B. Fibrinolysis

Main enzyme that breaks down fibrin is plasmin

Plasmin

Structure of plasminogen

• 560 amino-acid heavy chain + 241 amino-acid light chain
• Glutamate at amino terminal
• Folded into 5 loop structures
  * Each held together by 3 disulfide bonds

Function of plasmin

Plasmin
--> Lyses fibrin and fibrinogen
--> Produces fibrinogen degradation products (FDP)
* FDP also inhibits thrombin

NB:

• D-Dimers are cleavage products of cross-linked fibrin

Production of plasmin

Conversion of plasminogen to plasmin is by

• Thrombin
  * [WG21:P546]
• Tissue-type plasminogen activator (t-PA)
  * Released from local endothelium in response to local thrombin production
• Urokinase-type plasminogen activator (u-PA)
• Factor 12
  * [Lecture notes]
• Proteases released from leucocytes

Conversion of plasminogen to plasmin is inhibited by:

• Alpha2-antiplasmin
  --> Binds to plasmin and block its action on fibrin
  * Inhibits free plasmin in circulation
• Plasminogen activator inhibitor (PAI-1, PAI-2)
  * PAI is made in endothelium and also released by platelets
  * Found in plasma
  * Main inhibitor of t-PA and u-PA

• Antifibrinolytic agents
  * e.g. tranexamic acid

Plasminogen receptors

• Plasminogen receptors are located on many different types of cells
  * e.g. endothelial cells
• When plasminogen binds to plasminogen receptors
  --> Becomes activated
  --> Prevents clot formation at intact blood vessel walls
  * [WG21:p546]

Control of fibrinolysis

• When plasminogen is bound to fibrin
  --> Protected from alpha2-antiplasmin
• Systemic fibrinolysis is prevented by circulating alpha2-antiplasmin, which breaks down free plasmin in circulation