From the Guidelines
Protein C is activated by thrombin when it binds to thrombomodulin on the endothelial cell surface, as evidenced by the most recent study in 2023 1. This process occurs as part of the body's natural anticoagulation system. When thrombin binds to thrombomodulin, it undergoes a conformational change that alters its specificity, allowing it to efficiently activate protein C. The key points to consider are:
- Thrombomodulin is a cofactor for thrombin-catalyzed activation of protein C 1
- The activation of protein C is crucial for regulating blood clotting and preventing excessive coagulation
- Thrombomodulin plays important roles in both regulating thrombosis and inflammation, and its unique structure lectin-like domain expresses anti-inflammatory and cytoprotective properties 1 Once activated, protein C (now called activated protein C or APC) functions as an anticoagulant by inactivating factors Va and VIIIa, which are essential for continued thrombin generation. This mechanism helps regulate blood clotting and prevents excessive coagulation, as supported by the study in 2023 1. It's worth noting that while other studies, such as the one in 2013 1, also discuss the regulation of thrombin and fibrin, the most recent and highest quality study 1 provides the most relevant information on the activation of protein C.
From the Research
Activation of Protein C
- Protein C is activated on the surface of endothelial cells by the thrombin-thrombomodulin complex 2, 3, 4, 5, 6
- The endothelial cell protein C receptor (EPCR) binds protein C and presents it to the thrombin-thrombomodulin activation complex, enhancing protein C activation approximately 20-fold in vivo 3, 6
- The activation of protein C by the thrombin-thrombomodulin complex can be further enhanced when protein C binds to its membrane receptor, the endothelial-cell protein C receptor 2
Role of Thrombomodulin
- Thrombomodulin binds thrombin, directly inhibiting its clotting and cell activation potential while at the same time augmenting protein C activation 3, 5
- Thrombomodulin also has direct anti-inflammatory activity, minimizing cytokine formation in the endothelium and decreasing leukocyte-endothelial cell adhesion 3
Importance of Protein C Activation
- Activated protein C (APC) down-regulates thrombin formation by inactivating coagulation factors Va and VIIIa, thereby inhibiting further thrombin generation 2, 3, 4, 5, 6
- APC also exerts cytoprotective effects through endothelial protein C receptor binding, preventing the lethal effects of E. coli-associated sepsis in animal models and improving the outcome of patients with severe sepsis 2, 3, 4