Protein C, protein S and thrombomodulin
Fibrin and control · Vitamin K dep. Kills Va and VIIIa
Thrombin that binds endothelial thrombomodulin loses its procoagulant specificity and instead activates protein C on the endothelial protein C receptor. Activated protein C, with protein S as cofactor, proteolytically destroys factors Va and VIIIa, shutting down both prothrombinase and the intrinsic tenase. Both proteins are vitamin K dependent, which is why warfarin transiently removes them too.
Traced from the start
- Tissue factor and the extrinsic triggerVitamin K cycle and gamma-carboxylation
- Contact activation system (factor XII, prekallikrein, high-molecular-weight kininogen)
- Subendothelial collagen and von Willebrand factor
- Tissue factor-factor VIIa complex (extrinsic tenase)Factor IXaFactor VIIIa and its von Willebrand factor carrierActivated platelet phospholipid surface
- Factor XaFactor VaProthrombin (factor II)
- Thrombin (factor IIa)
- Protein C, protein S and thrombomodulin
Detail
- Activated by
- The thrombin-thrombomodulin complex, accelerated by the endothelial protein C receptor
- Action
- Activated protein C with protein S cleaves and inactivates factor Va (at Arg506 and Arg306) and factor VIIIa
- Vitamin K dependent
- Both; protein C has a short half-life of about 8 hours, which underlies warfarin-induced skin necrosis
- Protein S
- About 60% is bound to C4b-binding protein and inactive; only free protein S is a cofactor, and it falls in pregnancy, on the oral contraceptive pill and in acute inflammation
When it goes wrong
Homozygous protein C deficiency in a neonate
Neonatal purpura fulminans within hours of birth: widespread dermal microvascular thrombosis with skin necrosis and DIC; treat with protein C concentrate or fresh frozen plasma
Meningococcal sepsis acquiring severe protein C deficiency
Acquired purpura fulminans with symmetrical peripheral gangrene, and adrenal haemorrhage in Waterhouse-Friderichsen syndrome
Factor V Leiden making factor Va resistant to cleavage by activated protein C
Activated protein C resistance, the commonest inherited thrombophilia; screened by an APC resistance ratio and confirmed by genotyping
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