.329,331
Ticlopidine and clopidogrel differ from aspirin in the mechanism of their antiplatelet activity and in their toxicity profile. Both appear to be prodrugs that depend on metabolites for their effects.326 Ticlopidine at 250 mg by mouth twice a day or clopidogrel at 75 mg once per day has been shown to inhibit platelet aggregation ex vivo and to prolong the bleeding time in humans. The degree of prolongation of the bleeding time is equivalent to or greater than that of aspirin, and the effect of thienopyridines and aspirin appears additive.332 Effects of ticlopidine and clopidogrel on platelet aggregation and the bleeding time may be seen within 24 to 48 h of the first dose but are not maximal for 4 to 6 days. Moreover, the effects may last for 4 to 10 days after the drugs have been discontinued. This may be explained by their extended half-life after multiple dosing or by irreversible effects on platelets.326
Ex vivo studies indicate that ticlopidine and clopidogrel impair fibrinogen binding to its platelet receptor, GPIIb/IIIa, and inhibit platelet aggregation in response to many agonists, particularly ADP. The effect on ADP-induced platelet aggregation seems to account for the observed decrease in responses to low concentrations of other agonists, since ADP released from dense granules plays a role in those responses. Indeed, aggregation in response to high concentrations of thrombin or collagen are normal.326,333,334 ADP-induced platelet shape change and calcium transients are unimpaired, implying that the drugs do not affect the binding of ADP to receptors involved in these particular responses. Thus, the major effect of ticlopidine may be impairment of stimulus-response coupling between one or more ADP receptors and the fibrinogen receptor. Platelets contain at least three different ADP receptors (P2Y1, P2AC, and P2X),335,336 and the thienopyridines may selectively block the P2AC receptor.337,338 These drugs may work through noncompetitive inhibition of ADP binding to the receptor.339
Ticlopidine administration has been associated with potentially serious hematologic complications, including neutropenia (<1200/µl in 2.4 percent of individuals)326,340,341 and, less commonly, aplastic anemia, thrombotic thrombocytopenic purpura, and thrombocytopenia.342,346 Results from a large clinical trial suggest that these complications may be less common with clopidogrel327 but continued assessment is warranted.
GPIIB/IIIA Receptor Antagonists
Drugs that specifically impair the function of platelet GPIIb/IIIa have been developed for use as antithrombotic agents in the setting of ischemic coronary artery disease.347 Because inherited GPIIb/IIIa abnormalities result in the bleeding disorder Glanzmann thrombasthenia,348 it is not surprising that these drugs can predispose to bleeding. In EPIC, a clinical trial of the efficacy of abciximab, a chimeric human-murine anti-GPIIb/IIIa monoclonal antibody Fab fragment, in patients undergoing percutaneous coronary angioplasty, 14 percent of patients given abciximab experienced major bleeding, compared with 7 percent of patients given placebo.349 However, the patients were also given aspirin and heparin, and when the heparin dose was decreased in the subsequent EPILOG trial, the incidence of major bleeding in patients receiving abciximab decreased to 2.0 percent, compared with 3.1 percent in the control group receiving heparin and aspirin alone.350 Nonetheless, in both EPIC and EPILOG, minor bleeding was significantly more frequent in patients given abciximab and standard-dose heparin compared with patients given standard-dose heparin alone, attesting to the ability of a GPIIb/IIIa antagonist to impair normal hemostasis. In the PRISM-PLUS and PURSUIT trials of the synthetic low-molecular-weight GPIIb/IIIa inhibitors tirofiban and eptifibatide, respectively, major and minor bleeding were slightly more frequent in patients receiving the study drug than in control subjects.351,352 Similarly, patients receiving the oral GPIIb/IIIa inhibitors xemilofiban and sibrafiban for 30 and 28 days, respectively, frequently experienced mucocutaneous bleeding similar to that experienced by patients with thrombasthenia.353,354
The risk of bleeding in patients undergoing percutaneous coronary interventions given GPIIb/IIIa antagonists can be minimized by using low-dose heparin (e.g., 70 units/kg, as in EPILOG350), by avoiding treatment of patients who are receiving warfarin at therapeutic doses, by early vascular sheath removal, and by meticulous care of vascular puncture sites.355 Platelet transfusions appear to rapidly reverse the defect in platelet function in patients receiving abciximab, primarily by decreasing the extent of GPIIb/IIIa blockade. The ability of platelet transfusion to reverse the effects of the other GPIIb/IIIa antagonists is less clear, but these drugs have short half-lives if renal and hepatic function are normal.
Thrombocytopenia occurring within 24 h of initiating therapy has been observed in small numbers of patients following the administration of all types of GPIIb/IIIa antagonists.351,352,354,356 In the EPIC trial, the incidences of platelet counts less than 100,000/µl and less than 50,000/µl in patients receiving abciximab for the first time were 3.9 percent and 0.9 percent, respectively.356 There are also anecdotal reports of acute profound thrombocytopenia (platelet counts <20,000).357,358 The mechanism responsible for the decrease in platelet count is uncertain, but it may be related to the presence of preexisting anti-GPIIb/IIIa antibodies that recognize epitopes on GPIIb/IIIa exposed by binding of the GPIIb/IIIa antagonist.359 The thrombocytopenia usually reverses readily when the drug is stopped, but it may also be reversed by platelet transfusion if clinically indicated.355 Thrombocytopenia in patients receiving GPIIb/IIIa antagonists must be differentiated from pseudothrombopenia due to drug-induced platelet clumping, from heparin-induced thrombocytopenia in patients receiving heparin concurrently, and from other causes of thrombocytopenia, depending on the clinical circumstances. It is particularly important to identify thrombocytopenia early, since GPIIb/IIIa antagonists are administered as long infusions, and the drug should be stopped as soon as true thrombocytopenia has been confirmed. In most cases of profound thrombocytopenia, a platelet count obtained 2 to 4 h after initiating therapy will provide evidence of a significant decrease in platelet count.
The pyrimidopyrimidine derivative dipyridamole inhibits platelet function in vitro, but the clinical utility of this drug is controversial.360,361 Dipyridamole inhibits cyclic nucleotide phosphodiesterase, resulting in the intracellular accumulation of cAMP. Dipyridamole may also inhibit the breakdown of cGMP, resulting in the potentiation of a nitric oxide effect.362 Although several clinical trials failed to demonstrate a benefit of dipyridamole,361 the European Stroke Prevention Study 2 (ESPS 2) did show benefit from receiving dipyridamole in preventing stroke and transient ischemic attack, although there was no difference in mortality between patients taking dipyridamole and those taking placebo or among patients taking dipyridamole plus aspirin and those taking either agent alone.363 The basis for the different outcomes of the various trials is unclear but could be due to higher dipyridamole dosage or the sustained-release dipyridamole preparation used in ESPS 2.
Intravenous infusions of PGE1, prostacyclin, or stable analogs of prostacyclin stimulate platelet adenylyl cyclase, causing an increase in platelet cAMP levels and a decrease in platelet responsiveness.137,309,364 These agents cause a transient prolongation of the bleeding time and inhibit platelet shape change, aggregation, and secretion. However, their clinical utility is limited by their short half-life and side effects, which include peripheral vasodilatation.137,138 Cilostazol, a member of a new class of phosphodiesterase III inhibitors, has been approved in the United States for the treatment of peripheral vascular disease365 and may have utility in the prevention of cardiac stent occlusion.366 Nitric oxide and organic nitrates such as nitroglycerin inhibit platelet function in vitro, probably by activating guanylyl cyclase, thereby increasing cGMP.367 Their effect on in vivo platelet function is uncertain. High concentrations of caffeine and theophylline also inhibit platelet phosphodiesterases in vitro.
Heparin predisposes to bleeding primarily through its anticoagulant effect, but it may also affect platelet function. For example, a bolus injection of heparin (100 units/kg) can cause a significant prolongation of the bleeding time in normal subjects and in patients prior to cardiopulmonary bypass, suggesting that therapeutic doses of heparin may impair platelet function.103 Heparin likely impairs platelet function by inhibiting the generation and action of thrombin, a potent platelet agonist. In vitro studies also suggest that heparin can enhance platelet aggregation induced by other platelet agonists.368 Heparin binds to a single class of high-affinity binding sites on resting platelets and to an additional class of lower-affinity binding sites on fully activated platelets.369 High heparin doses have also been found to impair vWf-dependent platelet function, possibly by binding to the heparin-binding domain of vWf.370 The contribution of these effects on platelet function to the bleeding complications of heparin therapy are uncertain.
Bleeding during fibrinolytic therapy is due predominantly to the combined effects of structural lesions in blood vessels and the fibrin(ogen)olytic activity of the agent used. However, pharmacologic doses of streptokinase, urokinase, and tissue plasminogen activator (t-PA) can affect platelet function.371 High concentrations of plasmin ex vivo cause platelet aggregation.372 Moreover, marked increases in the urinary excretion of the thromboxane A2 metabolite 2,3-dinor-TxB2 have been detected in patients receiving streptokinase or t-PA for coronary thrombolysis, suggesting that in vivo platelet activation had occurred during infusion of the drug.373,374 Nevertheless, several in vitro studies indicate that plasmin generation has an inhibitory effect on platelet function. First, very high levels of fibrin(ogen) degradation products coupled with very low levels of fibrinogen may impair platelet aggregation.375 Second, plasminogen can bind to platelets376 and, after its conversion to plasmin, enzymatically degrades platelet GPIb, impairing the interaction of platelets with vWf.377,378 Third, plasmin can inhibit platelet arachidonic acid metabolism.379 Fourth, t-PA promotes the disaggregation of platelet aggregates, presumably by inducing lysis of the fibrinogen that mediates aggregate formation.380 Finally, after initial activation, platelets incubated with plasmin and recombinant t-PA in vitro become refractory to activation by other agonists.381 Whether any of the in vitro and ex vivo observations apply to the in vivo situation and are clinically significant remains to be determined.382 The antifibrinolytic drug e-aminocaproic acid can increase the bleeding time when administered for several days at doses greater than 24 g/day.383
Administration of nitroprusside (which increases platelet cGMP),384,385 nitroglycerin,386 and propranolol387,388 can decrease platelet aggregation and secretion ex vivo; nitroprusside can increase the bleeding time twofold when administered at infusion rates of 6 to 8 µg/kg per minute, whereas trimethaphan, another effective parenteral antihypertensive agent, does not.384,389 Inhalation of nitric oxide, advocated for the treatment of pulmonary hypertension and the adult respiratory distress syndrome, can impair agonist-induced platelet aggregation ex vivo, although effects on the bleeding time have been variable.390,391 and 392 The clinical significance of these observations is unclear. Organic “calcium channel blockers,” such as verapamil, nifedipine, and diltiazem, inhibit platelet aggregation when added at very high concentrations to washed platelets.393 This effect is seen primarily with epinephrine-induced aggregation and does not appear to be related to calcium channel blockade. For example, verapamil can act as an b2-adrenergic receptor antagonist at concentrations that inhibit platelet function.394 At therapeutic doses, calcium channel blockers do not prolong the bleeding time, although one agent, nisoldipine, has been reported to inhibit agonist-induced calcium transients and platelet aggregation after 10 days of oral administration.395 At high concentrations, the antiarrhythmic drug quinidine has been reported to cause a mild prolongation of the bleeding time and potentiate the effect of aspirin.396
Dextran is a neutral polysaccharide that is heterogeneous in molecular size. Two preparations with average molecular weights of 40,000 and 70,000 are in clinical use. Although dextran infusions may prolong the bleeding time in normal subjects and in patients with von Willebrand disease, this has not been observed in most of the normal subjects.397,398 and 399 Infused dextran adsorbs to the platelet surface and can impair platelet aggregation, secretion, and procoagulant activity. The maximal effect of dextran may require several hours, suggesting that larger molecules with a slower rate of clearance are responsible.397 Curiously, the drug has no effect when added to platelet-rich plasma.397 Dextran infusion produces a modest reduction in plasma vWf antigen and ristocetin cofactor activity.398 Despite these effects on primary hemostasis and the use of dextran in the operative setting as a volume expander or for antithrombotic prophylaxis, prospective studies indicate that dextran is not associated with significant postoperative bleeding unless it is administered together with low-dose heparin.400,401 Hydroxyethyl starch, another volume expander, while generally safe, may prolong the bleeding time and predispose to hemorrhage, particularly if it is administered in doses of a 6% solution exceeding 20 ml/kg. It may predispose to bleeding in lower doses if administered simultaneously with low-dose heparin or if given to patients with a preexistent hemostatic defect or after major cardiothoracic surgery.402,403 and 404 Different hydroxyethyl starch preparations vary in the average number of hydroxymethyl groups per glucose unit, and this may affect both intravascular survival and effects on hemostasis.405
Platelets from patients taking antidepressants or phenothiazines may exhibit impaired aggregation responses, but this is not associated with bleeding.406,407 The effect on aggregation has been attributed to inhibition of intracellular signaling molecules, such as PKC.408 Fluoxetine does not appear to impair in vitro platelet aggregation and has only rarely been associated with clinical bleeding.409,410 General anesthesia with halothane may cause a slight prolongation of the bleeding time, most likely due to an effect on calcium signaling, but this has no adverse effect on surgical hemostasis.411 In addition to an association with thrombocytopenia, cocaine has been reported to either inhibit platelet function412,413 or to induce platelet activation.414 The clinical relevance of these observations is unknown.
Administration of mithramycin to a total dose of 6 to 21 mg has been associated with mucocutaneous bleeding, an increase in the bleeding time, and decreased platelet aggregation.415 An ex vivo defect in platelet secretion and secondary aggregation has been reported in patients with solid tumors within 48 h of receiving infusions of autologous marrow and high-dose chemotherapy consisting of cisplatin, cyclophosphamide, and either BCNU or melphelan.416 Both daunorubicin and BCNU can inhibit platelet aggregation and secretion when added to platelet-rich plasma, but as single agents they have not been shown to cause clinically significant platelet dysfunction.417,418 and 419 Administration of recombinant forms of thrombopoietin to thrombocytopenic patients with cancer results in the production of normally functioning platelets.420,421
The immunosuppressive drug cyclosporine A has been reported to enhance ADP-stimulated platelet aggregation in vitro.422,423 and 424 A relationship of this effect to the thrombosis often suffered by patients receiving the drug is unclear. Antihistamines,425 the serotonin antagonist ketanserin,426 and some radiographic contrast agents427,428 can impair platelet aggregation responses ex vivo by unknown mechanisms.
The effect of certain foods and food additives on platelet function must be considered. For example, a diet rich in fish oils containing w3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) causes a slight prolongation of the bleeding time.429 These fatty acids act by reducing the platelet content of arachidonic acid and by competing with arachidonic acid for cyclooxygenase.430,431 Easy bruising noted after eating Chinese food has been attributed to an antiplatelet effect of the black tree fungus.432 A component of extract of onion can inhibit platelet arachidonic acid metabolism.433 Ajoene, a component of garlic, is an inhibitor of fibrinogen binding and platelet aggregation.434,435 Extracts of two commonly used spices, cumin and turmeric, inhibit platelet aggregation and eicosanoid biosynthesis.436

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Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology



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