Last updated:
12/19/2025
Years published: 2019, 2025
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders, for the preparation of this report.
Severe hereditary thrombophilia due to congenital protein S deficiency is a very rare and serious blood-clotting disorder.1, 2
Symptoms often begin very early in life, sometimes infancy. Some babies develop neonatal purpura fulminans (NPF), a life-threatening condition where blood clots form throughout the small blood vessels of the skin and other parts of the body. This can cause dark purple skin patches, tissue damage, and severe illness. Other babies may experience multifocal thrombosis, which means blood clots form in several areas of the body at the same time. Some infants also develop intracranial hemorrhage, which is bleeding inside the skull. Not all children show symptoms immediately. Some may instead experience repeated blood clots later in childhood.2,3
Severe hereditary thrombophilia due to congenital protein S deficiency is caused by changes (variants) in both copies (alleles) of the PROS1 gene, which lead to a severe lack of (deficiency of) protein S. Protein S is a natural substance in the body that helps prevent dangerous blood clots.2, 4-6 Specifically, protein S is involved in inhibiting coagulation (It helps to prevent the blood from clotting too much.).
This condition is inherited in an autosomal recessive pattern. 1, 2,5, 7 This means a child must inherit two changed copies of the PROS1 gene – one from each parent – to develop the severe form of the disease.
Neonatal purpura fulminans (NPF) is a medical emergency. Treatment requires immediate medical attention and ongoing care from a team of specialists who can monitor clotting risk and guide ongoing treatment.2, 3
Protein “S” deficiency was first identified in Seattle, which is the source of its name.1, 5 Protein S deficiency can also be inherited in an autosomal dominant pattern. This form is more common and usually milder, and it is mainly associated with an increased risk of developing blood clots rather than severe symptoms in infancy. This milder form may also be called “thrombophilia due to protein S deficiency (THPH5)” or “thrombophilia 5 due to protein S deficiency, autosomal dominant” or “autosomal dominant thrombophilia due to protein S deficiency.”1, 2, 5, 8
Occasionally, protein S deficiency is not inherited but develops later in life due to other conditions. These include kidney disease (such as nephrotic syndrome), pregnancy, or the use of oral contraceptives.1, 7, 9
The autosomal recessive form, known as severe hereditary thrombophilia due to congenital protein S deficiency, is the rarest and most severe form of protein S deficiency.1, 2
People with severe hereditary thrombophilia caused by congenital protein S deficiency can develop symptoms within hours to a few days after birth. One of the most serious and dangerous symptoms is purpura fulminans. This condition happens when blood clots form throughout the body, which prevents normal blood flow.2, 3
When blood clots block circulation, the affected skin and tissue may begin to die. This process is called necrosis. It can cause abnormal bleeding, large purple patches or spots on the skin, and areas of dark discoloration. These skin changes can spread quickly and may occur in repeated episodes. Without prompt treatment, purpura fulminans can be life-threatening.2, 3
Other possible signs and symptoms of severe protein S deficiency include:1, 2, 5
People with the autosomal dominant (milder) form of protein S deficiency are also at risk for developing blood clots. The level of risk varies widely from person to person. Factors such as the amount of residual protein S activity there is in the body influence when clots appear, how severe they are, and how often they occur. Some people with this form may never develop a blood clot, and others may not develop one until adulthood.
When clots do develop, they most often appear as deep vein thrombosis (DVT) in the legs or as a pulmonary embolism, which happens when part of a leg clot breaks off and lodges in the lungs, blocking blood flow. Clots can also form in veins that drain the intestines and, less commonly, in the cerebral veins of the brain, or veins in other areas of the body.4-6, 8
Protein S deficiency may be inherited (genetic) or acquired. Inherited deficiency occurs when a change (variant) in the PROS1 gene alters how protein S is made or how well it works. In severe hereditary thrombophilia due to congenital protein S deficiency the variants affect both copies (alleles) of the PROS1 gene.1, 2 4-6
Protein S is a natural anticoagulant protein produced mainly in the liver and activated with the help vitamin K. In the bloodstream, protein S exists in two forms – free and bound – but only the free form help regulate blood clotting. Protein S works with another protein, protein C, to shut down two key clotting factors, factor Va (pronounced 5a) and factor VIIIa (pronounced 8a). These clotting factors normally increase the production of thrombin, an enzyme that helps form blood clots. By shutting down these clot-promoting factors and supporting the body’s natural process of breaking down clots, protein S helps prevent clots from becoming too large or forming when they are not needed.
When protein S levels are very low, or the protein does not work properly, these protective control mechanisms fail, and the risk of developing blood clots increases.1, 5, 7
Inheritance
Genetic diseases are determined by the combination of genes a person inherits from their parents. Each gene has two copies (alleles) – one from the mother and one from the father.
The severe form of protein S deficiency, which usually begins in infancy, is inherited in an autosomal recessive pattern.1, 2 Recessive genetic disorders occur when a person inherits two disease-causing variants of the gene – one from each parent. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. The variants may be the same on both copies of the gene (homozygotes) or two different variants affecting each copy (compound heterozygous). 2, 4, 6
If a person inherits one normal gene and one disease-causing variant, they are considered a carrier and usually do not have symptoms. When both parents are carriers, each pregnancy has:
The risk is the same for males and females.1, 2
The milder form of protein S deficiency is autosomal dominant pattern and shows variable penetrance, meaning not everyone with the gene variant develops symptoms. Only about 50% of people who have the gene variant develop venous thromboembolism (VTE), while the other 50% never develop blood clots. Rarely, autosomal dominant cases can be more severe.1, 4, 5, 8
In autosomal dominant conditions, only one altered copy of the gene is needed to increase disease risk. The gene variant may be inherited from either parent or may arise as a new change in the affected individual. Each child of an affected parent has a 50% chance of inheriting the gene variant, regardless of sex.
Acquired Protein S Deficiency
Protein S deficiency can also be acquired, meaning it develops due to other medical conditions or life circumstances. Acquired protein S deficiency can develop during pregnancy, with the use of oral hormonal contraceptives, during severe clotting disorders such as disseminated intravascular coagulation, or during infections such as HIV.
Protein S levels may also decrease during active blood clots (acute thrombosis), with certain chemotherapy medications (such as L-asparaginase), or in conditions like nephrotic syndrome, where protein is lost in the urine, and liver disease, where protein production is reduced. Temporary decreases in protein S have been reported in children recovering from chickenpox due to antibodies that interfere with protein S activity.
These acquired conditions reduce the effectiveness of protein S and can disrupt the body’s natural control of the blood clotting proteins factor Va (pronounced 5a) and factor VIIIa (pronounced 8a), increasing the risk of abnormal blood clot formation.1, 5, 7, 9
How common protein S deficiency is depends on how it is measured.
When protein S deficiency is identified through blood tests (looking for protein S levels below 60% of normal), about 1 in 100 people have low protein S levels. However, this includes people whose low levels may not be caused by a genetic condition.
The hereditary (genetic) forms of protein S deficiency are less common, affecting about 1 in 500 people in the United Kingdom and United States. These cases are usually autosomal dominant. The most severe autosomal dominant form, where the gene variant completely stops protein S production, is genuinely rare and occurs in only about 1 in 10,000 people.1, 5
The autosomal recessive form, known as severe hereditary thrombophilia due to congenital protein S deficiency, is extremely rare and always results in severe protein S deficiency. Because this form is so rare, doctors usually report individual cases rather than studying large groups of patients. As a result, there are no reliable estimates of exactly how many people have this severe form, but it is thought to affect approximately 1 in 100 million people.2
Purpura fulminans, the life-threatening clotting condition seen in infancy, does not occur in individuals with autosomal dominant protein S deficiency on its own. In extremely rare cases, it may occur only when autosomal, dominant protein S deficiency is combined with another inherited clotting disorder and triggered by an infection. As noted earlier, purpura fulminans is the characteristic and defining presentation of the autosomal recessive form of protein S deficiency.2, 3
Protein S deficiency affects both men and women. Protein S deficiency is reported to be 5 to 10 times more common in Japanese populations than in white populations.1, 7
The acquired (non-genetic) form of protein S deficiency seems to be rare.1, 7, 9
A diagnosis of protein S deficiency is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation, and a variety of specialized tests.
Some indications of a possible protein S deficiency include:
Diagnosing the genetic form of protein S deficiency can be challenging because there are many different conditions that can temporarily lower the levels of protein S in the blood, leading to acquired protein S deficiency.1, 5, 7-9
Clinical Testing and Workup
Protein S deficiency is diagnosed by measuring the amount of protein S in the blood and how well it functions. These lab tests are called assays, and they measure the amount and activity of specific enzymes in the blood. The amount of protein S can vary based on several factors including age. Doctors look at two types of protein S levels:
There are three types of protein S deficiency:5, 7, 9, 10
Genetic (molecular) testing can identify the specific PROS1 gene change and can confirm the diagnosis, but it is not required to make the diagnosis. The diagnosis is based mainly on blood test results.1, 4, 6, 10
Babies with severe protein S deficiency and purpura fulminans need immediate emergency treatment to replace missing protein S and stabilize blood clotting. The first-line therapy is fresh frozen plasma (FFP), which provides protein S and other clotting factors. FFP is usually given repeatedly (often every 8-12 hours), with the dose adjusted based on the infant’s condition.
A newer treatment, plasma-derived protein C and protein S concentrate, is becoming available in some medical centers, although access may be limited.1-3, 5, 11 This early treatment aims to stop the progression of clotting in small and medium blood vessels, prevent tissue death, and avoid organ damage.
Supportive care may include blood products to maintain safe platelet counts and fibrinogen levels. Severe skin damage (lesions) may require surgical treatment, such as removal of dead tissue. Antibiotics are used if infection triggers or worsens the condition.1-3, 5
Without early and aggressive treatment, purpura fulminans can be fatal or cause serious long-term complications such as limb loss, blindness, or neurological disability.2, 3
Once the acute phase is controlled, children with severe protein S deficiency require long-term anticoagulation medicine to prevent future clots. Rivaroxaban is one of the main long-term anticoagulant options and has been used successfully in severe protein S deficiency, but the choice of medication should be individualized by a specialist.1, 12, 13 Lifelong anticoagulation is usually recommended because the risk of new clots remains high.1, 2, 5
Regular monitoring is essential to check for new clots, evaluate growth and development, and adjust treatment as needed.1, 5
For people diagnosed later in childhood or adulthood who have a milder disease, treatment depends on whether they have had blood clots. Blood clots are treated the same way as any venous thromboembolism (VTE), using medications such as heparin, warfarin, or direct oral anticoagulants (DOACs). Heparin is usually given first for at least five days, followed by either warfarin or a DOAC.1, 5, 7
People with protein S deficiency who have no symptoms may not need daily treatment but may take preventive anticoagulation during higher-risk situations such as surgery, long travel, pregnancy, or prolonged immobility. After a clot, warfarin is often used for 3–6 months, and longer if there are additional clotting risk factors present. Lifelong anticoagulation is recommended for life-threatening clots or clots in unusual locations, such as veins in the brain or abdomen.1, 5
During pregnancy, low-molecular-weight heparin is commonly used instead of warfarin during the first trimester and after 36 weeks, to protect both the pregnant individual and the baby.1, 5
Genetic counseling may be helpful for affected individuals and their families.1, 2
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
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Email: [email protected]
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https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
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