Page 2102 - Williams Hematology ( PDFDrive )

2076 Part XII: Hemostasis and Thrombosis Chapter 121: Acquired Qualitative Platelet Disorders 2077

the study, entry criteria were modified to eliminate patients with a his- rapidly reverse the platelet function defect in patients receiving abcixi-
tory of a stroke. At 3 years, the incidence of the primary end point (car- mab, presumably by decreasing the overall extent of integrin blockade.
diovascular death, myocardial infarction, and stroke) was significantly The ability of platelet transfusion to reverse the effects of the other inte-
reduced in vorapaxar-treated patients (9.3 percent vs. 11.2 percent, grin α β antagonists is less clear, but these drugs have very short half-
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p <0.001). However, moderate to severe bleeding, including intracranial lives if renal and hepatic function are normal.
bleeding, was significantly increased in the vorapaxar-treated patients Thrombocytopenia occurring within 24 hours of initiating therapy
(4.2 percent vs. 2.5 percent, p <0.001). Nonetheless, based on efficacy, has been observed in small numbers of patients following the adminis-
vorapaxar received FDA approval in 2014. Atopaxar, a second PAR-1 tration of all integrin α β antagonists. 102,105,108,109 In EPIC, the incidence
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antagonist, is currently being evaluated in clinical trials. Atopaxar has of platelet counts of less than 100 × 10 /L and of less than 50 × 10 /L
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a shorter half-life than vorapaxar, suggesting that potential bleeding in patients receiving abciximab for the first time was 3.9 percent and
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complications might be easier to manage. 0.9 percent, respectively. Thrombocytopenia has also been reported in
patients receiving eptifibatide, tirofiban, and a variety of small molecule
INTEGRIN α β RECEPTOR ANTAGONISTS RGD- and non–RGD-based integrin α β inhibitors with an incidence
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Drugs that specifically impair the function of the major platelet integrin The mechanism responsible for thrombocytopenia following the
α β (GPIIb/IIIa) have been developed for short-term use as antithrom- administration of these drugs is uncertain, but may be related to the
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botic agents in the setting of ischemic coronary artery disease. 95,96 Inte- presence of preexisting antiintegrin α β antibodies that recognize
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grin α β mediates platelet–platelet cohesion by binding the divalent epitopes exposed by the antagonist, or, in the case of abciximab, to
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ligand fibrinogen, thereby crosslinking the integrin on adjacent plate- murine sequences incorporated into the abciximab Fab fragment. The
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lets, causing the formation of platelet aggregates. Thus, integrin α β thrombocytopenia usually reverses readily when the drug is stopped, but
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is a viable therapeutic target to prevent arterial thrombosis. Abciximab, it may also be reversed by platelet transfusion if clinically indicated.
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eptifibatide, and tirofiban are three FDA-approved structurally dissim- Thrombocytopenia in patients receiving integrin α β antagonists must
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ilar integrin α β inhibitors that rapidly impair platelet aggregation. be differentiated from pseudothrombocytopenia as a result of drug-
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Abciximab is a human-murine chimeric Fab fragment, eptifibatide is a induced platelet clumping, from heparin-induced thrombocytopenia
cyclic heptapeptide based on the sequence Lys-Gly-Asp (KGD), and tiro- in patients receiving heparin concurrently, and from other causes of
fiban is an Arg-Gly-Asp (RGD)-based peptidomimetic. All three drugs thrombocytopenia, depending on the clinical circumstances. 115,116 It is
have demonstrated efficacy in the management of patients with acute important to identify thrombocytopenia early because integrin α β
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coronary syndromes, particularly in the setting of percutaneous coro- antagonists are administered as long infusions and the drug should
nary interventions (PCI) where iatrogenic artery wall injury occurs. 97 be stopped as soon as true thrombocytopenia has been confirmed.
Inherited integrin α β abnormalities cause the bleeding disorder In most cases of profound thrombocytopenia, a platelet count obtained
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Glanzmann thrombasthenia (Chap. 120). 98,99 Thus, it is not surprising 2 to 4 hours after initiating therapy will provide evidence of a significant
that integrin α β antagonists can predispose to bleeding. In EPIC, a decrease in platelet count, although cases of delayed thrombocytopenia
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clinical trial of abciximab in patients undergoing PCI, 14 percent of have been observed after treatment with abciximab. 114
patients given abciximab experienced major bleeding compared to
7 percent of patients given placebo. However, patients were also DRUGS THAT AFFECT PLATELET CYCLIC
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given aspirin and heparin. When the heparin dose was decreased in the
subsequent EPILOG trial, the incidence of major bleeding in patients NUCLEOTIDE LEVELS OR FUNCTION
receiving abciximab decreased to 2.0 percent compared to 3.1 percent The pyrimidopyrimidine derivative, dipyridamole, inhibits plate-
in the control group receiving heparin and aspirin alone. Nonethe- let cyclic nucleotide phosphodiesterase, resulting in the intraplatelet
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less, in both EPIC and EPILOG, minor bleeding was significantly more accumulation of the inhibitory cyclic nucleotide cyclic AMP (cAMP).
frequent in patients given abciximab and standard-dose heparin com- Dipyridamole may also inhibit the breakdown of cyclic guanosine
pared to patients given standard-dose heparin alone, attesting to the monophosphate (cGMP), resulting in potentiation of the platelet inhib-
ability of an integrin α β antagonist to impair normal hemostasis. In itory effect of nitric oxide. Although the platelet inhibitory effects
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the PRISM-PLUS trial of tirofiban and the PURSUIT trial of eptifibat- of dipyridamole are seen in vitro, the clinical utility of dipyridamole
ide, major and minor bleeding were slightly more frequent in patients has been controversial. 118,119 A meta-analysis failed to demonstrate the
receiving the study drug compared to controls. 102,103 Similarly, patients clinical benefit of adding dipyridamole to aspirin. However, many
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receiving the oral integrin α β inhibitors xemilofiban and sibrafiban older dipyridamole trials used formulations with limited dipyridamole
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for 30 and 28 days, respectively, frequently experienced mucocutaneous bioavailability. In the European Stroke Prevention Study 2 (ESPS 2),
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bleeding similar to that experienced by patients with congenital throm- dipyridamole was beneficial in preventing stroke and transient ischemic
basthenia. 104,105 Although short-term use of the parenteral integrin α β attack, but there was no difference in mortality between patients tak-
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antagonists is often beneficial in patients with acute coronary syndrome ing dipyridamole and placebo or among patients taking dipyridamole
of following PCI, paradoxically the long-term use of oral integrin α β plus aspirin compared to either dipyridamole or aspirin alone. The
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inhibitors was associated with an increase in mortality. The cause of basis for the benefit of dipyridamole in the ESPS 2 trial is unclear, but
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this paradoxical effect is not clear, but has been attributed by some to an could be from a higher dipyridamole dosage or to the sustained-release
antagonist-induced conformational change in integrin α β simulating dipyridamole preparation used in the trial.
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the effect of physiologic platelet agonists. 107 Intravenous infusions of PGE , PGI , or stable PGI analogues stim-
2
2
1
The risk of bleeding in patients undergoing PCI in the presence ulate platelet adenylyl cyclase, causing an increase in platelet cAMP and
of integrin α β antagonists can be minimized by using heparin on a decrease in platelet responsiveness. These agents cause a transient
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a weight basis, by avoiding treatment of patients who are receiving inhibition of platelet shape change, aggregation, and secretion. However,
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warfarin at therapeutic doses, by early vascular sheath removal, and by their clinical utility is limited by their short half-life and side effects that
meticulous care of vascular puncture sites. Platelet transfusions can include peripheral vasodilation. Cilostazol, a phosphodiesterase III
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Kaushansky_chapter 121_p2073-2096.indd 2077 9/18/15 10:28 AM