Splenic regulation of systemic platelet activation state

Platelets are essential to prevent blood loss and to orchestrate inflammation. Thrombotic complications of vascular disease and hyperresponsive platelets are associated with adverse outcomes, yet physiological mechanisms counteracting systemic platelet activation are poorly defined. In mice, we found that the spleen filters activated platelets in thrombotic and inflammatory conditions, limiting pathology by maintaining platelet quiescence. Glycoprotein VI-dependent activation of platelets initiated by extracellular matrix components in the splenic red pulp was counterbalanced by G6b-B-immunoreceptor tyrosine-based inhibitory motif signaling triggered by perlecan in quiescent platelets, allowing them to recirculate. By contrast, threshold activation signals in preactivated platelets could override inhibition, leading to splenic capture through inside-out signaling and β1-integrin engagement. Thus, the spleen acts as a modulator of platelet responsiveness and thrombo-inflammatory risk.