The Mechanism of Activation of the Contact System and Fibrinolytic System

Abstract

Roles for the contact system and fibrinolytic system beyond haemostasis? 6 Chapter 1The contact system and the fibrinolytic system are two enzymatic cascades with distinct roles in blood. The contact system is responsible for coagulation in vitro, but its physiological role is unknown. The fibrinolytic system is known for its role in the degradation of blood clots. Activation of both systems is seen under a remarkable number of (patho)physiological conditions, that are unrelated to haemostasis. This indicates additional roles for these systems. We here set out to investigate the activation mechanism of these systems in order to help explain what their activation signifies in physiology, as well as in pathology. Haemostasis and coagulationHaemostasis is the prevention of blood loss as a result of injury, requires a tightly regulated mechanism. Upon vascular injury, two events prevent excessive blood loss. Platelets adhere to the subendothelial matrix and become activated, leading to their aggregation. Simultaneously, exposure of plasma to the subendothelium results in coagulation. Together this results in the formation of a thrombus. Coagulation results from the activation of a cascade of enzymes 1 , that activate each other in a sequential order, eventually leading to the formation of the enzyme thrombin. Thrombin cleaves fibrinogen to yield monomeric fibrin, which assembles into insoluble fibrillar meshworks to support platelet aggregates. Defects in the production (or functioning) of coagulation enzymes or in platelets are associated with bleeding episodes, underlining the importance of both these systems for haemostasis. In the injured vessel, coagulation is induced by the transmembrane protein tissue-factor (TF), which is expressed by various cells in the subendothelium. The plasma protein coagulation factor VII (FVII) binds to TF and becomes susceptible for activation by a number of proteases, but most notably thrombin. Activated FVII (FVIIa) in complex with TF subsequently activates factor X into factor Xa, which, with factor Va as a cofactor, can cleave the zymogen prothrombin into thrombin. This process of TF-mediated coagulation is known as the extrinsic pathway of coagulation, since not all required components (i.e. TF) are present in blood. Besides this TF-driven coagulation cascade, there is a second coagulation cascade. It has been named the contact system, because it is responsible for the clotting of blood when it contacts a surface material such as plastic or glass (Figure 1). Activation of coagulation by the contact system is known as the intrinsic pathway of coagulation, because all protein components required for coagulation are present in blood. Next to glass, numerous other materials can induce coagulation of plasma, such as the clay-like materials kaolin and celite, metals such as aluminium or titanium 2 , the polysulfated sugar dextran sulfate, or the plant-derived compound ellagic acid. More physiologically relevant "surfaces" are amongst others endothelial cell-associated glycosaminoglyc...