The coagulation pathway

Factor number Common name Pathway in which it functions Function 

I Fibrinogen Both Forms structural basis of clot after its conversion to fibrin 

II Prothrombin Both Precursor of thrombin, which activates factors I, V, VII, VIII and XIII 

III Tissue factor (thromboplastin) Extrinsic Accessory tissue protein which initiates extrinsic pathway 

IV Calcium ions Both Required for activation of factor XIII and stabilizes some factors 

Although the final steps of the blood clotting cascade are identical, the initial steps can occur via two distinct pathways extrinsic and intrinsic. Both pathways are initiated when specific clotting proteins make contact with specific surface molecules exposed only upon damage to a blood vessel. Clotting occurs much more rapidly when initiated via the extrinsic pathway. 

Two coagulation factors function uniquely in the extrinsic pathway factor III (tissue factor) and factor VII. Tissue factor is an integral membrane protein present in a wide variety of tissue types (particularly lung and brain). This protein is exposed to blood constituents only upon rupture of 

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Hemostasis is the process that stops bleeding in a blood vessel. Normal hemostasis involves a complex process of extrinsic and intrinsic factors. Figure 44-1 shows the coagulation pathway and factors involved. The copulation cascade is so named because as each factor is activated it acts as a catalyst that enhances the next reaction, with the net result being a large collection of fibrin that forms a plug in the vessel. Fibrin is the insoluble protein that is essential to clot formation. 

We shall first describe the coagulation pathway leading to the formation of fibrin. Then we shall briefly describe some aspects of the involvement of platelets and blood vessel walls in the overall process. This separation of clotting factors and platelets is artificial, since both play intimate and often mutually interdependent roles in hemostasis and thrombosis, but it facifitates description of the overall processes involved. 

In chimpanzees, administration of Fab fragments of a monoclonal anti-F-VII antibody preceding an endotoxin bolus injection effectively blocked the activation of the coagulation pathway (B25). Administration of monoclonal anti-lL-6 under the same experimental conditions attenuated the activation of coagulation, while the fibrinolytic system remained unaltered. However, administration of monoclonal anti-TNF enhanced the tendency to microvascular thrombosis (P17,18). Monoclonal anti-TF antibodies administered to baboons as a pretreatment attenuated coagulopathy after induction of E. coli sepsis in these animals (T4). Primates pretreated with anti-C5a antibodies before infusion of E. coli developed less hypotension and had better survival rates than untreated animals, who developed ARDS and septic shock with a mortality rate of 75% (S35, Z6). No favorable treatment results have been published yet with one of these treatment modalities given to humans. 

The two commonly administered anticoagulant therapies3 are parenteral heparin, a highly sulfated glycosaminoglycan, and oral warfarin 2, a vitamin K antagonist (which acts by indirectly inhibiting several steps of the coagulation pathway). The major... 

The coagulation pathway can be activated by one of two pathways the extrinsic (tissue factor) pathway or the intrinsic (contact activation) pathway (Figure 13-1). The main coagulation pathway in vivo is the tissue factor pathway. Tissue factor is exposed by damaged endothelium. This exposed tissue factor binds and activates factor VII, which, in turn, activates factor X. Factor Xa results in the generation of a thrombin (factor lla) burst. Thrombin, in turn activates factors XI, VIII, and V, leading to the further generation of thrombin and clottable fibrin. Additionally, the tissue factor Vila complex activates factor IX, which further contributes to the activation of factor X. 

Activated protein C in conjunction with its cofactor, protein S, plays a key role in the anticoagulant system by inactivating membrane-bound factors Va and Villa, The inability to inactivate procoagulant factors Va or Villa could disturb hemostasis, heighten the coagulation pathway, increase the generation of thrombin, and promote clot formation. In 1993 Dahlback reported familial thrombophilia caused by resistance to activated protein C (APC). In 1994... 

DS has been shown to modulate the activity of heparin cofactor II to inhibit thrombin without interacting with other factors of the coagulation pathway/ It however has a lower affinity for HCII than heparin. DS also can bind activated protein C (APC), which can inhibit factor V. " ... 

How important these steps are in the initiation of the coagulation cascade is unknown. Individuals lacking HMWK, prekallikrein, or Factor XII do not suffer from bleeding disorders. Under usual conditions, activation of Factor VII with subsequent activation of Factors IX and X is thought to be sufficient to activate the coagulation pathway. 

The work discussed here has shown that suspensions of platelets and red cells in a physiological medium can provide information for platelet surface interactions. Evidence is provided on the dynamic features of platelet-surface adhesion and detachment which indicates that more than one sequence of adhesion, detachment and re-adhesion can lead to the same net platelet adhesion. Surface generated substances, such as A DP and serotonin from platelets and thrombin from the coagulation pathway, may strongly influence the function of platelets approaching a surface. The supply of these substances depends on the presence of flow and continued arrival of platelets at a surface. The reactivity of surface-bound protein may be altered by platelet adhesion and detachment. This may occur as a result of deposition of cell membrane components, replacement of the original substrate with protein secreted from platelets or possibly by enzymatic digestion of surface bound protein. 

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