Multiple ways to switch platelet integrins on and off

Abstract

In the classical concept of platelet integrin activation, it is considered that unidirectional conformational changes of αIIbβ3 and α2 β1 regulate the adhesiveness of platelets for fibrin(ogen) and collagen, respectively. Here, we summarize recent evidence that these conformational changes: (i) can also occur in the reverse direction; and (ii) are not independent events. Platelet stimulation through the P2Y12 receptors provokes only transient α11bβ3 activation via signaling routes involving phosphoinositide 3-kinases and Rap1b. Furthermore, αIIbβ3 can be secondarily inactivated in platelets with prolonged high Ca2+ rises, which expose phosphatidylserine and bind coagulation factors. Thus, platelet stimulation with strong agonists (collagen and thrombin) also results in transient integrin activation. Integrin α2 β1 is found to be activated by a mechanism that is directly linked to αIIbβ3 activation. Integrin α2β1 can adopt different activation states, depending on the trigger. Conclusively, reversibility and synchrony of platelet integrin activation are newly identified mechanisms to restrict thrombus growth and to allow optimal coagulation factor binding. Back-shifting of activated integrins towards their resting state may be a novel goal of antithrombotic medication. © 2008 International Society on Thrombosis and Haemostasis.