From the Guidelines
Protein C and protein S are crucial natural anticoagulant proteins that play a vital role in regulating blood clotting by inactivating clotting factors Va and VIIIa, thereby preventing excessive coagulation. These proteins are essential for maintaining the delicate balance between blood clotting and preventing abnormal blood clots, particularly deep vein thrombosis and pulmonary embolism 1. Protein C is a circulating vitamin K-dependent zymogen that is activated to APC, the active enzyme, by the thrombin-thrombomodulin complex, while protein S serves as a cofactor that enhances protein C's activity 1.
Key Functions and Deficiencies
- Protein C works by inactivating clotting factors Va and VIIIa, effectively slowing down the coagulation process.
- Protein S serves as a cofactor that enhances protein C's activity.
- Deficiencies in either protein can lead to hypercoagulable states, increasing the risk of abnormal blood clots.
- Protein C deficiency can be inherited as an autosomal dominant disorder or acquired through conditions like liver disease, vitamin K deficiency, or during warfarin therapy.
- Similarly, protein S deficiency can be genetic or acquired.
Clinical Implications and Management
- Testing for these proteins is important when evaluating patients with unexplained or recurrent thrombotic events, especially those occurring at a young age or in unusual locations.
- Treatment typically involves anticoagulation therapy to prevent clot formation in affected individuals.
- In severe cases, such as purpura fulminans in newborns, protein C deficiency can be life-threatening and may require aggressive management, including oral anticoagulants, low molecular weight heparin, and intravenous or subcutaneous protein C concentrate 1.
From the Research
Definition and Function of Protein C and Protein S
- Protein C (PC) and protein S (PS) are vitamin K-dependent glycoproteins that play a crucial role in regulating blood coagulation as natural anticoagulants 2, 3, 4.
- Protein C is activated by thrombin, and the resulting activated PC (APC) inactivates membrane-bound activated factor VIII and factor V 2.
- The free form of protein S is an important cofactor of APC, helping to inactivate activated factor V and factor VIII 2, 4.
Role in Thrombosis and Embolism
- Deficiencies in protein C and protein S can lead to an increased risk of venous thromboembolism, including deep vein thrombosis and pulmonary embolism 2, 3, 4, 5.
- There is also evidence to suggest that deficiencies in these proteins may be associated with arterial diseases, such as arterial thrombosis 3.
- The risk of thromboembolism in asymptomatic patients with protein C and protein S deficiency is significant, with an incidence of 2.5% per patient year for protein C deficient and 3.5% per patient year for protein S deficient patients 5.
Genetics and Diagnosis
- The molecular genetic background of protein C and protein S deficiencies is heterogeneous, with most mutations causing type I deficiency (quantitative disorder) 2.
- Type II deficiency (dysfunctional molecule) is diagnosed in approximately 5%-15% of cases 2.
- The diagnosis of protein C and protein S deficiencies can be challenging due to methodological variability and the presence of pseudogenes, which can make genetic diagnosis more complicated 2, 6.