Platelet dysfunction in uremia INTRODUCTION The association between renal dysfunction and bleeding was recognized more than

200 years ago [1]. However, there remains an incomplete understanding of the und erlying pathophysiology. The lack of effective therapies for this important clin ical problem was highlighted with the introduction of dialysis. Although uremic deaths declined, morbidity and mortality from bleeding remained a significant cl inical problem. There is good data, however, supporting the view that impaired platelet function is one of the main determinants of uremic bleeding. This impairment is multifac torial and includes defects intrinsic to the platelet as well as abnormal platel et-endothelial interaction. Uremic toxins and anemia also play a role. The subje ct of platelet dysfunction in uremia will be discussed here. A more general disc ussion of platelet dysfunction is presented separately CLINICAL MANIFESTATIONS Clinical bleeding in uremia is typically cutaneous, including easy bruising and mucosal bleeding, or may occur in response to injury or invasive procedures [2-4 ]. Less frequent is epistaxis, gingival bleeding, or hematuria. The actual incidence of spontaneous gastrointestinal bleeding is difficult to es timate, although with modern dialysis techniques it seems uncommon. In the early days of dialysis, fatal gastrointestinal bleeding was a major complication of t he anticoagulation required for this procedure. Although prolongation of the bleeding time and uremic bleeding have long been as sociated, there is very little justification for this widely held view. The most frequently cited reference on this subject involved only 26 subjects [5]. There are no large, prospective studies showing a clear association between bleeding time prolongation and risk of bleeding, either spontaneous or associated with a procedure. In addition, the degree of azotemia (elevation of the BUN or creatini ne) does not correlate with bleeding risk. Despite this, patients undergoing per cutaneous renal biopsy are often screened for bleeding risk by measuring the ble eding time.

~~~~~~~~~~~~~ Acquired qualitative platelet disorders are frequent causes of abnormal platelet function in vitro, prolonged bleeding times, and occasionally mild bleeding dia theses. However, their clinical importance increases in the presence of thromboc ytopenia or additional disorders of hemostasis. Acquired disorders of platelet f unction can be conveniently classified into those that result from systemic dise ases, hematologic diseases, and the effect of drugs. Of the systemic diseases, r enal 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 coag ulation. 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 s yndromes; dysproteinemias in which abnormal plasma proteins can impair platelet function; and acquired forms of von Willebrand disease. Drugs are the most frequ ent cause of acquired qualitative platelet dysfunction. Aspirin is the most nota ble drug in this regard because of its frequent use, its irreversible effect on platelet prostaglandin synthesis, and its documented effect on hemostatic compet ency, 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 ant icipated, excessive bleeding can be a complication of their use. In addition to

aspirin, these drugs include the thienopyridines ticlopidine and clopidogrel, wh ich primarily antagonize ADP-stimulated platelet aggregation, and drugs that spe cifically inhibit the platelet glycoprotein (GP) IIb/IIIa receptor. Other drugs used to treat thrombosis, such as heparin and fibrinolytic agents, can also impa ir platelet function in vitro and ex vivo, but the clinical significance of thes e observations is uncertain. High doses of the b-lactam antibiotics can impair p latelet function in vitro and prolong the bleeding time, while clinically signif icant bleeding is unusual in the absence of a coexisting hemostatic defect. Simi larly, a number of miscellaneous drugs, including a variety of psychotropic, che motherapeutic, and anesthetic agents, as well as a number of foods and food addi tives, have been reported to affect platelet function in vitro, but these effect s 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 vasopress in; DIC, disseminated intravascular coagulation; EPIC, evaluation of 7E3 for the prevention of ischemic complications; EPILOG, evaluation of PTCA to improve lon g-term outcome by c7E3 GPIIb/IIIa receptor blockade; GP, glycoprotein; Ig, immun oglobulin; ITP, idiopathic thrombocytopenic purpura; PG, prostaglandin; PKC, pro tein kinase C; PGHS-1, PG endoperoxide H synthase-1; SLE, systemic lupus erythem atosus; t-PA, tissue plasminogen activator; vWf, von Willebrand factor. Platelet function may be adversely affected by drugs and by hematologic and nonh ematologic disorders. Because the use of aspirin and other nonsteroidal anti-inf lammatory agents is pervasive in our society, acquired platelet dysfunction is m uch more frequent than inherited platelet dysfunction. Acquired disorders of pla telet 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 di sorders. On the one hand, their severity is usually mild. On the other hand, the re are important exceptions to this rule, particularly when platelet dysfunction is associated with other hemostatic defects. If the patient does not present wi th a history of bleeding, it may be difficult to predict the risk of future blee ding. This is not surprising, since even patients with thrombocytopenia may expe rience little or no spontaneous bleeding until their platelet count is less than 10,000/ l. Furthermore, clinical assessment of these disorders is made problemati c by difficulties in standardization and interpretation of the two most frequent ly used laboratory tests of platelet function: the bleeding time and platelet ag gregometry. These tests appear more useful in diagnosing platelet dysfunction th an in predicting the risk of bleeding.1,2 SYSTEMIC DISORDERS ASSOCIATED WITH ABNORMAL PLATELET FUNCTION UREMIA DEFINITION AND HISTORY Bleeding may be a serious complication of acute and chronic renal failure.3 In t he predialysis era, hemorrhage was a cause of morbidity in approximately 50 perc ent of uremic patients and a cause of death in approximately 30 percent.4 Sponta neous bleeding in patients with renal failure can involve the skin and the gastr ointestinal and genitourinary tracts.5 Bleeding into the central nervous system (e.g., subdural hematoma or subarachnoid hemorrhage), pericardial and pleural sp aces, anterior chamber of the eye, retroperitoneum, or internal organs is less c ommon. Gastrointestinal hemorrhage is common in patients with acute renal failur e, and patients with chronic renal failure account for a significant proportion of patients requiring endoscopy for upper gastrointestinal bleeding.6 It is note worthy, however, that 90 percent of patients with renal failure and gastrointest inal bleeding have an anatomic diagnosis at endoscopy, most commonly angiodyspla sia or peptic ulceration. Rectal ulcers in uremic individuals can cause sudden a nd 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 patien ts with renal disease supports the notion that the hemostatic defect in patients with renal disease is usually mild. Although the incidence of small perirenal h

ematomas following biopsy may be as high as 85 percent when patients are examine d 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 s urgical intervention is even less common and usually can be attributed to factor s other than a uremic hemostatic defect, such as needle lacerations of the kidne y or spleen, anomalous vessels, heparin anticoagulation, or the presence of amyl oid in the kidney. ETIOLOGY AND PATHOGENESIS The hemostatic defect in uremia has been attributed to abnormal platelet functio n.5 Defects in every phase of platelet function adhesion, aggregation, and procoag ulant activity have been reported in uremia. Adhesion of platelets to subendotheli al tissues is defective in uremia.9,10 and 11 In theory, an adhesion defect migh t be caused by factors in the circulating blood, by defects intrinsic to the pla telet, or by abnormalities of the vessel wall. One major factor is anemia. In pa tients with renal disease, the severity of anemia correlates with the severity o f 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 3 0 percent.9 Furthermore, in uremic patients, successful treatment of anemia with red blood cell transfusion or recombinant human erythropoietin results in parti al or complete correction of the bleeding time.13 This beneficial effect is seen w hen 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 uremi a. In normal individuals, the bleeding time correlates with the hematocrit even though both sets of values are in the normal range.18 Furthermore, bleeding time s can be prolonged in patients with severe anemia of any etiology.18,19 This eff ect 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 vi tro.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 ur emic 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 fo und in the capillary circulation, contact is dependent on the binding of von Wil lebrand factor (vWf) to the platelet GPIb-IX complex.22,23 This interaction is a lso necessary for ristocetin-induced platelet aggregation in vitro. Since the la tter 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 ab normalities of vWf have not been uniformly observed.10,25,26 Moreover, studies i n which uremic platelets were mixed with normal plasma or normal platelets were mixed with uremic plasma have failed to demonstrate consistent quantitative or q ualitative abnormalities in GPIb-IX.10,26,27 On the other hand, uremic plasma can inhibit platelet adhesion to everted, de-en dothelialized human umbilical artery segments, while uremic platelets adhere nor mally in the presence of normal plasma. High levels of vWf present in uremic pla sma could compensate for this relative adhesion defect.10 The component of uremi c plasma responsible for this defect remains to be identified. In another perfus ion system using rabbit vessels, uremic platelets exhibited markedly reduced spr eading on the subendothelium, attributed to impaired interaction of vWf with pla telet GPIIb/IIIa.28 Since vWf can bind to GPIIb/IIIa only after platelet activat ion, 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, aggreg ation, 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 T he ability of activated platelets to provide a procoagulant surface for the gene

ration of activated factor X and thrombin (referred to in the past as platelet f actor 3) is consistently reduced in uremia.30 Uremic platelets may also exhibit a reduction in several of the biochemical responses necessary for aggregation, s ecretion, and procoagulant activity, including a rise in cytoplasmic free calciu m levels,31 release of arachidonic acid from platelet phospholipids,4 and conver sion 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 ob served in uremia,35 as has an increase in the level of cyclic AMP.36 Since ADP a nd serotonin are platelet agonists and cyclic AMP is an inhibitor of platelet fu nction, decreased platelet ADP and serotonin stores could contribute to an activ ation defect. The cause of the platelet activation defects in uremia remains to be defined. Bo th 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 cha racterized 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 pr ostacyclin than their normal counterparts, and this is not corrected by dialysis .40,41 Moreover, in a rat model of uremia, prolonged bleeding times were normali zed by treatment with an inhibitor of nitric oxide formation,42 suggesting that this inhibitor of platelet function, which is produced and released from endothe lial 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 ex hibits 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 a nd correlates with blood levels of aspirin.44,45 Bleeding in uremia may be poten tiated 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 B eta-lactam antibiotics that prolong the bleeding time may have a greater effect in uremic patients and increase the occurrence of bleeding, particularly if rena l clearance of the antibiotic is reduced.46 Mild thrombocytopenia has been reported in chronic renal failure due to both dim inished marrow production and platelet survival.47 Although a slight reduction i n the number of normal platelets would not be expected to prolong the bleeding t ime, the mean platelet volume may also be decreased in uremia. This decreases th e circulating platelet mass (platelet count mean platelet volume). It is of intere st, therefore, that the circulating platelet mass is inversely related to the bl eeding time in uremic individuals.48 A platelet count below 100 105/ l should aler t the physician that the renal failure may be due to a systemic disease or medic ation that can also cause thrombocytopenia, such as multiple myeloma, systemic v asculitis, hemolytic-uremic syndrome, eclampsia, renal allograft rejection, or h eparin. 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 ga strointestinal 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 s ubject to a number of technical variables that affect its sensitivity. When a se nsitive version of the test is performed in uremic individuals, most patients ex hibit a prolonged bleeding time.3,40,49 Because the bleeding time is the only re adily available in vivo test of platelet function, reliance has been placed on i t as an indicator of hemorrhagic risk in uremia. However, recent critical review

s 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 th igh bleeding time has been introduced in the hopes of better correlating with cli nical 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 succe ssfully treated. SOURCE- http://medtextfree.wordpress.com/2012/02/09/chapter-120-acquired-qualita tive-platelet-disorders-due-to-diseases-drugs-and-foods/