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Thromb Haemost. 2014 Feb;111(2):279-89. doi: 10.1160/TH13-06-0490. Epub 2013 Oct 31.

Anfibatide, a novel GPIb complex antagonist, inhibits platelet adhesion and thrombus formation in vitro and in vivo in murine models of thrombosis.

Author information

1
Dr. Heyu Ni, MD, PhD, Canadian Blood Services and, Department of Laboratory Medicine and Pathobiology, St. Michael's Hospital, University of Toronto, Room 420, LKSKI - Keenan Research Center, 209 Victoria Street, Toronto, Ontario, M5B 1W8, Canada, Tel.: +1 416 847 1738, E-mail: nih@smh.ca.

Abstract

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) Ibα 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 GPIbα. 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.

KEYWORDS:

Antithrombotic agent; glycoprotein Ib-IX-V complex; platelet inhibitor; snake venoms

PMID:
24172860
DOI:
10.1160/TH13-06-0490
[Indexed for MEDLINE]

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