Coagu1ation

In the test tube, at least 12 plasma proteins interact in a series of reactions leading to blood clotting. Their designation as Roman numerals was made in order of discovery, often before their role in the clotting scheme was fully appreciated. Their biochemical properties are summarized in Table 1. Initiation of clotting occurs either intrinsically by surface-mediated reactions, or extrinsically through factors derived from tissues. The two systems converge upon a final common path which leads to the formation of an insoluble fibrin gel when thrombin acts on fibrinogen.

Coagulation proceeds through a "cascade" of reactions by which normally inactive factors (e.g., factor XII) become enzymatically active following surface contact, or after proteolytic cleavage by other enzymes (e.g., surface contact activates factor XII to factor XHa). The newly activated enzymes in turn activate other normally inactive precursor molecules (e.g., factor XHa converts factor XI to factor Xla). Because this sequence involves a series of steps, and because one enzyme molecule can activate many substrate molecules, the reactions are quickly amplified so that significant amounts of thrombin are produced, resulting in platelet activation, fibrin formation, and arrest of bleeding. The process is localized (i.e., widespread clotting does not occur) owing to dilution of activated factors by blood flow, the actions of inhibitors which are present or are generated in clotting blood, and because several reaction steps proceed at an effective rate only when catalyzed on the surface of activated platelets or at sites of tissue injury.

Figure 3 presents a scheme of the clotting factor interactions involved in both the intrinsic and extrinsic systems and their common path. Except for the contact phase, calcium is required for most reactions and is the reason why chelators of calcium (e.g., citrate) are effective anticoagulants. It is also clear that the in vitro interactions of clotting factors, clotting, is not identical with coagulation in vivo, which is triggered by artificial surfaces and by exposure of the cell-

TABLE 1 Properties of Human Clotting Factors

Clotting factor

Molecular weight (No. of chains)

Normal plasma concentration (¿tg/ml)

Active form

Intrinsic system Factor XII Prekallikrein High-molecular-weight kininogen

Factor XI Factor IX factor VIII VWF

Extrinsic system Factor VII Tissue factor Common pathway Factor X Factor V Prothrombin Fibrinogen Factor XIII

160,000 (2) 68,000 (1) 265,000 (1) 1-15,000,000"

56,000 (2) 330,000 (1) 72,000 (1) 340,000 (6) 320,000 (4)

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