Invitae Protein S Deficiency Test

• protein S deficiency

Protein S deficiency is an adult-onset condition that increases the risk of blood-clot formation. Protein S deficiency may be hereditary and due to pathogenic variants in PROS1, or acquired through hepatic disease or a vitamin K deficiency. This disorder is associated with an increased risk of developing blood clots in deep veins, especially in the legs (deep vein thrombosis), which can lead to the clots breaking off and blocking blood flow in other parts of the body like the lungs (where it would cause a pulmonary embolism). Approximately half of these events are unprovoked (i.e., they are not preceded by such typical transient risk factors as surgery, trauma, immobilization, air travel, pregnancy, or systemic hormonal contraception). Women with protein S deficiency also have an increased risk of miscarriage and other pregnancy complications.

Individuals with a pathogenic variant in both copies of their PROS1 gene can develop a rare, severe form of protein S deficiency that can cause a life-threatening clotting disorder in infants, called purpura fulminans. This causes blood clots to form in the small blood vessels throughout the body, blocking normal blood flow and potentially leading to localized necrosis.

Pathogenic variants in PROS1 are identified in approximately 43% of affected individuals.

Protein S deficiency is inherited in an autosomal dominant pattern.

While most people with protein S deficiency never develop abnormal blood clots, certain factors can increase the risk, including advanced age, surgery, trauma, inactivity, and pregnancy. Having another inherited disorder of blood clotting in addition to protein S deficiency can also influence the risk of abnormal blood clotting.

The lifetime risk for individuals with protein S deficiency of developing thrombosis is 30 times greater than that of the general population.

The prevalence of protein S deficiency is estimated at 3-13 per 10,000 individuals in the general population. Protein S deficiency is present in approximately 1%-3% of individuals presenting with venous thromboembolism.

Analysis of the PROS1 gene may be considered in individuals with the following:

• reduced protein S activity
• venous thromboembolism (VTE) at an unusual site (e.g., cerebral mesenteric, portal, hepatic)
• recurrent VTE
• idiopathic VTE (unrelated to surgery/trauma)
• VTE under the age of 50
• VTE during pregnancy or in the postpartum period
• recurrent fetal loss, especially in the second or third trimesters
• VTE while on oral contraceptives, hormone replacement, or methotrexate
• life-threatening venous thrombosis (e.g., pulmonary embolism, cerebral vein thrombosis)
• infants/children with purpura fulminans
• family history of VTE in first-degree relatives
• family history of protein S deficiency

Recommendations on when to test an individual for thrombophilias including protein S have been suggested:

• Baglin, T, et al. Clinical guidelines for testing for heritable thrombophilia. Br. J. Haematol. 2010; 149(2):209-20.
• Reich, LM, et al. Role of the geneticist in testing and counseling for inherited thrombophilia. Genet. Med. 2003; 5(3):133-43.

For management guidelines, please refer to:

• Varga, EA, Kujovich, JL. Management of inherited thrombophilia: guide for genetics professionals. Clin. Genet. 2012; 81(1):7-17.