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Nov 21, 2013
 |  BC Innovations  |  Targets & Mechanisms

Riding the integrin wave in thrombosis

The use of platelet integrin a2bb3 inhibitors in thrombosis, while clinically very effective, is associated with a high risk of bleeding that has limited their use. Now, researchers at the University of Illinois at Chicago have applied their new insights into the integrin-signaling mechanism to develop an integrin a2bb3 inhibitor that suppresses arterial thrombosis without triggering bleeding in mice.1

Next, the team will assess the inhibitor's therapeutic efficacy, toxicity and pharmacological profiles in animal models of thrombosis.

Integrin a2bb3 (GPIIb/IIIa; CD41/CD61) is a transmembrane adhesion protein expressed on the surface of platelets. Following injury, it is activated by thrombin, which makes it accessible to clotting factors such as fibrinogen and von Willebrand factor (vWF). This results in platelet adhesion to the blood vessel, followed by platelet aggregation and ultimately thrombus formation.

Because of its key role in platelet adhesion and aggregation, integrin a2bb3 has long been considered a prime target for disrupting thrombus formation. Indeed, there are three inhibitors on the market: Johnson & Johnson markets the mAb ReoPro abciximab to treat angioplasty and stroke and to accompany percutaneous coronary interventions, and Merck & Co. Inc. sells Integrilin eptifibatide, a cyclic heptapeptide derived from a snake venom protein, and the nonpeptide antagonist Aggrastat tirofiban. Both Merck drugs are marketed to treat coronary arterial indications and as a companion therapeutic for percutaneous coronary intervention.

Although the inhibitors are routinely used to prevent thrombosis during coronary interventions, and about 8 million patients worldwide have been treated with these inhibitors,2 the elevated bleeding risk they carry has limited their broader application.

The high bleeding risk results...

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