Naturally Occurring Inhibitors Ahmad Sh. Silmi Msc, FIBMS IUG Faculty of Science Medical Technology Dept

Coagulation Inhibitors The activity of coagulation system must be attenuated. Numerous inhibitors are found in blood. Coagulation is controlled by three types of actions. Inhibition of converting enzymes (e.g., AT III, C1 esterase inhibitor, a2-macroglobulin, a2-antiplasmin, a1-antitrypsin, HC-II). Act on one or more of the converting enzymes (activated factors). AT III-heparin pathway: major system - 80% of the thrombin inhibitory action in plasma. Destruction of protein cofactors (e.g., TM-PC-PS system). TM-PC-PS system degrades cofactors V & VIII:C, inhibiting prothrombinase and tenase complexes, respectively. Blocking receptor availability needed for complex formation (e.g., Tissue factor pathway inhibitor (TFPI) and annexin V).

Antithrombin III (AT III) naturally-occuring anticoagulant binds to factors IXa, Xa, XIa, XIIa (slow) accelerated by heparin manyfold Implication: Heparin has almost NO anticoagulant action without AT III

Proposed Mechanism of AT III-Heparin System Lysine sites AT III Th H Serine site Arginine site Heparin Thrombin Antithrombin III H AT III Th

Proposed Mechanism of Thrombomodulin, Protein C and Protein S (TM-PC-PS) System F-Xa Prothrombin Activated platelet F-Va PS Thrombin x Ca++ Ca++ Protein C Activated Protein C Thrombin Thrombomodulin

Proposed Mechanism of Tissue Factor Pathway Inhibitor (TFPI) Activity F-Xa F-Xa TFPI TFPI F-Xa TFPI Tissue factor F-VIIa Endothelium

Anticoagulant Factors

INHIBITORS (cont.)