The body has a complex system to manage blood clotting, ensuring bleeding stops when necessary while preventing unnecessary clot formation. Proteins C and S are natural anticoagulants in the blood that help maintain this balance. When these proteins are insufficient or don’t function properly, this equilibrium is disrupted, increasing the risk of various health complications.
Understanding Protein C and S and Their Deficiencies
Proteins C and S are vitamin K-dependent glycoproteins primarily synthesized in the liver, working together as a natural anticoagulant system. Protein C, an inactive enzyme precursor, becomes activated protein C (aPC) when it binds to thrombomodulin on endothelial cell surfaces, a process catalyzed by thrombin. Once activated, aPC, with protein S as a cofactor, inactivates clotting factors Va and VIIIa. This inactivation slows the coagulation cascade, preventing uncontrolled clot formation.
A deficiency in either protein C or S means there are low levels of these proteins or they do not function effectively. This imbalance shifts the body towards a procoagulant state, significantly increasing the risk of developing abnormal blood clots, a condition known as thrombosis.
Deficiencies can be inherited or acquired. Inherited forms are genetic, typically passed down in an autosomal dominant pattern, meaning a single copy of an abnormal gene can lead to the condition. Approximately 1 in 200 to 500 individuals may have an inherited protein C deficiency, while protein S deficiency occurs in about 1 in 500 people.
Acquired deficiencies are more frequently identified and can arise from various medical conditions or treatments. Common causes include severe liver disease, severe infections like sepsis or disseminated intravascular coagulation (DIC), severe vitamin K deficiency, ongoing warfarin therapy, certain hormones, and pregnancy. Newborns can also have physiologically low levels of protein C, which typically increase to adult ranges by 6 to 12 months of age.
Recognizing the Signs
The most common clinical manifestation of protein C or S deficiency is venous thromboembolism (VTE). This involves blood clots forming within veins, primarily deep vein thrombosis (DVT), often in the legs or arms. Symptoms of DVT include swelling, pain, and redness or purple discoloration in the affected limb, often described as a cramp. The area may also feel warm to the touch.
A more serious complication arises if a piece of a DVT breaks off and travels to the lungs, leading to a pulmonary embolism (PE). Symptoms of PE include difficulty breathing, chest pain (especially when breathing deeply), a rapid heart rate, and sometimes fainting or coughing up blood. Prompt medical attention is necessary for these signs.
While less common, a severe complication seen primarily in infants with severe congenital deficiency is purpura fulminans. This rare condition is characterized by widespread skin necrosis, presenting as large purple patches or reddish-black lesions on the skin, often with central hemorrhagic necrosis. It is a rapidly progressive thrombotic disorder that can be life-threatening and may also involve disseminated intravascular coagulation.
Clots can also occur in less common locations. Cerebral venous sinus thrombosis might present with headaches, numbness, weakness in the face, arm, or leg, confusion, or slurred speech. Mesenteric ischemia, involving clots in the abdominal veins, can lead to symptoms associated with injury to the liver, spleen, or intestines. Recognizing these diverse signs is important for early diagnosis, which can help prevent serious complications.
Diagnosis and Treatment Approaches
Diagnosing protein C and S deficiencies primarily involves specialized blood tests that measure both the activity and antigen levels of these proteins. Functional assays are preferred for screening as they can identify both quantitative (Type I, low protein amount) and qualitative (Type II, normal amount but poor function) deficiencies. If a low activity level is detected, an immunoassay for antigen levels helps distinguish between these types.
Proper sample collection is important; blood samples are typically collected in citrate and plasma should be frozen within four hours. Factors that can influence test results, such as acute clotting events or certain medications like warfarin, must be considered. Patients on warfarin should generally discontinue the medication for at least two weeks before testing, or be transitioned to low molecular weight heparin if stopping anticoagulation is not feasible.
The main goals of treating protein C and S deficiencies are to prevent and treat blood clots. For active blood clots, acute treatment typically involves anticoagulant medications. Heparin, often administered intravenously or as low molecular weight heparin, is frequently used as an initial therapy, followed by a transition to oral anticoagulants.
Long-term management often involves prophylactic (preventive) anticoagulation for individuals at high risk, especially those with a history of recurrent clots or a strong family history of the deficiency. Warfarin, a vitamin K antagonist, has historically been a mainstay for long-term anticoagulation, with a target International Normalized Ratio (INR) typically between 2.0 and 3.0. However, warfarin can paradoxically increase clotting risk initially by rapidly decreasing protein C levels, potentially leading to warfarin-induced skin necrosis, so it is often initiated with a heparin bridge. Direct oral anticoagulants (DOACs) such as rivaroxaban and apixaban are also used and may be preferred due to their comparable efficacy and lower bleeding risk compared to warfarin in some cases.
General lifestyle considerations can also help manage the risk of clotting. These include maintaining adequate hydration, engaging in regular physical activity, and avoiding prolonged immobility, such as during long flights or bed rest. For individuals with protein C or S deficiency, avoiding estrogen-containing hormonal therapies may also be advised due to their potential to increase clotting risk.
Management during specific periods, like pregnancy or before surgical procedures, requires careful consideration. Pregnancy naturally increases the risk of venous thromboembolism, and protein C or S deficiency further elevates this risk. Prophylactic low molecular weight heparin (LMWH) is often recommended during pregnancy and for six weeks postpartum for these individuals. Before surgery, anticoagulation may need to be adjusted or temporarily discontinued, with decisions made in consultation with specialists to balance clotting and bleeding risk.