La voie d'inhibition dynamique

C'est la voie de la PC qui inhibe la génération de thrombine et la génération de la prothrombinase via la régulation de l'activité des cofacteurs activés (46,47).

La PC est une protéine plasmatique dont l'activation est régulée par un récepteur membranaire de la cellule endothéliale: la thrombomoduline (TM). La TM est présente en grande quantité dans la microcirculation. En se fixant à la TM, la thrombine perd ses

70 propriétés procoagulantes et acquiert des propriétés anticoagulantes: elle devient incapable de coaguler le fibrinogène et d'activer les cofacteurs V et VIII ou les plaquettes mais devient capable d'activer la PC (48). Un second récepteur, l’EPCR (endothelial protein C receptor) dont la densité est très élevée dans les gros vaisseaux (aorte) fixe la PC et accélère son activation par le complexe thrombine/TM. Son rôle pourrait être de concentrer la protéine C sur des sites où la TM est peu présente (gros vaisseaux) (49-50). La PCa est une sérine protéase. Son cofacteur, la protéine S (PS) favorise sa fixation sur les phospholipides acides des membranes cellulaires, lui permettant d'inactiver par protéolyse les FVa et VIIIa. Les complexes d’activation des FII et X ne peuvent plus se former efficacement puisque les cofacteurs Va et VIIIa ne sont plus actifs et la cinétique de production de la thrombine devient très lente. La PS circule dans le sang, liée en partie à une protéine du système du complément: la C4b Binding protein (C4bBp). Seule la PS libre (soit environ 40% de la protéine S totale) a une activité cofacteur de la PC (51-54).

Les deux systèmes associés inhibent la génération et l'activité de la thrombine ainsi que celle des complexes enzymatiques (Figure II- 9).

Facteur Tissulaire VIIa Xa XII a XI a IXa IIa Va Fibrine AT VIIIa PCa/PS TFPI HCII PZ/ZPI

71

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