A.2. Control of clot formation

Inhibitors of clot formation:

1. Antithrombin III (AT3)
2. Heparin cofactor II
3. Thrombomodulin, Protein C and protein S
4. Tissue factor inhibitor
5. Endothelium
6. Dilution

A.2.1. Antithrombin III (AT3)

[WG21:p546]

• Circulating protease inhibitor that binds to serine proteases (e.g. thrombin and factor 10a)
  --> Blocking their activities
• Accounts for 70% of plasma capacity to inhibit coagulation
  * 75% according to HH26
• Produced by liver
• Factors 9-12 are inhibited by AT3
  * [WG21:p546]
• Thrombin and Factor 7/TF complex are also inhibited by AT3
  * [HH26:p603]
• Binding is facilitated by heparin
  * Action is accelerated 1000 times by heparin
• Hemoglobin also facilitates AT3 action
  * [WG21:p547] (but didn't elaborate on the mechanism)

A.2.2. Heparin cofactor II

• Inhibits thrombin
• Reaction greatly enhanced by heparin
• Exact physiological role unclear

A.2.3. Thrombomodulin and protein C

All endothelial cells (except for those in cerebral microcirculation) produce thrombomodulin

Thrombomodulin binds to thrombin
--> Forms thrombomodulin-thrombin complex
--> Activates protein C

Activated protein C

[WG21:p546]

• Protein S act as a co-factor
• Activated by thrombomodulin-thrombin complex
• Inactivates factor 5 and 8
• Inactivates an inhibitor of tissue plasminogen activator (thus increasing plasmin formation)

A.2.4. Tissue factor inhibitor

(Referred to as tissue factor pathway inhibitor in WG21)

• Synthesized by endothelium and also released by platelets
• Binds factor 10a and inhibits Factor 7-TF complex
• Main role: Removal of excessive Factor 10a

Extrinsic pathway is inhibited by a tissue factor pathway inhibitor that forms a quaternary structure with TPL, factor 7a and factor 10a

A.2.5. Role of endothelium in preventing clotting

1. Anticoagulant surface (Heparan sulfate)
2. Thrombomodulin
3. Cell surface ADPase
   --> This enzyme metabolises ADP released from platelets
   * ADP otherwise would cause platelet aggregation
4. Release prostacycline
   --> Inhibits platelet aggregation and a vasodilator
5. Release NO
   --> Inhibits platelet aggregation and a vasodilator
6. Production of tPA
   * Activates plasmin
   * Stimulated by local production of thrombin
7. Production of prostacyclin
   * Synthesized by endothelium
   * Prevents platelet aggregation
   * Vasodilator
   * Also see Endothelium-related vasoactive substances

A.2.6 Dilution

Blood flow dilutes the level of active mediators and limits buildup