Protein S deficiency is a condition that disrupts the body’s natural ability to regulate blood clotting, leading to an increased risk of forming abnormal clots. This disorder is classified as a type of thrombophilia, meaning the blood has an exaggerated tendency to coagulate. Protein S is a natural anticoagulant that helps keep the clotting mechanism in check. When levels of this protein are too low or its function is impaired, the body loses an important brake on the coagulation process, resulting in the formation of clots that restrict blood flow.
The Role of Protein S in Blood Clotting
Protein S is a vitamin K-dependent protein primarily synthesized in the liver. Its central function is to act as a cofactor for Activated Protein C (APC). Together, the APC/Protein S complex works to slow down the coagulation cascade.
This complex specifically targets and inactivates two key clotting factors, Factor Va and Factor VIIIa. By neutralizing them, Protein S limits the generation of thrombin, the enzyme that ultimately forms the clot. Protein S circulates in the blood in two forms, where only the “free” form is functionally active as a cofactor for APC. A deficiency in this protein removes a major regulatory step designed to prevent clot formation.
Types and Causes of Protein S Deficiency
The deficiency can arise from two main sources: inherited or acquired. Inherited Protein S deficiency is caused by a mutation in the PROS1 gene, which provides the instructions for making the protein. This genetic condition is most often passed down in an autosomal dominant pattern, meaning inheriting one copy of the altered gene is enough to cause the condition.
Hereditary deficiency is classified into three subtypes based on how the protein is affected. Type I involves a quantitative defect, where both the total amount and the function of the protein are reduced. Type II is a qualitative defect, meaning the total amount of protein is normal, but its function is impaired. Type III is a mixed defect, where the total protein level is normal, but the level of the active “free” protein S is low.
Acquired deficiency is more common and is linked to various underlying medical conditions or circumstances. Causes include:
- Conditions that impair protein synthesis, such as liver disease.
- Issues affecting vitamin K utilization, such as a severe deficiency in the vitamin.
- Kidney disease or certain infections.
- The use of specific medications like warfarin.
- Physiological states such as pregnancy or an acute thrombosis.
Recognizing the Symptoms and Diagnosis
The primary clinical manifestation of Protein S deficiency is an increased risk of Venous Thromboembolism (VTE), which is the formation of a blood clot in a vein. The most common VTE events are Deep Vein Thrombosis (DVT), which occurs in the deep veins of the legs, and Pulmonary Embolism (PE), which happens when a DVT breaks off and travels to the lungs. Symptoms of a DVT can include swelling, pain, and redness in the affected limb, while a PE may cause chest pain, shortness of breath, and palpitations.
While many individuals with the inherited form remain asymptomatic, a first clotting event often occurs before age 55, and women may experience recurrent miscarriages. In rare and severe inherited cases, usually seen in newborns who inherit the defective gene from both parents, a condition called purpura fulminans can occur. This involves widespread clotting in small blood vessels, leading to skin and tissue death.
Diagnosis begins with a review of the patient’s symptoms and family history of blood clots. Confirmation requires specific blood tests that measure the amount and function of Protein S. These laboratory tests measure the total Protein S antigen level and the level of the free, functionally active Protein S. Testing should be performed when a patient is stable, as acute clotting events, pregnancy, or certain anticoagulant medications can temporarily lower Protein S levels and skew the results.
Management and Treatment Options
The management of Protein S deficiency is dependent on whether a person has already experienced a blood clot. For an acute VTE event, treatment focuses on dissolving the existing clot and preventing its growth with anticoagulant medications. Initial treatment often involves an injectable anticoagulant, such as unfractionated heparin or low-molecular-weight heparin (LMWH).
This initial therapy is usually followed by long-term oral anticoagulation, which may include a vitamin K antagonist like warfarin or a Direct Oral Anticoagulant (DOAC) such as rivaroxaban or apixaban. For individuals who have experienced a clot, long-term or lifelong anticoagulation may be necessary to prevent recurrence.
Individuals with Protein S deficiency who have never had a clot may not require daily medication, but management is risk-based. Prophylactic anticoagulation is often recommended during periods of high risk, such as before and after major surgery, during prolonged immobilization like long-distance travel, or throughout pregnancy. These temporary measures help ensure the body’s clotting system remains adequately regulated when the risk of VTE is elevated.