The main goal of blood coagulation is to diminish blood loss and to support vessel damage repair. The initial step in primary hemostasis is the adhesion of platelets to the exposed subendothelial extracellular matrix which contains several adhesive macromolecules such as collagen, von Willebrand factor (vWF), laminin, fibronectin and thrombospondin. These adhesive macromolecules are ligands for different platelet-surface receptors. Upon binding, platelets can be activated by different signal transduction pathways. Platelet adhesion and activation is followed by platelet aggregation, which involves fibrinogen binding to an integrin on the surface of the activated platelet. Secondary hemostasis is initiated by exposure of tissue factor (TF) to blood by endothelial damage. TF forms a complex with coagulation factor VII which activates factor IX and factor X. Activated factor X (FXa) forms the prothrombinase complex together with activated factor V (FVa) on a phospholipid membrane surface, which is provided by, for example, activated platelets and microparticles, and which converts prothrombin into thrombin. Thrombin can amplify its own generation by activating FXI, and FXIa activates FIX, that together with activated FVIII forms more FX. Thrombin is an important enzyme that cleaves fibrinogen into fibrin monomer. Fibrin monomers polymerize and the resulting network is stabilized by factor XIIIa-catalyzed cross-linking. This tight fibrin network together with activated platelets occludes the site of vascular injury. After its formation, the clot will retract. The speed and degree of clot retraction are proportional to the number of platelets. Neither the significance of in vivo clot retraction for hemostasis as well as the mechanism of clot retraction are well understood. Retraction may improve the mechanical stability of clots. To maintain a balance, the coagulation pathway is inhibited by several inhibitors. Tissue factor pathway inhibitor (TFPI) inhibits the TF-induced coagulation firstly by binding to FXa. Secondly, this TFPI-FXa complex binds to the TF-FVIIa complex resulting in the formation of an inactive quaternary complex. TFPI can also inhibit the initiation phase of coagulation in one step by binding to activated FX that is not yet released from its complex with TF-FVIIa. Thrombin is directly inhibited by the serine protease inhibitor antithrombin as well as heparin cofactor II. Thrombin can also bind to thrombomodulin and form a complex that activates protein C. Activated protein C (APC), with its cofactor protein S, has anticoagulant properties through proteolytic inactivation of factors Va and VIIIa.

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F.W.G. Leebeek (Frank)
Erasmus University Rotterdam
Financial support by the Dutch Heart Foundation for the publication of this thesis is gratefully acknowledged. Printing of this thesis was financially supported by TEM International GmbH, J.E. Jurriaanse stichting and Erasmus University Rotterdam.
Erasmus MC: University Medical Center Rotterdam

Talens, S. (2013, March 15). Novel fibrin clot components : identification, characterization and function. Erasmus University Rotterdam. Retrieved from