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 microg/ml], arachidonate [0.1 mM], and collagen [10 microml]) 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 ( approximately 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.
Mousa
Shaker A
SA
Pharmaceutical Research Institute, Albany College of Pharmacy, Albany, New York 12208, USA. mousas@acp.edu
Ahmad
Sarfraz
S
D000596:Amino Acids / Q000494:pharmacology*; D002478:Cells, Cultured; D006493:Heparin / Q000009:adverse effects*; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D051741:Kruppel-Like Transcription Factors / Q000276:immunology; D015539:Platelet Activation / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010979:Platelet Function Tests / Q000379:methods; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors; D012097:Repressor Proteins / Q000276:immunology; D012680:Sensitivity and Specificity; D013921:Thrombocytopenia / Q000097:blood / Q000139:chemically induced* / Q000188:drug therapy
D000596:Amino Acids; D007555:Isoxazoles; D051741:Kruppel-Like Transcription Factors; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D012097:Repressor Proteins; C104284:XV 459; C115768:ZNF85 protein, human; D006493:Heparin