Platelet-fibrin(ogen) interactions in flowing blood

Abstract

Fibrinogen plays a major role in haemostatic plug formation, not only as the precursor of fibrin and as a mediator in platelet thrombus formation, but also as an adhesive molecule for platelets. Insight in the process underlying thrombosis and haemostasis is of importance in the development of therapeutic anti-thrombotic agents. In vivo, these processes are strongly dependent upon the presence of flowing blood. Therefore, in the present thesis the interactions between platelets and fibrinogen/fibrin during the formation and degradation of a platelet-fibrin(ogen) plug have been investigated under well-defined physiological flow conditions. In Chapter 2 the contribution of fibrinogen in the formation and packing of a platelet thrombus has been investigated under flow conditions. A perfusion model is developed to study thrombus growth and stability in real-time. For this study, blood was used from a patient suffering from congenital afibrinogenemia. Chapter 3 describes the genetic characterization of the fibrinogen disorder underlying the haemorrhagic condition of this patient. In Chapter 4 the role of ADP was examined in platelet adhesion to fibrinogen and in thrombus formation on collagen. Fibrinogen contains a fibrin-specific region (?312-322), which becomes exposed upon polymerization to fibrin. The participation of this epitope in platelet adhesion to immobilized fibrinogen has been investigated under conditions of flow in Chapter 5. Adhesion of platelets to a fibrin network during fibrinolysis is compared to neutrophil adhesion in Chapter 6. In Chapter 7 a newly developed model is described to study the dynamics of fibrin formation and deposition of flow. Using this model the binding of fibrin was studied to proteins present in the extracellular matrix. In Chapter 8, the findings of the studies described in this thesis are integrated and discussed in broader context and future prospects are presented