The Role Of Fibrinogen In Hemostasis

Fibrinogen is the principal substrate of the coagulation and fibrinolytic system. This clotting factor has the highest molecular weight of all of the clotting factors, and it is the substrate upon which the coagulation system is centered. This factor is heat labile but stable in storage. When fibrinogen is transformed to fibrin under the influence of thrombin, it is the onset of solid clot formation. The formation of fibrin occurs within minutes due in part to a positive feedback mechanism within the hemostasis system. Once clotting factors are activated, they accelerate the activity of the next factor, pushing the reaction to conclusion. Negative feedback occurs when the activity of the reaction is delayed. This is the role played by naturally occurring inhibitors within the hemostatic system. With the assistance of factor XIII and thrombin, the fibrinogen molecule is stabilized by cross-linked fibrin. Within hours, the fibrinolytic system swoops in to dissolve the clots that have formed and to restore blood flow. The creation of cross-linked fibrin is an orderly process by which fibrinogen is cleaved into fibrinopeptides A and B by thrombin. Fibrinogen is composed of three pairs of polypeptide chains: alpha, beta, and gamma. When thrombin is generated, it cleaves small portions of the alpha and beta chains, creating fibrinopeptides A and B. The remaining portions of the alpha and beta chains stay attached to the fibrinogen molecule. With fibrinopeptides A and B cleaved, the fibrin monomer is created. These monomers spontaneously polymerize by hydrogen bonding to form a loose fibrin network, which is soluble. Trapped within the soluble clot are thrombin, antiplasmins, plasmino-gen, and tissue plasminogen activator (tPA). Because thrombin is now protected from its inhibitors, it activates factor XIII and calcium and then catalyzes the formation of peptide bonds between monomers, forming fibrin polymers that lead to an insoluble and resistant clot1 (Fig. 18.1). Balance between the coagulation and fibrinolytic systems is critical for maintenance of circulation and injury repair. An imbalance in the coagulation system could cause excess clotting; an imbalance of the fibrinolytic system could cause hemorrhaging. Several other components may play a role in hemostatic balance. In early studies, it has been suggested that individuals with a high concentration of lipoprotein A may have reduced fibrinolytic activity due to decreased plasmin generation. Cholesterol and triglycerides are all fatty components of lipoproteins. It is conceivable that reduced plasmin generating activity in individuals with increased levels of lipoprotein will lead to less clot dissolution, leaving clots available for a pathological outcome.2

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