Following initiation of coagulation as part of the hemostatic response to injury, thrombin is generated from its inactive precursor prothrombin by factor Xa as part of the prothrombinase complex. Thrombin then has multiple roles. The way in which thrombin interacts with its many substrates has been carefully scrutinized in the past decades, but until recently there has been little consideration of how its many functions are coordinated or directed. Any understanding of how it is directed requires knowledge of its structure, how it interacts with its substrates, and the role of any cofactors for its interaction with substrates. Recently, many of the interactions of thrombin have been clarified by crystal structure and site-directed mutagenesis analyses. These analyses have revealed common residues used for recognition of some substrates and overlapping surface exosites used for recognition by cofactors. As many of its downstream reactions are cofactor driven, competition between cofactors for exosites must be a dominant mechanism that determines the fate of thrombin. This review draws together much recent work that has helped clarify structure function relationships of thrombin. It then attempts to provide a cogent proposal to explain how thrombin activity is directed during the hemostatic response. ( Introduction: natural hemostatic substrates of thrombinProteinases play crucial roles in biologic processes involved in organism homeostasis. Their actions require tight regulation and coordination. Failure of regulation and coordination leads to disease. The hemostasis system involves activation, regulation, and coordination of numerous proteinases. The complex reactions occur on activated or damaged cells, platelets, and endothelial cells. In normal physiologic conditions hemostasis is exquisitely initiated, controlled, and terminated. Genetic or physiologic perturbations, however, can lead to severe dysfunction, resulting in either hemorrhagic disorders or thromboembolic disease, illustrating the need for tight regulation of these proteolytic reactions.Central to the functioning of hemostasis are the roles of thrombin. Numerous potential substrates have been identified for thrombin, 1,2 suggesting diverse roles. Only those substrates related to hemostasis are considered here. A prime function of thrombin is the conversion of fibrinogen to fibrin. Two fibrinopeptides (FPs) are cleaved, FPA (the 16-residue N-terminal peptide from the A␣ chain) and FPB (the 14-residue peptide from the B␤ chain). Cleavage of FPA occurs first, and this forms a fibrin monomer (termed fibrin I) which spontaneously polymerizes to form protofibrils. Cleavage of FPB generates fibrin II protofibrils that undergo lateral aggregation. In the dynamic process of thrombin generation in blood, some of the early generated thrombin feeds back on the cascade system to activate factors V and VIII, enabling more sustained generation of thrombin. 3,4 Thrombin activates factors V and VIII by excision of their central B domains. In factor V, R709, R1018...

Summary. Coagulation factor activity (fibrinogen, VII, VIII and IX), coagulation inhibitor activity (antithrombin, protein C, protein S), and coagulation activation markers (prothrombin fragment F1, 2; thrombin-antithrombin complexes) were measured in 747 men and 817 women aged 25-74 years, randomly sampled from the north Glasgow population in the Third MONICA Survey. Significant effects of age, sex, menopause and hormone use were observed and specific reference ranges are presented to illustrate these effects. Significant correlations were observed between several coagulation factors and inhibitors. Increased levels of factors VII, VIII and IX and decreased levels of protein C were associated with increased coagulation activation. In general, increases in coagulation factors with age were greater than increases in coagulation inhibitors, especially in men; this imbalance may favour increased coagulation activation and hence increased thrombotic risk with age.

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