Journal
THROMBOSIS AND HAEMOSTASIS
Volume 111, Issue 2, Pages 279-289Publisher
SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN
DOI: 10.1160/TH13-06-0490
Keywords
Antithrombotic agent; snake venoms; platelet inhibitor; glycoprotein Ib-IX-V complex
Categories
Funding
- Canadian Institutes of Health Research
- National Natural Science Foundation of China (China-Canada Joint Health Research Initiative Program)
- Lee's Pharmaceutical Holdings limited
- Canadian Institutes of Health Research [MOP 119540]
- Heart and Stroke Foundation of Canada
- Canadian Foundation for Innovation
- China Scholarship Council (CSC)
- Canadian Blood Services
- Department of Laboratory Medicine and Pathobiology, University of Toronto
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Platelet adhesion and aggregation at the sites of vascular injury are key events for thrombosis and haemostasis. It has been well demonstrated that interaction between glycoprotein (GP) Ib alpha and von Willebrand factor (VWF) initiates platelet adhesion and contributes to platelet aggregation, particularly at high shear. GPIb has long been suggested as a desirable antithrombotic target, but anti-GPIb therapy has never been successfully developed. Here, we evaluated the antithrombotic potential of Anfibatide, a novel snake venom-derived GPIb antagonist. We found Anfibatide inhibited washed murine platelet aggregation induced by ristocetin and recombinant murine VWF It also blocked botrocetin-induced binding of murine plasma VWF to recombinant human GPIb alpha. Interestingly, Anfibatide did not inhibit botrocetin-induced aggregation of platelet-rich plasma, indicating that its binding site may differ from other snake venom-derived GPIb antagonists. Anfibatide strongly inhibited platelet adhesion, aggregation, and thrombus formation in perfusion chambers at high shear conditions and efficiently dissolved preformed thrombi. Anfibatide also inhibited thrombus growth at low shear conditions, though less than at high shear. Using intravital microscopy, we found that Anfibatide markedly inhibited thrombosis in laser-injured cremaster vessels and prevented vessel occlusion in FeCl3-injured mesenteric vessels. Importantly, Anfibatide further inhibited residual thrombosis in VWF-deficient mice, suggesting that Anfibatide has additional antithrombotic effect beyond its inhibitory role in GPIb-VWF interaction. Anfibatide did not significantly cause platelet activation, prolong tail bleeding time, or cause bleeding diathesis in mice. Thus, consistent with the data from an ongoing clinical trial, the data from this study suggests that Anfibatide is a potent and safe antithrombotic agent.
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