Journal of thrombosis and haemostasis : JTH · 2026
Sphingosine-1-phosphate regulates platelet fibrinogen binding via sphingosine-1-phosphate receptor type 4.
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Riese Janik, Palankar Rhagavendra, Wesche Jan, Hannemann Maurice, Lührs Felix, Hähnel Celine, Kersting Stephan, Schulze Tobias
Аннотация
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 (S1PR4).
METHODS: Thrombus formation and platelet function on an S1PR4-deficient (S1pr4-/-) 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 S1pr4-/- mice. Murine platelets from S1pr4-/- 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 S1pr4-/- mice. Flow cytometry analysis of glycoprotein IIb/IIIa expression indicated an increased low-to-high-affinity switch for increased fibrinogen binding in S1pr4-/- platelets. Analysis of human platelets using a specific antagonist showed that S1PR4 signaling impacted fibrinogen binding.
CONCLUSION: These findings strongly suggest that S1P signaling via S1PR4 acts as a negative regulator of fibrinogen binding in activated platelets.
OBJECTIVES: Here, we describe the regulation of fibrinogen binding in activated platelets via S1P receptor type 4 (S1PR4).
METHODS: Thrombus formation and platelet function on an S1PR4-deficient (S1pr4-/-) 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 S1pr4-/- mice. Murine platelets from S1pr4-/- 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 S1pr4-/- mice. Flow cytometry analysis of glycoprotein IIb/IIIa expression indicated an increased low-to-high-affinity switch for increased fibrinogen binding in S1pr4-/- platelets. Analysis of human platelets using a specific antagonist showed that S1PR4 signaling impacted fibrinogen binding.
CONCLUSION: These findings strongly suggest that S1P signaling via S1PR4 acts as a negative regulator of fibrinogen binding in activated platelets.
Предметные рубрики MeSH
AnimalsBlood PlateletsHumansLysophospholipidsFibrinogenSphingosineMice, KnockoutThrombosisReceptors, LysosphingolipidPlatelet ActivationProtein BindingMice, Inbred C57BLDisease Models, AnimalSphingosine-1-Phosphate ReceptorsBlood CoagulationSignal TransductionMiceDisseminated Intravascular CoagulationMaleSepsis