Protein C deficiency: causes, symptoms, diagnosis, treatment

Protein C is a natural anticoagulant, a vitamin K-dependent glycoprotein, synthesized in the liver in an inactive form.

Activated protein C is a serine protease whose function is aimed at inactivating factors Va and VIIIa, an important regulator of thrombin activity on the endothelial surface. Protein C is activated by the interaction of thrombin with thrombomodulin. This bond accelerates the formation of thrombin in the form of activated protein C. The activity of protein C is enhanced by its cofactor, protein S. Activated protein C proteolytically inactivates factors Va and VIIIa in the presence of protein S, phospholipid (endothelial surface) and calcium, inhibiting further activation of thrombin.

Since activated protein C causes the breakdown of factors Va and VIIIa, it is thus a natural plasma anticoagulant. A decrease in protein C due to genetic or acquired causes provokes the occurrence of venous thrombosis.

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Epidemiology

The prevalence of heterozygous plasma protein C deficiency is 0.2 to 0.5%; about 75% of people with this anomaly have a history of venous thromboembolism (50% before age 50). Homozygous or double heterozygous deficiency results in purpura fulminans neonatorum, a severe neonatal DIC. Acquired deficiency occurs in patients with liver disease, DIC, during cancer chemotherapy (including L-asparaginase administration), and during warfarin therapy.

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Causes of protein C deficiency

Normally, the level of protein C is 65–145%. During pregnancy, it increases slightly and is 70–150%, and it increases even more in the postpartum period.

Congenital protein C deficiency is caused by a gene mutation. The protein C gene is located on chromosome 2. More than 150 gene mutations are known. Very often, protein C deficiency is combined with a factor V mutation.

Protein C deficiency is inherited in an autosomal dominant manner. Heterozygous carriers have protein C levels of 30–60% of normal, while homozygous carriers have virtually no protein C and die in utero or immediately after birth.

Symptoms of protein C deficiency

Clinical manifestations of protein C deficiency:

• recurrent pregnancy loss, stillbirth, fetal loss (up to 27.9%);
• venous thrombosis and thromboembolism at the age of 20–30 years of any localization;
• necrosis of the skin, subcutaneous tissue (especially when treated with indirect anticoagulants);
• increased risk of thrombosis when using oral contraceptives;
• practical absence of arterial thrombosis.

Forms

Protein C deficiency is encountered somewhat more frequently than antithrombin III deficiency; among patients with thrombosis and thromboembolism, this pathology is observed in approximately 10% of patients.

There are 2 types of hereditary protein C deficiency:

1. Type I - decreased amount of protein C;
2. Type II - decreased activity of protein C with its normal level.

Diagnostics of protein C deficiency

The diagnosis is based on the determination of protein C antigen and functional studies of plasma coagulation (the degree of increase in partial thromboplastin time of normal plasma, the use of plasma without protein C with the addition of patient plasma and snake venom).

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Treatment of protein C deficiency

Patients with thrombotic symptoms require anticoagulation with unfractionated or low-molecular-weight heparin followed by warfarin. The use of vitamin K antagonists, warfarin as initial therapy sometimes causes thrombotic cutaneous infarction induced by a decrease in vitamin K-dependent protein C, which occurs before the decrease in other vitamin K-dependent coagulation factors occurs. Purpura fulminans neonatorum is fatal without protein C replacement (normal plasma or factor concentrate) and heparin anticoagulation.