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2082 Part XII: Hemostasis and Thrombosis Chapter 121: Acquired Qualitative Platelet Disorders 2083

family history of bleeding. This is especially important in patients with induces a defect in platelet adhesion that can be corrected by increasing
a known autoimmune, lymphoproliferative, or myeloproliferative dis- the hematocrit to 30 percent or more. In uremic patients, success-
427
order. 315,381 Diagnostic evaluation includes measurements of factor VIII ful treatment of anemia with red blood cell transfusion or recombinant
activity, VWF antigen, ristocetin cofactor activity, and VWF multimer human erythropoietin (EPO) results in partial or complete correction
407
analysis. The presence of an in vitro inhibitor may, or may not, be of prolonged bleeding times when the hematocrit is increased to 27
detected depending on whether the antibody binds to VWF and neu- to 32 percent. 428–431 The effect of anemia on primary hemostasis is not
tralizes its function or merely leads to accelerated VWF clearance by unique to uremia. In normal individuals, the bleeding time correlates
the reticuloendothelial system. An abnormally high ratio of VWF with the hematocrit and bleeding times can be prolonged in patients
315
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propeptide to von Willebrand antigen may be present as a result of the with severe anemia of any etiology. Red cells may have a beneficial
rapid clearance of von Willebrand antigen but not VWF. 44 effect on hemostasis both because they displace platelets toward the
432
Given the uncommon prevalence of this syndrome, reports of periphery of the column of circulating blood and they may enhance
patient management have been retrospective and largely anecdotal. platelet reactivity. 14
Treatment should be reserved for patients with active bleeding or those Because correction of anemia does not always return the bleeding
who are likely to bleed if left untreated. 352,381 Infusions of DDAVP 321,398,400 time to normal, other factors present in renal failure may perturb plate-
427
or factor VIII/VWF concentrates 408,409 may be useful, although the rapid let function. Ristocetin-induced platelet aggregation, a surrogate for
clearance of VWF may limit efficacy. Treatment has included gluco- VWF binding to the platelet GPIb–IX–V complex, may be decreased in
corticoids or rituximab in patients with lupus, 231,385,410 and recombinant uremia. However, plasma VWF concentrations are normal or elevated
411
factor VIIa, or high-dose IVIG. 190,384,412 High-dose IVIG is particularly in renal failure and qualitative VWF abnormalities have not been
433
effective when acquired von Willebrand syndrome is associated with a uniformly observed. 434,435 Mixing studies using uremic platelets and
lymphoproliferative disorder or, as discussed in the section “Dyspro- normal plasma, and vice versa, do not demonstrate consistent quan-
teinemias.” with an IgG monoclonal gammopathy of undetermined titative or qualitative abnormalities in GPIb–IX–V. 434–436 Nonetheless,
significance. IVIG likely acts by delaying VWF clearance via reticu- uremic plasma can inhibit the adhesion of normal platelets to deen-
loendothelial cell blockade, although other mechanisms have been dothelialized human umbilical artery segments, whereas uremic plate-
postulated. 297,369,370,379,380,397,413 Treatment of the underlying disease can be lets adhere normally in the presence of normal plasma. Because the
434
effective in some situations 381,414,415 (e.g., hypothyroidism with thyroid defective adhesion appears independent of VWF, an unidentified com-
434
replacement, 416,417 Gaucher disease with enzyme replacement therapy, ponent of uremic plasma may be responsible for the adhesion defect.
391
and extreme thrombocytosis with cytoreduction 233,315,323,418 ). As with Uremic platelets also exhibit markedly reduced spreading on the sub-
inherited von Willebrand disease, longstanding acquired von Wille- endothelium of rabbit vessels, a defect attributed to impaired VWF
437
brand syndrome can be associated with and complicated by gastrointes- binding to platelet integrin α β . Because VWF binding to integrin
IIb 3
tinal tract arteriovenous malformations, resulting in severe bleeding. α β requires platelet stimulation, this observation suggests a uremia-
419
IIb 3
An example of such gastrointestinal bleeding is found in patients with induced defect in platelet signal transduction.
severe aortic stenosis and referred to as Heyde syndrome. In this situa- There are a number of reports describing defective agonist-
tion, valve replacement can correct the hemostatic defect. 387,420 induced platelet activation in uremic patients, including reduced
fibrinogen binding, aggregation, and secretion. These abnormalities
SYSTEMIC DISORDERS ASSOCIATED may be retained after platelets are separated from uremic plasma and
438
in some cases, uremic plasma imparts the defect to normal platelets.
WITH ABNORMAL PLATELET Furthermore, the ability of activated platelets to express procoagulant
439
FUNCTION activity is reduced in uremia. These functional defects likely result
from uremia-induced abnormalities in platelet biochemistry, includ-
440
ing reduced agonist-induced increases in cytoplasmic free calcium,
UREMIA reduced release of arachidonic acid from platelet phospholipids, and
421
Definition and History reduced conversion of released arachidonic acid to PG endoperoxides
In the predialysis era, hemorrhage occurred in approximately 50 per- and TXA . 2 138,441,442
cent of uremic patients and was a cause of death in approximately A number of dialyzable and nondialyzable substances have been
443
30 perccent. 421,422 With the advent of dialysis, the frequency of sponta- reported to be responsible for the platelet function defects in uremia,
neous hemorrhage in patients with renal failure has decreased. Expe- but urea itself is not responsible. Ex vivo platelet aggregation can be
422
rience with percutaneous renal biopsy in several thousand patients with inhibited by small dialyzable substances, such as guanidinosuccinic
renal disease supports the notion that the hemostatic defect in patients acid and phenolic acids, as well as by poorly characterized “middle
with renal disease is usually mild. Although the incidence of small peri- molecules” at concentrations found in uremic plasma. 444,445 Venous and
renal hematomas following biopsy may be as high as 85 percent when arterial segments from uremic patients have been reported to produce
patients are examined by computerized tomography, gross hematuria is more PGI than segments from normal individuals, an abnormality not
2
446
observed in only 5 to 10 percent of cases and is usually transient. 423,424 corrected by dialysis. Altered NO metabolism has been observed in
Severe bleeding following biopsy requiring surgical intervention is uremia. 447,448 In a uremic rat model, defective platelet adhesion was nor-
449
even less common and usually can be attributed to factors other than malized by an inhibitor of NO formation, suggesting that increased
a uremic hemostatic defect, such as needle lacerations of the kidney or NO synthesis by endothelial cells or platelets is at least partially respon-
450
spleen, anomalous vessels, heparin anticoagulation, or the presence of sible for the defective platelet function. Why renal failure increases
amyloid in the kidney. NO synthesis is not entirely clear, although exposing endothelial cells
to guanidinosuccinic acid can mimic the effects of NO, suggesting that
Etiology and Pathogenesis retained guanidinosuccinic acid may be the relevant substrate. Uremia
451
+
The hemostatic defect in uremia has been attributed to defects in plate- has been reported to upregulate the y L system for L-arginine transport
let function and appears to be multifactorial. One prominent fac- into platelets, enabling platelets to maintain or enhance NO synthe-
425
tor is renal failure-associated anemia. A lowered hematocrit ex vivo sis, even in the face of low circulating L-arginine concentrations. 452,453
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Kaushansky_chapter 121_p2073-2096.indd 2083 9/18/15 10:28 AM