Protein S Deficiency: Understanding Its Clotting Complications (2025)

Protein S deficiency is a rare inherited blood clotting disorder that can cause dangerous blood clots. It is caused by a mutation in the PROS1 gene, which results in decreased levels or impaired function of protein S. Protein S is a natural anticoagulant that controls blood clotting by blocking the activity of certain proteins that promote the formation of blood clots. When there is not enough functional protein S, the risk of developing blood clots increases. This can lead to deep vein thrombosis (DVT) or pulmonary embolism (PE), which can be life-threatening.

Protein S deficiency and pregnancy

Protein S deficiency is a rare inherited disorder that increases the risk of developing blood clots. It is caused by variants or mutations in the PROS1 gene, which result in a reduction of functional protein S. This protein is responsible for blocking the activity of certain proteins that promote blood clotting. While many people with this disorder never develop blood clots, those who do are at risk of deep vein thrombosis (DVT) and pulmonary embolism (PE).

Pregnancy is one of the factors that can increase the risk of clotting in individuals with protein S deficiency. During a normal pregnancy, there is an increase in procoagulants and a decrease in anticoagulants, leading to a hypercoagulable state. This, coupled with the decreased levels of free protein S during the first and second trimesters, can result in placental thrombosis, hypoperfusion, fetal growth retardation, and fetal death. Women with protein S deficiency are at a particularly high risk of developing blood clots in the placenta, which can lead to placental insufficiency and miscarriage.

Protein S deficiency is associated with an increased risk of thrombophilia, which can lead to recurrent pregnancy loss. In a study of 40 pregnant women with a history of recurrent miscarriages, protein S deficiency was found to be more common than protein C deficiency, constituting an overall 15-fold increased risk of pregnancy loss. Screening for thrombophilia in women who have experienced pregnancy loss may be appropriate, and treatment with low molecular weight heparin (LMWH) is an option.

Pregnant women with protein S deficiency are typically advised to receive thromboprophylaxis during pregnancy and puerperium to prevent venous thromboembolism. Subcutaneous unfractionated or low molecular weight heparins (LMWH) are the anticoagulants of choice. In one case, a pregnant woman with protein S deficiency was successfully treated with low-dose aspirin and unfractionated heparin (UFH) until 20 weeks of gestation, with increased doses until delivery. The patient was monitored weekly with APTT levels and platelet counts during pregnancy.

Genetic causes of protein S deficiency

Protein S deficiency is a rare disorder that increases the risk of developing blood clots. It is a clotting problem that can be inherited from parents or acquired. The acquired form of protein S deficiency is more common and can be caused by conditions such as liver disease, kidney disease, nephrotic syndrome, chemotherapy, infections, and vitamin K deficiency.

Protein S is found in the bloodstream and is important for the control of blood clotting. It helps block the activity of certain proteins that promote the formation of blood clots. The PROS1 gene provides instructions for making protein S. Most variants that cause protein S deficiency change single DNA building blocks (base pairs) in the PROS1 gene. These gene variants change the amount of functional protein S. Individuals with protein S deficiency may not have enough functional protein S to inactivate clotting proteins, which increases the risk of developing blood clots.

Protein S deficiency can be inherited in an autosomal dominant or autosomal recessive pattern. In autosomal dominant inheritance, only one copy of the altered gene in each cell is sufficient to increase the risk of clotting. In autosomal recessive inheritance, both copies of the gene in each cell must have a variant to cause the disorder. The severe form of protein S deficiency that develops in infancy is inherited in an autosomal recessive pattern and is rare. Individuals with this form of protein S deficiency have a variant in both copies of the PROS1 gene.

There are three types of hereditary protein S deficiency: Type I, characterised by decreased protein S activity and decreased total and free protein S levels; Type II, which is related to decreased cofactor activity of the protein; and Type III, which is associated with normal protein S antigen levels and decreased protein S activity.

Acquired protein S deficiency

Protein S deficiency is a rare disorder that increases the risk of developing blood clots. It is typically an inherited condition, passed down from parents, but some cases are acquired. The acquired form of protein S deficiency is more common and can be caused by a variety of factors, including:

• Liver disease
• Kidney disease
• Nephrotic syndrome
• Chemotherapy
• Infections
• Vitamin K deficiency
• Pregnancy
• Taking birth control pills

The risk of developing blood clots in individuals with protein S deficiency can be influenced by additional factors such as age, surgery, immobility, and pregnancy. Treatment for this condition typically involves the use of blood thinners or anticoagulants to prevent excessive clotting.

Treatment for protein S deficiency

Protein S deficiency is a rare disorder that increases the risk of developing blood clots. It is typically inherited, but it can also be acquired. People with protein S deficiency are at risk of developing a type of clot called a deep vein thrombosis (DVT) that occurs in the deep veins of the arms or legs. A DVT can travel through the bloodstream and lodge in the lungs, causing a life-threatening clot called a pulmonary embolism (PE).

For pregnant women with protein S deficiency, treatment options vary. Some experts recommend prophylaxis only during the six weeks postpartum, while others suggest prophylaxis for the entire pregnancy and six weeks postpartum. In some cases, active prophylaxis with low molecular weight heparin (LMWH) may be recommended during pregnancy and for six weeks after giving birth.

In the case of acquired protein S deficiency, the underlying condition must be addressed. For example, if the deficiency is caused by liver disease or kidney disease, treating these conditions can help resolve the protein S deficiency. Additionally, addressing nutritional deficiencies, such as vitamin K deficiency, can help improve protein S levels.

While there is no specific cure for protein S deficiency, early diagnosis and proper management can help prevent the formation of blood clots and reduce the risk of potentially life-threatening complications.

Protein S deficiency in infants

Protein S deficiency is a rare disorder that increases the risk of developing blood clots. It is typically inherited in an autosomal dominant pattern, meaning that only one copy of the altered gene in each cell is required to heighten the risk of clotting. However, in infants, the severe form of protein S deficiency is inherited in an autosomal recessive pattern, necessitating both copies of the gene in each cell to be altered to cause the disorder.

The PROS1 gene is responsible for producing protein S, which is found in the bloodstream and plays a crucial role in controlling blood clotting. Protein S acts by blocking the activity of certain proteins that promote blood clot formation. Variants or mutations in the PROS1 gene can lead to reduced levels of functional protein S, resulting in protein S deficiency. This deficiency increases the likelihood of developing blood clots, particularly deep vein thrombosis (DVT) and pulmonary embolism (PE).

Affected infants with protein S deficiency typically develop a life-threatening blood clotting disorder called purpura fulminans. This condition is characterized by the formation of blood clots within the small blood vessels throughout the body, disrupting normal blood flow. These clots can lead to tissue death (necrosis) and widespread blood clotting, resulting in bleeding in various parts of the body. The abnormal bleeding often manifests as large, purple skin lesions.

The severe form of protein S deficiency in infancy is rare, and its exact prevalence is unknown. However, it is estimated that protein S deficiency affects approximately 1 in 500 individuals. Treatment for infants with this condition may include the use of blood thinners or anticoagulants to prevent excessive clotting. Additionally, infants may need to be monitored and treated by a metabolic doctor and a dietician to manage their condition effectively.

It is important to note that not all individuals with protein S deficiency will develop blood clots. However, certain factors, such as surgery, immobility, or underlying conditions like vitamin K deficiency, liver disease, or kidney disorders, can further increase the risk of clotting in those with protein S deficiency.

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