Acquired Platelet Dysfunction

Hematol Oncol Clin N Am 21 (2007) 647–661

HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA

Acquired Platelet Dysfunction Yu-Min P. Shen, MD*, Eugene P. Frenkel, MD The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-8852, USA

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cquired platelet dysfunction is encountered frequently in clinical practice. The usual clinical presentation is that of mucosal bleeding, epistaxis, or superficial epidermal bleeds; in general, the bleeding is modest in degree. Often, the dysfunctional platelets are related to a medication or a systemic disorder. Normally, when platelets are exposed to damaged endothelium, they adhere to the exposed basement membrane collagen and change their shape from smooth disks to spheres with pseudopodia. Then, they secrete the contents of their granules, a process referred to as the release reaction. Additional platelets form aggregates on those platelets that have adhered to the vessel wall. As a result, the primary hemostatic plug is formed, and bleeding is arrested. This article reviews the various forms of acquired platelet dysfunction that result in decreased platelet aggregation, adhesion, or secretion. Please refer to the article elsewhere in this issue for a comprehensive review of the laboratory assessment for platelet function. These tests are appropriate and important when the bleeding is significant or persistent and is not clearly explained by the clinical and drug causes defined in this article. In addition to the classic mechanisms of platelet dysfunction resulting in decreased function of the platelets, platelet defects with gain-of-function abnormality are being recognized increasingly as a clinical entity. For instance, heparin-induced thrombocytopenia results in a transient, but highly thrombogenic, condition that is due to ‘‘hyperfunction’’ of platelets. The hyperactive platelet syndrome (or sticky platelet syndrome) is an uncommon, but well-described, entity that results in thrombosis of arterial or venous systems as well as complications during pregnancy. These gain-of-function platelet abnormalities are reviewed elsewhere in this issue. PLATELET DYSFUNCTION ASSOCIATED WITH SYSTEMIC DISEASE Uremia Uremic patients have complex hemostatic defects that include thrombocytopenia, coagulation abnormalities, and platelet dysfunction. Clearly, platelet *Corresponding author. E-mail address: [email protected] (Y-M.P. Shen).

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dysfunction is the most consistent and clinically relevant change. Commonly, patients in renal failure have prolonged bleeding times that actually correlate better with the degree of anemia than with the expected platelet numbers [1]. The basis of the dysfunction seems to be complex; however, increased concentrations of L-arginine and cyclic guanosine monophosphate, as well as increased nitric oxide production by uremic platelets, seem to provide the most important pathophysiologic mechanism and pose a possible role for nitric oxide in uremic bleeding [2]. In addition, abnormal platelet adhesion to the subendothelial surface has been demonstrated [3]. A variety of studies has implicated other mechanisms, but the findings have been inconsistent and difficult to assess. For instance, the amount of von Willebrand factor (VWF), as well as its multimer pattern, antigen to activity ratios have been described as normal and abnormal [4]. Similarly, platelet glycoprotein (GP) Ib/IX receptor number and function have been shown to be normal and reduced [5]. Platelets from uremic patients show reduced shear-induced platelet aggregation with high shear rates [6], possibly due to increased proteolysis by ADAMTS13 VWF metalloprotease. Defective activation-dependent receptor function of GP IIb/ IIIa for binding fibrinogen and VWF in uremic patients has been reported, even though the number of receptors was normal [5]. In the laboratory, the classic evaluation examines aggregation with exogenous agents (collagen, ADP, and epinephrine); this is reduced in most uremic patients, with a higher threshold minimum concentration needed to induce platelet aggregation [7]. Indeed, altered aggregation is used commonly as the laboratory documentary test. Finally, defective platelet secretion of ADP has been reported with increased platelet concentrations of adenylate cyclase and cyclic adenosine monophosphate, as well as a diminished increase in platelet cytosolic calcium concentration [8,9]. Thus, a dazzling array of multiple abnormalities in various aspects of platelet function has been described. There is no unifying pathophysiologic mechanism that accounts for all of the recognized platelet defects that are seen in uremic patients, nor is there a crisp relationship of these findings to the bleeding diathesis. Therapy for uremic platelet dysfunction with bleeding is hemodialysis or peritoneal dialysis, despite a transient worsening of platelet function immediately after dialysis [10]. The clear role of dialysis has led to the legendary exploration of the many soluble factors discussed above. The relevance of such factors has been emphasized further by the observation that platelet function returns to normal 8 weeks after renal transplant [11]. The rheologic effect from transfusion of packed red blood cells or improvement of anemia by erythropoietin therapy also is associated with decreased uremic bleeding, shortening of the bleeding time, and increased platelet adhesiveness [12,13]; however, caution must be exercised when instituting erythropoietin therapy, because an increase in fistula thrombosis was observed in a placebo-controlled trial [14]. The administration of cryoprecipitate or 1-desamino-8d-arginine vasopressin (DDAVP) shortens the bleeding time and is temporarily effective in the control of uremic bleeding in some patients [15,16], which may relate to improvement

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in platelet adhesion and enhanced VWF activity [17]. Reduction in the severity of uremic bleeding was reported after administration of conjugated estrogens [18], but a single perioperative dose did not improve hemostasis [19]. Liver Disease Often, platelet dysfunction is overlooked in patients who have acute or chronic liver disease with a bleeding diathesis. As in uremia, platelet dysfunction associated with liver disease is multifactorial. Aggregation studies demonstrated blunted aggregation to collagen, thrombin, and ristocetin and absent secondary aggregation waves after aggregation with ADP and epinephrine [20]. Altered platelet membrane palmate and stearate metabolism also may contribute to the platelet dysfunction [20]. Ingestion of alcohol may worsen the observed underlying dysfunction by inducing a storage pool–type defect with decreased ADP and ATP, as well as inhibition of thromboxane A2 synthesis [21]. Increased fibrin split products that are due to a primary activation of the fibrinolytic system—compounded by decreased clearance—interfere with the function of platelet surface glycoproteins and result in clinically significant platelet dysfunction [22]. If platelet dysfunction is documented in a bleeding patient who has liver disease, platelet concentrates should be given along with careful use of DDAVP [23]. Paraproteinemia Bleeding diathesis often complicates paraproteinemia because of multiple myeloma, Waldenstro¨m’s macroglobulinemia, monoclonal gammopathy of undetermined significance, or polyclonal hypergammaglobulinemia [24–26]. Proposed mechanisms include thrombocytopenia, qualitative platelet dysfunction, inhibitors to plasma coagulation factors, enhanced clearance of plasma coagulation factors, and hyperviscosity syndrome [24]. Bleeding is more common in patients who have IgA myeloma and macroglobulinemia and usually is limited to purpura and mucous membrane bleeding [27]. Abnormalities in bleeding time and other platelet function tests have been documented. The platelet dysfunction is believed to result from nonspecific binding of the immunoglobulins to the platelet surface [28], although specific antigen–antibody interactions have been reported in a few patients [29]. Plasmapheresis is an effective therapeutic approach for clinically significant bleeding. Platelet transfusion likely is not beneficial unless the paraproteinemia is well controlled. Myeloproliferative Disorders Chronic myeloproliferative disorders (CMPD) are characterized by thrombotic and hemorrhagic complications. Patients frequently present with ecchymoses, epistaxis, gastrointestinal bleeding, and a propensity for serious hemorrhage after trauma or even minor surgical procedures. Often, the laboratory abnormalities demonstrated are inconsistent, and the correlation with severity of the bleeding diathesis is poor [30]. The platelet dysfunction in CMPD seems to be determined at the level of the committed megakaryocyte [31]. The abnormalities described include defective aggregation and release reaction, deficient

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lipid peroxidation and responses to thromboxane A2, subnormal serotonin uptake and storage, abnormal expression of Fc receptors, and a combined defect in membrane expression and activation of GP IIb/IIIa complexes [32–37]. Acquired storage pool disorder [38] and platelet dysfunction that are due to a reduction in the high molecular weight forms of plasma and platelet VWF [39] are well-characterized defects in CMPD. The VWF-like defect is believed to result from increased proteolysis of the high molecular weight VWF that is due to increased binding to platelets and, thus, enhanced proteolysis by ADAMTS13 [40]. In support of this hypothesis, VWF multimer analysis normalizes with the reduction in the cell counts [41]. Platelet function studies are prudent in patients who have CMPD and are suffering from excessive bleeding (or clotting, which can happen with gain-of-function defects [42]). Myelodysplastic Syndrome Patients who have the myelodysplastic syndrome (MDS) often have a bleeding diathesis that is due to thrombocytopenia or chronic disseminated intravascular coagulation; however, as a result of dysplastic megakaryopoiesis, specific platelet dysfunction also may contribute to the bleeding manifestations of the patient who has MDS. Often, the megakaryocytes are small with decreased lobation and decreased granularity [43,44]. Ultrastructural studies with electron microscopy demonstrate dilated canalicular system and abnormal microtubular formation [45]. Changes in granules are variable and can be reduced or giant granules may form by the fusion of several single granules [46]. An acquired membrane defect with abnormal glycoprotein expression occurs [32]. The delineation of platelet dysfunction in MDS is difficult to define because of the frequent presence of thrombocytopenia; however, platelet numbers do not explain the bleeding diathesis well because the bleeding time commonly is prolonged well out of proportion to the platelet count, and multiple platelet aggregation defects can be documented [47]. Antiplatelet Antibody Lesions Normally, about 100 IgG molecules are found on the surface of platelets [48]. Most tests evaluating increased IgG on the platelet surface do not distinguish between pathogenic autoantibodies and nonspecific antibodies. Thus, despite reports of increased antibody binding to platelets in immune-mediated thrombocytopenic purpura, systemic lupus erythematosus, and platelet alloimmunization, it is difficult to assess the potential adverse effects of these antiplatelet antibodies. In most instances, the surviving platelets function normally; in a minority of patients with antiplatelet antibodies, the degree of bleeding manifestation is clearly out of proportion to the decreases in platelet count [49]. Most antibodies specific for platelet antigens are directed against the GP IIb/ IIIa complex [50]; antibodies against GP Ib/IX/V [51], GP Ia/Iia [52], and GP IV [50] have been described as well. These antibodies interfere with the normal functions of the respective target antigens to result in platelet dysfunction that is due to impaired aggregation. Platelet aggregation studies demonstrated decreased aggregation in response to ristocetin, ADP, epinephrine, or collagen

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[53,54]. In addition, acquired storage pool deficiency may result from antibodyinduced platelet activation by way of Fc receptors or from interference with uptake of substances into platelet granules during megakaryopoiesis [55,56]. Patients who have storage pool defects are expected to have absent second wave aggregation or decreased ATP secretion on lumiaggregation study. Treatment is directed at the underlying autoimmune process. Disseminated Intravascular Coagulation In addition to a bleeding diathesis from the consumption of coagulation factors and platelets, patients who have disseminated intravascular coagulation experience qualitative platelet defects with reduced platelet aggregation and an acquired storage pool deficiency [57]. These result from in vivo platelet activation by thrombin or other agonists. Also, fibrin and fibrinogen degradation products interfere with platelet function as has been shown in ex vivo studies with purified low molecular weight fibrinogen degradation products; however, the true clinical relevance is uncertain, because a significantly high concentration of fibrinogen degradation products is unlikely to occur in vivo [58]. Typically, the significance of platelet dysfunction in disseminated intravascular coagulation is overshadowed by the hemostatic defects resulting from the thrombocytopenia and consumptive coagulopathy. PLATELET DYSFUNCTION ASSOCIATED WITH CARDIOPULMONARY BYPASS Patients undergoing cardiopulmonary bypass may experience a variety of hemostatic problems, including thrombocytopenia, hyperfibrinolysis, and qualitative platelet defects. The platelet dysfunction induced by the bypass circuit is manifested as a prolonged bleeding time, abnormal ex vivo platelet aggregation in response to several agonists, decreased platelet agglutination in response to ristocetin, and deficiency of a and dense granules [59–62]. The severity of these abnormalities correlates with the duration of extracorporeal bypass, and the abnormalities resolve within 2 to 24 hours after the patient comes off bypass [63]. The bypass-induced platelet defects likely result from platelet activation and fragmentation [64,65] that are due to hypothermia, contact with fibrinogencoated synthetic surfaces, contact with blood–air interface, damage caused by blood suctioning, and exposure to traces of thrombin, plasmin, ADP, or complement [66,67]. Drugs (eg, heparin, protamine, and aspirin) and production of fibrin degradation products can be expected to impair platelet function further [68–70]. The therapy for bypass-induced platelet dysfunction includes DDAVP, prostacyclin or its analog Iloprost, protease inhibitor aprotinin, and antifibrinolytic agents, such as e-aminocaproic acid and tranexamic acid. DDAVP can shorten the bleeding time, but trials in patients who have undergone bypass have shown contradictory results [71,72]. With the assumption that the platelet dysfunction results from platelet activation, activation inhibitors (eg, prostacyclin and prostaglandin E2) have been studied in human and animal models;

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however, randomized trials with prostacyclin and Iloprost did not show a clear benefit, perhaps limited by significant toxicities [73,74]. Aprotinin and the antifibrinolytic agents can reduce or inhibit the hyperfibrinolysis that is seen with cardiopulmonary bypass, thus reducing the fibrin degradation products present [75,76]. After a careful evaluation for surgical causes of bleeding, judicious transfusion of platelets and plasma is appropriate. If the bleeding manifestation is that of platelet dysfunction with mucocutaneous bleeding, DDAVP should be considered. If excessive wound bleeding is observed after initial hemostasis to suggest hyperfibrinolysis, aprotinin or -aminocaproic acid and tranexamic acid should be considered. PLATELET DYSFUNCTION ASSOCIATED WITH DRUGS Drug-induced qualitative platelet dysfunction is clearly the most common cause of acquired platelet dysfunction. The list of medications or dietary supplements that are associated with platelet dysfunction is long and growing (Box 1). These include aspirin and other nonsteroidal anti-inflammatory drugs, thienopyridine, antibiotics, cardiovascular drugs, psychotropic drugs, and dietary items, such as herbal supplements, among others. In a healthy individual, druginduced platelet dysfunction is usually of no clinical significance; however, in a patient who has coagulation disorders, uremia, or thrombocytopenia and in patients who are undergoing surgery or anticoagulation therapy, impairment of platelet function by drugs may lead to serious bleeding. Some drugs may lead to prolonged bleeding time without clinical bleeding, whereas others only cause dysfunction when added to platelets in vitro. Aspirin Acetylsalicylic acid is a potent and irreversible inhibitor of the platelet cyclooxygenase (COX-1 > COX-2), the enzyme responsible for the conversion of arachidonic acid into prostaglandins, in particular, thromboxane A2 [77]. Consequently, the platelet release reaction is inhibited—an event that occurs within 15 to 30 minutes after ingestion with doses as low as 40 to 80 mg—and persists as long as the affected platelet survives (8–10 days). Thus, a single small dose of aspirin impairs the release reaction for up to 96 hours [78]. Although prostacyclin synthesis by endothelial cells also is inhibited by aspirin, the endothelial cell with a nucleus is able to replenish the cyclooxygenase. With the incomplete inhibition of prostacyclin production by endothelial cells, coupled with the complete irreversible inhibition of thromboxane A2 synthesis by platelets, the overall result is an antithrombotic effect [78]. The effect of aspirin on platelet function is highly variable, with a significant minority of the population considered resistant to aspirin [79]. Aspirin-induced platelet dysfunction results from interference with platelet aggregation rather than adhesion. Aspirin-treated platelets adhere normally when perfused through denuded arterial segments; however, they do not interact with one another [80]. Aggregometry tracings from aspirin-treated platelets show absence of arachidonic acid–induced aggregation, impaired collagen-induced

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Box 1: Common drugs affecting platelet function Analgesics Aspirin Nonsteroidal anti-inflammatory drugs Thienopyridines Ticlopidine Clopidogrel b-Lactam antibiotics Penicillins Cephalosporins Cardiovascular Nitrates Calcium channel blockers Quinidine GP IIb/IIa antagonists Abciximab Tirofiban Eptifibatide Psychotropic Antidepressants Phenothiazines Herbal supplements Fish oil Garlic Black tree fungus Ginkgo biloba Cumin Turmeric

aggregation, and the absence of the secondary wave of aggregation induced by epinephrine and ADP. Aspirin-treated platelets also fail to release normal amounts of ADP, ATP, and serotonin [81]. Aspirin has a dose-dependent toxic effect on the gastrointestinal mucosa, with a predictable blood loss from ingestion of aspirin [82]. Studies have shown that aspirin primarily affects surgical bleeding in patients who are undergoing surgery in areas of increased fibrinolytic activity (oral cavity or genitourinary tract) or in patients with other coexisting coagulopathy [83]. In general, aspirin

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should be avoided before cardiothoracic, plastic, and neurosurgical procedures in which the limits of tolerable bleeding are narrow [84]. Infusion of DDAVP has been effective in correcting a prolonged bleeding time that is due to aspirin [85]. In more emergent cases of hemorrhage, platelet transfusion should be given. Nonsteroidal Anti-Inflammatory Drugs Nonsteroidal anti-inflammatory drugs, such as ibuprofen, indomethacin, naproxen, phenylbutazone, and sulfinpyrazone, also inhibit prostaglandin synthesis by inhibition of COX [86]. In contrast to aspirin, their inhibition of COX-1 is reversible and generally short acting. The exception is piroxicam, which has a long half-life measured in days [81]. These drugs may cause a transient prolongation of the bleeding time that usually is clinically insignificant. In fact, ibuprofen can be given safely to hemophiliacs [87]. The COX-2 inhibitors interfere with COX without affecting platelet function [88], whereas acetaminophen, salicylate, and narcotics do not inhibit COX [87]. Thienopyridines Ticlopidine and clopidogrel are antithrombotic agents that are used extensively in the treatment of arterial diseases. They are more effective than aspirin in the secondary prevention of cerebrovascular and cardiovascular events [89]. The thienopyridines are additive with aspirin in preventing thrombotic complications after coronary artery stent placement [90]. The effects of ticlopidine and clopidogrel on platelet aggregation and the bleeding time may be seen within 24 to 48 hours of the first dose but do not reach maximum for 4 to 6 days. The effects on platelet function may last for 4 to 10 days after the drugs have been discontinued, suggesting that the megakaryocytes also may be affected [89]. The thienopyridines interfere with platelet function through a noncompetitive inhibition of ADP binding to its low-affinity receptor, P2Y12 [91]. Platelet aggregation studies demonstrated decreased aggregation to low concentrations of many agonists, particularly ADP. Because ADP released from platelet-dense granules and red blood cells at the site of injury plays a major role in the platelet responses to the other agonists, interference with the ADP effect by thienopyridine may account for the observed effect on platelet aggregation. The antithrombotic effect of thienopyridine results from impaired fibrinogen binding to GP IIb/IIIa, which is uncoupled from the ADP receptor [92]. Antibiotics b-Lactam antibiotics can produce platelet dysfunction in vitro and ex vivo. Patients receiving b-lactam antibiotics may have prolonged bleeding time with a propensity for bleeding, especially if they have renal insufficiency or are undergoing surgical procedures. The effect can be well documented by aggregation studies, which demonstrate a dose-dependent reduction in aggregation in response to ADP, epinephrine, and collagen. Ristocetin-induced platelet agglutination also is reduced, providing evidence that platelet adhesion also is

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impaired [93]. These drugs seem to bind to and modify the platelet membrane, resulting in decreased agonist binding and decreased calcium influx [94]. These effects can be observed after several days of antibiotic treatment and may not resolve for 7 to 10 days after discontinuation of the drugs. From these observations, it can be inferred that the antibiotic effects are irreversible or that the megakaryocyte membrane is similarly affected. Penicillins and cephalosporins that have an a-carboxy group adjacent to the b-lactam ring are most likely to produce platelet dysfunction and clinical bleeding [95]. Glycoprotein IIb/IIIa Antagonists GP IIb/IIIa antagonists are antithrombotic agents that are used extensively in the setting of ischemic coronary artery disease and interventions [96]. Because the absence or defective GP IIb/IIIa results in the inherited bleeding disorder Glanzmann thrombasthenia, it is not surprising that patients receiving the GP IIb/IIIa antagonists can have a bleeding diathesis with mucocutaneous bleeding [97]. In addition to qualitative platelet dysfunction, a small percentage of patients receiving these drugs may develop moderate to severe thrombocytopenia [98]. These must be differentiated from drug-induced platelet clumping and heparin-induced thrombocytopenia. The risk for bleeding can be decreased by using a lower dose of heparin and avoiding treatment of patients who are receiving warfarin at therapeutic doses [99]. The platelet dysfunction is reversed rapidly by platelet transfusion. Examples of GP IIb/IIIa inhibitors in clinical use include abciximab (chimeric human-murine anti-GP IIb/IIIa monoclonal antibody Fab fragment), tirofiban, and eptifibatide (synthetic low molecular weight GP IIb/IIIa inhibitors). Cardiovascular Drugs Several vasodilators in clinical use have been shown to decrease platelet aggregation and secretion ex vivo. These include nitroprusside, nitroglycerin, nitric oxide [100], and propranolol [101]. Calcium channel blockers, such as verapamil, nifedipine, and diltiazem, also can inhibit platelet aggregation at high concentrations. This effect is seen primarily with epinephrine-induced aggregation and does not seem to be related to calcium channel blockade. At therapeutic doses, calcium channel blockers do not prolong the bleeding time, although nisoldipine was reported to inhibit agonist-induced calcium transients and platelet aggregation after 10 days of oral administration [102–104]. In addition, at high concentration, quinidine was reported to cause a mild prolongation of the bleeding time and potentiate the effect of aspirin [105]. Psychotropic Drugs Patients receiving antidepressants or phenothiazines may exhibit impaired aggregation responses attributed to a direct effect of the drugs on the phospholipid bilayer and by inhibition of arachidonic liberation from platelet membranes [106]. Inhibition of intracellular signaling molecules, such as protein kinase C, also is described [107]; however, this usually is not associated with bleeding. Fluoxetine, one of the most popular antidepressants available,

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does not seem to impair in vitro platelet aggregation and only rarely has been associated with clinical bleeding [108]. Herbal Supplements With the ever-increasing popularity of herbal or natural supplements for their healing properties, the effect of these supplements on platelet function must be considered. Fish oils containing x3 fatty acids cause a slight prolongation of the bleeding time. These fatty acids reduce the platelet content of arachidonic acid and compete with arachidonic acid for COX [109]. Black tree fungus and garlic, used commonly in Chinese cooking, contain substances that can inhibit platelet function [110,111]. Onion, Gingko biloba, cumin, and turmeric are common supplements and spices that have been shown to inhibit platelet aggregation and eicosanoid biosynthesis [112–114]. SUMMARY Acquired platelet dysfunction, with or without clinically significant bleeding, is observed frequently and is associated with a plethora of pathogenic mechanisms affecting platelet adhesion, aggregation, or secretion. In many cases it can be traced to commonly prescribed and over-the-counter medications. With the popularity of herbal or natural supplements, a careful drug history is essential for the evaluation of a patient who has mucocutaneous bleeding that is suggestive of platelet dysfunction. Astute evaluation for the associated systemic disorders should be conducted. Judicious use of an experienced hemostasis laboratory and close liaison with the coagulation specialist to facilitate the definition of the platelet dysfunction facilitates the proper diagnosis and management. References [1] Remuzzi G, Perico N, Zoja C, et al. Role of endothelium-derived nitric oxide in the bleeding tendency of uremia. J Clin Invest 1990;86(5):1768–71. [2] Noris M, Benigni A, Boccardo P, et al. Enhanced nitric oxide synthesis in uremia: implications for platelet dysfunction and dialysis hypotension. Kidney Int 1993;44(2):445–50. [3] 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 1990;76(7): 1336–40. [4] Gralnick HR, McKeown LP, Williams SB, et al. Plasma and platelet von Willebrand factor defects in uremia. Am J Med 1988;85(6):806–10. [5] Salvati F, Liani M. Role of platelet surface receptor abnormalities in the bleeding and thrombotic diathesis of uremic patients on hemodialysis and peritoneal dialysis. Int J Artif Organs 2001;24(3):131–5. [6] Yoshida E, Fujimura Y, Ikeda Y, et al. Impaired high-shear-stress-induced platelet aggregation in patients with chronic renal failure undergoing haemodialysis. Br J Haematol 1995;89(4):861–7. [7] Di Minno G, Martinez J, McKean ML, et al. Platelet dysfunction in uremia. Multifaceted defect partially corrected by dialysis. Am J Med 1985;79(5):552–9. [8] Escolar G, Diaz-Ricart M, Cases A, et al. Abnormal cytoskeletal assembly in platelets from uremic patients. Am J Pathol 1993;143(3):823–31. [9] Vlachoyannis J, Schoeppe W. Adenylate cyclase activity and cAMP content of human platelets in uraemia. Eur J Clin Invest 1982;12(5):379–81.

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[10] Sreedhara R, Itagaki I, Lynn B, et al. Defective platelet aggregation in uremia is transiently worsened by hemodialysis. Am J Kidney Dis 1995;25(4):555–63. [11] Campistol JM, Cofan F, Diaz Ricart M, et al. Correction of uremic platelet dysfunction after renal transplantation. Transplant Proc 1995;27(4):2244–5. [12] Cases A, Escolar G, Reverter JC, et al. Recombinant human erythropoietin treatment improves platelet function in uremic patients. Kidney Int 1992;42(3):668–72. [13] Moia M, Mannucci PM, Vizzotto L, et al. Improvement in the haemostatic defect of uraemia after treatment with recombinant human erythropoietin. Lancet 1987;2(8570):1227–9. [14] Canadian Erythropoietin Study Group. Association between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving haemodialysis. Canadian Erythropoietin Study Group. BMJ 1990;300(6724):573–8. [15] Janson PA, Jubelirer SJ, Weinstein MJ, et al. Treatment of the bleeding tendency in uremia with cryoprecipitate. N Engl J Med 1980;303(23):1318–22. [16] Mannucci PM, Remuzzi G, Pusineri F, et al. Deamino-8-D-arginine vasopressin shortens the bleeding time in uremia. N Engl J Med 1983;308(1):8–12. [17] Zeigler ZR, Megaludis A, Fraley DS. Desmopressin (d-DAVP) effects on platelet rheology and von Willebrand factor activities in uremia. Am J Hematol 1992;39(2):90–5. [18] Livio M, Mannucci PM, Vigano G, et al. Conjugated estrogens for the management of bleeding associated with renal failure. N Engl J Med 1986;315(12):731–5. [19] Jacobs P, Jacobson J, Kahn D. Perioperative administration of a single dose of conjugated oestrogen to uraemic patients is ineffective in improving haemostasis. Am J Hematol 1994;46(1):24–8. [20] Thomas DP, Ream VJ, Stuart RK. Platelet aggregation in patients with Laennec’s cirrhosis of the liver. N Engl J Med 1967;276(24):1344–8. [21] Cowan DH. Effect of alcoholism on hemostasis. Semin Hematol 1980;17(2):137–47. [22] Mammen EF. Coagulopathies of liver disease. Clin Lab Med 1994;14(4):769–80. [23] 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 1986;67(4):1148–53. [24] Robert F, Mignucci M, McCurdy SA, et al. Hemostatic abnormalities associated with monoclonal gammopathies. Am J Med Sci 1993;306(6):359–66. [25] Rozenberg MC, Dintenfass L. Platelet aggregation in Waldenstrom’s macroglobulinaemia. Thromb Diath Haemorrh 1965;14(1–2):202–8. [26] Wallace MR, Simon SR, Ershler WB, et al. Hemorrhagic diathesis in multiple myeloma. Acta Haematol 1984;72(5):340–2. [27] Vigliano EM, Horowitz HI. Bleeding syndrome in a patient with IgA myeloma: interaction of protein and connective tissue. Blood 1967;29(6):823–36. [28] McGrath KM, Stuart JJ, Richards F 2nd. Correlation between serum IgG, platelet membrane IgG, and platelet function in hypergammaglobulinaemic states. Br J Haematol 1979;42(4):585–91. [29] 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 1986; 77(1):157–64. [30] Waddell CC, Brown JA, Repinecz YA. Abnormal platelet function in myeloproliferative disorders. Arch Pathol Lab Med 1981;105(8):432–5. [31] Tinggaard Pedersen N, Laursen B. Megakaryocytes in cubital venous blood in patients with chronic myeloproliferative diseases. Scand J Haematol 1983;30(1):50–8. [32] Berndt MC, Kabral A, Grimsley P, et al. An acquired Bernard-Soulier-like platelet defect associated with juvenile myelodysplastic syndrome. Br J Haematol 1988;68(1):97–101. [33] Caranobe C, Sie P, Fernandez F, et al. Abnormal platelet serotonin uptake and binding sites in myeloproliferative disorders. Thromb Haemost 1984;51(3):349–53. [34] Kaplan R, Gabbeta J, Sun L, et al. Combined defect in membrane expression and activation of platelet GPIIb–IIIa complex without primary sequence abnormalities in myeloproliferative disease. Br J Haematol 2000;111(3):954–64.

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