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Genetic and Rare Diseases Information Center (GARD)

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Protein S deficiency


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What is protein S deficiency?

Protein S deficiency is a disorder that causes abnormal blood clotting. When someone bleeds, the blood begins a complicated series of rapid chemical reactions involving proteins called blood coagulation factors to stop the bleeding.  Other proteins in the blood, such as protein S, usually regulate these chemical reactions to prevent excessive clotting. When protein S is missing (deficient), clotting may not be regulated normally and affected individuals have an increased risk of forming a blood clot called a thrombosis.  People at risk to have protein S deficiency are those with an individual or family history of multiple blood clots in the veins.  Treatment may include taking medication known as blood thinners to decrease the chance of developing a blood clot.[1]
Last updated: 3/4/2013

Are there different types of protein S deficiency?

Scientists classify protein S deficiency into 3 types based on the measurement of protein S antigen (presence of the protein in the blood stream), functional protein S activity (ability of protein S to appropriately perform its function), the free protein S (or unbound protein S) and total protein S (includes free protein S and protein S that is bound to another protein in the blood):       

Type I deficiency.
Characterized by a decrease in the total protein S antigen and free protein S antigen together (quantitative deficiency).

Type II deficiency.
Characterized by normal total and free antigen levels but reduced protein S activity (functional deficiency).

Type III deficiency.
Characterized by low free protein S levels, whereas the total plasma concentration of protein S is normal.

Types I and III are most common and result in the same types of symptoms.  Type II is considered to be very rare.[2]
Last updated: 10/17/2008

How common is protein S deficiency?

Protein S deficiency is estimated to occur in 1 out of every 20,000 individuals.[1]
Last updated: 7/2/2013

What causes protein S deficiency?

Protein S deficiency is usually hereditary, but may be acquired.  The hereditary form of protein S deficiency is caused by a mutation in a gene called PROS1.  This condition is inherited in an autosomal dominant manner, which means that an individual who inherits only one mutated copy of PROS1 has an increased chance of developing symptoms of this disease.  Individuals who inherit one mutated copy of the PROS1 gene are said to be heterozygotes while those that inherit two mutated copies of the PROS1 gene are called homozygotes.  Blood clots (thrombosis) may occur in both heterozygotes and homozygotes; however, homozygotes may develop a severe form of thrombosis called purpura fulminans. Purpura fulminans involves severe clotting throughout much of the body and is a life-threatening condition.

Rarely, protein S deficiency is acquired, meaning it develops as a result of another condition such as liver disease or vitamin K deficiency.[3]

Last updated: 10/26/2012

What complications may be associated with protein S deficiency?

The following complications may arise due to protein S deficiency:

The most common manifestation is venous thrombosis of the lower extremities (i.e. the legs), and this accounts for approximately 90% of all events associated with protein S deficiency.  The other 10% of manifestations include those listed above.  The warning signs for a venous thrombosis are generally pain, tenderness, redness, or swelling in extremity or affected areas.  Approximately 60-80% of individuals with the inherited form of protein S deficiency will go on to have a venous thrombosis at some point in their life, with the majority occurring before ages 40-45.  The remaining 20-40% are considered asymptomatic, meaning that they never go on to develop these clots.  For individuals whose lives are shortened by protein S deficiency, the cause of death is a pulmonary embolism, or the passage of a blood clot to the lungs. Symptoms of a pulmonary embolus include difficulty breathing, abnormal coughing, chest pain, fainting or heart palpitations.[1][3]

Last updated: 3/7/2012

How is protein S deficiency treated?

Treatment of protein S deficiency occurs either in patients who have had a venous thrombosis or in patients with asymptomatic carrier states without a thrombotic event, depending on the decisions made by the patient's health care provider. Following a venous thrombosis, patients are treated with anticoagulant drugs (blood thinners) including heparin followed by warfarin.  In most patients, specialists recommend 6-9 months of initial treatment with warfarin. The question of whether to continue lifelong warfarin in patients with identified protein S deficiency after their first thrombotic event is controversial. If the first thrombotic event was life threatening or occurred in multiple or unusual sites (i.e. cerebral veins, mesenteric veins), most experts recommend lifelong therapy initially. If brought about especially abruptly by a strong event (i.e. trauma, surgery) and the thrombosis did not meet the criteria of life threatening or multiple or unusual sites, some experts argue that these patients may have a lower risk of recurrence and deserve a trial without warfarin after 9 months.[3][2]

In patients who are asymptomatic carriers of protein S deficiency, the goal of therapy is prevention of the first thrombosis. In such patients, drugs that predispose to thrombosis, including oral contraceptives should be avoided. If these patients require surgery or an orthopedic injury occurs, prophylaxis with heparin may become necessary.[3][2]

Last updated: 3/4/2013

References
See Disclaimer regarding information on this site. Some links on this page may take you to organizations outside of the National Institutes of Health.