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Chapter 130 Acquired Disorders of Platelet Function 1941

SYSTEMIC METABOLIC DISORDERS appears to correlate with the benefit of conjugated estrogens in
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improving the bleeding time in uremia. Increased expression of
End-Stage Renal Disease vascular prostacyclin has also been described in uremic rats, a factor
that would further depress in vivo platelet function. 232
The pathogenesis of the hemorrhagic diathesis in patients with end- Dialysis itself may be associated with alterations in platelet func-
stage renal disease (ESRD) is complex (Chapter 154). Factors such tion. For example, hemodialysis can reduce the responsiveness of
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as platelet function abnormalities caused by uremic toxins, anemia, platelets to agonists in vitro, and chronic hemodialysis and perito-
hemodialysis procedures (both the artificial circulation and the use neal dialysis are associated with an increase in reticulated platelets,
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of anticoagulation), and decreased drug clearance may impair suggesting accelerated platelet turnover. Of the two forms of dialy-
hemostasis. sis, hemodialysis appears to have the greatest effect on platelet func-
In ESRD patients both platelet hypofunction and platelet hyper- tion, with one study noting abnormal cytoskeletal assembly and
reactivity can occur. 220 defective tyrosine phosphorylation to thrombin stimulation in the
Deficiencies in the number of GPIb complexes in uremic platelets platelets of patients on hemodialysis, parameters that returned almost
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have been reported, the number inversely correlating with the creati- to normal with the institution of ambulatory peritoneal dialysis.
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nine level. Consistent with this finding, another study demonstrated The cause of the defect associated with hemodialysis is likely to be
that defective ristocetin-induced platelet aggregation of uremic the chronic low-level platelet activation associated with the procedure.
platelet-rich plasma was not corrected by resuspending the platelets In particular, polymerization and depolymerization of actin, release
in normal platelet-poor plasma. Likewise, uremic platelets suspended of granule proteins and their binding to the platelet surface, and
in normal plasma were defective in their adhesion to deendothelial- shedding of membrane proteins may render the platelets relatively
ized rabbit vessels at high shear, a test of the competency of the refractory to activation.
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interaction between GPIb and vWF. Conversely, the same study Uremia and artificial surfaces during hemodialysis also affect plate-
demonstrated that plasma factors also influence platelet function by let mRNA and microRNA profiles, and alter protein expression. 235
showing that normal platelets suspended in uremic plasma acquired As would be expected, platelets from uremic patients may be
an adhesion defect possibly related to an abnormal interaction of unusually sensitive to medicines that decrease platelet function.
vWF with the subendothelium. This led to the suggestion that vWF Aspirin has been reported to produce a greater prolongation of the
may be abnormal in uremia. Two studies have demonstrated normal- bleeding time in uremic patients than in controls, an effect that may
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to-elevated vWF antigen and activity (measured as ristocetin cofactor be attributable to more than the irreversible inhibition of COX-1.
activity) in uremic patients but decreased levels of the largest, most Similarly, β-lactam antibiotics that prolong the bleeding time can also
hemostatically active multimers, 223,224 reflected in one study as a have a greater effect in uremic patients and may increase the risk of
decreased ratio of activity to antigen level compared with the vWF bleeding, particularly those antibiotics cleared by the kidney. 173,237
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from normal subjects. Taken together, the various studies consis- Anemia, which does correlate with the severity of renal failure, is
tently indicate that the first step of platelet adhesion at sites of vessel an independent cause of a prolonged bleeding time, 237–240 and the
wall injury is abnormal, a defect that could be clinically significant if defect correlates with the severity of the anemia. The relationship of
coupled with other defects of platelet function. 220 the bleeding time to hematocrit in uremic patients has been con-
The platelets of uremic patients frequently exhibit reduced firmed by its correction with the transfusion of red blood cells and
fibrinogen binding, aggregation, and secretion in response to a wide by treatment with erythropoietin. 220,240,241
variety of agonists. This abnormality may persist when the platelets In contrast to the studies of platelet function performed to
are removed from uremic plasma, and in some studies, uremic plasma understand the possible increased risk for bleeding in patients with
has induced these defects in normal platelets. One potential mecha- chronic renal failure, the coagulation and fibrinolytic systems have
nism is provided by the demonstration that fibrinogen fragment levels been interrogated to understand the increased risk for thrombotic
are elevated in patients with ESRD and bind to platelet α IIb β 3 , complications, a major cause of mortality. 242
inhibiting platelet aggregation. 225 Uremia-related contributions to a thrombotic tendency include
Uremic platelets can also exhibit a reduction in several of the endothelial dysfunction, increased TF expression, increased mic-
biochemical responses necessary for aggregation and secretion, roparticle generation, increased coagulation factors (fibrinogen,
including the rise in cytoplasmic calcium ion concentration, release FXIIa, FVIIa) and proinflammatory markers, decreased natural
of arachidonic acid from membrane phospholipids, conversion of anticoagulant levels, and changes related to renal replacement therapy
arachidonic acid to TXA 2 , and dense-granule and α-granule secre- as extracorporeal thrombin generation, decreased fibrinolysis, and
tion. Abnormal cytoskeletal assembly and deficient tyrosine phos- membrane-induced platelet activation. 220,243
phorylation have also been noted in uremic platelets, abnormalities
only partially corrected by dialysis. 220,226
The accumulation of dialyzable platelet-inhibitory substances in Liver Disease
the plasma of uremic patients has long been recognized. The ability
of uremic plasma to inhibit platelet function was demonstrated in The bleeding diathesis observed with fulminant or end-stage liver
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the late 1960s by Horowitz and colleagues, who showed reduced disease (Chapter 153) is multifactorial, with contributing causes
ADP-induced platelet aggregation and a prolonged Stypven clotting including thrombocytopenia, anemia, deficiencies in liver-synthesized
time, a measure of platelet procoagulant activity. This activity, previ- coagulation factors, and excessive fibrinolysis. 244,245 Patients with
ously called platelet factor 3, is vital for the support of coagulation chronic liver disease and hepatic cirrhosis of various causes have been
factor complex assembly on the platelet surface and requires exter- reported to have prolonged bleeding times, and these disorders are
nalization of the anionic phospholipid phosphatidylserine. One associated with other platelet function abnormalities possibly related
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uremic substance with platelet inhibitory properties described by to a decrease in GPIb. Although an association between prolonged
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Horowitz and coworkers was guanidinosuccinic acid, which accu- bleeding time and GI hemorrhage has been demonstrated in some
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mulates in uremic plasma as an alternative byproduct of L-arginine studies of cirrhotic patients, other studies showed that the bleeding
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metabolism, a consequence of the inhibitory effect of high urea time and platelet aggregation abnormalities correlated best with the
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levels on enzymes of the urea cycle. Similar to L-arginine, guanidino- degree of thrombocytopenia, suggesting that no specific platelet
succinic acid is a precursor of nitric oxide, which is produced in function defect exists in liver disease. An aspirin-like defect has been
increased quantities in the endothelial cells and platelets of uremic reported in patients with severe liver disease, with defective aggrega-
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patients and experimental animals. Consistent with an important tion and TXA 2 production. Interestingly, one study showed that
role for nitric oxide in uremia, infusion of the nitric oxide synthesis platelets obtained from the portal circulation of patients with hepa-
inhibitor monomethyl L-arginine reduced the bleeding time in tocellular cancer on a background of cirrhosis showed decreased
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uremic rats. Furthermore, suppression of nitric oxide production and delayed aggregation in response to collagen compared with