Platelet activation via PAR4 is involved in the initiation of thrombin generation and in clot elasticity development

Karin Vretenbrant; Sofia Ramström; Maria Bjerke; Tomas L. Lindahl

doi:10.1160/TH06-07-0397

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2007; 97(03): 417-424
DOI: 10.1160/TH06-07-0397

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Platelet activation via PAR4 is involved in the initiation of thrombin generation and in clot elasticity development

Karin Vretenbrant

¹Department of Biomedicine and Surgery, Division of Clinical Chemistry, University Hospital, Linköping, Sweden

,

Sofia Ramström

¹Department of Biomedicine and Surgery, Division of Clinical Chemistry, University Hospital, Linköping, Sweden

,

Maria Bjerke

²Department of Clinical Chemistry, Laboratory Medicine, University Hospital, Linköping, Sweden

,

Tomas L. Lindahl

¹Department of Biomedicine and Surgery, Division of Clinical Chemistry, University Hospital, Linköping, Sweden

²Department of Clinical Chemistry, Laboratory Medicine, University Hospital, Linköping, Sweden

› Institutsangaben

Abstract

Summary

Thrombin is a pivotal enzyme formed in the coagulation cascade and an important and potent platelet activator. The two pro-tease-activated thrombin receptors on human platelets are denoted PARI and PAR4. The physiological relevance of PAR4 is still unclear, as both aggregation and secretion can be accomplished by PARI activation alone. In the present study we have investigated the role of PARs in platelet activation, blood coagulation, clot elasticity and fibrinolysis. Flow cytometry, free oscillation rheometry and thrombin generation measurements were used to analyze blood or platelet-rich plasma from healthy individuals. Maximum PARI activation with the peptide SFLLRN gave fewer fibrinogen-binding platelets with lower mean fluorescent intensity than maximum PAR4 activation with AYPGKF. Inhibition of any of the receptors prolonged clotting times. However, PARI is more important for fibrinolysis; inhibition of this receptor prolonged all the steps in the fibrinolytic process. Clot elasticity decreased significantly when the PAR4 receptor was inhibited. In the thrombin generation measurements, PAR4 inhibition delayed the thrombin generation start and peak, but did not affect the total amount of thrombin generated. PAR I inhibition had no significant impact on thrombin generation. We found that PAR4 is most likely activated by low concentrations of thrombin during the initial phase of thrombin generation and is of importance to the clotting time. Furthermore, we suggest that the PAR4 receptor may have a physiological role in the stabilisation of the coagulum.

Keywords

Blood coagulation - clot elasticity - fibrinolysis - PAR receptors

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Referenzen

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