Blood Clotting

Blood clots are composed of striated fibers of a protein called fibrin. Fibrin fibers stick together in a staggered array. Before fibrin fibers can stick together, however, they must be derived from a zymogen precursor, called fibrinogen, by proteolytic cleavages that release fibrinopeptides A and B from the molecule. Removal of these small fibrinopeptides exposes sites in the fibrin molecules that allows them to stick together. Covalent cross-links between glutamine and lysine residues also form to help stabilize the structure. Thus, activation of zymogens is a key aspect to clotting of blood in vertebrates.

As can be seen in Figure 11.42, production of fibrin is the product of action of a cascade of proteases. These are summarized as follows:

> In damaged tissue, the proteins kininogen and kallikrein activate factor XII (part of the intrinsic pathway).

> Factor XII activates factor XI (part of the intrinsic pathway).

> Alternatively, damage to blood vessels leads to release of tissue factor and activation of factor VII (start of the extrinsic pathway).

> The extrinsic and intrinsic pathways merge with activation of factor X. Activation of factor X by factor IX of the intrinsic pathway requires factor VIII (antihemophilic factor).

> Factor X activates prothrombin to thrombin.

> Thrombin removes small fibrinopeptides from fibrinogen to form fibrin.

Note that the absence of factor VIII is the cause of classic hemophilia. Factor VIII is encoded on the X chromosome, so the disease is much more prominent in males, because they have only one X chromosome.

As wounds heal, clots must be removed. The principal agent for dissolving clots is an enzyme called plasmin, which is synthesized as the inactive zymogen called plasminogen. Plasminogen is activated by a number of proteases, the most important of which is tissue-type plasminogen activator (t-PA). t-PA can be extremely effective in initiating the cascade to dissolve the unwanted blood clot involved in stroke or heart attack.

See also: Covalent Modifications to Regulate Enzyme Activity, Covalent Modification of Proteins (from Chapter 27), Thrombin

INTERNET LINKS:

> 1. Blood Clot Micrograph

> 2. Clotting

> 3. Royal Hemophilia Tree