Severe hereditary thrombophilia due to congenital protein C deficiency (ORPHA:745)
A rare inherited coagulation disorder characterized by deep venous thrombosis symptoms due to reduced synthesis and/or activity levels of protein C.
Epidemiology
Prevalence of severe protein C deficiency (homozygous or compound heterozygous forms) is estimated at 1/ 500,000. Partial deficiencies (heterozygous forms) are much more frequent (1/200-1/500). Men and women are equally affected.
Clinical description
Patients with undetectable protein C levels usually manifest the disease 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. Patients with low but detectable protein C levels have milder symptoms generally similar to those of heterozygous individuals. Usually, patients with heterozygous protein C deficiency are 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. Cerebral or mesenteric venous thrombosis may also occur.
Etiology
Protein C deficiency is caused by mutations in the PROC (2q13-q14) gene controlling the production of protein C. Transmission is autosomal recessive.
Diagnostic methods
Diagnosis is based on the measurement of protein C levels. Protein C activity levels range from 0 to 30% in case of severe deficiencies and from 30 to 70% in case of partial defects. There are two biological forms of the disease. Type I deficiency is characterized by concordant reduction in protein C activity and antigen. In type II deficiency, protein C activity is reduced but protein C antigen is normal. Molecular testing is available, but is unnecessary for diagnosis.
Differential diagnosis
Differential diagnoses include other inherited thrombophilias including antithrombin and protein S deficiencies (see these terms).
Antenatal diagnosis
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.
Management and treatment
Administration of protein C concentrates or fresh frozen plasma is critical 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, warfarin). Attention should be paid to the risk of coumarin-induced skin necrosis. Preventive treatment is indicated in cases with a strong positive family history of thrombotic diseases, during the peripartum period or perioperatively.
Prognosis
Prognosis may be 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.

                            Last update: 
                            November 2009


                            - Expert reviewer(s): 
                            Pr Jenny GOUDEMAND