Sphingosine-1-phosphate regulates platelet fibrinogen binding via sphingosine-1-phosphate receptor type 4

Background Sphingosine-1-phosphate (S1P) is a bioactive signaling sphingolipid secreted by platelets during activation. Platelets express distinct S1P receptors on their surface, and a comprehensive understanding of their effects is yet to be achieved. Objectives Here, we describe the regulation of fibrinogen binding in activated platelets via S1P receptor type 4 (S1PR 4 ). Methods Thrombus formation and platelet function on an S1PR4-deficient ( S1pr 4 −/− ) background were assessed in an ex vivo flow chamber setting and by rotational thromboelastometry. In vivo coagulation was studied in a murine model of polymicrobial abdominal sepsis. Fibrinogen binding was assessed by flow cytometry in the murine and human systems. Results In the colon ascendens stent peritonitis model, an increased incidence of disseminated intravascular coagulation was observed in S1pr 4 –/– mice. Murine platelets from S1pr 4 –/– mice showed excessive fibrinogen binding and disorganized thrombus formation compared with wild-type platelets. Rotational thromboelastometry confirmed these results, showing a reduced clotting time and an increased clot size in S1pr 4 –/– mice. Flow cytometry analysis of glycoprotein IIb/IIIa expression indicated an increased low-to-high-affinity switch for increased fibrinogen binding in S1pr 4 –/– platelets. Analysis of human platelets using a specific antagonist showed that S1PR 4 signaling impacted fibrinogen binding. Conclusion These findings strongly suggest that S1P signaling via S1PR 4 acts as a negative regulator of fibrinogen binding in activated platelets.