Drmsaiem FIBRINOLSIS SYSTEM DR MOHAMMED SAIEMALDAHR Faculty of Applied Medical Sciences Medical...

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FIBRINOLSIS SYSTEMFIBRINOLSIS SYSTEM

DR MOHAMMED DR MOHAMMED SAIEMALDAHRSAIEMALDAHR

Faculty of Applied Medical SciencesFaculty of Applied Medical Sciences

Medical Technology Dep.Medical Technology Dep.

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Fibrinolysis System in HomeostasisFibrinolysis System in Homeostasis In 1937 MaCfarlane reported that In 1937 MaCfarlane reported that damage tissuesdamage tissues

release a substance (activator that activates the release a substance (activator that activates the inert precursor called inert precursor called PlasminogenPlasminogen).).

PlasminogenPlasminogen: is normally circulates in the plasma : is normally circulates in the plasma to its active form called, to its active form called, PlasminPlasmin..

PlasminPlasmin is anon-specific is anon-specific ProteolyticProteolytic enzyme enzyme capable of degrading capable of degrading fibrinfibrin as well as as well as fibrinogenfibrinogen and factors and factors V & VIII.V & VIII.

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Function of Fibrinolysis in HomeostasisFunction of Fibrinolysis in Homeostasis

FibrinolysisFibrinolysis is the system whereby the temporary is the system whereby the temporary fibrin clot is systematically and gradually fibrin clot is systematically and gradually dissolveddissolved as the vessel heals in order to restore normal as the vessel heals in order to restore normal blood blood flowflow..

Is the body’s defense against Is the body’s defense against occlusionocclusion of blood of blood vesselsvessels

There are number of There are number of substancessubstances responsible for responsible for fibrinolysis (Fig).fibrinolysis (Fig).

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FIBRINOLSIS SYSTEM

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FIG. Simple overview of Fibrinolytic pathway. FIG. Simple overview of Fibrinolytic pathway. Tissue Tissue plasminogen activatorsplasminogen activators activateactivate

plasminogenplasminogen within clot to within clot to plasminplasmin, which slowly , which slowly dissolves fibrin clot. dissolves fibrin clot.

Inhibitors areInhibitors are neutralized by protein neutralized by protein C—S complexC—S complex, , thus enhancing thus enhancing fibrinolysisfibrinolysis..

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Tissue Tissue Plasminogen ActivatorsPlasminogen Activators, which convert , which convert PlasminogenPlasminogen to to PlasminPlasmin are released from are released from injured injured vessel wallsvessel walls..

Plasmin is Plasmin is trapped within the clottrapped within the clot, and clot lysis begin , and clot lysis begin slowly as soon as the clot is formed, slowly as soon as the clot is formed, with fibrin with fibrin degradationdegradation products being released in the plasma. products being released in the plasma.

Lysis is slow because of Lysis is slow because of fibrin clotfibrin clot stabilization by stabilization by factor factor XIIIXIII..

Protein Protein S and CS and C are two substance that are two substance that enhance enhance fibrinolysisfibrinolysis and and inactivateinactivate Tissue PlasminogenTissue Plasminogen ActivatorsActivators ( (tPA inhibitor)tPA inhibitor)..

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Physiologic FibrinolysisPhysiologic Fibrinolysis

Many similarities exist between Coagulation and Many similarities exist between Coagulation and Fibrinolytic systems.Fibrinolytic systems.

• • AS there are checks and balances in the formation AS there are checks and balances in the formation of clotof clot

• • There are similar mechanism for dissolution of the There are similar mechanism for dissolution of the clot to promote wound Healing.clot to promote wound Healing.

• • Important that bleeding does not recur because of Important that bleeding does not recur because of premature lysing of the clot.premature lysing of the clot.

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Activation of Plasminogen to PlasminActivation of Plasminogen to Plasmin Fibrinolysis is dependent on the enzyme Fibrinolysis is dependent on the enzyme PLASMINPLASMIN

Normally is not present in the blood Normally is not present in the blood in an in an activeactive form.form.

Can digest or destroy Can digest or destroy fibrinogenfibrinogen, , fibrinfibrin and and factors factors V & VIIIV & VIIIPromotes Coagulation and activates the Kinine and Promotes Coagulation and activates the Kinine and Complement systems.Complement systems.

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Plasmin's RolesPlasmin's RolesCommentsComments

Activates FibrinolysisActivates FibrinolysisCleaves Fibrin and Fibrinogen Cleaves Fibrin and Fibrinogen to fibrin (ogen) degradation to fibrin (ogen) degradation

products X, Y and D-E products X, Y and D-E

Activates Intrinsic Coagulation Activates Intrinsic Coagulation PathwayPathway

Factors XII----XIIa is amplified Factors XII----XIIa is amplified indirectly by plasmin indirectly by plasmin

Interferes with intrinsic and Interferes with intrinsic and common pathways common pathways

Destroys factors Destroys factors VIII and VVIII and V

Block Thrombin conversion of Block Thrombin conversion of fibrinogen to fibrinfibrinogen to fibrin

FDP interfere with thrombin FDP interfere with thrombin

influence on fibrinogeninfluence on fibrinogen

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Activation of Plasminogen to PlasminActivation of Plasminogen to Plasmin

• • A zymogen known as A zymogen known as PlasminogenPlasminogen which normally which normally present in plasma is converted to Plasmin by the action present in plasma is converted to Plasmin by the action of specific of specific enzymeenzyme called called Plasminogen Activators.Plasminogen Activators.

• • Plasminogen is a single-chain glycoprotein with a Mwt of Plasminogen is a single-chain glycoprotein with a Mwt of 90,000 d90,000 d

• • Synthesized in the liverSynthesized in the liver

• • Increased concentrations are found in association with Increased concentrations are found in association with inflammation.inflammation.

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Activation of PlasminogenActivation of Plasminogen can occurs due tocan occurs due to

• • Intrinsic Plasminogen ActivationIntrinsic Plasminogen Activation • • Extrinsic Plasminogen ActivationExtrinsic Plasminogen Activation • • Exogenous Plasminogen ActivationExogenous Plasminogen Activation • • Plasminogen Activation in Secretory Ducts. (Fig)Plasminogen Activation in Secretory Ducts. (Fig)

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For For therapeutic destructiontherapeutic destruction of thrombosis, of thrombosis, Urokinase, a trypsin-like protease, may be Urokinase, a trypsin-like protease, may be administered to a patient to activate plasminogen administered to a patient to activate plasminogen to plasmin and induce Fibrinolysis.to plasmin and induce Fibrinolysis.

Streptokinase is another agent used to activate Streptokinase is another agent used to activate Plasminogen to plasminPlasminogen to plasmin

Tissue Plasminogen activatorTissue Plasminogen activator (tPA) is an agent (tPA) is an agent used for the treatment of thrombosis. It released in used for the treatment of thrombosis. It released in vivovivo on endothelial cell damage and can be on endothelial cell damage and can be manufactured in manufactured in vitrovitro through recombinant DNA through recombinant DNA techniques.techniques.

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SummarySummary Fibrinolysis is dependent on the enzyme Fibrinolysis is dependent on the enzyme PLASMINPLASMIN Tissue Plasminogen Activators, which convert Tissue Plasminogen Activators, which convert

Plasminogen to Plasmin are released from injured Plasminogen to Plasmin are released from injured vessel walls.vessel walls.

Plasminogen (A zymogen) which normally present Plasminogen (A zymogen) which normally present in plasma is converted to Plasmin by the action of in plasma is converted to Plasmin by the action of specific specific enzymeenzyme called called Plasminogen Activators.Plasminogen Activators.

Activation of PlasminogenActivation of Plasminogen can occurs due tocan occurs due to Intrinsic, Extrinsic, Exogenous Plasminogen Intrinsic, Extrinsic, Exogenous Plasminogen

Activation, andActivation in Secretory Ducts.Activation, andActivation in Secretory Ducts.

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PlasminogenPlasminogen is a part of any clot because of the is a part of any clot because of the tendency of tendency of fibrinfibrin to absorb plasminogen from the to absorb plasminogen from the plasma in normal circumstances.plasma in normal circumstances.

When plasminogen activators performed their When plasminogen activators performed their function, function, plasminplasmin is formed within the clot, which is formed within the clot, which gradually dissolves the clot while leaving time for gradually dissolves the clot while leaving time for tissue repair.tissue repair.

Free Plasmin is released to the plasma, however, Free Plasmin is released to the plasma, however, anti-plasmin anti-plasmin is there immediately destroy any is there immediately destroy any plasmin released from the clot.plasmin released from the clot.

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When Pathologic Coagulation processes are When Pathologic Coagulation processes are involved, excessive involved, excessive free plasminfree plasmin is released to the is released to the plasmaplasma

In these situation, the available In these situation, the available anti-plasmin is anti-plasmin is depleteddepleted and plasmin begins destroying and plasmin begins destroying components other than components other than fibrinfibrin, including, , including, fibrinogen, factor V and VIIIfibrinogen, factor V and VIII and other factors. and other factors.

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FIBRIN(OGEN) DEGRADATION by PLASMINFIBRIN(OGEN) DEGRADATION by PLASMIN

In the process of fibrinogen or fibrin degradation by In the process of fibrinogen or fibrin degradation by plasmin within a clot, plasmin within a clot, specific molecular fragments specific molecular fragments areare produced called produced called FFibrin (ogen) ibrin (ogen) DDegradation egradation PProducts (roducts (FDPFDP) or ) or FFibrin (ogen) ibrin (ogen) SSplit plit PProducts (roducts (FSPFSP))

These degradation products are removed by the These degradation products are removed by the reticuloendothelial system and other organs.reticuloendothelial system and other organs.

The sequence of reaction in the degradation of The sequence of reaction in the degradation of Fibrin(ogen) by plasmin are Fibrin(ogen) by plasmin are X, Y, D (D-D dimer) and X, Y, D (D-D dimer) and EE..

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Fibrin(ogen) Degradation by PlasminFibrin(ogen) Degradation by Plasmin

Fragment Fragment XX and and YY are referred to as are referred to as early early degradationdegradation products products

Fragment Fragment DD and and EE are are late degradationlate degradation products products Fragment Fragment XX is the first and the largest fragment is the first and the largest fragment

formed (Mwt 250,000 d)formed (Mwt 250,000 d) Fragment Fragment XX is the results of Plasmin ( is the results of Plasmin (PP) cleavage ) cleavage

of the terminal portion of the of the terminal portion of the alpha (alpha (αα)) chains from chains from a a fibrin polymerfibrin polymer

Fragment Fragment XX is cleaved by Plasmin ( is cleaved by Plasmin (PP) to form two ) to form two fragments called fragments called Y (YY)Y (YY) and an intermediate and an intermediate complex complex (DXD)(DXD)

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This complex is further cleaved into intermediate This complex is further cleaved into intermediate complexes complexes DED DED and and DY/DYDY/DY until finally, fragment until finally, fragment E E and and DD ( (D-D dimerD-D dimer) are formed.) are formed.

A single fragment A single fragment DD has Mwt 90,000 d and that the has Mwt 90,000 d and that the D-D dimer is 180,000 dD-D dimer is 180,000 d

Presence of Presence of D-D dimerD-D dimer is a specific is a specific indication indication of in of in vivo vivo fibrinolysisfibrinolysis, namely, , namely, intravascular thrombin intravascular thrombin formationformation leading to leading to fibrin formation and its fibrin formation and its subsequent degradationsubsequent degradation

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Pathologic Effect of FDPsPathologic Effect of FDPs The FDPs are significant because of their The FDPs are significant because of their

haemostatic effects, which include;haemostatic effects, which include; Anti-thrombin activityAnti-thrombin activity Interference with polymerization of fibrin monomerInterference with polymerization of fibrin monomer Interference with platelet activityInterference with platelet activity

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The early and large fragments (The early and large fragments (X and YX and Y) along with the ) along with the intermediate FDPs, are important in intermediate FDPs, are important in exerting exerting

anticoagulant anticoagulant EffectEffect

• • Fragment Fragment YY and and DD inhibit inhibit fibrin polymerizationfibrin polymerization• • Fragment Fragment E is a powerful inhibitor of thrombinE 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 FDP, have an effinity coating platelet membrane and therefore, cause a clinically significant platelet therefore, cause a clinically significant platelet dysfunction dysfunction

by by inhibiting aggregation.inhibiting aggregation.

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Fibrinolytic InhibitorsFibrinolytic Inhibitors 1-1- Alpha-2- Anti-plasmin ( Alpha-2- Anti-plasmin (αα2 anti-plasmin)2 anti-plasmin) An (An (αα2) glyco-protein2) glyco-protein Most important naturally occurring inhibitorMost important naturally occurring inhibitor The The principleprinciple inhibitors of fibrinolysis by binding with inhibitors of fibrinolysis by binding with

plasmin that is free in the plasma (plasmin that is free in the plasma (neutralizing plasminneutralizing plasmin)) Inhibits the clot-promoting activities of plasma Inhibits the clot-promoting activities of plasma

kallikreinkallikrein Inhibits the serine proteases Inhibits the serine proteases Xlla, XIa, IIa and XaXlla, XIa, IIa and Xa Hereditary Hereditary deficienciesdeficiencies have been associated with, have been associated with,

Excessive clotting (DIC)Excessive clotting (DIC)Excessive fibrinolysisExcessive fibrinolysis

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2-2- Alpha 2 Macroglobulin Alpha 2 Macroglobulin Large naturally occurring plasma GPLarge naturally occurring plasma GP Inhibits component in both the fibrinolysis and Inhibits component in both the fibrinolysis and

coagulation systemscoagulation systems Inhibits plasmin after Inhibits plasmin after alpha 2 anti-plasmin depletionalpha 2 anti-plasmin depletion

3- 3- Alpha 1 AntitrypsinAlpha 1 Antitrypsin The third most important naturally occurring The third most important naturally occurring

inhibitor of fibrinolytic system. inhibitor of fibrinolytic system. Inactivates plasminInactivates plasmin slowly and does not bind plasmin until both slowly and does not bind plasmin until both alpha2 alpha2 anti-plasmin and alpha 2 macroglobulin are anti-plasmin and alpha 2 macroglobulin are saturatedsaturated

Inhibits coagulation by its potent inhibitory effects Inhibits coagulation by its potent inhibitory effects on factor on factor XIaXIa

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Other InhibitorsOther Inhibitors Anti-thrombin III, inhibits fibrinolysis by inhibiting Anti-thrombin III, inhibits fibrinolysis by inhibiting

plasmin and kallikreinplasmin and kallikrein

The C1 inactivator also inhibits plasmin.The C1 inactivator also inhibits plasmin.

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