SearchPublisher and Institutes
You are here: Home :: Area NEM :: Medical science :: Human medicine
Donna L. Pedicord, Ira Dicker, Karyn O'Neil, Leah Breth, Richard Wynn, Greogory F. Hollis, Jeffrey T. Billheimer, Andrew M. Stern, Dietmar Seiffert
CD32-dependent platelet activation by a drug-dependent antibody to glycoprotein IIb/IIIa antagonists
Thrombocytopenia is observed with a frequency of up to 2% in patients treated with glycoprotein (GP) IIb/IIIa antagonists. We recently provided evidence that thrombocytopenia is caused by antibody binding to drug-induced conformational changes in GP IIb/IIIa. Here, we report that a murine monoclonal antibody binds to GP IIb/IIIa in an antagonist-dependent manner and activates platelets. Platelet stimulation is associated with a disruption of the phospholipid asymmetry, resulting in the assembly of catalytic active intrinsic Xase and prothrombinase complexes. Further mechanistic studies revealed that this response is (I) mediated in cis, (II) not associated with the formation of prothrombotic microparticles, and (III) requires intact platelet signaling and (IV) is blocked by increases in cAMP. The prothrombotic response is not observed using F(ab')2 fragments and is blocked by incubation of platelets with neutralizing antibodies to the platelet FcRIIa receptor (CD 32).Taken together, these observations suggest that GPIIb/IIIa antagonist-dependent antibody binding to the platelet fibrinogen receptor has the propensity to lead to CD32-mediated platelet activation and accelerated platelet clearance, leading to thrombocytopenia.
Thrombosis and Haemostasis, Schattauer
Print ISSN: 0340-6245
Volume: 89, 03/2003
Pages: 513 - 521