Fibrinolysis PDF

10 FIBRINOLYSIS FIBRINOLYSIS Primary purpose is to digest fibrin clots as they are formed in order to keep vascular system free of deposited fibrin and fibrin clots Occurs when plasminogen is converted to plasmin, which dissolves the fibrin or fibrinogen into smaller fragments termed FDP (Fibrin deg...

10 FIBRINOLYSIS FIBRINOLYSIS Primary purpose is to digest fibrin clots as they are formed in order to keep vascular system free of deposited fibrin and fibrin clots Occurs when plasminogen is converted to plasmin, which dissolves the fibrin or fibrinogen into smaller fragments termed FDP (Fibrin degradation product) or FSP (Fibrin split product) Plasmin a serine protease that systematically digest fibrin polymer by the hydrolysis of arginine-related and lysine related peptide bonds Free plasmin capable of digesting plasma fibrinogen, factor V, Factor VIII, and fibronectin. Activation of fibrinolytic system Intrinsic activation Factor XIia, kallikrein, HMWK, and a specific plasma protein (proactivator) can activate plasminogen to plasmin EXTRINSIC activation plasminogen activators are present in organ tissues and endothelial cells (TPA) Activators in secretions urokinase, tears, saliva, semen, milk Exogenous activation Therapeutic destruction of thrombi (urokinase, streptokinase, manufactured TPAs) Fibrin(ogen) Degradation by Plasmin The process of fibrin degradation by plasmin produces fragments called fibrin(ogen) degradation products or fibrin(ogen) split products The four principal fragments are X, Y, D, E Fragment X is the first and largest fragment, it results from the cleavage of the alpha chains by plasmin When fragment X is cleaved by plasmin, two fragments called Y and an intermediate complex DED, is formed The complex is further cleaved into DED complex and DY/YD complex, until finally fragments E and D are formed D-dimer is an indicator of in vivo fibrinolysis, it indicates the presence of fibrin (not fibrinogen) split products Fragments X and Y, along with intermediate FDPs, appear to be the most important in exerting anticoagulant effects, fragments Y and D inhibit fibrin polymerization, fragment E is a powerful inhibitor of thrombin Primary Fibrinolysis Excessive amount of plasminogen activator from damaged cells or malignant cells Examples are from malignancy like prostatic carcinoma NO D-DIMER NO FIBRIN MONOMER NO FIBRIN POLYMER Decrease Fibrinogen Normal platelet count Secondary Fibrinolysis DIC: uncontrolled, Inappropriate formation of fibrin within the blood vessels Examples are seen in infection and HTR (+) D DIMER (+) FIBRIN MONOMER (+) FIBRIN POLYMER Decrease fibrinogen Decreased platelet count FIBRIN DEGRADATION PRODUCTS Fragment X Excessive amount of plasminogen activator from damaged cells or malignant cells Examples are from malignancy like prostatic carcinoma NO D-DIMER NO FIBRIN MONOMER NO FIBRIN POLYMER Decrease Fibrinogen Normal platelet count Fragment Y is the E domain after cleavage of one D domain (D-E) D-D fragment called D-dimer, is composed of two D domains from separate fibrin molecules (not fibrinogen) crosslinked by the action of factor XIIIa PLASMINOGEN ACTIVATORS Intrinsic factors = factor XIIa, Kallikrein, and HMWK Tissue type urokinase = secreted by the kidney, activates plasminogen Therapeutic activators such as treatment for thromboemboli Streptokinase, urokinase, Tissue like PA Tissue plasminogen activator INHIBITORS OF FIBRINOLYSIS Alpha 2 antiplasmin - primary inhibitor of plasmin Alpha 2 macroglobulin Thrombospondin - released by the platelets, inhibits activation of fibrin-bound plasminogen Plasminogen activator inhibitor 1 (PAI-1) and Plasminogen activator inhibitor 2 (PAI-2) Alpha 1 antitrypsin