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Congenital protein S deficiency
This inherited disorder affects the blood's clotting system, making it more prone to excessive clotting. It can lead to health complications such as deep vein thrombosis and pulmonary embolism, affecting individuals from adolescence onwards.
Overview
Congenital protein S deficiency is a lifelong, inherited condition where the body does not produce enough functional protein S, a substance important for regulating blood clotting. Protein S is a natural anticoagulant, meaning it helps to prevent blood from clotting too much. When there is insufficient protein S, the blood has a higher tendency to form clots within blood vessels [PMID:33678077]. These clots can block blood flow, potentially leading to serious health issues.
This condition is considered a thrombophilia, which is a predisposition to develop thrombosis (blood clots). While some individuals with congenital protein S deficiency may never experience symptoms, others can face significant health challenges due to recurrent or severe clotting events. The condition affects both men and women equally, as it is not linked to sex chromosomes.
Symptoms & clinical features
The main symptom associated with congenital protein S deficiency is the formation of blood clots, particularly in the veins. These clots commonly occur in the deep veins of the legs, a condition known as deep vein thrombosis (DVT). Symptoms of DVT can include pain, swelling, tenderness, and warmth in the affected leg. The skin over the clot may also appear red or discoloured.
Occasionally, a piece of a DVT can break off and travel to the lungs, causing a pulmonary embolism (PE). A PE is a serious and potentially life-threatening condition, with symptoms such as sudden shortness of breath, chest pain that worsens with breathing, a cough (sometimes with bloody sputum), and a rapid heartbeat. In rare cases, clots can form in other parts of the body, including the brain or abdomen. Symptoms typically begin from adolescence or early adulthood, but can occur at any age [PMID:33678077].
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Affected organs
The organs most directly affected by congenital protein S deficiency are those supplied by blood vessels where clots form. The legs are a common site for deep vein thrombosis (DVT), which can lead to swelling and pain. Lungs are significantly impacted if a pulmonary embolism (PE) occurs, potentially causing respiratory distress and, in severe cases, damage to lung tissue.
Less commonly, clots can affect blood vessels in the brain, leading to a stroke, or in the abdomen, causing conditions like mesenteric ischaemia. Skin necrosis, a rare but severe complication, involves tissue death in the skin due to severe clotting in small blood vessels. The heart may also be indirectly affected due to the increased strain from a pulmonary embolism.
Risks & severity
The severity of congenital protein S deficiency can vary greatly among individuals, even within the same family. Some people may never experience a blood clot, while others may have recurrent and serious clotting episodes. The lifetime risk of developing a blood clot in individuals with protein S deficiency is elevated compared to the general population, with estimates suggesting a risk of up to 50% by age 55 [PMID:19361622].
The risk of developing a clot can be further increased by other factors, including surgery, prolonged immobility (such as long-haul flights or bed rest), pregnancy, oral contraceptive use, and certain medical conditions like cancer. The first thrombotic event often occurs between adolescence and middle age. While congenital protein S deficiency can increase the risk of serious complications, proactive management can help to reduce these risks.
Genetic causes
Congenital protein S deficiency is caused by pathogenic variants, also known as mutations, in the PROS1 gene. This gene provides instructions for making protein S, a vitamin K-dependent protein produced primarily in the liver. Protein S plays a crucial role in the body's natural anticoagulant system by helping to inactivate specific clotting factors, thereby preventing excessive blood clotting [PMID:33678077].
When a pathogenic variant occurs in the PROS1 gene, it can lead to either reduced levels of protein S (Type I deficiency) or the production of protein S that does not function correctly (Type II and Type III deficiencies). In both scenarios, the natural ability to regulate blood clotting is impaired, increasing the risk of thrombotic events.
- PROS1 protein S
Inheritance pattern
Congenital protein S deficiency is inherited in an autosomal dominant pattern. This means that a person only needs to inherit one copy of the altered PROS1 gene from one parent to develop the condition. If one parent has congenital protein S deficiency, there is a 50% chance with each pregnancy that their child will inherit the pathogenic variant and also have the condition, regardless of the child's sex.
Individuals who inherit two altered copies of the PROS1 gene (one from each parent) can experience a much more severe form of the disorder, often presenting with life-threatening clotting complications in infancy, known as purpura fulminans. However, this homozygous form is extremely rare.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosis of congenital protein S deficiency typically involves blood tests to measure the levels and activity of protein S. These tests are usually performed by a haematologist, a doctor specialising in blood disorders, or other specialists if a clotting event has occurred. If deficiency is suspected, further genetic testing of the PROS1 gene can confirm the diagnosis by identifying a pathogenic variant [PMID:33678077].
In the UK, genetic testing for inherited thrombophilias, including protein S deficiency, can be accessed through the NHS Genomic Medicine Service (GMS) via an appropriate clinical referral, often following a thrombotic event or family history of the condition. Relevant R-codes for genetic testing for PROS1 are available on PanelApp, such as R86 Thrombophilia. Referrals are typically made by GPs to clinical genetics services or by specialist teams like haematology.
Management & lifestyle
Management of congenital protein S deficiency focuses on preventing blood clots and treating them if they occur. Individuals diagnosed with the condition often receive personalised advice and care through multidisciplinary teams, including haematologists and genetic counsellors within the NHS. Regular monitoring may be advised, particularly during periods of increased risk such as surgery, prolonged travel, or pregnancy.
During times of high risk, preventative measures such as anticoagulant medication (blood thinners) may be prescribed to reduce the likelihood of clot formation. For those who experience a clot, treatment usually involves extended courses of anticoagulant therapy. Lifestyle adjustments, such as maintaining a healthy weight, regular exercise, and avoiding prolonged immobility, may also be recommended to reduce overall risk. Genetic counsellors can provide essential information about the inheritance pattern, implications for family members, and reproductive options.
UK care pathway
In the UK, individuals suspected of having congenital protein S deficiency often enter the NHS Genomic Medicine Service (GMS) pathway. Following a clinical assessment, typically by a haematologist or general practitioner, a referral to a clinical genetics service or specialist team may be made. Genetic testing for the PROS1 gene is available through the GMS, guided by specific R-codes listed on PanelApp, such as R86 Thrombophilia. Genetic counsellors play a vital role in explaining the condition, its inheritance, and implications for a family.
Frequently asked questions
What is protein S and why is it important?
Protein S is a natural substance in your blood that helps prevent it from clotting too much. It works by inactivating certain clotting factors, acting as a brake on the clotting process. Without enough functional protein S, your blood is more prone to forming dangerous clots.
Can I pass protein S deficiency on to my children?
Yes, if you have congenital protein S deficiency, there is a 50% chance with each pregnancy that your child will inherit the altered gene and also have the condition, regardless of whether the child is a boy or a girl. This is because it is an autosomal dominant inherited condition.
What increases my risk of a blood clot if I have protein S deficiency?
Several factors can further increase your risk of developing a blood clot, such as surgery, long periods of immobility (e.g., long journeys or bed rest), pregnancy, and taking oestrogen-containing medications like the combined contraceptive pill. Your doctor can discuss specific risks and preventative measures with you.
How is congenital protein S deficiency managed?
Management focuses on preventing blood clots. This can involve lifestyle adjustments, careful monitoring during high-risk periods, and potentially taking anticoagulant medications (blood thinners) if you are facing increased risk or have already experienced a clot. Your care will be managed by specialists, typically a haematologist.
Is a protein S deficiency the same as a vitamin K deficiency?
No, they are different but related. Protein S is a 'vitamin K-dependent' protein, meaning vitamin K is needed for its proper function. However, congenital protein S deficiency results from a genetic fault in the PROS1 gene, leading to insufficient or faulty protein S, distinct from a simple lack of dietary vitamin K.
References
- Adachi T. Protein S and congenital protein S deficiency: the most frequent congenital thrombophilia in Japanese. Current drug targets. 2005. PMID: 16026279
- Boerger LM, Morris PC, Thurnau GR. Oral contraceptives and gender affect protein S status. Blood. 1987. PMID: 2948582
- Taniguchi F, Morishita E, Sekiya A. Gene analysis of six cases of congenital protein S deficiency and functional analysis of protein S mutations (A139V, C449F, R451Q, C475F, A525V and D599TfsTer13). Thrombosis research. 2017. PMID: 28088608
- Okada K, Tamura S, Suzuki N. Protein S-Leu17Pro disrupts the hydrophobicity of its signal peptide causing a proteasome-dependent degradation. Thrombosis research. 2022. PMID: 34968852
- Maillard C, Berruyer M, Serre CM. Protein-S, a vitamin K-dependent protein, is a bone matrix component synthesized and secreted by osteoblasts. Endocrinology. 1992. PMID: 1531628
- Ogawa S, Koizumi S, Hirata T. Multidisciplinary Treatment for Multiple Dural Arteriovenous Fistulas/Arteriovenous Malformation Associated with Congenital Protein S Deficiency: A Case Report and Literature Review. NMC case report journal. 2025. PMID: 41542355
- Yoshida S, Miyakoshi A, Arai D. A Case of an Early Pregnant Woman with Congenital Protein S Deficiency Who Underwent Mechanical Thrombectomy. Journal of neuroendovascular therapy. 2022. PMID: 37502450
- Tripodi A, Martinelli I, Chantarangkul V. Thrombin generation and other coagulation parameters in a patient with homozygous congenital protein S deficiency on treatment with rivaroxaban. International journal of hematology. 2016. PMID: 26586461