Anticoagulants

        The characteristic feature of the coagulation pathway is that upon activation the individual glycoprotein serves as a enzyme to convert the zymogen form of the succeeding glycoprotein to its protease form only in the presence of Ca⁺² cations and on an appropriate phospholipid membrane. The activated forms of the glycoproteins are identified by symbol 'a'.

        Both the intrinsic and the extrinsic coagulation pathways proceed through a common pathway by forming activated factor X. Prothrombin is cleaved at two sites by factor Xa  to yied thrombin (To see a structure of thrombin molecule click here). Ten g-carboxyglutamic acid residues are located on the N-terminal end of the prothrombin molecule. Vitamin K is required in the liver biosynthesis of the prothrombin g-carboxyglutamic groups by participating in the carboxylation of the g-carbon of glutamic acid. These carboxy groups are required for binding calcium to prothrombin, which induce a conformation change in prothrombin enabling it to bindi to co-factors on the phospholipid surfaces during its conversion to thrombin by factor Xa, factor V, and platelet phospholipids in the presence of calcium.

     Thrombin, in turn, cleaves fibrinogen. Fibrinogen comprises 2-3% of plasma protein. Thrombin specifically cleaves the Arg-X (X is mostly Gly) peptide bond in fibrinogen to form soluble fibrin monomers. These monomers spontaneously aggregate to form a polymeric structure called "soft clot". This polymer is rapidly converted to a more stable "hard clot" by the covalent cross-linking of neighboring fibrin molecules in a reaction catalyzed by fibrin-stabilizing factor (FSF or XIIIa).

        The multilevel cascade of blood clotting system permits enormous amplification of its triggering signals. Moving down the extrinsic pathway, for example, proconvertin (VII), Stuart factor (X), prothrombin, and fibrinogen are present in plasma in concentrations of <1, 8, 150, and ~4000 mg^.mL^-1, respectively. Thus a small signal is very quickly amplified to bring about effective hemostatic control.

        On the other hand, clotting must be very strictly regulated because even one inappropriate clot can have fatal consequences. Indeed, blood clots are the leading cause of strokes and heart attack, the two major causes of human death.

       Endogenous Inhibitors of Clotting

        Thrombin plays a pivotal role in blood coagulation and Nature has designed several serine protease inhibitors (SERPINS) to regulate the its activity. These include antithrombin (major), heparin cofactor II, a₂-macroglobulin, and a₁-proteinase inhibitor.

        Antithrombin is present in the plasma in significant concentrations (~2-3 mM). Antithrombin primarily neutralizes factor Xa and thrombin, in addition to inhibiting most active serine proteases of the clotting system.

        Protein C is another plasma protein that limits clotting by being activated by thrombin to proteolytically inactivate proaccelerin (V) and antihemophilic factor (VIII).

        Thrombomodulin, a cell membrane bound glycoprotein lining the vascular endothelium, specifically binds thrombin so as to convert it to a form with decreased ability to catalyze clot formation but with a >1,000-fold increased capacity to activate protein C.

        Exogenous Inhibitors of Clotting

        The control of clotting is a major medical concern. Several inhibitors have been developed with different mechanisms of anticoagulant action. These include the heparins, the coumarins, and the 1,3-indanediones.