3. Old stuff
          3.1. Old pharm stuff (pre 2009)
              3.1.4. Physiology
                  3.1.4.4. Haematology
                      3.1.4.4.1. Haemostasis
 3.1.4.4.1.2. Fibrinolysis 

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