CHAPTER 120 ACQUIRED QUALITATIVE PLATELET DISORDERS DUE TO DISEASES, DRUGS, AND FOODS
CHAPTER 120 ACQUIRED QUALITATIVE PLATELET DISORDERS DUE TO DISEASES, DRUGS, AND FOODS
SANFORD J. SHATTIL
CHARLES S. ABRAMS
JOEL S. BENNETT
Systemic Disorders Associated with Abnormal Platelet Function
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
Psychotropic Drugs, Anesthetics, and Cocaine
Foods and Food Additives
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).
TABLE 120-1 ACQUIRED QUALITATIVE PLATELET DISORDERS
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
SYSTEMIC DISORDERS ASSOCIATED WITH ABNORMAL PLATELET FUNCTION
DEFINITION AND HISTORY
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.
ETIOLOGY AND PATHOGENESIS
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.
CLINICAL AND LABORATORY FEATURES
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.
DEFINITION AND HISTORY
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.
ETIOLOGY AND PATHOGENESIS
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
CLINICAL AND LABORATORY FEATURES
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.
DEFINITION AND HISTORY
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.
ETIOLOGY AND PATHOGENESIS
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.
HEMATOLOGIC DISORDERS ASSOCIATED WITH ABNORMAL PLATELET FUNCTION
CHRONIC MYELOPROLIFERATIVE DISORDERS
DEFINITION AND HISTORY
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.
ETIOLOGY AND PATHOGENESIS
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
CLINICAL AND LABORATORY FEATURES
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
LEUKEMIAS AND MYELODYSPLASTIC SYNDROMES
CLINICAL AND LABORATORY FEATURES
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
DEFINITION AND HISTORY
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
ETIOLOGY AND PATHOGENESIS
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
ACQUIRED VON WILLEBRAND DISEASE
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 THAT AFFECT PLATELET FUNCTION
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.
TABLE 120-2 DRUGS THAT INHIBIT PLATELET FUNCTION
ASPIRIN AND OTHER NONSTEROIDALDANTI-INFLAMMATORY DRUGS
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
OTHER NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
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.
DRUGS THAT AFFECT PLATELET CYCLIC NUCLEOTIDE LEVELS OR FUNCTION
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.
ANTICOAGULANTS, FIBRINOLYTIC AGENTS, AND ANTIFIBRINOLYTIC AGENTS
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
PSYCHOTROPIC DRUGS, ANESTHETICS, AND COCAINE
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.
FOODS AND FOOD ADDITIVES
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
Rodgers RPC, Levin J: A critical reappraisal of the bleeding time. Semin Thromb Hemost 16:1, 1990.
Lind SE: The bleeding time does not predict surgical bleeding. Blood 77:3547, 1991.
Remuzzi G: Bleeding disorders in uremia: Pathophysiology and treatment. Adv Nephrol 18:171, 1989.
Rao AK: Uraemic platelets. Lancet 1:913, 1986.
Weigert AL, Schafer AI: Uremic bleeding: Pathogenesis and therapy. Am J Med Sci 316:94, 1998.
Akmal M, Sawelson S, Karubian F, Gadallah M: The prevalence and significance of occult blood loss in patients with predialysis advanced renal failure (CRF), or receiving dialytic therapy. Clin Nephrol 42:198, 1994.
Rosenbaum R, Hoffstein PE, Stanley RJ, Klahr S: Use of computerized tomography to diagnose complications of percutaneous renal biopsy. Kidney Int 14:87, 1978.
Diaz-Buxo JA, Donadio JVJ: Complications of percutaneous renal biopsy: An analysis of 1000 consecutive biopsies. Clin Nephrol 4:223, 1975.
Castillo R, Lozano T, Escolar G, et al: Defective platelet adhesion on vessel subendothelium in uremic patients. Blood 68:337, 1986.
Zwaginga JJ, Ijsseldijk MJW, Beeser-Visser N, et al: High von Willebrand factor concentration compensates a relative adhesion defect in uremic blood. Blood 75:1498, 1990.
Zwaginga JJ, Ijsseldijk I, de Groot PG, et al: Defects in platelet adhesion and aggregate formation in uremic bleeding disorder can be attributed to factors in plasma. Arteriosc Thromb 11:733, 1991.
Gordge MP, Faint RW, Rylance PB, Neild GH: Platelet function and the bleeding time in progressive renal failure. Thromb Haemost 60:83, 1988.
Tang WW, Stead RA, Goodkin DA: Effects of epoetin alfa on hemostasis in chronic renal failure. Am J Nephrol 18:263, 1998.
Fernandez F, Goudable C, Sie P, et al: Low haematocrit and prolonged bleeding time in uraemic patients: Effect of red cell transfusions. Br J Haematol 59:139, 1985.
Livio M, Gotti E, Marchesi D, et al: Uraemic bleeding: Role of anaemia and beneficial effect of red cell transfusions. Lancet 2:1013, 1982.
Moia M, Mannucci PM, Vizzotto L, et al: Improvement in the haemostatic defect of uraemia after treatment with recombinant human erythropoietin. Lancet 2:1227, 1987.
Vigano G, Benigni A, Mendogni D, et al: Recombinant human erythropoietin to correct uremic bleeding. Am J Kidney Dis 18:44, 1991.
Small M, Lowe GDO, Cameron E, Forbes CD: Contribution of the hematocrit to the bleeding time. Haemostasis 13:379, 1983.
Anonymous: The bleeding time and the haematocrit. Lancet 1:997, 1984.
Turrito VT, Weiss HJ: Red blood cells: Their dual role in thrombus formation. Science 207:541, 1980.
Marcus AJ, Safier LB: Thromboregulation: Multicellular modulation of platelet reactivity in hemostasis and thrombosis. FASEB J 7:516, 1993.
Weiss JH, Turrito VT, Baumgartner HR: Effect of shear rate in platelet interaction with subendothelium in citrated native blood: Shear-dependent increase in adherence in von Willebrand’s disease and the Bernard-Soulier syndrome. J Lab Clin Med 92:750, 1978.
Sakariassen KS, Bolhuis PA, Sixma JJ: Platelet adherence to subendothelium of human arteries in pulsatile and steady flow. Thromb Res 19:547, 1980.
Deykin D: Uremic bleeding. Kidney Int 24:698, 1983.
Livio M, Mannucci PM, Vigano G, et al: Conjugated estrogens for the management of bleeding associated with renal failure. N Engl J Med 315:731, 1986.
Sloand EM, Sloand JA, Prodouz K, et al: Reduction of platelet glycoprotein Ib in uremia. Br J Haematol 77:375, 1991.
Gralnick HR, McKeown LP, Williams SB, et al: Plasma and platelet von Willebrand factor defects in uremia. Am J Med 85:806, 1988.
Escolar G, Cases A, Bastida E, et al: Uremic platelets have a functional defect affecting the interaction of von Willebrand factor with glycoprotein IIb-IIIa. Blood 76:1336, 1990.
Di Minno G, Cerbone A, Usberti M, et al: Platelet dysfunction in uremia: II. Correction by arachidonic acid of the impaired exposure of fibrinogen receptors by adenosine diphosphate or collagen. J Lab Clin Med 108:246, 1986.
Rabiner SF, Hrodek O: Platelet factor 3 in normal subjects and patients with renal failure. J Clin Invest 47:901, 1968.
Ware JA, Clark BA, Smith M, Salzman EW: Abnormalities of cytoplasmic Ca2+ in platelets from patients with uremia. Blood 73:172, 1989.
Remuzzi G, Benigni A, Dodesini P, et al: Reduced platelet thromboxane formation in uremia: Evidence for a functional cyclooxgenase defect. J Clin Invest 71:762, 1983.
Winter M, Frampton G, Bennett A, Machin SJ, et al: Synthesis of thromboxane B2 in uraemia and the effects of dialysis. Thromb Res 30:265, 1983.
Bloom A, Greaves M, Preston FE, Brown CB: Evidence against a platelet cyclooxygenase defect in uraemic subjects on chronic haemodialysis. Br J Haematol 62:143, 1986.
Eknoyan G, Brown CH: Biochemical abnormalities of platelets in renal failure: Evidence for decreased platelet serotonin, adenosine diphosphate and Mg-dependent adenosine triphosphatase. Am J Nephrol 1:17, 1981.
Vlachoyannis J, Schoeppe W: Adenylate cyclase activity and cAMP content of human platelets in uraemia. Eur J Clin Invest 12:379, 1982.
Bazilinski N, Shaykh M, Dunea G, et al: Inhibition of platelet function by uremic middle molecules. Nephron 40:423, 1985.
Remuzzi G, Livio M, Marchiaro G, et al: Bleeding in renal failure: Altered platelet function in chronic uraemia only partially corrected by haemodialysis. Nephron 22:347, 1978.
Castaldi PA, Sydney MB: The bleeding disorder of uraemia. Lancet 2:66, 1966.
Livio M, Benigni A, Remuzzi G: Coagulation abnormalities in uremia. Semin Neprhol 5:82, 1985.
Remuzzi G, Cavenaghi AE, Mecca G, et al: Prostacyclin-like activity and bleeding in renal failure. Lancet 2:1195, 1977.
Remuzzi G, Perico N, Zoja C, et al: Role of endothelium-derived nitric oxide in the bleeding tendency of uremia. J Clin Invest 86:1768, 1990.
Aiello S, Noris M, Todeschini M, et al: Renal and systemic nitric oxide synthesis in rats with renal mass reduction. Kidney Int 52:171, 1997.
Livio M, Benigni A, Vigano G, et al: Moderate doses of aspirin and risk of bleeding in renal failure. Lancet 1:414, 1986.
Gaspari F, Vigano G, Orisio S, et al: Aspirin prolongs bleeding time in uremia by a mechanism distinct from platelet cyclooxygenase inhibition. J Clin Invest 79:1788, 1987.
Andrassy K, Ritz E: Uremia as a cause of bleeding. Am J Nephrol 5:313, 1985.
George CRP, Slichter SJ, Quadracci LJ: A kinetic evaluation of hemostasis in renal disease. N Engl J Med 291:1111, 1974.
Michalak E, Walkowiak B, Paradowski M, Cieriewski CS: The decreased circulating platelet mass and its relation to bleeding time in chronic renal failure. Thromb Haemost 65:11, 1991.
Mannucci PM, Remuzzi G, Pusineri F, et al: Deamino-8-arginine vasopressin shortens the bleeding time in uremia. N Engl J Med 308:8, 1983.
Peterson P, Hayes TE, Arkin CF, et al: The preoperative bleeding time test lacks clinical benefit. Arch Surg 133:134, 1998.
Liu YK, Goldstein DM, Arora K, et al: Thigh bleeding time as a valid indicator of hemostatic competency during surgical treatment of patients with advanced renal disease. Surg Gynecol Obstet 172:269, 1991.
Hutton RA, O’Shea MJ: Haemostatic mechanism in uraemia. J Clin Pathol 21:406, 1968.
Stewart JH, Castaldi PA: Uraemic bleeding: A reversible platelet defect corrected by dialysis. Q J Med 36:409, 1967.
Lindsay RM, Friesen M, Koens F, et al: Platelet function in patients on long-term peritoneal dialysis. Clin Nephrol 6:335, 1976.
Mannucci PM: Desmopressin: A non-transfusional form of treatment for congenital and acquired bleeding disorders. Blood 72:1449, 1988.
Rose EH, Aledort LM: Nasal spray desmopressin (DDAVP) for mild hemophilia A and von Willebrand disease. Ann Intern Med 114:563, 1991.
Mannucci PM: Desmopressin (DDAVP) for treatment of disorders of hemostasis. Prog Hemost Thromb 8:19, 1986.
Mannucci PM: Desmopressin (DDAVP) in the treatment of bleeding disorders: The first 20 years. Blood 90:2515, 1997.
Canavese C, Salomone M, Pacitti A, et al: Reduced response of uraemic bleeding time to repeated doses of desmopressin. Lancet 1:867, 1985.
Bichet DG, Razi M, Lonegran M, Arthur M-F: 1-Desamino [8-D-arginine] vasopressin (dDAVP) decreases blood pressure and increases pulse rate in normal individuals. Thromb Haemost 60:348, 1988.
Byrnes JJ, Larcada A, Moake JL: Thrombosis following desmopressin for uremic bleeding. Am J Hematol 28:63, 1988.
Anonymous: Desmopressin and arterial thrombosis. Lancet 1:938, 1989.
Mannucci PM: Desmopressin and thrombosis. Lancet 2:675, 1989.
Gotti E, Mecca G, Valentino C, et al: Renal biopsy in patients with acute renal failure and prolonged bleeding time. Lancet 2:978, 1984.
Tassies D, Reverter JC, Cases A, et al: Effect of recombinant human erythropoietin treatment on circulating reticulated platelets in uremic patients: Association with early improvement in platelet function. Am J Hematol 59:105, 1998.
Liu YK, Kosfeld RE, Marcum SG: Treatment of uremic bleeding with conjugated estrogen. Lancet 2:887, 1984.
Vigano G, Gaspari F, Locatelli M, et al: Dose-effect and pharmacokinetics of estrogens given to correct bleeding time in uremia. Kidney Int 34:853, 1988.
Heistinger M, Stockenhuber F, Schneider B, et al: Effect of conjugated estrogens on platelet function and prostacyclin generation in CRF. Kidney Int 38:1181, 1990.
Bronner MH, Pate MD, Cunningham JT: Estrogen-progesterone therapy for bleeding of gastrointestinal telangiectasias in chronic renal failure. Ann Intern Med 105:371, 1986.
Shemin D, Elnour M, Amarantes B, Abuelo JG: Oral estrogens decrease bleeding time and improve clinical bleeding in patients with renal failure. Am J Med 89:436, 1990.
Vigano G, Zoja C, Corna D, et al: 17 b-estradiol is the most active component of the conjugated estrogen mixture active on uremic bleeding by a receptor mechanism. Mol Pharmacol 252:344, 1990.
Juhl A: DDAVP, cryoprecipitate and highly “purified” factor VIII concentrate in uremia. Nephron 43:305, 1986.
Janson PA, Jubelirer SJ, Weinstein MS, Deykin D: Treatment of bleeding tendency in uremia with cryoprecipitate. N Engl J Med 303:1318, 1980.
Triulzi DJ, Blumber N: Variability in response to cryoprecipitate treatment for hemostatic defects in uremia. Yale J Biol Med 63:1, 1990.
George JN: Platelet membrane microparticles in blood bank fresh frozen plasma and cryoprecipitate. Blood 68:307, 1986.
George JN: Platelet IgG: Measurement, interpretation, and clinical significance. Prog Hemost Thromb 10:97, 1991.
Thompson AR, Harker LA: Approach to Bleeding Disorders: Manual of Hemostasis and Thrombosis, 3rd ed, p 57. FA Davis, Philadelphia, 1983.
George JN, Woolf SH, Raskob GE, et al: Idiopathic thrombocytopenic purpura: A practice guideline developed by explicit methods for the American Society of Hematology. Blood 88:3, 1996.
George JN, El-Harake MA, Raskob GE: Chronic idiopathic thrombocytopenic purpura. N Engl J Med 331:1207, 1994.
Uesugi Y, Fuse I, Toba K, et al: Acquired immune thrombocytopenia caused by IgG antiglycoprotein Ib antibody in a patient with Hodgkin’s disease. Acta Haematol 98:217, 1997.
Meyer M, Kirchmaier CM, Schirmer A, et al: Acquired disorder of platelet function associated with autoantibodies against membrane glycoprotein IIb-IIIa complex-1: Glycoprotein analysis. Thromb Haemost 65:491, 1991.
Balduini CL, Grignani G, Sinigaglia F, et al: Severe platelet dysfunction in a patient with autoantibodies against membrane glycoproteins IIb-IIIa. Haemostasis 7:98, 1987.
Balduini CL, Bertolino G, Noris P, et al: Defect of platelet aggregation and adhesion induced by autoantibodies against platelet glycoprotein IIIa. Thromb Haemost 68:208, 1992.
Fuse I, Higuchi W, Narita M, et al: Overproduction of antiplatelet antibody against glycoprotein IIb after splenectomy in a patient with Evans syndrome resulting in acquired thrombasthenia [comments]. Acta Haematol 99:83, 1998.
Stricker RB, Wong D, Saks SR, et al: Acquired Bernard-Soulier syndrome: Evidence for the role of a 210,000–molecular weight protein in the interaction of platelets with von Willebrand factor. J Clin Invest 76:1274, 1985.
Devine DV, Currie MS, Rosse WF, Greenberg CS: Pseudo-Bernard-Soulier syndrome: Thrombocytopenia caused by autoantibody to platelet glycoprotein Ib. Blood 70:428, 1987.
Deckmyn H, Zhang J, Van Houtte E, Vermylen J: Production and nucleotide sequence of an inhibitory human IgM autoantibody directed against platelet glycoprotein Ia/IIa. Blood 84:1968, 1994.
Dromigny A, Triadou P, Lesavre P, et al: Lack of platelet response to collagen associated with autoantibodies against glycoprotein (GP) Ia/IIa and Ib/IX leading to the discovery of SLE. Hematol Cell Ther 38:355, 1996.
Xu H, Frojmovic MM, Wong T, Rauch J: p32, a platelet autoantigen recognized by an SLE-derived autoantibody that inhibits platelet aggregation. J Autoimmun 8:97, 1995.
Wiedmer T, Ando B, Sims PJ: Complement C5b-9-stimulated platelet secretion is associated with a calcium-initiated activation of cellular protein kinases. J Biol Chem 262:13674, 1987.
Sugiyama T, Okuma M, Ushikubi F, et al: A novel platelet aggregating factor found in a patient with defective collagen-induced platelet aggregation and autoimmune thrombocytopenia. Blood 69:1712, 1987.
Handagama PJ, George JN, Shuman MA, et al: Incorporation of a circulating protein into megakaryocyte and platelet granules. Proc Nat Acad Sci USA 84:861, 1987.
Weiss HJ, Rosove MH, Lages BA, Kaplan KL: Acquired storage pool deficiency with increased platelet-associated IgG. Am J Med 69:711, 1980.
Stuart MJ, Kelton JG, Allen JB: Abnormal platelet function and arachidonate metabolism in chronic idiopathic thrombocytopenic purpura. Blood 58:326, 1981.
Lackner H, Karpatkin S: On the “easy bruising” syndrome with normal platelet count: A study of 75 patients. Ann Intern Med 83:190, 1975.
Clancy R, Jenkins E, Firkin B: Qualitative platelet abnormalities in idiopathic thrombocytopenic purpura. N Engl J Med 286:622, 1972.
Heyns DA, Fraser J, Retief FP: Platelet aggregation in chronic idiopathic thrombocytopenic purpura. J Clin Pathol 31:1239, 1978.
Regan MG, Lackner H, Karpatkin S: Platelet function and coagulation profile in lupus erythematosus. Am J Med 81:462, 1974.
Dorsch CA, Meyerhoff J: Mechanisms of abnormal platelet aggregation in systemic lupus erythematosus. Arthritis Rheum 25:966, 1982.
Nieuwenhuis HK, Zwaginga JJ, Sixma JJ: Analysis of patients with a prolonged bleeding time. Thromb Haemost 58:527, 1987.
Meyerhoff J, Dorsch CA: Decreased platelet serotonin levels in systemic lupus erythematosus. Arthritis Rheum 24:1495, 1981.
Harker LA, Malpass TW, Branson HE, et al: Mechanism of abnormal bleeding in patients undergoing cardiopulmonary bypass: Acquired transient platelet dysfunction associated with selective alpha-granule release. Blood 56:824, 1980.
Khuri SF, Valeri CR, Loscalzo J, et al: Heparin causes platelet dysfunction and induces fibrinolysis before cardiopulmonary bypass [comments]. Ann Thorac Surg 60:1008, 1995.
Colman RW: Platelet and neutrophil activation in cardiopulmonary bypass. Ann Thorac Surg 49:32, 1990.
Mammen EF, Koets MH, Washington BC, et al: Hemostasis changes during cardiopulmonary bypass surgery. Semin Thromb Hemost 11:281, 1985.
Khuri SF, Wolfe JA, Josa M, et al: Hematologic changes during and after cardiopulmonary bypass and their relationship to the bleeding time and nonsurgical blood loss. J Thorac Cardiovasc Surg 104:94, 1992.
Martin JF, Daniel TD, Trowbridge EA: Acute and chronic changes in platelet volume and count after cardiopulmonary bypass induced thrombocytopenia in man. Thromb Haemost 57:55, 1987.
Chandler AB, Hutson MS: Platelet plug formation in an extracorporeal unit. Am J Clin Pathol 64:101, 1975.
Uniyal S, Brash JL: Patterns of adsorption of proteins from human plasma onto foreign surfaces. Thromb Haemost 47:285, 1982.
Lindon JN, McManama, Kushner L: Does the conformation of adsorbed fibrinogen dictate platelet interactions with artificial surfaces? Blood 68:355, 1986.
Singer RL, Mannion JD, Bauer TL, et al: Complications from heparin-induced thrombocytopenia in patients undergoing cardiopulmonary bypass. Chest 104:1436, 1993.
Woodman RC, Harker LA: Bleeding complications associated with cardiopulmonary bypass. Blood 76:1680, 1990.
Bick RL: Hemostasis defects associated with cardiac surgery, prosthetic devices, and other extracorporeal circuits. N Engl J Med 22:1446, 1986.
McKenna R, Bachmann F, Whittaker B, et al: The hemostatic mechanism after open heart surgery: II. Frequency of abnormal platelet functions during and after extracorporeal circulation. J Thorac Cardiovasc Surg 70:298, 1975.
Beurling-Harbury C, Galvan CA: Acquired decrease in platelet secretory ADP associated with increased post-operative bleeding in post-cardiopulmonary bypass patients and in patients with severe valvular heart disease. Blood 52:13, 1978.
Abrams CS, Ellison N, Budzynski AZ, Shattil S: Direct detection of activated platelets and platelet-derived microparticles in humans. Blood 75:128, 1990.
George JN, Pickett EB, Saucerman S, et al: Platelet surface glycoproteins: Studies on resting and activated platelets and platelet membrane microparticles in normal subjects, and observations in patients during adult respiratory distress syndrome and cardiac surgery. J Clin Invest 78:340, 1986.
Bachmann F, McKenna R, Cole ER, Najafi H: The hemostatic mechanism after open heart surgery: I. Studies on plasma coagulation factors and fibrinolysis in 512 patients after extracorporeal circulation. J Thorac Cardiovasc Surg 70:76, 1975.
Gluszko P, Ricinski B, Musial J, et al: Fibrinogen receptors in platelet adhesion to surfaces of extracorporeal circuit. Am J Physiol 252:H615, 1987.
van den Dungen JJ, Karliczek GF, Brenken U, et al: Clinical study of blood trauma during perfusion with membrane and bubble oxygenators. Thorac Cardiovasc Surg 83:108, 1982.
Ferraris VA, Ferraris SP, Singh A, et al: The platelet thrombin receptor and postoperative bleeding. Ann Thorac Surg 65:352, 1998.
Kestin AS, Valeri CR, Khuri SF, et al: The platelet function defect of cardiopulmonary bypass. Blood 82:107, 1993.
Weksler BB, Pett SB, Alonso D, et al: Differential inhibition of aspirin of vascular prostaglandin synthesis in atherosclerotic patients. N Engl J Med 308:800, 1983.
Hunt BJ, Parratt RN, Segal HC, et al: Activation of coagulation and fibrinolysis during cardiothoracic operations. Ann Thorac Surg 65:712, 1998.
Tabuchi N, de Haan J, Boonstra PW, van Oeveren W: Activation of fibrinolysis in the pericardial cavity during cardiopulmonary bypass. J Thorac Cardiovasc Surg 106:828, 1993.
Rapaport SI: Preoperative hemostatic evaluation: which tests, if any? Blood 61:229, 1983.
Magovern JA, Sakert T, Benckart DH, et al: A model for predicting transfusion after coronary artery bypass grafting. Ann Thorac Surg 61:27, 1996.
Simon TA, Akl BF, Murphy W: Controlled trial of routine administration of platelet concentrates in cardiopulmonary bypass surgery. Ann Thorac Surg 37:359, 1987.
Wasser MNJM, Houbiers JGA, D’Amaro J, et al: The effect of fresh versus stored blood on post-operative bleeding after coronary bypass surgery: A prospective randomized study. Br J Haematol 72:81, 1989.
Sowade O, Warnke H, Scigalla P, et al: Avoidance of allogeneic blood transfusions by treatment with epoetin beta (recombinant human erythropoietin) in patients undergoing open-heart surgery. Blood 89:411, 1997.
Shimpo H, Mizumoto T, Onoda K, et al: Erythropoietin in pediatric cardiac surgery: Clinical efficacy and effective dose. Chest 111:1565, 1997.
Schmoeckel M, Nollert G, Mempel M, et al: Effects of recombinant human erythropoietin on autologous blood donation before open heart surgery. Thorac Cardiovasc Surg 41:364, 1993.
Axford TC, Dearani JA, Ragno G, et al: Safety and therapeutic effectiveness of reinfused shed blood after open heart surgery. Ann Thorac Surg 57:615, 1994.
Griffith LD, Billman GF, Daily PO, Lane TA: Apparent coagulopathy caused by infusion of shed mediastinal blood and its prevention by washing of the infusate. Ann Thorac Surg 47:400, 1989.
Hackmann T, Gascoyne R, Naiman SC, et al: A trial of desmopressin to reduce blood loss in uncomplicated cardiac surgery. N Engl J Med 321:1437, 1989.
Seear MD, Wadsworth LD, Rogers PC, et al: The effect of desmopressin acetate (DDAVP) on postoperative blood loss after cardiac operations in children [comments]. J Thorac Cardiovasc Surg 98:217, 1989.
Walker ID, Davidson JF, Faichney A, et al: A double-blind study of prostacyclin in cardiopulmonary bypass surgery. Br J Haematol 49:415, 1981.
Fish KJ, Sarnquist FH, van Steennis C, et al: A prospective, randomized study of the effects of prostacyclin on platelets and blood loss during coronary bypass operations. J Thorac Cardiovasc Surg 91:436, 1986.
van Oeveren W, Harder MP, Roozendaal KJ, et al: Aprotinin protects platelets against the initial effect of cardiopulmonary bypass. J Thorac Cardiovasc Surg 99:788, 1990.
Hardy J-F, Desroches J: Natural and synthetic antifibrinolytics in cardiac surgery. Can J Anesthesiol 39:353, 1992.
Speekenbrink RG, Wildevuur CR, Sturk A, Eijsman L: Low-dose and high-dose aprotinin improve hemostasis in coronary operations. J Thorac Cardiovasc Surg 112:523, 1996.
Orchard MA, Goodchild CS, Prentice CR, et al: Aprotinin reduces cardiopulmonary bypass-induced blood loss and inhibits fibrinolysis without influencing platelets. Br J Haematol 85:533, 1993.
Wahba A, Black G, Koksch M, et al: Aprotinin has no effect on platelet activation and adhesion during cardiopulmonary bypass. Thromb Haemost 75:844, 1996.
Mastroroberto P, Chello M, Zofrea S, Marchese AR: Suppressed fibrinolysis after administration of low-dose aprotinin: Reduced level of plasmin-alpha2–plasmin inhibitor complexes and postoperative blood loss. Eur J Cardiothorac Surg 9:143, 1995.
Rich JB: The efficacy and safety of aprotinin use in cardiac surgery. Ann Thorac Surg 66:S6, 1998.
Bidstrup BP, Underwood SR, Sapsford RN, Streets EM: Effect of aprotinin (Trasylol) on aorta-coronary bypass graft patency. J Thorac Cardiovasc Surg 105:147, 1993.
Dietrich W, Spath P, Ebell A, Richter JA: Prevalence of anaphylactic reactions to aprotinin: Analysis of two hundred forty-eight reexposures to aprotinin in heart operations. J Thorac Cardiovasc Surg 113:194, 1997.
Miller JM: Trasylol in primary acute pancreatitis [letter]. Br J Surg 65:887, 1978.
Pinosky ML, Kennedy DJ, Fishman RL, et al: Tranexamic acid reduces bleeding after cardiopulmonary bypass when compared to epsilon aminocaproic acid and placebo. J Cardiac Surg 12:330, 1997.
Penta de Peppo A, Pierri MD, Scafuri A, et al: Intraoperative antifibrinolysis and blood-saving techniques in cardiac surgery: Prospective trial of 3 antifibrinolytic drugs. Tex Heart Inst J 22:231, 1995.
Krauss JS, Jonah MH: Platelet dysfunction (thrombocytopathy) in extra-hepatic biliary obstruction. South Med J 75:506, 1982.
Hillbom M, Muuronen A, Neiman J: Liver disease and platelet function in alcoholics. Br Med J 295:581, 1987.
Mannucci PM, Vicente V, Vianello L, et al: Controlled trial of desmopressin in liver cirrhosis and other conditions associated with a prolonged bleeding time. Blood 67:1148, 1986.
Stein SF, Harker LA: Kinetic and functional studies of platelets, fibrinogen, and plasminogen in patients with hepatic cirrhosis. J Lab Clin Med 99:217, 1982.
Violi F, Leo R, Vezza E, et al: Bleeding time in patients with cirrhosis: Relation with degree of liver failure and clotting abnormalities. Coagulation Abnormalities in Cirrhosis Study Group. J Hepatol 20:531, 1994.
Pareti FI, Capitanio A, Mannucci L: Acquired storage pool disease in platelets during disseminated intravascular coagulation. Blood 48:511, 1976.
Pareti FI, Capitanio A, Mannucci L, et al: Acquired dysfunction due to the circulation of “exhausted” platelets. Am J Med 69:235, 1980.
Solum NO, Rigollot C, Budzynski A, Marder VJ: A quantitative evaluation of the inhibition of platelet aggregation by low molecular weight degradation products of fibrinogen. Br J Haematol 24:619, 1973.
Bennett JS, Vilaire G: Exposure of platelet fibrinogen receptors by ADP and epinephrine. J Clin Invest 64:1393, 1979.
Stoff JS, Stemerman M, Steer M, et al: A defect in platelet aggregation in Bartter’s syndrome. Am J Med 68:171, 1980.
Lim SH, Tan CE, Agasthian T, Chew LS: Acquired platelet dysfunction with eosinophilia: Review of seven adult cases. J Clin Pathol 42:950, 1989.
Poon MC, Ng SC, Coppes MJ: Acquired platelet dysfunction with eosinophilia in white children. J Pediatr 126:959, 1995.
Szczeklik A, Milner PC, Birch J, et al: Prolonged bleeding time, reduced platelet aggregation, altered PAF-acether sensitivity and increased platelet mass are a trait of asthma and hay fever. Thromb Haemost 56:283, 1986.
Carvalho AC, Quinn DA, DeMarinis SM, et al: Platelet function in acute respiratory failure. Am J Hematol 25:377, 1987.
Bracey AW, Wu AH, Aceves J, et al: Platelet dysfunction associated with Wilms tumor and hyaluronic acid. Am J Hematol 24:247, 1987.
Landolfi R, Rocca B, Patrono C: Bleeding and thrombosis in myeloproliferative disorders: Mechanisms and treatment. Crit Rev Oncol Hematol 20:203, 1995.
Murphy S: Polycythemia vera. Dis Mon 38:165, 1992.
Wasserman LR, Gilbert H: Complications of polycythemia vera. Semin Hematol 3:199, 1966.
Schafer AI: Essential thrombocythemia. Prog Hemost Thromb 10:69, 1991.
Mitus AJ, Barbui T, Shulman LN, et al: Hemostatic complications in young patients with essential thrombocythemia. Am J Med 88:371, 1990.
Lahuerta-Palacios JJ, Bornstein R, Fernandez-Debora FJ, et al: Controlled and uncontrolled thrombocytosis: Its clinical role in essential thrombocytosis. Cancer 61:1207, 1988.
Kessler CM, Klein HG, Havlik RJ: Uncontrolled thrombocytosis in chronic myeloproliferative disorders. Br J Haematol 50:157, 1982.
McIntyre KJ, Hoagland HC, Silverstein MN, Petitt RM: Essential thrombocythemia in young adults. Mayo Clin Proc 66:149, 1991.
Bellucci S, Janvier M, Tobelem G, et al: Essential thrombocythemias: Clinical evolutionary and biological data. Cancer 58:2440, 1986.
Maldonado JE, Pintado T, Pierre RV: Dysplastic platelets and circulating megakaryocytes in chronic myeloproliferative diseases: I. The platelets: Ultrastructure and peroxidase reaction. Blood 43:797, 1974.
Bautista AP, Buckler PW, Towler HM, et al: Measurement of platelet life-span in normal subjects and patients with myeloproliferative disease. Br J Haematol 58:679, 1984.
Ginsberg AD: Platelet function in patients with high platelet counts. Ann Intern Med 82:506, 1975.
Jubilirer SJ, Russell F, Faillacourt R, Deykin D: Platelet arachidonic acid metabolism and platelet function in ten patients with chronic myelogenous leukemia. Blood 56:728, 1980.
Pareti FI, Gugliotta L, Mannucci L, et al: Biochemical and metabolic aspects of platelet dysfunction in chronic myeloproliferative disorders. Thromb Haemost 47:84, 1982.
Schafer AI: Deficiency of platelet lipoxygenase activity in myeloproliferative disorders. N Engl J Med 306:381, 1982.
Okuma M, Takayama H, Uchino H: Subnormal platelet response to thromboxane A2 in a patient with chronic myeloid leukaemia. Br J Haematol 51:469, 1982.
Ushikubi F, Okuma M, Kanaji K, et al: Hemorrhagic thrombocytopathy with platelet thromboxane A2 receptor abnormality: Defective signal transduction with normal binding activity. Thromb Haemost 57:158, 1987.
Malpass TW, Savage B, Hanson SR, et al: Correlation between prolonged bleeding time and depletion of platelet dense granule ADP in patients with myelodysplastic and myeloproliferative disorders. J Lab Clin Med 103:894, 1984.
Mohri H: Acquired von Willebrand disease and storage pool disease in chronic myelocytic leukemia. Am J Hematol 22:391, 1986.
Handa M, Wantanabe K, Kawai Y, et al: Platelet unresponsiveness to collagen: Involvement of glycoprotein Ia-IIa (a2b1 integrin) deficiency associated with a myeloproliferative disorder. Thromb Haemost 73:521, 1995.
Kaywin P, McDonough M, Insel PA, Shattil SJ: Platelet function in essential thrombocythemia: Decreased epinephrine responsiveness associated with a deficiency of platelet alpha-adrenergic receptors. N Engl J Med 299:505, 1978.
Swart SS, Pearson D, Wood JK, Barnett DB: Functional significance of the platelet alpha2-adrenoceptor: Studies in patients with myeloproliferative disorders. Thromb Res 33:531, 1984.
Nurden P, Bihour C, Smith M, et al: Platelet activation and thrombosis: Studies in a patient with essential thrombocythemia. Am J Hematol 51:79, 1996.
Rocca B, Ciabattoni G, Tartaglione R, et al: Increased thromboxane biosynthesis in essential thrombocythemia. Thromb Haemost 74:1225, 1995.
Landolfi R, Ciabattoni G, Patrignani P, et al: Increased thromboxane biosynthesis in patients with polycythemia vera: Evidence for aspirin-suppressible platelet activation in vivo. Blood 80:1965, 1992.
Walsh PN, Murphy S, Barry WE: The role of platelets in the pathogenesis of thrombosis and hemorrhage in patients with thrombocytosis. Thromb Haemost 38:1085, 1977.
Berndt MC, Kabral A, Grimsley P, et al: An acquired Bernard-Soulier-like platelet defect associated with juvenile myelodysplastic syndrome. Br J Haematol 68:97, 1988.
Cooper B, Schafer AI, Puchalsky D, Handin RI: Platelet resistance to prostaglandin D2 in patients with myeloproliferative disorders. Blood 52:618, 1978.
Moore A, Nachman RL: Platelet Fc receptor: Increased expression in myeloproliferative disease. J Clin Invest 67:1064, 1981.
Bolin RB, Okumura T, Jamieson GA: Changes in distribution of platelet membrane glycoproteins in patients with myeloproliferative disorders. Am J Hematol 3:63, 1977.
Eche N, Sie P, Caranobe C, et al: Platelets in myeloproliferative disorders: III. Glycoprotein profile in relation to platelet function and platelet density. Scand J Haematol 26:123, 1981.
Thibert V, Bellucci S, Cristofari M, et al: Increased platelet CD36 constitutes a common marker in myeloproliferative disorders. Br J Haemtol 91:618, 1995.
Moliterno AR, Hankins D, Spivak JL: Impaired expression of the thrombopoietin receptor by platelets from patients with polycythemia vera. N Engl J Med 338:572, 1998.
Budde U, Schaefer G, Mueller N, et al: Acquired von Willebrand’s disease in the myeloproliferative syndrome. Blood 64:981, 1984.
van Genderen PJJ, Budde U, Michiels JJ, et al: The reduction in large von Willebrand factor multimers in plasma in essential thrombocythemia is related to platelet count. Br J Haematol 93:962, 1996.
Mohri H, Ohkubo T: Acquired von Willebrand’s syndrome due to an inhibitor of IgG specific for von Willebrand’s factor in polycythemia rubra vera. Acta Haematol 78:258, 1987.
van Genderen PJJ, Prins FJ, Lucas IS, et al: Decreased half-life of plasma von Willebrand factor collagen binding activity in essential thrombocythemia: Normalization after cytoreduction of the increased platelet count. Br J Haematol 99:832, 1997.
Schafer AI: Bleeding and thrombosis in the myeloproliferative disorders. Blood 64:1, 1984.
Murphy S: Thrombocytosis and thrombocythaemia. Clin Haematol 12:89, 1983.
Mitchell MC, Boitnott JK, Kaufman S, et al: Budd-Chiari syndrome: Etiology, diagnosis and management. Medicine 61:199, 1982.
Valla D, Casadevall N, Huisse MG, et al: Etiology of portal vein thrombosis in adults: A propspective evaluation of primary myeloproliferative disorders. Gastroenterology 94:1063, 1988.
Singh AK, Wetherley-Mein G: Microvascular occlusive lesions in primary thrombocythaemia. Br J Haematol 36:553, 1977.
van Genderen PJJ, Michiels JJ, van Strik R, et al: Platelet consumption in thrombocythemia complicated by erythromelalgia: reversal by aspirin. Thromb Haemost 73:210, 1995.
Kessler CM, Klein HG, Havlik RJ: Uncontrolled thrombocytosis in chronic myeloproliferative disorders. Br J Haematol 50:157, 1982.
Rinder HM, Schuster JE, Rinder CS, et al: Correlation of thrombosis with increased platelet turnover in thrombocytosis. Blood 91:1288, 1998.
Besses C, Cervantes F, Pereira A, et al: Major vascular complications in essential thrombocythemia: A study of the predictive factors in a series of 148 patients. Leukemia 13:150, 1999.
Kaplan ME, Mack K, Goldberg JD: Long-term management of polycythemia vera with hydroxyurea: A progress report. Semin Hematol 23:167, 1986.
Cortelazzo S, Finazzi G, Ruggeri M, et al: Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med 332:1132, 1995.
Group AS: Anagrelide, a therapy for thrombocythemic states: Experience in 577 patients. Am J Med 92:69, 1992.
Solberg LA, Tefferi A, Oles KJ, et al: The effects of anagrelide on human megakaryocytopoiesis. Br J Haematol 99:174, 1997.
Preston FE: Aspirin, prostaglandins, and peripheral gangrene. Am J Med 74(suppl):55, 1983.
Michiels JJ, Abels J, Steketee J, et al: Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia. Ann Intern Med 102:466, 1985.
van Genderen PJJ, Mulder PGH, Waleboer M, et al: Prevention and treatment of thrombotic complications in essential thrombocythemia: Efficacy and safety of aspirin. Br J Haematol 97:179, 1997.
Sultan Y, Caen JP: Platelet dysfunction in preleukemic states and in various types of leukemia. Ann NY Acad Sci 201:300, 1972.
Cowan DH, Haut JJ: Platelet function in acute leukemia. J Lab Clin Med 79:893, 1972.
Cowan DH, Graham RR Jr, Baunach D: The platelet defect in leukemia, platelet ultrastructure, adenine nucleotide metabolism and the release reaction. J Clin Invest 56:188, 1975.
Meschengieser S, Blanco A, Maugeri N, et al: Platelet function and intraplatelet von Willebrand factor antigen and fibrinogen in myelodysplastic syndromes. Thromb Res 46:601, 1987.
Pui C-H, Jackson CW, Chesney C: Normal platelet function after therapy for acute lymphocytic leukemia. Arch Intern Med 143:73, 1983.
Westbrook CA, Golde DW: Clinical problems in hairy cell leukemia: Diagnosis and management. Semin Oncol 11:514, 1984.
Levine PH, Katayama I: The platelet in leukemic reticuloendotheliosis. Cancer 36:1353, 1975.
Feiner AS, Myers AM, Moore GE: Leukemic reticuloendotheliosis: Loss of platelet defect after splenectomy. J Am Med Assoc 241:1684, 1979.
Sweet DL, Golomb HM: Correction of platelet defect after splenectomy in hairy cell leukemia. J Am Med Assoc 241:1684, 1979.
Zuzel M, Cawley JC, Paton RC, et al: Platelet function in hairy-cell leukaemia. J Clin Pathol 32:814, 1979.
Rosove MH, Naeim F, Harwig S, Zighelboim J: Severe platelet dysfunction in hairy cell leukemia with improvement after splenectomy. Blood 55:903, 1980.
Roussi JH, Houbouyan LL, Alterescu R, et al: Acquired von Willebrand’s syndrome associated with hairy cell leukemia. Br J Haematol 46:503, 1980.
Lackner H: Hemostatic abnormalities associated with dysproteinemias. Semin Hematol 10:125, 1973.
Perkins HA, McKenzie MR, Fudenberg HH: Hemostatic defects in dysproteinemias. Blood 35:695, 1970.
Rapoport M, Yona R, Kaufman S, et al: Unusual bleeding manifestations of amyloidosis in patients with multiple myeloma. Clin Lab Haematol 16:349, 1994.
Furie B, Greene E, Furie BC: Syndrome of acquired factor X deficiency and systemic amyloidosis. N Engl J Med 297:81, 1977.
McPherson RA, Onstad JW, Ugoretz RJ, Wolf PL: Coagulopathy in amyloidosis: Combined deficiency of factors IX and X. Am J Hematol 3:225, 1977.
Palmer RN, Rick ME, Rick PD, et al: Circulating heparan sulfate anticoagulant in a patient with a fatal bleeding disorder. N Engl J Med 310:1696, 1984.
Chapman GS, George CB, Danley DL: Heparin-like anticoagulant associated with plasma cell myeloma. Am J Clin Pathol 83:764, 1985.
Liebman H, Chinowsky M, Valdin J, et al: Increased fibrinolysis and amyloidosis. Arch Intern Med 143:678, 1983.
Meyer K, Williams EC: Fibrinolysis and acquired alpha-2 plasmin inhibitor deficiency in amyloidosis. Am J Med 79:394, 1985.
McGrath KM, Stuart JJ, Richards F II: Correlation between serum IgG, platelet membrane IgG and platelet function in hypergammaglobulinemic states. Br J Haematol 42:585, 1979.
Kasturi J, Saraya AK: Platelet functions in dysproteinemia. Acta Haematol 59:104, 1978.
Vigliano EM, Horowitz HI: Bleeding syndrome in a patient with IgA myeloma: Interaction of protein and connective tissue. Blood 29:823, 1967.
DiMinno G, Coraggio F, Cerbone AM, et al: A myeloma paraprotein with specificity for platelet glycoprotein IIIa in a patient with a fatal bleeding disorder. J Clin Invest 77:157, 1986.
Mohri H, Noguchi T, Kodama F, et al: Acquired von Willebrand disease due to inhibitor of human myeloma protein specific for von Willebrand factor. J Clin Pathol 87:663, 1987.
Takahashi H, Nagayama R, Tanabe Y, et al: DDAVP in acquired von Willebrand syndrome associated with multiple myeloma. Am J Hematol 22:421, 1986.
Mannucci PM, Lombardi R, Bader R, et al: Studies of the pathophysiology of acquired von Willebrand’s disease in seven patients with lymphoproliferative disorders or benign monoclonal gammopathies. Blood 64:614, 1984.
Wallace MR, Simon SR, Ershler WB, Burns SL: Hemorrhagic diathesis in multiple myeloma. Acta Haematol 72:340, 1984.
Hyman BT, Westrick MA: Multiple myeloma with polyneuropathy and coagulopathy. Arch Intern Med 146:993, 1986.
Bovill EG, Ershler WB, Golden EA, et al: A human myeloma-produced monoclonal protein directed against the active subpopulation of von Willebrand factor. Am J Clin Pathol 85:115, 1986.
Silberstein LE, Abrahm J, Shattil SJ: The efficacy of intensive plasma exchange in acquired von Willebrand’s disease. Transfusion 27:234, 1987.
Bovill EG, Ershler WB, Golden EA, et al: A human myeloma-produced monoclonal protein directed against the active subpopulation of von Willebrand factor. Am J Clin Pathol 85:115, 1986.
Mohri H, Noguchi T, Kodama F, et al: Acquired von Willebrand disease due to inhibitor of human myeloma protein specific for von Willebrand factor. Am J Clin Pathol 87:663, 1987.
Mazurier C, Parquet-Gernez A, Descamps J, et al: Acquired von Willebrand’s syndrome in the course of Waldenstrom’s disease. Thromb Haemost 44:115, 1980.
van Genderen PJ, Vink T, Michiels JJ, et al: Acquired von Willebrand disease caused by an autoantibody selectively inhibiting the binding of von Willebrand factor to collagen. Blood 84:3378, 1994.
Handin RI, Martin V, Moloney WC: Antibody-induced von Willebrand’s disease: A newly defined inhibitor syndrome. Blood 48:393, 1976.
Goudemand J, Samor B, Caron C, et al: Acquired type II von Willebrand’s disease: Demonstration of a complexed inhibitor of the von Willebrand factor-platelet interaction and response to treatment. Br J Haematol 68:227, 1988.
Budde U, Schaefer G, Mueller N, et al: Acquired von Willebrand’s disease in the myeloproliferative syndrome. Blood 64:981, 1984.
Mohri H, Hisanaga S, Mishima A, et al: Autoantibody inhibits binding of von Willebrand factor to glycoprotein Ib and collagen in multiple myeloma: recognition sites present on the A1 loop and A3 domains of von Willebrand factor. Blood Coag Fibrinol 9:91, 1998.
Igarashi N, Miura M, Kato E, et al: Acquired von Willebrand’s syndrome with lupus-like serology. Am J Pediatr Hematol Oncol 11:32, 1989.
Scott JP, Montgomery RR, Tubergen DG, Hays T: Acquired von Willebrand’s disease in association with Wilm’s tumor: Regression following treatment. Blood 48:665, 1981.
Rao KP, Kizer J, Jones TJ, et al: Acquired von Willebrand’s syndrome associated with an extranodal pulmonary lymphoma. Arch Pathol Lab Med 112:47, 1988.
Levesque H, Borg JY, Cailleux N, et al: Acquired von Willebrand’s syndrome associated with decrease of plasminogen activator and its inhibitor during hypothyroidism. Eur J Med 2:287, 1993.
Aylesworth CA, Smallridge RC, Rick ME, Alving BM: Acquired von Willebrand’s disease: A rare manifestation of postpartum thyroiditis. Am J Hematol 50:217, 1995.
Tefferi A, Nichols WL: Acquired von Willebrand disease: Concise review of occurrence, diagnosis, pathogenesis, and treatment. Am J Med 103:536, 1997.
Joist JH, Cowan JF, Zimmerman TS: Acquired von Willebrand’s disease: Evidence for a quantitative and qualitative factor VIII disorder. N Engl J Med 298:988, 1978.
Macik BG, Gabriel DA, White GC 2d, et al: The use of high-dose intravenous gamma-globulin in acquired von Willebrand syndrome. Arch Pathol Lab Med 112:143, 1988.
White LA, Chisholm M: Gastro-intestinal bleeding in acquired von Willebrand’s disease: efficacy of high-dose immuno-globulin where substitution treatments failed. Br J Haematol 84:332, 1993.
Rinder MR, Richard RE, Rinder HM: Acquired von Willebrand’s disease: A concise review. Am J Hematol 54:139, 1997.
van Genderen PJJ, Terpstra W, Michiels JJ, et al: High-dose intravenous immunoglobulin delays clearance of von Willebrand factor in acquired von Willebrand disease. Thromb Haemost 73:890, 1995.
van Genderen PJJ, Papatsonis DNM, Michiels JJ, et al: High-dose intravenous immunoglobulin therapy for acquired von Willebrand disease. Postgrad Med J 70:916, 1994.
George J, Shattil SJ: The clinical importance of acquired abnormalities of platelet function. N Engl J Med 324:27, 1991.
Wisloff F, Godal HC: Prolonged bleeding time with adequate platelet count in hospital patients. Scand J Haematol 27:45, 1981.
Smith WL, Garavito RM, DeWitt DL: Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and -2. J Biol Chem 271:33157, 1996.
Weiss HJ, Aledort LM: Impaired platelet/connective tissue reaction in man after aspirin ingestion. Lancet 2:495, 1967.
O’Brien JR: Effect of salicylates on human platelets. Lancet 1:779, 1968.
Patrono C: Aspirin as an antiplatelet drug. N Engl J Med 330:1287, 1994.
Kyrle PA, Eichler HG, Jager U, Lechner K: Inhibition of prostacyclin and thromboxane A2 generation by low-dose aspirin at the site of plug formation in man in vivo. Circulation 75:1025, 1987.
Clarke RJ, Mayo G, Price P, FitzGerald GA: Suppression of thromboxane A2 but not systemic prostacyclin by controlled-release aspirin. N Engl J Med 325:1137, 1991.
Jaffe EQ, Weksler BB: Recovery of endothelial cell prostacyclin production after inhibition by low doses of aspirin. J Clin Invest 63:532, 1979.
Santos MT, Valles J, Aznar J, et al: Prothombotic effects of erythrocytes on platelet reactivity. Circulation 95:63, 1997.
Kallmann R, Nieuwenhuis HK, de Groot PG, et al: Effects of low doses of aspirin, 10 mg and 30 mg daily, on bleeding time, thromboxane production and 6-keto-PGF1a excretion in healthy subjects. Thromb Res 45:355, 1987.
Nakajima H, Takami H, Yamagata K, et al: Aspirin effects on colonic mucosal bleeding. Dis Colon Rectum 40:1484, 1997.
Mielke CH Jr: Aspirin prolongation of the template bleeding time: Influence of venostasis and direction of incision. Blood 60:1139, 1982.
Hirsh J, Salzman EW, Harker L, et al: Aspirin and other platelet active drugs: Relationship among dose, effectiveness, and side effects. Chest 95:12S, 1989.
Steering Committee of the Physicians’ Health Study Research Group: Final report on the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med 321:129, 1989.
Page IH: Salicylate damage to the gastric mucosal barrier. N Engl J Med 276:1307, 1967.
Leonards JR, Levy G: The role of dosage form in aspirin-induced gastrointestinal bleeding. Clin Pharmacol Ther 8:400, 1969.
Stuart MJ, Gross SJ, Elrad H, Graeber JE: Effects of acetylsalicylic acid ingestin on maternal and neonatal hemostasis. N Engl J Med 307:909, 1982.
Ferraris VA, Ferraris S, Lough FC, Berry WR: Preoperative aspirin ingestion increases operative blood loss after coronary artery bypass grafting. Ann Thorac Surg 45:71, 1988.
Sethi GK, Copeland JG, Goldman S, et al: Implications of preoperative administration of aspirin in patients undergoing coronary artery bypass grafting: Department of Veterans Affairs cooperative study of antiplatelet therapy. J Am Coll Cardiol 15:15, 1990.
Horlocker TT, Wedel DJ, Offord KP: Does preoperative antiplatelet therapy increase the risk of hemorrhagic complications associated with regional anesthesia? Anesth Analg 70:631, 1990.
Kitchen L, Erichson RB, Sideropoulos H: Effect of drug-induced platelet dysfunction on surgical bleeding. Am J Surg 143:215, 1982.
Kennedy BM: Aspirin and surgery: A review. Ir Med J 77:363, 1984.
Chesebro JH, Fuster V, Elveback LR, et al: Trial of combined warfarin plus dipyridamole or aspirin therapy in prosthetic heart valve replacement: Danger of aspirin compared to dipyridamole. Am J Cardiol 51:1537, 1983.
Deykin D, Janson P, McMahon L: Ethanol potentiation of aspirin-induced prolongation of the bleeding time. N Engl J Med 306:852, 1982.
Rosove HH, Harwig SSL: Confirmation that ethanol potentiates aspirin-induced prolongation of the bleeding time. Thromb Res 31:525, 1983.
Kobrinsky NL, Israels ED, Gerrard JM, et al: Shortening of bleeding time by 1-deamino-8-arginine vasopressin in various bleeding disorders. Lancet 1:1145, 1984.
Lethagen S, Rugarn P: The effect of DDAVP and placebo on platelet function and prolonged bleeding time induced by oral acetyl salicylic acid intake in healthy volunteers. Thromb Haemost 67:185, 1992.
Simon SL, Mills JA: Non-steroidal anti-inflammatory drugs. N Engl J Med 302:1119, 1980.
McAueen EG, Facoory B: Non-steroidal anti-inflammatory drugs and platelet function. NZ Med J 99:358, 1986.
Buchanan GR, Martin V, Levine PH, et al: The effects of “anti-platelet” drugs on bleeding time and platelet aggregation in normal human subjects. Am J Clin Pathol 68:355, 1977.
Nadell J, Bruno J, Varady J, Segre EJ: Effect of naproxen and of aspirin on bleeding time and platelet aggregation. J Clin Pharmacol 14:176, 1974.
Mielke CH Jr, Kahn SB, Muschek LL, et al: Effects of zomepirac on hemostasis in healthy adults and on platelet function in vitro. J Clin Pharmacol 20:409, 1980.
Thomas P, Hepburn B, Kim HC, Saidi P: Nonsteroidal anti-inflammatory drugs in the treatment of hemophilic arthropathy. Am J Hematol 12:131, 1982.
McIntyre BA, Philip RB, Inwood JJ: Effect of ibuprofen on platelet function in normal subjects and hemophiliac patients. Clin Pharmacol Ther 24:616, 1978.
Ragni MV, Miller BJ, Whalen R, Ptachcinski R: Bleeding tendency, platelet function, and pharmacokinetics of ibuprofen and zidovudine in HIV(+) hemophilic men. Am J Hematol 40:176, 1992.
Kasper CK, Rapaport SI: Bleeding times and platelet aggregation after analgesics in hemophilia. Ann Intern Med 77:189, 1972.
Mielke CH Jr: Comparative effects of aspirin and acetaminophen on hemostasis. Arch Intern Med 141:305, 1981.
Huddleston CB, Wareing TH, Clanton JA, Bender HW Jr: Amelioration of the deleterious effects of platelets activated during cardiopulmonary bypass: Comparison of a thromboxane synthetase inhibitor and a prostacylin analogue. J Thorac Cardiovasc Surg 89:190, 1985.
Ito T, Ogawa K, Sakai K, et al: Effects of a selective inhibitor of thromboxane synthetase (OKY-1581) in humans. Adv Prostaglandin Thromboxane Leukotriene Res 11:245, 1983.
Sattler FR, Weitekamp MR, Ballard JO: Potential for bleeding with the new beta-lactam antibiotics. Ann Intern Med 105:924, 1986.
Pillgram-Larsen J, Wisloff F, Jorgensen JJ, et al: Effect of high-dose ampicillin and cloxacillin on bleeding time and bleeding in open-heart surgery. Scand J Thorac Cardiovasc Surg 19:45, 1985.
Fass RJ, Copelan EA, Brandt JT, et al: Platelet-mediated bleeding caused by broad-spectrum penicillins. J Infect Dis 155:1242, 1987.
Cazenave JP, Packman MA, Guccione MA, Mustard JF: Effects of penicillin G on platelet aggregation, release and adherence to collagen. Proc Soc Exp Biol Med 142:159, 1973.
Shattil SJ, Bennett JS, McDonough M, Turnbull J: Carbenicillin and penicillin G inhibit platelet function in vitro by impairing the interaction of agonists with the platelet surface. J Clin Invest 65:329, 1980.
Henry D, Audet P, Shattil SJ: Relationships between the structure of penicillins and their anti-platelet activity. Blood 54(suppl 1):243a, 1979.
Fletcher C, Pearson C, Choi SC, et al: In vitro comparison of antiplatelet effects of b-lactam penicillins. J Lab Clin Med 108:217, 1986.
Packham MA, Rand ML, Perry DW, et al: Probenecid inhibits platelet responses to aggregating agents in vitro and has a synergistic inhibitory effect with penicillin G. Thromb Haemost 76:239, 1996.
Burroughs SF, Johnson GJ: b-Lactam antibiotic-induced platelet dysfunction: Evidence for irreversible platelet activation in vitro and in vivo after prolonged exposure to penicillin. Blood 75:1473, 1990.
Sattler FR, Weitekamp MR, Sayegh A, Ballard JO: Impaired hemostasis caused by beta-lactam antibiotics. Am J Surg 155:30, 1988.
Giles AR, Greenwood P, Tinlin S: A platelet release defect induced by aspirin or penicillin G does not increase gastrointestinal blood loss in thrombocytopenic rabbits. Br J Haematol 57:17, 1984.
Andrassy K, Koderisch J, Trenk D, et al: Hemostasis in patients with normal and inpaired renal function under treatment with cefodizime. Infection 15:348, 1987.
Brown RB, Klar J, Lemeshow S, et al: Enhanced bleeding with cefoxitin or moxalactam: statistical analysis within a defined population of 1,493 pateints. Arch Intern Med 146:2159, 1986.
Rossi EC, Levin NW: Inhibition of primary ADP-induced platelet aggregation in normal subjects after the administration of nitrofurantoin (Furadantin). J Clin Invest 52:2457, 1973.
Ishikawa S, Manabe S, Wada O: Miconazole inhibition of platelet aggregation by inhibiting cyclooxygenase. Biochem Pharmacol 35:1787, 1986.
McTavish D, Faulds D, Goa KL: Ticlopidine: An updated review of its pharmacology and therapeutic use in platelet-dependent disorders. Drugs 40:238, 1992.
CAPRIE Steering Committee: A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 48:1329, 1996.
Bennett CL, Connors JM, Carwile JM, et al: Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med 342:1773, 2000.
Rupprecht HJ, Darius H, Borkowski U, et al: Comparison of antiplatelet effects of aspirin, ticlopidine, or their combination after stent implantation. Circulation 97:1046, 1998.
Leon MB, Baim DS, Popma JJ, et al: A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting: Stent Anticoagulation Restenosis Study investigators [comments]. N Engl J Med 339:1665, 1998.
Sharis PJ, Cannon CP, Loscalzo J: The antiplatelet effects of ticlopidine and clopidogrel. Ann Intern Med 129:394, 1998.
Bossavy JP, Thalamas C, Sagnard L, et al: A double-blind randomized comparison of combined aspirin and ticlopidine therapy versus aspirin or ticlopidine alone on experimental arterial thrombogenesis in humans. Blood 92:1518, 1998.
De Caterina R, Sicari R, Bernini W, et al: Benefit/risk profile of combined antiplatelet therapy with ticlopidine and aspirin. Thromb Haemost 65:504, 1991.
Hardisty RM, Powling MJ, Nokes TJC: The action of ticlopidine on human platelets: Studies on aggregation, secretion, calcium mobilization and membrane glycoproteins. Thromb Haemost 64:150, 1990.
Humbert M, Nurden P, Bihour C, et al: Ultrastructural studies of platelet aggregates from human subjects receiving clopidogrel and from a patient with an inherited defect of an ADP-dependent pathway of platelet activation. Arteriosc Thromb Vasc Biol 16:1532, 1996.
Daniel JL, Dangelmaier C, Jin JG, et al: Molecular basis for ADP-induced platelet activation: I. Evidence for three distinct ADP receptors on human platelets. J Biol Chem 273:2024, 1998.
Jantzen HM, Gousset L, Bhaskar V, et al: Evidence for two distinct G-protein-coupled ADP receptors mediating platelet activation. Thromb Haemost 81:111, 1999.
Hechler B, Eckly A, Ohlmann P, et al: The P2Y1 receptor, necessary but not sufficient to support full ADP-induced platelet aggregation, is not the target of the drug clopidogrel. Br J Haematol 103:858, 1998.
Geiger J, Honig-Liedl P, Schanzenbacher P, Walter U: Ligand specificity and ticlopidine effects distinguish three human platelet ADP receptors. Eur J Pharmacol 351:235, 1998.
Savi P, Laplace MC, Maffrand JP, Herbert JM: Binding of [3H]-2-methylthio ADP to rat platelets: Effect of clopidogrel and ticlopidine. J Pharmacol Exp Ther 269:772, 1994.
Hass WK, Easton JD, Adams HP, et al: A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N Engl J Med 321:501, 1989.
Gent M, Blakely JA, Easton JD, et al: The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1:1215, 1989.
Mataiz R, Ojeda E, Perez MDC, Jiminez S: Ticlopidine and severe aplastic anemia. Br J Haematol 80:125, 1992.
Garnier G, Taillan B, Pesce A, et al: Ticlopidine and severe aplastic anemia. Br J Haematol 81:459, 1992.
Bennett CL, Weinberg PD, Rozenberg-Ben-Dror K, et al: Thrombotic thrombocytopenic purpura associated with ticlopidine: A review of 60 cases [comments]. Ann Intern Med 128:541, 1998.
Steinhubl SR, Tan WA, Foody JM, Topol EJ: Incidence and clinical course of thrombotic thrombocytopenic purpura due to ticlopidine following coronary stenting: EPISTENT investigators evaluation of platelet IIb/IIIa inhibitor for stenting. J Am Med Assoc 281:806, 1999.
Chen DK, Kim JS, Sutton DM: Thrombotic thrombocytopenic purpura associated with ticlopidine use: A report of 3 cases and review of the literature. Arch Intern Med 159:311, 1999.
Lefkovits J, Plow EF, Topol EJ: Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine. N Engl J Med 332:1553, 1995.
George JN, Caen JP, Nurden AT: Glanzmann’s thrombasthenia: The spectrum of clinical disease. Blood 75:1383, 1990.
The EPIC Investigators: Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high risk coronary angioplasty. N Engl J Med 330:956, 1994.
The EPILOG Investigators: Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 336:1689, 1997.
Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM PLUS) Study Investigators: Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. N Engl J Med 338:1488, 1998.
The PURSUIT Trial Investigators: Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med 339:436, 1998.
Simpfendorfer C, Kottke-Marchant K, Lowrie M, et al: First chronic platelet glycoprotein IIb/IIIa blockade: A randomized, placebo-controlled pilot study of xemilofiban in unstable angina with percutaneous coronary interventions. Circulation 96:76, 1997.
Cannon CP, McCabe CH, Borzak S, et al: Randomized trial of an oral platelet glycoprotein IIb/IIIa antagonist, sibrafiban, in patients after an acute coronary syndrome. Circulation 97:340, 1998.
Ferguson JJ, Kereiakes DJ, Adgey J, et al: Safe use of platelet GP IIb/IIIa inhibitors. Am Heart J 135:577, 1998.
Berkowitz SD, Sane DC, Sigmon KN, et al: Occurrence and clinical significance of thrombocytopenia in a population undergoing high-risk percutaneous coronary revascularization. J Am Coll Cardiol 32:311, 1998.
Kereiakes DJ, Essell JH, Abbottsmith CW, et al: Abciximab-associated profound thrombocytopenia: Therapy with immunoglobulin and platelet transfusion. Am J Cardiol 78:1161, 1996.
Berkowitz SD, Harrington RA, Rund MM, Tcheng JE: Acute profound thrombocytopenia after c7E3 Fab (abciximab) therapy. Circulation 95:809, 1997.
Bednar B, Cook JJ, Holahan MA, et al: Fibrinogen receptor antagonist-induced thrombocytopenia in chimpanzee and rhesus monkeys associated with preexisting drug-dependent antibodies to platelet glycoprotein IIb/IIIa. Blood 94:1, 1999.
Gresele P, Arnout J, Deckmyn H, Vermylen J: Mechanism of the antiplatelet action of dipyridamole in whole blood: Modulation of adenosine concentration and activity. Thromb Haemost 55:12, 1986.
FitzGerald GA: Dipyridamole. N Engl J Med 316:1247, 1987.
Ivy DD, Kinsella JP, Ziegler JW, Abman SH: Dipyridamole attenuates rebound pulmonary hypertension after inhaled nitric oxide withdrawal in postoperative congenital heart disease. J Thorac Cardiovasc Surg 115:875, 1998.
Diener HC, Cunha L, Forbes C, et al: European Stroke Prevention Study: II. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 143:1, 1996.
Fisher CA, Kappa JR, Sinha AK, et al: Comparison of equimolar concentratons of iloprost, prostacyclin, and prostaglandin E1 on human platelet function. J Lab Clin Med 109:184, 1987.
Sorkin EM, Markham A: Cilostazol. Drugs Aging 14:63, 1999.
Yoshitomi Y, Kojima S, Sugi T, et al: Antiplatelet treatment with cilostazol after stent implantation. Heart 80:393, 1998.
Loscalzo J, Welch G: Nitric oxide and its role in the cardiovascular system. Prog Cardiovasc Dis 38:87, 1995.
Salzman EW, Rosenberg RD, Smith MH, et al: Effect of heparin and heparin fractions on platelet aggregation. J Clin Invest 65:64, 1980.
Horne MKI, Chao ES: Heparin binding to resting and activated platelets. Blood 74:238, 1989.
Sobel M, McNeill PM, Carlson PL, et al: Heparin inhibition of von Willebrand factor-dependent platelet function in vitro and in vivo. J Clin Invest 87:1787, 1991.
Coller BS: Platelets and thrombolytic therapy. N Engl J Med 322:33, 1990.
Niewiarowski S, Senyi AF, Gillies P: Plasmin-induced platelet aggregation and platelet release reaction. J Clin Invest 52:1647, 1973.
Fitzgerald DJ, Catella F, Roy L, FitzGerald GA: Marked platelet activation in vivo after intravenous streptokinase in patients with acute myocardial infarction. Circulation 77:142, 1988.
Kerins DM, Roy L, FitzGerald GA, Fitzgerald DJ: Platelet and vascular function during coronary thrombolysis with tissue-type plasminogen activator. Circulation 80:1718, 1989.
Thorsen LI, Brosstad F, Gogstad G, et al: Competitions between fibrinogen with its degradation products for interactions with the platelet-fibrinogen receptor. Thromb Res 44:611, 1986.
Miles LA, Ginsberg MH, White JG, Plow EF: Plasminogen interacts with human platelets through two distinct mechanisms. J Clin Invest 77:2001, 1986.
Adelman B, Michaelson AD, Loscalzo J, et al: Plasmin effect on platelet glycoprotein Ib-von Willebrand factor interactions. Blood 65:32, 1985.
Stricker RB, Wong D, Shiu DT, et al: Activation of plasminogen by tissue plasminogen activator on normal and thrombasthenic platelets: Effects on surface proteins and platelet aggregation. Blood 68:275, 1986.
Schafer AI, Adelman B: Plasmin inhibition of platelet function and of arachidonic acid metabolism. J Clin Invest 75:456, 1985.
Loscalzo J, Vaughn DE: Tissue plasminogen activator promotes platelet disaggregation in plasma. J Clin Invest 79:1749, 1987.
Penny WF, Ware JA: Platelet activation and subsequent inhibition by plasmin and recombinant tissue-type plasminogen activator. Blood 79:91, 1992.
Winters KJ, Eisenberg PR, Jaffe AS, Santoro SA: Dependence of plasmin-mediated degradation of platelet adhesive receptors on temperature and Ca2+. Blood 76:1546, 1990.
Green D, Tsao C-H, Cerullo L, et al: Clinical and laboratory investigation of the effects of e-aminocaproic acid on hemostasis. J Lab Clin Med 105:321, 1985.
Hines R, Barash PG: Infusion of sodium nitroprusside induces platelet dysfunction in vitro. Anesthesia 70:611, 1989.
Kroll MH, Schafer AI: Biochemical mechanisms of platelet activation. Blood 74:1181, 1989.
Schafer AI, Alexander RW, Handin RI: Inhibition of platelet function by organic nitrate vasodilators. Blood 55:649, 1980.
Weksler B, Gillick M, Pink J: Effect of propranolol on platelet function. Blood 49:185, 1977.
Leon R, Tiarks CY, Pechet L: Some observations on the in vivo effect of propranolol on platelet aggregation and release. Am J Hematol 5:117, 1978.
Hines R: Preservation of platelet function during trimethaphan infusion. Anesthesia 72:834, 1990.
Hogman M, Frostell C, Arnberg H, Hedenstierna G: Bleeding time prolongation and NO inhalation. Lancet 341:1664, 1993.
Samama CM, Diaby M, Fellahi JL, et al: Inhibition of platelet aggregation by inhaled nitric oxide in patients with acute respiratory distress syndrome. Anesth 83:56, 1995.
Gries A, Bode C, Peter K, et al: Inhaled nitric oxide inhibits human platelet aggregation, P-selectin expression, and fibrinogen binding in vitro and in vivo. Circulation 97:1481, 1998.
Ring ME, Corrigan JJ Jr, Fenster PE: Effects of oral diltiazem on platelet function: Alone and in combination with “low dose” aspirin. Thromb Res 44:391, 1986.
Barnathan E, Addonizio VP, Shattil SJ: Interaction of verapamil with human platelet alpha-adrenergic receptors. Am J Physiol 242:H19, 1982.
Fujinishi A, Takahara K, Ohba C, et al: Effects of nisoldipine on cytosolic calcium, platelet aggregation, and coagulation/fibrinolysis in patients with coronary artery disease. Angiology 48:515, 1997.
Lawson D, Mehta J, Mehta P, et al: Cumulative effects of quinidine and aspirin on bleeding time and platelet a2-adrenoceptors: Potential mechanism of bleeding diathesis in patients receiving this combination. J Lab Clin Med 108:581, 1986.
Weiss HJ: The effect of clinical dextran on platelet aggregation, adhesion, and ADP release in man: In vivo and in vitro studies. J Lab Clin Med 69:37, 1967.
Aberg M, Hedner U, Bergentz S-E: Effect of dextran 70 on factor VIII and platelet function in von Willebrand’s disease. Thromb Res 12:629, 1978.
Mishler JM IV: Synthetic plasma volume expanders: Their pharmacology, safety and clinical efficacy. Clin Haematol 13:75, 1984.
Kelton JG, Hirsh J: Bleeding associated with antithrombotic therapy. Semin Hematol 17:259, 1980.
Korttila K, Lauritsalo K, Särmö A: Suitability of plasma expanders in patients receiving low-dose heparin for prevention of venous thrombosis after surgery. Acta Anaesthesiol Scand 27:104, 1983.
Cope JT, Banks D, Mauney MC, et al: Intraoperative hetastarch infusion impairs hemostasis after cardiac operations. Ann Thorac Surg 63:78, 1997.
Ruttmann TG, James MF, Aronson I: In vivo investigation into the effects of haemodilution with hydroxyethyl starch (200/0.5) and normal saline on coagulation. Br J Anaesth 80:612, 1998.
Roberts JS, Bratton SL: Colloid volume expanders: Problems, pitfalls and possibilities. Drugs 55:621, 1998.
Treib J, Haass A, Pindur G: Coagulation disorders caused by hydroxyethyl starch. Thromb Haemost 78:974, 1997.
Rysanek R, Svelha S, Spankova H, Mlejnkova M: The effect of tri-cyclic antidepressive drugs on adrenaline and adenosine diphosphate induced platelet aggregation. J Pharmacol 18:616, 1966.
Warlow C, Ogston D, Douglas AS: Platelet function after administration of chlorpromazine to human subjects. Haemostasis 5:21, 1976.
Morishita S, Aoki S, Watanabe S: Different effect of desipramine on protein kinase C in platelets between bipolar and major depressive disorders. Psychiatry Clin Neurosci 53:11, 1999.
Alderman CP, Seshadri P, Ben-Tovim DI: Effects of serotonin reuptake inhibitors on hemostasis. Ann Pharmacother 30:1232, 1996.
Pai VB, Kelly MW: Bruising associated with the use of fluoxetine. Ann Pharmacother 30:786, 1996.
Corbin F, Blaise G, Sauve R: Differential effect of halothane and forskolin on platelet cytosolic Ca2+ mobilization and aggregation. Anesthesiology 89:401, 1998.
Heesch CM, Negus BH, Steiner M, et al: Effects of in vivo cocaine administration on human platelet aggregation. Am J Cardiol 78:237, 1996.
Jennings LK, White MM, Sauer CM, et al: Cocaine-induced platelet defects. Stroke 24:1352, 1993.
Togna G, Graziani M, Sorrentino C, Caprino L: Prostanoid production in the presence of platelet activation in hypoxic cocaine-treated rats. Haemostasis 26:311, 1996.
Ahr DJ, Scialla SJ, Kimball DB Jr: Acquired platelet dysfunction following mithramycin therapy. Cancer 41:448, 1978.
Panella TJ, Peters W, White JG, et al: Platelets acquire a secretion defect after high-dose chemotherapy. Cancer 65:1711, 1990.
Pogliani EM, Fantasia R, Lambertenghi-Deliliers G, Cofranesco E: Daunorubicin and platelet function. Thromb Haemost 45:38, 1981.
McKenna R, Ahmad T, Ts’ao C-H, Frischer H: Glutathione reductase deficiency and platelet dysfunction induced by 1,3-bis(2-chloroethyl)-1-nitrosourea. J Lab Clin Med 102:102, 1983.
Karolak L, Chandra A, Kahn W, et al: High-dose chemotherapy-induced platelet defect: Inhibition of platelet signal transduction pathways. Mol Pharmacol 43:37, 1993.
O’Malley CJ, Rasko JEJ, Basser RL, et al: Administration of pegylated recombinant human megakaryocyte growth and development factor in humans stimulates the production of functional platelets that show no evidence of in vivo activation. Blood 88:3288, 1996.
Vadhan-Rai S, Murray LJ, Bueso-Ramos C, et al: Stimulation of megakaryocyte and platelet production by a single dose of recombinant human thrombopoietin in patients with cancer. Ann Intern Med 126:673, 1997.
Vanrenterghem Y, Roels L, Lerut T, et al: Thromboembolic complications and hemostatic changes in cylcosporine-treated cadaveric kidney allograft recipients. Lancet 1:999, 1985.
Cohen H, Neild GH, Patel R, et al: Evidence for chronic platelet hyperaggregability and in vivo platelet activation in cyclosporine treated renal allograft recipients. Thromb Res 49:91, 1988.
Grace AA, Barradus MA, Mikhailidis DP, et al: Cyclosporine A enhances platelet aggregation. Kidney Int 32:889, 1987.
Thomson C, Forbes CD, Prentice CRM: A comparison of the effects of antihistamines on platelet function. Thromb Diath Haemorrh 30:547, 1973.
Group TPT: Platelet function during long-term treatment with ketanserin of claudicating patients with peripheral atherosclerosis: A multicenter, double-blind, placebo-controlled trial. Thromb Res 55:13, 1989.
Parvez Z, Moncada R, Fareed J, Messmore HL: Antiplatelet action of intravascular contrast media. Invest Radiol 19:208, 1984.
Rao AK, Rao VM, Willis J, et al: Inhibition of platelet function by contrast media: Iopamidol and Hexabrix are less inhibitory than Conray-60. Radiology 156:311, 1985.
Goodnight SH, Harris WS, Conner WE: The effects of w3 fatty acids on platelet composition and function in man: A prospective, controlled study. Blood 58:880, 1981.
Moncada S, Higgs EA: Arachidonate metabolism in blood cells and the vessel wall. Clin Haematol 15:273, 1986.
Leaf A, Weber PC: Cardiovascular effects of w-3 fatty acids. N Engl J Med 318:549, 1988.
Hammerschmidt DE: Szechwan purpura. N Engl J Med 302:1191, 1980.
Srivastava KC: Onion exerts antiaggregatory effects by altering arachidonic acid metabolism in platelets. Prostaglandins Leukotrienes Med 24:43, 1986.
Apitz-Castro R, Ledezma E, Escalante J, Jain MK: The molecular basis of the antiplatelet action of ajoene: Direct interaction with the fibrinogen receptor. Biochem Biophys Res Commun 141:145, 1986.
Apitz-Castro R, Escalante J, Vargas R, Jain MK: Ajoene, the antiplatelet principle of garlic, synergistically potentiates the antiaggregatory action of prostacylin, forskolin, indomethacin and dipyridamole on human platelets. Thromb Res 42:303, 1986.
Srivastava KC: Extracts from two frequently consumed spices—cumin (Cuminum cyminum) and turmeric (Curcuma longa)—inhibit platelet aggregation and alter eicosanoid biosynthesis in human blood platelets. Prostaglandins Leukotrienes Essential Fatty Acids 37:57, 1993.
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn