Platelets are extremely sensitive to activation by shear forces in disturbed blood flow induced by atherosclerotic plaques, vessel stenosis or medical device intervention, resulting in thrombosis and cardiovascular disease or medical device failure. In contrast to the aggregation of platelets by agonists (biochemical aggregation), the aggregation of platelets in response to shear forces (biomechanical aggregation) is not eliminated by aspirin and clopidogrel. Drs. Ju and Zhu, via a stenosed microfluidic model, demonstrated that biomechanical platelet aggregation was mainly induced by the binding of platelet GPIb to VWF under force and supported by integrin αIIbβ3 with an extended-closed (EC) conformation. The EC conformation is an intermediate activation state between resting and fully activated state αIIbβ3. As Dr. Ju stated, “We also developed a dual biomembrane force probe to visualize integrin biomechanical activation on a living platelet. We found that biomechanical activation of GPIb, initiates a signaling pathway that leads to αIIbβ3 adopting the EC conformation. The EC conformation the affinity and bond lifetime of an intermediate state between the well-characterized active and resting state of aIIbb3.” This biomechanical signaling is distinct from the biochemical signaling by agonists and potentiates affinity maturation of αIIbβ3. They concluded that the existence, genesis and regulation of a semi-stable intermediate state of αIIbβ3 is fundamental in mechanically-driven thrombosis.

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