Background: Platelet activation plays a critical role in thrombosis and thrombo-inflammation. Inhibition of platelet activation is a cornerstone in treatment of acute organ ischemia, however with an increased risk of bleeding. Strategies to limit platelet-mediated thrombosis and inflammation with favorable bleeding complications are warranted. We hypothesized that modulation of the platelet chemokine receptor CXCR7 both interferes with thrombosis and thrombo-inflammation and modulates organ injury following ischemia/reperfusion.

Methods: We studied the prognostic impact of CXCR7 expressed on platelets in a large consecutive cohort of patients with coronary artery disease (n=389). We generated a megakaryocyte/platelet-specific knock-out mouse (PF4-Cre-CXCR7^flox/flox) and characterized platelet function in vitro and in vivo. Further, we performed ischemia/reperfusion experiments (transient LAD-ligation and tMCAO) in mice to assess the effect of genetic CXCR7 deficiency in platelets on tissue inflammation and injury both in ischemic myocardium and brain. Tissue inflammation and injury was characterized by gross pathology, histochemistry, immunophenotyping of infiltrating inflammatory cells, and analysis of the transcriptome of inflammatory genes (Nano-String). In addition, we characterized the effects of CXCR7 activation on platelet function and systemic administration of specific CXCR7 agonists on I/R organ injury in myocardium and brain.

Results: We found that expression of CXCR7 on platelets in patients with symptomatic CAD is associated with clinical prognosis. Genetic deficiency of platelet CXCR7 promotes platelet activation (a-granula release, aggregation, intracellular Ca²⁺, and platelet-mediated thrombus formation ex vivo and in vivo). Further, loss of platelet CXCR7 enhances tissue injury in ischemic myocardium and brain and aggravates tissue inflammation and systemic thrombo-inflammation. Activation of platelet-CXCR7 via specific CXCR7 agonists inhibits platelet activation and thrombus formation and attenuates tissue injury in ischemic myocardium and brain.

Conclusions: We demonstrate that the platelet chemokine receptor CXCR7 is a critical regulator of platelet activation, thrombus formation and organ injury following ischemia/reperfusion. Thus, targeting platelet CXCR7 may be an attractive strategy to control thrombus formation and thrombo-inflammation in the early phase of acute organ ischemia.