Platelet GPIIb/IIIa antagonist, XV459, in heparin-induced thrombocytopenia.

Abstract

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.

• Authors: Shaker A Mousa, Sarfraz Ahmad
• Journal: American journal of hematology (Am J Hematol) Vol. 82 Issue 4 Pg. 276-82 (Apr 2007) ISSN: 0361-8609 [Print] United States
• PMID: 17039513 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acids
• Isoxazoles
• Kruppel-Like Transcription Factors
• Platelet Aggregation Inhibitors
• Platelet Glycoprotein GPIIb-IIIa Complex
• Repressor Proteins
• XV 459
• ZNF85 protein, human
• Heparin

Topics

• Amino Acids (pharmacology)
• Cells, Cultured
• Heparin (adverse effects)
• Humans
• Isoxazoles (pharmacology)
• Kruppel-Like Transcription Factors (immunology)
• Platelet Activation (drug effects)
• Platelet Aggregation (drug effects)
• Platelet Aggregation Inhibitors (pharmacology)
• Platelet Function Tests (methods)
• Platelet Glycoprotein GPIIb-IIIa Complex (antagonists & inhibitors)
• Repressor Proteins (immunology)
• Sensitivity and Specificity
• Thrombocytopenia (blood, chemically induced, drug therapy)