University of Surrey, Faculty of Health and Medical SciencesMolecular Medicine Group, John McVey
 

More About Blood Coagulation . . .


Blood coagualation network, click for vector image enlargement (PDF)Blood coagulation occurs when the enzyme thrombin is generated and proteolyses soluble fibrinogen, forming an insoluble fibrin polymer or clot. The normal role of blood coagulation is to rapidly prevent the loss of body fluids following vascular injury without compromising blood flow through either the uninjured or damaged blood vessels. To achieve this a complex network of reactions have evolved that result in controlled fibrin deposition only at the site of injury.

Blood coagulation is initiated by the exposure of factor VII (a protein found in blood) to cells expressing tissue factor (TF) on their plasma membrane. The primary control of haemostasis is therefore the anatomical segregation of cells that express functional TF from other components of the coagulation network present in blood. TF is constitutively expressed by cells that form biological boundaries such as skin, organ surfaces and vascular adventitia. This expression pattern has been described as forming a 'haemostatic envelope', which ensures that following disruption of vascular integrity FVII/FVIIa in blood is rapidly exposed to cells that express TF, leading to the initiation of blood coagulation. The formation of the TF-FVII complex results in the activation of FIX and FX. In the absence of its cofactor, FVa, FXa generates only trace amounts of thrombin. Although insufficient to generate significant fibrin polymerisation, the thrombin generated in this initiation phase of coagulation is able to activate FV and FVIII in a positive feedback loop. In the propagation phase FVIIIa forms a complex with FIXa (tenase complex) and activates further FX which in complex with its cofactor FVa (prothrombinase complex) leads to an explosive generation of thrombin that ultimately leads to a fibrin clot. Thrombin also activates FXI leading to further FIXa generation independent of the TF-FVIIa complex.

Following the initiation of coagulation, various inhibitory mechanisms prevent extension of the process beyond the site of vascular injury which might otherwise result in occlusion of the blood vessel. TFPI associated with the endothelial cell surface inactivates the initiation complex by forming a quaternary inhibited complex (TFPI-TF-FVIIa-FXa). Thrombin generated at the endothelial surface binds the cellular receptor thrombomodulin and activates protein C. The activation of protein C is promoted by endothelial protein C receptor (EPCR) which provides a direct binding site for protein C on endothelial cells and increases the affinity of the thrombin-thrombomodulin complex for protein C. Activated protein C in complex with its cofactor protein S, rapidly inactivates the procoagulant cofactors FVa and FVIIIa by limited proteolysis forming a negative feedback loop. The activated coagulation proteases are inhibited by antithrombin, the rate of which is substantially increased by binding glycosaminoglycans on the surface of endothelial cells.