1. drmsaiem FIBRINOLSIS SYSTEM DR MOHAMMED SAIEMALDAHR Faculty of Applied Medical Sciences Medical Technology Dep.

2. drmsaiem FIBRINOLSIS SYSTEM Fibrinolysis System in Homeostasis  In 1937 MaCfarlane reported that damage tissues release a substance (activator that activates the inert precursor called Plasminogen).  Plasminogen: is normally circulates in the plasma to its active form called, Plasmin.  Plasmin is anon-specific Proteolytic enzyme capable of degrading fibrin as well as fibrinogen and factors V & VIII.

3. drmsaiem FIBRINOLSIS SYSTEM Function of Fibrinolysis in Homeostasis  Fibrinolysis is the system whereby the temporary fibrin clot is systematically and gradually dissolved as the vessel heals in order to restore normal blood flow.  Is the body’s defense against occlusion of blood vessels  There are number of substances responsible for fibrinolysis (Fig).

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5. drmsaiem FIBRINOLSIS SYSTEM  FIG. Simple overview of Fibrinolytic pathway.  Tissue plasminogen activators activate plasminogen within clot to plasmin, which slowly dissolves fibrin clot.  Inhibitors are neutralized by protein C—S complex, thus enhancing fibrinolysis.

6. drmsaiem FIBRINOLSIS SYSTEM  Tissue Plasminogen Activators, which convert Plasminogen to Plasmin are released from injured vessel walls.  Plasmin is trapped within the clot, and clot lysis begin slowly as soon as the clot is formed, with fibrin degradation products being released in the plasma.  Lysis is slow because of fibrin clot stabilization by factor XIII.  Protein S and C are two substance that enhance fibrinolysis and inactivate Tissue Plasminogen Activators (tPA inhibitor).

7. drmsaiem FIBRINOLSIS SYSTEM Physiologic Fibrinolysis Many similarities exist between Coagulation and Fibrinolytic systems. AS there are checks and balances in the formation of clot AS there are checks and balances in the formation of clot There are similar mechanism for dissolution of the clot to promote wound Healing. There are similar mechanism for dissolution of the clot to promote wound Healing. Important that bleeding does not recur because of premature lysing of the clot. Important that bleeding does not recur because of premature lysing of the clot.

8. drmsaiem FIBRINOLSIS SYSTEM Activation of Plasminogen to Plasmin  Fibrinolysis is dependent on the enzyme PLASMIN Normally is not present in the blood in an active form. Can digest or destroy fibrinogen, fibrin and factors V & VIII Promotes Coagulation and activates the Kinine and Complement systems.

9. drmsaiem FIBRINOLSIS SYSTEM Comments Plasmin's Roles Cleaves Fibrin and Fibrinogen to fibrin (ogen) degradation products X, Y and D-E Activates Fibrinolysis Factors XII----XIIa is amplified indirectly by plasmin Activates Intrinsic Coagulation Pathway Destroys factors VIII and V Interferes with intrinsic and common pathways FDP interfere with thrombin influence on fibrinogen Block Thrombin conversion of fibrinogen to fibrin

10. drmsaiem FIBRINOLSIS SYSTEM  Activation of Plasminogen to Plasmin A zymogen known as Plasminogen which normally present in plasma is converted to Plasmin by the action of specific enzyme called Plasminogen Activators. A zymogen known as Plasminogen which normally present in plasma is converted to Plasmin by the action of specific enzyme called Plasminogen Activators. Plasminogen is a single-chain glycoprotein with a Mwt of 90,000 d Plasminogen is a single-chain glycoprotein with a Mwt of 90,000 d Synthesized in the liver Synthesized in the liver Increased concentrations are found in association with inflammation. Increased concentrations are found in association with inflammation.

11. drmsaiem FIBRINOLSIS SYSTEM Activation of Plasminogen can occurs due to  Intrinsic Plasminogen Activation  Extrinsic Plasminogen Activation  Exogenous Plasminogen Activation  Plasminogen Activation in Secretory Ducts. (Fig)

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13. drmsaiem FIBRINOLSIS SYSTEM  For therapeutic destruction of thrombosis, Urokinase, a trypsin-like protease, may be administered to a patient to activate plasminogen to plasmin and induce Fibrinolysis.  Streptokinase is another agent used to activate Plasminogen to plasmin  Tissue Plasminogen activator (tPA) is an agent used for the treatment of thrombosis. It released in vivo on endothelial cell damage and can be manufactured in vitro through recombinant DNA techniques.

14. drmsaiem FIBRINOLSIS SYSTEM  Summary  Fibrinolysis is dependent on the enzyme PLASMIN  Tissue Plasminogen Activators, which convert Plasminogen to Plasmin are released from injured vessel walls.  Plasminogen (A zymogen) which normally present in plasma is converted to Plasmin by the action of specific enzyme called Plasminogen Activators.  Activation of Plasminogen can occurs due to  Intrinsic, Extrinsic, Exogenous Plasminogen Activation, andActivation in Secretory Ducts.

15. drmsaiem FIBRINOLSIS SYSTEM  Plasminogen is a part of any clot because of the tendency of fibrin to absorb plasminogen from the plasma in normal circumstances.  When plasminogen activators performed their function, plasmin is formed within the clot, which gradually dissolves the clot while leaving time for tissue repair.  Free Plasmin is released to the plasma, however, anti- plasmin is there immediately destroy any plasmin released from the clot.

16. drmsaiem FIBRINOLSIS SYSTEM  When Pathologic Coagulation processes are involved, excessive free plasmin is released to the plasma  In these situation, the available anti-plasmin is depleted and plasmin begins destroying components other than fibrin, including, fibrinogen, factor V and VIII and other factors.

17. drmsaiem FIBRINOLSIS SYSTEM FIBRIN(OGEN) DEGRADATION by PLASMIN  In the process of fibrinogen or fibrin degradation by plasmin within a clot, specific molecular fragments are produced called Fibrin (ogen) Degradation Products (FDP) or Fibrin (ogen) Split Products (FSP)  These degradation products are removed by the reticuloendothelial system and other organs.  The sequence of reaction in the degradation of Fibrin(ogen) by plasmin are X, Y, D (D-D dimer) and E.

18. drmsaiem FIBRINOLSIS SYSTEM  Fibrin(ogen) Degradation by Plasmin  Fragment X and Y are referred to as early degradation products  Fragment D and E are late degradation products  Fragment X is the first and the largest fragment formed (Mwt 250,000 d)  Fragment X is the results of Plasmin (P) cleavage of the terminal portion of the alpha (α) chains from a fibrin polymer  Fragment X is cleaved by Plasmin (P) to form two fragments called Y (YY) and an intermediate complex (DXD)

19. drmsaiem FIBRINOLSIS SYSTEM  This complex is further cleaved into intermediate complexes DED and DY/DY until finally, fragment E and D (D-D dimer) are formed.  A single fragment D has Mwt 90,000 d and that the D-D dimer is 180,000 d  Presence of D-D dimer is a specific indication of in vivo fibrinolysis, namely, intravascular thrombin formation leading to fibrin formation and its subsequent degradation

20. drmsaiem FIBRINOLSIS SYSTEM Pathologic Effect of FDPs  The FDPs are significant because of their haemostatic effects, which include;  Anti-thrombin activity  Interference with polymerization of fibrin monomer  Interference with platelet activity

21. drmsaiem FIBRINOLSIS SYSTEM The early and large fragments (X and Y) along with the intermediate FDPs, are important in exerting anticoagulant Effect Fragment Y and D inhibit fibrin polymerization Fragment Y and D inhibit fibrin polymerization Fragment E is a powerful inhibitor of thrombin Fragment E is a powerful inhibitor of thrombin All four fragments, but particularly low molecular weight All four fragments, but particularly low molecular weight FDP, have an effinity coating platelet membrane and therefore, cause a clinically significant platelet dysfunction by inhibiting aggregation.

22. drmsaiem FIBRINOLSIS SYSTEM Fibrinolytic Inhibitors  1- Alpha-2- Anti-plasmin (α2 anti-plasmin)  An (α2) glyco-protein  Most important naturally occurring inhibitor  The principle inhibitors of fibrinolysis by binding with plasmin that is free in the plasma (neutralizing plasmin)  Inhibits the clot-promoting activities of plasma kallikrein  Inhibits the serine proteases Xlla, XIa, IIa and Xa  Hereditary deficiencies have been associated with, Excessive clotting (DIC) Excessive fibrinolysis

23. drmsaiem FIBRINOLSIS SYSTEM 2- Alpha 2 Macroglobulin  Large naturally occurring plasma GP  Inhibits component in both the fibrinolysis and coagulation systems  Inhibits plasmin after alpha 2 anti-plasmin depletion 3- Alpha 1 Antitrypsin  The third most important naturally occurring inhibitor of fibrinolytic system. Inactivates plasmin slowly and does not bind plasmin until both alpha2 anti-plasmin and alpha 2 macroglobulin are saturated  Inhibits coagulation by its potent inhibitory effects on factor XIa

24. drmsaiem FIBRINOLSIS SYSTEM Other Inhibitors  Anti-thrombin III, inhibits fibrinolysis by inhibiting plasmin and kallikrein  The C1 inactivator also inhibits plasmin.