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.