Journal
THROMBOSIS RESEARCH
Volume 115, Issue 4, Pages 301-307Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.thromres.2004.09.004
Keywords
platelets; platelet aggregation inhibitors; P2 receptor; heparin; cangrelor
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Introduction: Unfractionated heparin (UFH) potentiates platelet aggregation induced by some agonists. P2Y(12) and P2Y(1), receptors play a major role in amplifying platelet aggregation. We assessed the ability of cangrelor, a selective P2Y(1) antagonist, A2P5P, a selective P2Y(1), antagonist, and aspirin to block the potentiating effects of heparin. Materials and methods: Whole blood from healthy human volunteers was anticoagulated with either hirudin or UFH 10 IU/ml. Some tubes anticoagulated with hirudin also contained UFH 1 or 10 IU/ml. The low-molecular-weight heparin dalteparin was also assessed. Platelet aggregation was performed using whole blood single-platelet counting. Dense granule release was assessed using C-14-5HT-labelled platelets. Results: UFH and, to a lesser extent, dalteparin potentiated platelet aggregation induced by ADP, PAF, 5HT, U46619, epinephrine and TRAP in a concentration-dependent manner but inhibited aggregation induced by collagen. Cangrelor effectively opposed the potentiating effects of heparins on sustained aggregation induced by ADP, PAF, 5HT, U46619 and TRAP but had less effect on epinephrine induced aggregation, whereas A2P5P was more effective at blocking both the initial phase of ADP-induced aggregation and the aggregation response to epinephrine, reflecting the differences in G protein coupling between the agonist receptors. Aspirin had no effect on potentiation by heparin. Heparins did not increase ADP- or TRAP-induced C-14-5HT release. Conclusions: Heparins potentiate platelet responses to ADP and numerous other agonists. This potentiation is attenuated by cangrelor and A2P5P, and is not mediated by increased dense granule release. ADP receptor antagonists but not aspirin may have potential therapeutic benefits in counteracting the pro-thrombotic effects of heparins. (C) 2004 Elsevier Ltd. All rights reserved.
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