Protein S Deficiency - Causes, Symptoms, Diagnosis, and Treatment

Introduction:

Protein S is a vitamin K-dependent anticoagulant protein that aids in regulating coagulation, inflammation, and apoptosis (biologically induced cellular death). The deficiency of protein S results in excessive formation of blood clots like deep vein thrombosis or pulmonary embolism (a clot in a vein or artery). These deficiencies are often transmitted from parents to children (an autosomal dominant trait). They may also occur due to acquired deficiencies like hepatic (liver) disease, nephrotic (kidney) syndrome, or vitamin K deficiency. They are often treated with anticoagulants followed by vitamin K therapy.

What Is the Defining Feature of Protein S Deficiency?

Protein S is an anticoagulant protein discovered in Seattle that inhibits or blocks the action of specific proteins that aid in the production of blood clots. Hence, both quantitative and qualitative abnormalities of protein S result in thrombosis (a blood clot). The protein S deficiency is differentiated into three types:

• Type 1: A quantitative defect associated with the hereditary disorder that causes a decrease in protein production.

• Type 2: A qualitative or functional deficiency that can be hereditary or acquired.

• Type 3: Characterized by antigen defect of protein S.

What Are the Causes of Protein S Deficiency?

The mutation gene results in a protein S deficiency, which can be innate or acquired. The innate deficiency is transmitted from parents to offspring, with a 50 % chance of transmission among each child. The acquired protein S deficiency involves the following conditions:

• Acute thrombosis.

• Vitamin K deficiency.

• Chronic infections.

• Nephrotic syndrome (a kidney disorder in which protein is excreted in the urine).

• Chemotherapy (cancer treatment).

• Higher risk of a blood clot in patients taking long-term oral contraceptives.

• Pregnancy.

• Systemic lupus erythematosus (an autoimmune disease that affects the joints, skin, kidneys, blood cells, brain, heart, and lungs).

• Disseminated intravascular coagulation (clotting disorder results in excessive bleeding).

What Are the Symptoms and Risk Factors of Protein S Deficiency?

Blood clots in arteries and veins (thrombosis) are common symptoms of protein S deficiency, which can cause a stroke in a child with the severe form of the disorder. Thrombosis is more common in people over 40 to 45 years of age and pregnant women with traumatic injuries and a recent history of surgery. A higher risk of thrombosis or emboli is seen in long-term immobilized patients and those under hormonal therapy. The predominant clinical manifestation of protein S deficiency are:

• Deep Vein Thrombosis: Deep vein thrombosis occurs when blood clot or thrombus accumulates in the vein, resulting in unilateral leg or calf swelling with mild-to-moderate pain. However, the initial vein inflammation can occur with or without deep vein thrombosis.

• Pulmonary Embolism: Pulmonary embolism occurs when a blood clot or thrombus accumulates in the arteries of the lungs, which is characterized by tachypnea (abnormal or faster breathing), chest pain, sudden unconsciousness or fainting, and an increased heart rate.

How to Diagnose Protein S Deficiency?

The diagnosis of protein S deficiency is significantly based on familial history, a coagulation test, and functional protein S antigens.

• Familial History: The deficiency of protein S is predominantly due to a hereditary autosomal dominant trait with an increased chance of transmission among all biological children. Hence, familial history plays an important role in assessing deficiency and thrombotic diseases.

• Protein S Antigen: The protein S antigen and free protein are detected by laboratory testing called ELISA (enzyme-linked immunosorbent assay). The level of free protein confirms deficiency, which does not increase with age, whereas the protein S antigen increases with the age.

• Functional Protein S: Functional protein S is based on the production and function of activated protein C. Vitamin K deficiency, pregnancy, sudden onset of blood clot or thrombosis, liver disease, and warfarin antagonism (an anticoagulant called warfarin, a vitamin K antagonist, is used to treat and prevent a number of coagulopathic and thromboembolic illnesses) are all conditions that interfere with protein C.

• Coagulation Tests: Evaluation of bleeding and clotting time, fibrinogen level, fibrin degradation, and the D-dimer (a protein fragment noticed when there is the presence of a blood clot in the body) test.

• Other Tests: Other tests for thrombosis are genetic test, doppler ultrasonography (to evaluate the movements of tissue and blood flow within the vessels), contrast venography (a vein x-ray by incorporating the contrast dye within a vein or bone marrow), magnetic resonance imaging (MRI scan to aid in the identification of vessel wall inflammation and swelling), and a chest scan for evaluation of blood flow.

What Are the Treatment Options for Protein S Deficiency?

The treatment is based on the severity of the disease and blood stability. Thrombosis is most commonly treated with anticoagulants (blood thinners). The widely prescribed anticoagulants are heparin, warfarin, Rivaroxaban, Apixaban, and Dabigatran. Initially, low-molecular-weight heparin is prescribed, which induces widespread clotting in the skin and soft tissues and is followed by a vitamin K antagonist or oral anticoagulant.

The standard treatment for genetically inherited protein S deficiency is lengthy until blood clot regulation is achieved. Then, prophylactic anticoagulation therapy with a low molecular weight of heparin is indicated before surgery, pregnancy (which decreases maternal bleeding), and long-term immobilization. Unfortunately, cerebral and mesenteric vein thrombosis, a potentially fatal condition, necessitates lifelong anticoagulant therapy.

What Are the Complications of a Protein S Deficiency?

Most of the cases of protein S deficiency are harmless, but it raises the risk of deep vein thrombosis and embolism at regular intervals. The thrombophilia associated with protein S deficiency results in higher morbidity (disease rate) and mortality (death rate). Additionally, prolonged warfarin anticoagulant therapy increases the risk of bleeding and skin necrosis (cellular tissues of skin begin to deteriorate). Protein S deficiency in neonates results in the clotting of the vessels known as purpura fulminates, which can be fatal if left untreated.

Conclusion:

Protein S deficiency is a rare condition, either acquired or congenital. Thrombosis is seen in the legs, brains, intestines, and lungs. The deficiency can also result in preterm birth and other pregnancy complications. The acquired deficiency can be prevented by withdrawing oral contraceptives and increasing vitamin K intake. In some cases, deep vein thrombosis can lead to post-thrombotic phlebitis (pain and swelling at the affected site); hence, compression stockings are recommended by medical professionals.