Platelet GPIIb/IIIa antagonist, XV459, in heparin‐induced thrombocytopenia

Heparin‐induced thrombocytopenia (HIT) is a serious, immune‐related complication of heparin therapy. One of the most severe manifestations of HIT is the development of thromboembolic events, which is based on platelet activation and aggregation caused by HIT‐associated antibodies. Therapeutic options for patients with HIT are limited despite advancement toward the development of alternative (nonheparin) anticoagulants, such as direct thrombin inhibitors and indirect anti‐factor Xa agents. Platelet GPIIb/IIIa receptor antagonists have been shown to be the final common pathway for platelet aggregation regardless of the use of activator or anticoagulant. In this study, the ability of a novel platelet GPIIb/IIIa antagonist, a free acid form of roxifiban (XV459), to block platelet activation/aggregation in response to highly characterized heparin‐PF4 antibody‐positive plasma/heparin was examined using light transmittance aggregometry, serotonin release, and 125 I‐fibrinogen binding assays to human platelets. XV459 at 20 nM maximally inhibited ( P < 0.001) the platelet‐activation/aggregation responses as mediated by the HIT antibody‐positive plasma (in the presence of therapeutic heparin concentrations). Compared with controls, both HIT antibodies/heparin and TEAC (a mixture of thrombin [0.1 IU/ml], epinephrine [1 μg/ml], arachidonate [0.1 mM], and collagen [10 μg/ml]) resulted in significantly higher levels of fibrinogen binding to human platelets (5–7‐fold increase; P < 0.001). Concentration‐dependent profiles of XV459 on the mean percent inhibition of 125 I‐fibrinogen binding in the presence of HIT antibodies and TEAC were achieved (∼50% inhibition at 10 nM XV459). The platelet GPIIb/IIIa receptor antagonist (XV459) might be of potential benefit in the management of thrombotic thrombocytopenia produced by heparin and/or related glycosaminoglycans. Am. J. Hematol., 2006. © 2006 Wiley‐Liss, Inc.