• Blood under normal condition is kept in a fluid state, the coagulation

pathway is kept under control via the following mechanism

• Fibrinolytic system
• Protease Inhibitors
• These act on coagulation factors so as to oppose the formation of
thrombin.
• Eg:
• Antithrombin
• Protein C
• Alpha 1 antiplasmin
• Alpha 2 macroglobulin
• Plasminogen
• Plasmin
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 Fibrinolysis System in Homeostasis

• 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. fibronectin
• Alpha 2 antiplasmin

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 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 .

Physiologic Fibrinolysis
Many similarities exist between Coagulation and Fibrinolytic
systems.
• AS there are checks and balances in the formation of clot
• 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.
 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.
• TPA : ,tissue plasminogen activator
• Urokinase ( like) Plasminogen activator
• Tissue Plasminogen Activators, convert Plasminogen to Plasmin are
released from injured vessel walls.

• ECs secretes TPA, (hydrolysis of Plasminogen)

• PAI-1 bound TPA*

• 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).
• Urokinase Plasminogen Activator
• E.Cs derived
• Monocytes
• Macrophages
• Circulates in plasma

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 Comments Plasmin's Roles

Cleaves Fibrin and Fibrinogen to Activates Fibrinolysis

fibrin (ogen) degradation products
X, Y and D-E
Factors XII----XIIa is amplified Activates Intrinsic Coagulation
indirectly by plasmin Pathway

Destroys factors VIII and V Interferes with intrinsic and

common pathways

FDP interfere with thrombin Block Thrombin conversion of

influence on fibrinogen fibrinogen to fibrin
 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.

• Plasminogen is a single-chain glycoprotein with a Mwt of

90,000 d

• Synthesized in the liver

• Increased concentrations are found in association with

inflammation.
• • Intrinsic Plasminogen Activation
• • Extrinsic Plasminogen Activation
• • Exogenous Plasminogen Activation
• • Plasminogen Activation in Secretory Ducts.
• Plasminogen Activator Inhibitor 1 (PAI 1)

• Ecs, Megakaryocytes, Smooth Muscles, fibroblasts, monocytes, adiposcytes,

heapatocytes
• Stored in patelets
• Principal inhibitor of plasminogen
• Inactivating both TPA and UPA

• Increased in :
• Obesity, atherosclerosis, sepsis and stroke

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• 1- Alpha-2- Anti-plasmin (α2 anti-plasmin)
• An (α2) glyco-protein
• SYNTHESIZED IN THE LIVER
• 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
 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
• Thrombin –thrombomodulin complex
• Prevents binding of TPA and Plasminogen to fibrin
• Decreased thrombin = reduced TAFI

• Seen in hemophilia

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 Other Inhibitors
• Anti-thrombin III, inhibits fibrinolysis by inhibiting plasmin and kallikrein

• The C1 inactivator also inhibits plasmin.

Thrombin
TAFI
• 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.
• 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.
• 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.
• 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.
 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.
• 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)
• 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
 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
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 E is a powerful inhibitor of thrombin
• 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.
Thrombin
TAFI
The End