CHAPTER 36, FIG URE 2 Classical “cascade” or “waterfall” model for coagulation. This model represents the

ordered sequence of

in vitro

transformations of precursor molecules from their inactive forms to their catalytically

active forms. The publication of the “cascade” model for the coagulation system provided a milestone in rationalizing

a confusing biological system. The figure has been corrected to place factors V and VIII outside the linear sequence

that differs from the proposals made in 1964. Two components, TF (tissue factor) and factor VII, were designated as

the “extrinsic pathway” components because the TF is provided by thromboplastin, a tissue-derived material extrinsic

to the circulating blood. Four components—factors XII, XI, IX and VIII—were designated as “intrinsic pathway”

components because they are always present in blood. Two other plasma proteins—prekallikrein and high-molecular-

weight kininogen—were discovered later to be involved in the process by which factor XI becomes activated.

CHA PTER 36, FIG URE 3 Contemporary model for the procoagulant subsystem. This model recognizes that the

transformations of proteinase precursors to active proteinases are organized on the surface to which the proteins bind.

The binding of the freely circulating coagulation proteins to these surfaces localizes the reactions that make up the

hemostatic response, as well as increases the rates of the reactions. Unlike the other coagulation factors, tissue factor

does not circulate freely. It is an integral membrane protein that is exposed as a result of exposure of the subendotheli-

um. In each stage of the sequence, a proteinase precursor (shown in orange), a proteinase from the preceding complex

(shown in dark green), and an activated cofactor protein (shown in yellow-green) form a noncovalent complex on the

membrane surface (shown as a blue “island”). Dissociation of the proteinase formed in one complex (the product pro-

teinase) permits that proteinase to diffuse to the next complex and catalyze the transformation of a different precusor

protein into an active proteinase. Thrombin is the only proteinase that does not bind to the surface of the membrane; it

dissociates and diffuses so that it can convert the soluble fibrinogen into the insoluble fibrin clot. Vitamin K-depen-

dent proteins are not shown, protein C and protein S. The

u n a c tiv a ted

cofactor proteins, tissue factor, and factors V

and VIII, are shown in yellow.