Talin is a master regulator of platelet integrin activation in vivo

Abstract

Primary hemostasis following vascular injury is dependent on the integrin‐mediated adhesion of platelets to exposed subendothelium and subsequent aggregation. In vitro studies suggest that activation of β1 and β3 integrins depends on talin, a protein that links integrins to the actin cytoskeleton. To assess the role of talin in integrin function in vivo, we generated a platelet precursor‐specific talin1 KO mouse (fl/fl,Cre+). Platelets from fl/fl,Cre+ mice showed profound defects in agonist‐induced activation of both αIIbβ3 and β1 integrins and exhibited a profound bleeding diathesis. To test whether impaired talin‐dependent β1 integrin activation contributed to the hemorrhagic phenotype observed in flox/flox,Cre+ mice, the adhesion of talin‐deficient platelets to collagen was examined in flowing blood. Platelets from fl/fl,Cre‐mice, but not fl/fl,Cre+ mice, adhered to collagen and subsequently formed platelet‐rich thrombi, processes dependent on β1 and αIIbβ3 integrins, respectively. Consistent with ex vivo results, fl/fl,Cre+ mice showed markedly prolonged tail bleeding times and failed to form occlusive thrombi in response to ferric chloride injury of the common carotid artery. Together, our data show that talin is essential in platelets for normal hemostasis because it is required for the activation of β1 and β3 integrins and for platelet adhesion and thrombus formation in flowing blood.