hematology and oncology
Overview of Hemostasis
Regulation of Coagulation
Several inhibitory mechanisms prevent activated coagulation reactions from amplifying uncontrollably, causing extensive local thrombosis or Disseminated Intravascular Coagulation (DIC) . These mechanisms include Inactivation of coagulation factors Fibrinolysis Hepatic clearance of activated clotting factors Plasma protease inhibitors (antithrombin, tissue factor pathway inhibitor, alpha 2-macroglobulin, andheparincofactor II) inactivate coagulation enzymes. Antithrombin inhibitsthrombin,factor Xa, factor XIa, and factor IXa. Two vitamin K–dependent proteins, protein C and free protein S, form a complex that inactivates factors VIIIa and Va by proteolysis.Thrombin, when bound to a receptor on endothelial cells (thrombomodulin [CD141]), activates protein C. Activated protein C, in combination with free protein S and an endothelial cell protein C receptor, proteolyzes and inactivates factors VIIIa and Va. In addition to normally present inactivators, there are a number of anticoagulant medications that potentiate the inactivation of coagulation factors (see figure). Heparinenhances antithrombin activity. Unfractionatedheparin(UFH) and low molecular weightheparins(LMWH) enhance activity of antithrombin to inactivate factors IIa (thrombin) and Xa. LMWHs includeenoxaparin,dalteparin, and tinzaparin. Warfarinis a vitamin K antagonist. It inhibits regeneration of the active form of vitamin K and, therefore, inhibits generation of functional forms of the vitamin K–dependent clotting factors II, VII, IX, and X (as well as proteins C and S). Fondaparinux, a small, synthetic molecule containing the essential pentasaccharide portion of theheparinstructure, enhances antithrombin inactivation offactor Xabut not factor IIa (thrombin). Parenteral directthrombininhibitors includeargatrobanandbivalirudin. ). The use of these medications, including risks, benefits, and reversal agents, are discussed in The Manual's sections on Prevention of thromboembolism , LMWH = low molecular weightheparin; TF = tissue factor; UFH = unfractionatedheparin. Fibrin deposition and lysis are normally balanced to maintain temporarily, and subsequently remove, the hemostatic seal during repair of an injured vessel wall. The fibrinolytic system dissolves fibrin by means of plasmin, a proteolytic enzyme. Fibrinolysis is activated byplasminogenactivators released from vascular endothelial cells.Plasminogenactivators andplasminogen(from plasma) bind to fibrin, andplasminogenactivators cleaveplasminogeninto plasmin (see figure). Plasmin then proteolyzes fibrin into soluble fibrin degradation products that are swept away in the circulation and metabolized by the liver. Fibrin deposition and fibrinolysis must be balanced during repair of an injured blood vessel wall. Injured vascular endothelial cells releaseplasminogenactivators (tissueplasminogenactivator, urokinase), activating fibrinolysis.Plasminogenactivators cleaveplasminogeninto plasmin, which dissolves clots. Fibrinolysis is controlled byplasminogenactivator inhibitors (PAIs; eg, PAI-1) and plasmin inhibitors (eg, alpha 2-antiplasmin). There are severalplasminogenactivators: Tissueplasminogenactivator(tPA), from endothelial cells, is a poor activator ofplasminogenwhen free in solution but an efficient activator when bound to fibrin in proximity toplasminogen. Urokinaseexists in single-chain and double-chain forms with different functional properties. Single-chain urokinase cannot activate freeplasminogenbut, like tPA, can readily activateplasminogenbound to fibrin. A trace concentration of plasmin cleaves single-chain to double-chain urokinase, which activatesplasminogenin solution, as well asplasminogenbound to fibrin. Epithelial cells that line excretory passages (eg, renal tubules, mammary ducts) release urokinase, which is the physiologic activator of fibrinolysis in these channels. Streptokinase,a bacterial product not normally found in the body, is another potentplasminogenactivator. Streptokinase, urokinase, and recombinant tPA (alteplase) have all been used therapeutically to induce fibrinolysis in patients with acute thrombosis. Fibrinolysis is regulated byplasminogenactivator inhibitors (PAIs) and plasmin inhibitors that slow fibrinolysis. PAI-1, the most important PAI, inactivates tPA, and urokinase and is released from vascular endothelial cells and activated platelets. The primary plasmin inhibitor is alpha 2-antiplasmin, which quickly inactivates any free plasmin escaping from clots. Some alpha 2-antiplasmin is also cross-linked to fibrin polymers by the action of factor XIIIa during clotting. This cross-linking may prevent excessive plasmin activity within clots. Tissueplasminogenactivator and urokinase are rapidly cleared by the liver, which is another mechanism of preventing excessive fibrinolysis. 