From the Guidelines
Protein C plays a crucial role in regulating blood clotting by preventing excessive clot formation and promoting fibrinolysis, thereby reducing the risk of abnormal blood clots and associated conditions like deep vein thrombosis and pulmonary embolism. When activated, protein C works to inactivate clotting factors Va and VIIIa, which are essential components of the coagulation cascade, effectively slowing down thrombin generation and limiting clot formation to areas of injury 1. Protein C also requires vitamin K for its synthesis in the liver and is activated by thrombin when bound to thrombomodulin on endothelial cells.
Some key points about protein C include:
- It helps regulate blood clotting and prevent excessive clot formation
- It promotes fibrinolysis, the breakdown of blood clots, by neutralizing plasminogen activator inhibitor-1
- Deficiencies in protein C can lead to hypercoagulable states, increasing the risk of abnormal blood clots, particularly in veins
- Protein C deficiency is associated with conditions like deep vein thrombosis, pulmonary embolism, and in severe cases, purpura fulminans in newborns 1
In the context of protein C deficiency, protein C replacement therapy is considered optimal, but its high cost often makes anticoagulation a more feasible alternative. However, using a combination of anticoagulation and protein C replacement may be preferable to using anticoagulation alone, especially in acute settings like purpura fulminans 1. The role of liver transplant in managing protein C deficiency also varies depending on patient and family preferences, with optimal timing of this therapy being unknown 1.
From the Research
Role of Protein C in Coagulation
- Protein C is a major regulator of blood coagulation, controlling the conversion of prothrombin to thrombin through a feedback inhibition mechanism 2.
- It circulates in plasma as an inactive zymogen and is activated on the surface of endothelial cells by the thrombin-thrombomodulin complex 2, 3.
- Activated protein C (APC) inhibits thrombin formation by inactivating coagulation factors Va and VIIIa, with the help of its cofactor protein S 2, 3, 4.
Mechanism of Action
- The activation of protein C is accelerated by the presence of endothelial protein C receptors 2, 3.
- APC limits coagulation by inactivating factors Va and VIIIa, which decreases thrombin-mediated inflammation 3.
- APC also has anti-inflammatory, cytoprotective, and barrier-protective activities by inducing cell signaling and modulating the cellular response to infection 3.
Clinical Significance
- Deficiencies in protein C and protein S are associated with an increased risk of venous thromboembolism (VTE) 2, 5, 6.
- Low levels of protein C are correlated with morbidity and mortality outcomes in sepsis and other critical illnesses 3.
- The use of anticoagulants such as apixaban may be effective in preventing recurrent thrombotic events in patients with inherited thrombophilia, including protein C deficiency 5.