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Severe hereditary thrombophilia due to congenital protein S deficiency
An inherited coagulation disorder characterized by recurrent venous thrombosis symptoms due to reduced synthesis and/or activity levels of protein S.
ORPHA:743Classification level: Disorder
Prevalence of partial protein S deficiency (heterozygous individuals) is estimated at 0.16-0.21% in the general population. Prevalence of severe protein S deficiency (homozygous or compound heterozygous individuals) is unknown but is probably comparable to that of severe protein C deficiency which is estimated at 1/500,000. Men and women are equally affected.
In severe protein S deficiency, the disease manifests several hours to days after birth, with purpura fulminans (see this term) or massive venous thrombosis. Purpura fulminans is a life-threatening condition involving severe clotting throughout the body and causing necrosis of tissues. Severe retinopathy of prematurity (ROP) (see this term) may also occur. Heterozygous patients are usually asymptomatic until adulthood. Thrombotic episodes are mainly provoked by other risk factors such as surgery, pregnancy or immobilization. Deep vein thrombosis of the lower limbs with or without pulmonary embolism is the most common manifestation of the disease. Arterial thrombosis may also occur.
Protein S deficiency is caused by mutations in the PROS1 gene (3q11-q11.2).
Diagnosis is based on the measurement of protein S antigen levels (total protein S or free protein S) and anticoagulant activity. There are three biological forms. Type I and type III are quantitative deficiencies with low free antigen levels (with normal total protein S levels in type III and decreased total protein S levels in type I deficiency). Type II is a qualitative deficiency with normal total and free protein S levels. Molecular testing is available, but is unnecessary for diagnosis.
Differential diagnoses include other inherited thrombophilias including antithrombin and protein C deficiencies (see these terms).
Antenatal diagnosis is feasible for families with affected children and is based on the identification of the causal mutation on DNA obtained by chorionic villus sampling.
Transmission is autosomal recessive.
Management and treatment
Administration of fresh frozen plasma may be required for the initial treatment of neonatal purpura fulminans. Surgical procedures may be required for excision of thrombotic lesions. Patients with thromboses are treated with anticoagulant therapy (heparin, wafarin). Attention should be paid to the risk of coumarin-induced skin necrosis. Preventive treatment is indicated in cases with strong positive family history of thrombotic diseases, during the peripartum period or perioperatively.
Prognosis is severe in homozygous or compound heterozygous patients. Prognosis is good for heterozygous patients. With adequate treatment and monitoring, the risk of thromboembolic disease is markedly reduced. Mortality may result from pulmonary embolism.