The body maintains hemostasis, a balance between forming blood clots to stop bleeding and dissolving them to keep blood flowing freely. Protein C and Protein S are vitamin K-dependent proteins that function as the body’s intrinsic “braking system” for this process. A deficiency in either protein disrupts this balance, leading to excessive clotting, known as a pro-thrombotic state. When these natural anticoagulants are dysfunctional, the mechanism designed to prevent clots from growing fails, increasing the risk of forming dangerous blood clots.
The Critical Function of Protein C and Protein S
These proteins are central to the protein C anticoagulant pathway, which regulates the coagulation cascade. Protein C circulates in the blood as an inactive precursor (zymogen) until it encounters a complex of thrombin and thrombomodulin on the surface of endothelial cells. This interaction activates Protein C into Activated Protein C (APC), a powerful enzyme.
The newly formed APC targets and degrades two specific pro-clotting factors: Factor Va and Factor VIIIa. By inactivating these factors, APC slows or stops the clotting process by cutting off the supply line for further thrombin generation. Protein S serves as a cofactor that significantly enhances APC’s ability to inactivate both factors. A deficiency in either protein compromises this negative feedback loop, allowing clot formation to proceed unchecked.
Inherited Versus Acquired Deficiency
Deficiencies in Protein C and Protein S stem from two origins: genetic inheritance or acquired conditions that develop later in life. Inherited forms are typically passed down through an autosomal dominant pattern, meaning only one copy of the mutated gene is needed to be affected. Inherited deficiencies are classified into subtypes based on how the protein is affected.
Inherited Subtypes
In Protein C deficiency, Type I is a quantitative defect characterized by a reduced amount of protein. Type II is a qualitative defect where the protein is present but does not function correctly. For Protein S, Type I involves a reduction in both total and free protein, while Type III involves a normal total level but a low level of the active, free form.
Acquired Causes
Acquired deficiencies are more common and result from underlying medical issues that impair protein synthesis or increase consumption. Secondary causes include severe liver disease, as the liver is the primary site of synthesis for both proteins. Deficiency can also result from Vitamin K deficiency or treatment with vitamin K antagonist medications like warfarin, since both proteins require Vitamin K for production. Severe systemic inflammation, such as sepsis or disseminated intravascular coagulation (DIC), can also lead to rapid consumption and depletion of these anticoagulants.
Clinical Manifestations and Associated Risks
The primary clinical risk associated with Protein C and Protein S deficiency is venous thromboembolism (VTE), which encompasses deep vein thrombosis (DVT) and pulmonary embolism (PE). DVT is a clot usually formed in the deep veins of the legs, causing pain and swelling. PE occurs if a portion of the clot breaks off and travels to the lungs, obstructing blood flow and gas exchange.
Individuals who inherit a heterozygous deficiency typically experience their first thrombotic event later in life. These events are often triggered by additional risk factors like surgery, prolonged immobilization, or pregnancy. The overall risk of VTE in heterozygous carriers is significantly higher than in the general population, estimated to be up to seven times greater for Protein C deficiency.
Neonatal Purpura Fulminans (NPF)
A rare, life-threatening complication is neonatal purpura fulminans (NPF). This occurs almost exclusively in infants who inherit the severe, homozygous form of the deficiency from both parents. NPF presents shortly after birth with widespread, rapidly progressive skin lesions caused by extensive microvascular thrombosis and disseminated intravascular coagulation. This pediatric emergency can quickly lead to skin necrosis, limb loss, and multiorgan failure.
Warfarin-Induced Skin Necrosis (WISN)
Another specific risk is warfarin-induced skin necrosis (WISN), a paradoxical complication when starting warfarin in deficient patients. Warfarin initially lowers the levels of Protein C and Protein S faster than it lowers pro-clotting factors, creating a temporary, highly pro-thrombotic state. This imbalance causes blood clots to form in the small vessels of the skin, leading to painful, purplish, and necrotic lesions, most commonly on the breasts, buttocks, and thighs.
Diagnostic Testing and Management Strategies
The diagnosis of Protein C and S deficiency relies on specialized blood tests that measure both the functional activity and the total quantity of the proteins. A functional assay, often clot-based, determines how well the protein is performing its anticoagulant role, while an antigen assay measures the actual amount of the protein present in the plasma. Comparing these two results helps classify the type of deficiency—whether it is a quantitative lack or a qualitative dysfunction.
Proper timing of these tests is paramount because the results can be temporarily skewed by acute events and certain medications. Testing should generally be deferred until after an acute thrombotic event has resolved, as the clotting process itself consumes and lowers the levels of these proteins. Furthermore, patients must often stop taking vitamin K antagonist medications for several weeks before testing to obtain an accurate baseline level.
Management focuses on preventing and treating thrombotic events, primarily through anticoagulation therapy. Symptomatic patients usually require long-term anticoagulation with medications like heparin derivatives, warfarin, or direct oral anticoagulants (DOACs). When initiating warfarin, careful bridging with a fast-acting injectable anticoagulant is mandatory to prevent the risk of WISN. For acute, severe manifestations like neonatal purpura fulminans, immediate treatment involves the administration of a purified Protein C concentrate or fresh frozen plasma to rapidly replace the missing protein and halt the clotting cascade.