Protein S deficiency

Protein S deficiency is a disorder associated with increased risk of venous thrombosis. Protein S, a vitamin K-dependent physiological anticoagulant, acts as a nonenzymatic cofactor to activated protein C in the proteolytic degradation of factor Va and factor VIIIa. Decreased (antigen) levels or impaired function (activity) of protein S, leads to decreased degradation of factor Va and factor VIIIa and an increased propensity to venous thrombosis. Protein S circulates in human plasma in two forms: approximately 60 percent is bound to complement component C4b β-chain while the remaining 40 percent is free. Only free protein S has activated protein C cofactor activity.

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Types

There are three types of hereditary protein S deficiency:

• Type I - decreased protein S activity: decreased total protein S (=both bound and free protein S) levels AND decreased free protein S levels (quantitative defect)
• Type II - decreased protein S activity: normal free protein S levels AND normal total protein S levels (qualitative defect)
• Type III - decreased protein S activity: decreased free protein S levels AND normal total protein S levels (quantitative defect)

Protein S deficiency can also be acquired due to vitamin K deficiency or treatment with warfarin, systemic sex hormone therapy and pregnancy, liver disease, and certain chronic infections (for example HIV). Vitamin K deficiency or treatment with warfarin generally also impairs the coagulation system itself (factors II, VII, IX and X), and therefore predisposes to bleeding rather than thrombosis. Protein S deficiency is the underlying cause of a small proportion of cases of disseminated intravascular coagulation (DIC), deep venous thrombosis (DVT) and pulmonary embolism (PE).

Hereditary PSD is an autosomal dominant condition, resulting in a 50 percent chance of passing the disease to offspring. Less than half of those diagnosed with PSD will experience thrombosis, and those who do usually are affected only from the age of the late teens onwards. A positive blood test can lead to the loss of health insurance benefits and/or employment, and the social downsides need to be balanced against the actual medical benefit of accurate diagnosis. Screening of young children is usually deferred because early testing is often inaccurate, and it is better to wait until they are old enough to decide for themselves whether they want to be tested.

Articles

ten Kate M, Mulder R, Platteel M, Brouwer J, van der Steege G, van der Meer J (2006). "Identification of a novel PROS1 c.1113T-->GG frameshift mutation in a family with mixed type I/type III protein S deficiency". Haematologica 91 (8): 1151-2. PMID 16885060.