Because activated protein C degrades coagulation factors Va and VIIIa, deficiency of protein C predisposes to venous thrombosis.
(See also Overview of Thrombotic Disorders.)
Protein C is a vitamin K–dependent protein, as are coagulation factors II (prothrombin), VII, IX, and X and proteins S and Z. Because activated protein C (APC) degrades factors Va and VIIIa, APC is a natural plasma anticoagulant. Decreased protein C due to a genetic or an acquired abnormality predisposes to venous thrombosis (1).
Heterozygous deficiency of plasma protein C has a prevalence of 0.2 to 0.5% (2); in family studies of symptomatic probands, the life-time risk of venous thromboembolism (VTE) is high. Also, the risk of recurrent VTE is high (3). It is important to recognize that outcomes observed in family studies may not be generalizable to all patients with protein C deficiency.
Homozygous deficiency or doubly heterozygous deficiency causes neonatal purpura fulminans, ie, a severe neonatal type of disseminated intravascular coagulation (DIC), which manifests with ecchymoses and extensive venous and arterial thromboses, usually on the first day of life.
Acquired decreases in protein C occur in patients with liver disease or disseminated intravascular coagulation (DIC) and during warfarin therapy.
Diagnosis is based on antigenic and functional plasma assays of protein C.
Довідкові матеріали загального характеру
1. Dinarvand P, Moser KA. Protein C Deficiency. Arch Pathol Lab Med 2019;143(10):1281-1285. doi:10.5858/arpa.2017-0403-RS
2. Tait RC, Walker ID, Reitsma PH, et al. Prevalence of protein C deficiency in the healthy population. Thromb Haemost 1995;73(1):87-93.
3. Lijfering WM, Brouwer JL, Veeger NJ, et al. Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives. Blood 2009;113(21):5314-5322. doi:10.1182/blood-2008-10-184879
Treatment of Protein C Deficiency
Anticoagulation
Patients with symptomatic thrombosis can be treated with direct oral anticoagulants (DOACs) or warfarin.
When initiating warfarin therapy, it is important for clinicians to use therapeutic doses of heparin or low molecular weight heparin for initial anticoagulation and avoid warfarin loading doses. Instead, once patients are therapeutically anticoagulated with a parenteral agent, warfarin should be started at the estimated maintenance dose (eg, 5 mg daily) and parenteral anticoagulation should continue for at least 5 days and until the INR is ≥ 2.
Since protein C is a vitamin K–dependent protein and has a short half life compared to factors II and X, discontinuation of parenteral anticoagulants before factor II and X levels have fallen sufficiently (to 20 to 40% of normal activity) can precipitate warfarin skin necrosis. This complication is avoided by using DOACs, which appear to be as effective as warfarin for prevention of venous thromboembolism in patients with protein C deficiency.
Neonatal purpura fulminans is fatal without replacement of protein C (using normal plasma or purified concentrate), along with anticoagulation with heparin or low molecular weight heparin.
