TRANS-FibrinolysisHEMA2-Lec.pdf

FIBRINOLYSIS PLASMIN ★ Bound plasmin digests clots and restores blood FIBRINOLYSIS vessel patency....

FIBRINOLYSIS PLASMIN ★ Bound plasmin digests clots and restores blood FIBRINOLYSIS vessel patency. ★ Free plasmin can be found in the circulation ❖ Fibrinolysis - The final stage of hemostatic and is capable of digesting plasma fibrinogen, activation factor V, factor VIII, and fibronectin. ❖ It is the systematic, accelerating hydrolysis of ★ Plasma a2-antiplasmin rapidly binds and fibrin inactivates any free plasmin. Removing the mesh from secondary ★ Destroys: Factors V, VIII, IX, and XI hemostasis ★ Its localization to fibrin through lysine binding ❖ To concentrate and localize fibrinolysis to the prevents systemic activity. site of injury where the clot has formed, ★ Primary fibrinolysis occurs when free plasmin fibrinolytic proteins become incorporated into circulates unchecked, breaking down the fibrin clot as it is forming. fibrinogen and formed clots, causing Upon the activation and formation of potentially fatal hemorrhage outcome. fibrin mesh, fibrinolytic enzymes are incorporated simultaneously. PLASMINOGEN ACTIVATION ❖ The fibrinolytic process degrades fibrin, restoring normal blood flow during vascular repair ACTIVATORS OF FIBRINOLYSIS The plasmin, the one that hydrolyzes 1. Tissue Plasminogen Activator (TPA) – Serine the cloth. protease secreted by activated endothelium, Several hours after fibrin polymerization activates plasminogen. and cross-linking (thrombus formation), 2. Urokinase Plasminogen Activator (UPA) – Serine and in response to inflammation and protease secreted by kidney cells, activates coagulation, the fibrinolytic process is plasminogen. activated. ○ These convert fibrin-bound ❖ Excessive fibrinolysis can cause bleeding as a plasminogen into the principal enzyme result of fibrinogen consumption as well as of the fibrinolytic system, plasmin. premature clot lysis before wound healing is ○ Streptokinase is also an enzyme that established. converts plasminogen to plasmin ❖ Inadequate fibrinolysis can lead to clot extension and thrombosis. TISSUE PLASMINOGEN ACTIVATOR ★ ECs secrete TPA, which hydrolyzes fibrin-bound PLASMINOGEN AND PLASMIN plasminogen, converting it to plasmin, thus ★ Plasminogen – Active form is the plasma serine initiating fibrinolysis. protease plasmin, digests fibrin/fibrinogen. ★ TPA forms covalent lysine bonds with fibrin ○ Plasminogen is an example of during polymerization and localizes at the zymogen (inactive form of enzyme) surface of the thrombus with plasminogen, ○ As plasmin becomes digested, the where it begins the digestion process by exposed carboxy-terminal lysine converting plasminogen to plasmin. (through residues bind additional plasminogen kringle regions) and TPA, which further accelerates ○ TPA has 2 kringle regions, for stable clot digestion binding to fibrin ★ It is also a plasma zymogen produced by the ★ Circulating TPA is bound to inhibitors such as liver. PAI-1. ★ Fibrin-bound plasminogen becomes converted into a two-chain active plasmin molecule. UROKINASE PLASMINOGEN ACTIVATOR ★ Plasmin is a serine protease that systematically Urinary tract epithelial cells, monocytes, and digests fibrin polymers by the hydrolysis of macrophages secrete another intrinsic arginine-related and lysine-related peptide plasminogen activator called urokinase bonds. plasminogen activator. UPA circulates in plasma and becomes incorporated into the mix of fibrin-bound plasminogen and TPA at the time of thrombus formation. NATHALIA COLEEN FAVILA | HEMATOLOGY 2 LEC 1  UPA does not bind firmly to fibrin and has a The Kunitz-2 domain binds to and inhibits factor relatively minor physiologic effect. Xa, and Kunitz-1 binds to and inhibits the VIIa:TF ○ Because UPA has only 1 kringle region complex ○ Forms a quarternary complex that CONTROL OF FIBRINOLYSIS prevents further activation of factor X and IX PLASMINOGEN ACTIVATOR INHIBITOR 1 (PAI-1) Synthesized primarily by ECs and is also ★ PAI-1 is the principal inhibitor of plasminogen expressed on platelets. activation, inactivating both TPA and UPA. Protein S is its cofactor in which it enhances the ★ Produced by ECs, megakaryocytes, smooth inhibition of TFPI tenfold muscle cells, fibroblasts, monocytes, adipocytes, hepatocytes, and other cell types. ANTITHROMBIN ★ Binding of TPA to fibrin protects TPA from PAI-1 ★ A serine protease inhibitor (serpin) that binds inhibition. and neutralizes serine proteases, including ★ Platelet store a pool of PAI-1, accounting for thrombin (factor IIa) and factors IXa, Xa, XIa, more than half of its availability and for its XIIa, prekallikrein, and plasmin. delivery to the fibrin clot ★ AT’s activity is amplified 2000-fold by binding to ★ PAI-1 is present in excess of the TPA heparin. concentration in plasma, and circulating TPA ○ Heparin induces a conformational normally becomes bound to PAI-1 change in the AT molecule that allows ★ After trauma, the level of TPA secretion exceed binding of activated coagulation of that PAI-1 to initiate fibrinolysis. factors, which causes them to be activated. a2 ANTIPLASMIN Synthesized in the liver and is the primary OTHER SERINE PROTEASE INHIBITORS inhibitor of free plasmin. ZPI – cofactor for protein Z, a potent inhibitor of ○ Free plasmin produced by activation Factor Xa and XIa. of plasminogen can bind either to ○ Protein Z increases the ability of ZPI to fibrin, where it is protected from AP inhibit factor Xa 2000-fold because its lysine binding site is ○ Xa requires: Phospolipid, protein Z, and occupied, or to the C-terminus of AP, Ca2+ for inhibition of 2000 fold which rapidly and irreversibly ○ XIa requires: Heparin for inhibition of inactivates it. two fold During thrombus formation, the N-terminus of Protein C inhibitor – non-specific, inhibits a AP is covalently linked to fibrin by factor XIIIa. variety of proteases, including APC, thrombin, The C-terminal contains lysine, which is factor Xa, factor XIa, and urokinase. capable of reacting with the lysine-binding ○ Depending on its target, it can function kringles of plasmin. as an anticoagulant, prosgulant, or fibrinolyic inhibitor THROMBIN ACTIVATABLE FIBRINOLYSIS INHIBITOR (TAFI) ★ A plasma procarboxypeptidase synthesized in FIBRIN DEGRADATION PRODUCTS AND D-DIMER the liver that becomes activated by the thrombin-thrombomodulin complex. FIBRIN DEGRADATION PRODUCTS ★ It inhibits fibrinolysis by cleaving exposed ★ Plasmin cleaves fibrin (and fibrinogen) carboxy-terminal lysine residues from partially producing a series of identifiable fibrin degraded fibrin fragments: X, Y, D, E, and D-D. ★ TAFI also prevent the binding of TPA and ★ Several of these fragments inhibit hemostasis plasminogen to fibrin and blocking the and contribute to hemorrhage by preventing formation of plasmin. platelet activation and by hindering fibrin polymerization. INHIBITORS OF COAGULATION ★ Fragment X is described as the central E domain with the two D domains (D-E-D) TISSUE FACTOR PATHWAY INHIBITOR ★ Fragment Y is the E domain after cleavage of The principal regulator of the TF pathway one D domain (D-E). (extrinsic pathway) ★ Eventually these fragments are further digested to individual D and E domains. NATHALIA COLEEN FAVILA | HEMATOLOGY 2 LEC 2 D-DIMER Composed of two D domains from separate fibrin molecules (not fibrinogen) crosslinked by the action of factor XIIIa. ○ Factor XIIIa further stabilizes mesh Fragments X, Y, D, and E are produced by digestion of either fibrin or fibrinogen by plasmin, but D-dimer is a specific product of digestion of cross-linked fibrin only and is therefore a marker of thrombosis and fibrinolysis ○ D-dimer is generated via thrombin, factor XIIIa, and plasmin activity ○ Assessing D-dimer levels is an important diagnostic tool to identify disseminated intravascular coagulation and to rule out venous thromboembolism and pulmonary embolism. NATHALIA COLEEN FAVILA | HEMATOLOGY 2 LEC 3