Pathway: Extrinsic Pathway of Fibrin Clot Formation
Reactions in pathway: Extrinsic Pathway of Fibrin Clot Formation :
Extrinsic Pathway of Fibrin Clot Formation
Factor VII, the protease that initiates the normal blood clotting cascade, circulates in the blood in both its proenzyme (factor VII) and its activated (factor VIIa) forms. No clotting occurs, however, because neither form of the protein has any catalytic activity when free in solution. Blood clotting is normally initiated when tissue factor (TF), an intrinsic plasma membrane protein, is exposed to the blood by injury to the wall of a blood vessel. TF is then able to bind factor VIIa from plasma, and possibly also factor VII, to form complexes capable of catalyzing the conversion of factor X, from plasma, into its activated form, factor Xa. Factor Xa catalyzes the conversion of additional factor VII molecules to their activated form, increasing the amount of tissue factor:factor VIIa complex available at the site of injury, accelerating the generation of factor Xa, and allowing the activation of factor IXa as well. This process is self-limiting because as levels of factor Xa increase, tissue factor:factor VIIa complexes become trapped in the form of catalytically inactive heterotetramers with factor Xa and the protein TFPI (tissue pathway factor inhibitor). At this point the intinsic pathway, as an independent source of activated factor X, is thought to become critical for the continuation of clot formation (Broze 1995; Mann et al. 2003).
The nature of the initial tissue factor:factor VII complexes formed is controversial. One model, building on the observation that the complex of factor VII and TF has low but measurable proteolytic activity on factor X, suggests that this complex begins the activation of factor X, and that as factor VIIa accumulates, tissue factor:factor VIIa complexes also form, accelerating the process (Nemerson 1988). A second model, building on the observation that normal plasma contains low levels of activated factor VII constitutively, suggests that complexes with factor VIIa form immediately at the onset of clotting (Rapaport and Rao 1995). The two models are not mutually exclusive, and in any event, the central roles of tissue factor and factor VIIa in generating an initial supply of factors IXa and Xa, and the self-limiting nature of the process due to the action of TFPI, are all well-established.
The nature of the initial tissue factor:factor VII complexes formed is controversial. One model, building on the observation that the complex of factor VII and TF has low but measurable proteolytic activity on factor X, suggests that this complex begins the activation of factor X, and that as factor VIIa accumulates, tissue factor:factor VIIa complexes also form, accelerating the process (Nemerson 1988). A second model, building on the observation that normal plasma contains low levels of activated factor VII constitutively, suggests that complexes with factor VIIa form immediately at the onset of clotting (Rapaport and Rao 1995). The two models are not mutually exclusive, and in any event, the central roles of tissue factor and factor VIIa in generating an initial supply of factors IXa and Xa, and the self-limiting nature of the process due to the action of TFPI, are all well-established.
The formation of a fibrin clot at the site of an injury to the wall of a normal blood vessel is an essential part of the process to stop blood loss after vascular injury. The reactions that lead to fibrin clot formation are commonly described as a cascade, in which the product of each step is an enzyme or cofactor needed for following reactions to proceed efficiently. The entire clotting cascade can be divided into three portions, the extrinsic pathway, the intrinsic pathway, and the common pathway. The extrinsic pathway begins with the release of tissue factor at the site of vascular injury and leads to the activation of factor X. The intrinsic pathway provides an alternative mechanism for activation of factor X, starting from the activation of factor XII. The common pathway consists of the steps linking the activation of factor X to the formation of a multimeric, cross-linked fibrin clot. Each of these pathways includes not only a cascade of events that generate the catalytic activities needed for clot formation, but also numerous positive and negative regulatory events.
Hemostasis is a physiological response that culminates in the arrest of bleeding from an injured vessel. Under normal conditions the vascular endothelium supports vasodilation, inhibits platelet adhesion and activation, suppresses coagulation, enhances fibrin cleavage and is anti-inflammatory in character. Under acute vascular trauma, vasoconstrictor mechanisms predominate and the endothelium becomes prothrombotic, procoagulatory and proinflammatory in nature. This is achieved by a reduction of endothelial dilating agents: adenosine, NO and prostacyclin; and by the direct action of ADP, serotonin and thromboxane on vascular smooth muscle cells to elicit their contraction (Becker et al. 2000).
The chief trigger for the change in endothelial function that leads to the formation of a haemostatic thrombus is the loss of the endothelial cell barrier between blood and extracellular matrix components (Ruggeri 2002). Circulating platelets identify and discriminate areas of endothelial lesions; here, they adhere to the exposed sub endothelium. Their interaction with the various thrombogenic substrates and locally generated or released agonists results in platelet activation. This process is described as possessing two stages, firstly, adhesion - the initial tethering to a surface, and secondly aggregation - the platelet-platelet cohesion (Savage & Cattaneo et al. 2001).
Three mechansism contribute to the loss of blood following vessel injury. The vessel constricts, reducing the loss of blood. Platelets adhere to the site of injury, become activated and aggregate with fibrinogen into a soft plug that limits blood loss, a process termed primary hemostasis. Proteins and small molecules are released from granules by activated platelets, stimulating the plug formation process. Fibrinogen from plasma forms bridges between activated platelets. These events initiate the clotting cascade (secondary hemostasis). Negatively-charged phospholipids exposed at the site of injury and on activated platelets interact with tissue factor, leading to a cascade of reactions that culminates with the formation of an insoluble fibrin clot.