Vitamin KDependent Proteins in Blood Clotting

The formation of blood clots is the result of the conversion of the soluble protein fibrinogen into fibrin, an insoluble network of fibers. This is achieved by specific proteolysis of fibrinogen at two arginine-glycine junctions, removing two pairs of small peptides (fibrinopeptides), catalyzed by thrombin. The resultant fibrin monomer aggregates into the insoluble fibrin polymer, which undergoes further covalent cross-linkage, catalyzed by a transamidase, the so-called fibrin-stabilizing factor or Factor XIII. Fibrin-stabilizing factor is normally present as an inactive dimer that is activated by thrombin. By the formation of an insoluble clot, bleeding is rapidly stopped.

Thrombin, which catalyzes the proteolysis of fibrinogen, circulates as an inactive precursor, prothrombin, which in turn is activated by partial proteolysis to remove a peptide sequence that masks the catalytic site. There are two distinct pathways leading to the activation of prothrombin to thrombin (see Figure 5.3):

1. The extrinsic pathway, which is initiated by thromboplastin released from injured tissues and the protease proconvertin (Factor VII).

2. The intrinsic pathway, which is initiated by the activation of Factor XII as a result of adsorption onto collagen, platelet membranes, or (under laboratory conditions) glass.

FactorX can also be activated by kallikrein - in turn prekallikrein is activated to kallikrein by activated Factor XII, thus prolonging the initial contact activation of Factor XII.

The intrinsic pathway is involved in the clotting of blood in glass tubes and in the undesirable intravascular clotting that results in thrombosis. Control of the clotting mechanism is thus central to hemostasis to avoid bothhemorrhage and thrombosis.

surface adsorption or kallikrein

Factor XII

active Factor XII

Factor XI

active Factor XI

thromboplastin + Factor VII

injury

Factor IX

Factor VIII

active Factor VIII-

Factor X

active Factor X-

Factor V-

prothrombin thrombin fibrinogen fibrin

Figure 5.3. Intrinsic and extrinsic blood clotting cascades. Factor I, fibrinogen; Factor II, prothrombin (vitamin K-dependent); Factor III, thromboplastin; Factor V, proac-celerin; Factor VII, proconvertin (vitamin K-dependent); Factor VIII, antihemophilic factor; Factor IX, Christmas factor (vitamin K-dependent); Factor X, Stuart factor (vitamin K-dependent); Factor XI, plasma thromboplastin; Factor XII, Hageman factor; Factor XIII, fibrin-stabilizing factor; and Factor XIV, protein C (vitamin K-dependent). What was at one time called Factor IV is calcium; no factor has been assigned number VI.

As shown in Figure 5.3, both the intrinsic and extrinsic pathways for the activation of prothrombin and hence initiation of blood clotting involve a number of intermediate factors. The nomenclature of the factors is based on the history of their discovery, which was largely as a result of studies in patients with various congenital clotting defects. Most of the clotting factors are serine proteases, which circulate as inactive zymogens. Each factor is activated by partial proteolysis and then in turn activates the next factor - a cascade that results in considerable amplification of the original stimulus.

The cascade is not a simple linear one. The concerted action of activated Factors VIII and IX is required in the intrinsic pathway for the activation of Factor X. The rate of prothrombin activation by activated Factor X alone is inadequate to meet physiological needs; an additional protein, proaccelerin or Factor V, is also required. In addition to prothrombin, Factors VII, IX, and X contain y-carboxyglutamate and hence are vitamin K-dependent, as are three further proteins: proteins C, S, and Z, which are anticoagulants. Protein C is a protease thathydrolyzes activated Factor V and activates clot lysis. It circulates as a zymogen and is activated by thrombin. Protein Z serves as the cofactor for the inhibition of activated FactorX by a protease inhibitor; in turn, the protease inhibitor-protein Z complex is hydrolyzed by activated Factors X and XI (Furie and Furie, 1988; Broze, 2001).

The initiation of the clotting process occurs on phospholipid surfaces, and the y-carboxyglutamate residues in the various vitamin K-dependent clotting factors are essential for the calcium-dependent binding of the proteins to phospholipid. In the absence of calcium, the y-carboxyglutamate residues are exposed, and the Gla domain has no affinity for lipid surfaces. After binding calcium ions, the protein undergoes a conformational change, so that the Gla residues are internalized and hydrophobic amino acids are exposed. These penetrate into phospholipid membranes and bind the protein to the cell surface.

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