63. Homeostasis. Proteases and Cofactors. Role of Single Nucleotide Polymorphisms of Coagulation Factors for the Development of Thrombosis.

Homeostasis, Proteases and Cofactors

• Hemostasis is the body’s mechanism to prevent blood loss after vascular injury. It works through a tightly controlled balance between clot formation and clot breakdown.
• It involves three major steps: – Vasoconstriction to reduce blood flow. – Platelet plug formation at the site of injury (primary hemostasis). – Coagulation cascade forming a fibrin mesh that stabilizes the plug (secondary hemostasis).
• The coagulation cascade is made of inactive zymogens circulating in plasma. When activated, many of them become serine proteases that cleave the next factor in the chain. This ensures amplification: small signals create a large clotting response.
• The cascade has two pathways: intrinsic (activated by surface contact) and extrinsic (activated by tissue factor exposed from injured endothelium). Both pathways converge into a common pathway where Factor Xa converts prothrombin to thrombin.
• Thrombin is the central enzyme: it converts fibrinogen to fibrin, activates Factor XIII (cross-links fibrin), and also activates platelets. It essentially builds and strengthens the clot.
• The cascade relies on cofactors that accelerate or support activation steps. Examples: – Factor V is a cofactor for Factor Xa. – Factor VIII is a cofactor for Factor IXa. – They don’t have enzymatic activity themselves, but without them, clotting efficiency drops dramatically.
• Many coagulation enzymes require calcium ions (Ca²⁺) and phospholipid surfaces (like activated platelet membranes) to function. Calcium binds to vitamin K–dependent gamma-carboxylated glutamate residues on factors II, VII, IX, and X, allowing them to anchor to cell surfaces.
• Vitamin K is therefore crucial. Without it, factors cannot bind cell membranes, and coagulation fails (basis for warfarin therapy).