Fibrinolytic system

Fibrinolysis is the plasmin-mediated enzymatic breakdown of fibrin. The fibrinolytic system is usually activated in concert with the coagulation system. The procoagulant, anticoagulant and fibrinolytic systems are tightly inter-regulated in order to maintain the fluidity of blood, while allowing controlled clot formation for haemostatic purposes followed by clot dissolution.

Table 8.2 Factors affecting fibrinolysis

Activation Tissue activator

Vascular wall activator PLASMINOGEN

Inhibition

Urokinase

(beta globulin) PLASMIN

Anti-activators

Plasminogen activation inhibitor Antiplasmins

* Alpha 2-antiplasmin

* Alpha 2-macroglobulin

* Alpha 1-antitrypsin

* C1 inactivator

* Interalpha-trypsin

* ATIII

FIBRIN

Fibrin degradation products

Plasminogen activators can be intrinsic (or blood-borne) such as factor XII, pre-kallikrein, high molecular weight kininogen and pro-urokinase; or may be extrinsic, such as tissue plasminogen activator, urokinase and streptokinase.

Endogenous extrinsic plasminogen activators are of two distinct structural, immunological and functional types: tissue-type plasminogen activator and urokinase-like plasminogen activator. They are serine proteases, which convert the inactive zymogen plasminogen to plasmin. Tissue type plasminogen activator is the major activator in the intravascular space and is released from stimulated endothelial cells. Urokinase is the major activator in the extravascular space and is synthesised by a range of cell types.

Plasminogen is a 790 amino acid with a 77 amino acid pre-activation peptide sequence, 5 homologous triple-loop structures called kringle domains, an activation cleavage site and a catalytic domain. Thrombolytic agents act by the hydrolysis of the arginine 560-valine 561 peptide bond in plasminogen to form plasmin.

Plasmin, a non-specific serine protease, brings about enzymatic degradation of fibrinogen, cross-linked fibrin and other plasma procoagulant proteins including factors V, VIII and XII. D-dimer is a degradation product of cross-linked fibrin. Fibrin degradation products result from the breakdown of cross-linked fibrin, fibrin monomers and uncross-linked polymers, and hence are less reliable markers of active thrombosis.

Resistance to thrombolysis may arise from selective lysis of fibrin, leaving activated platelets as a source of re-thrombosis. Platelets can release plasminogen activation inhibitor-1 and thromboxane A2. Clot-bound thrombin remains catalytically active, promoting thrombolysis.

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