Protein C Deficiency Profile

Plasma, frozen

1 mL (each tube)

Blue-top (sodium citrate) tubes (2 tubes)

Avoid warfarin (Coumadin®) therapy for two weeks and heparin therapy for two days prior to the test. Do not draw from an arm with a heparin lock or heparinized catheter.

Confirmation and characterization of protein C deficiency

Individuals with heterozygous PC deficiency may have low normal PC levels.⁷ Treatment with warfarin decreases the levels of vitamin K-dependent factors including PC. PC levels start to drop after six hours of warfarin treatment and do not regain pretreatment levels until generally two weeks after cessation of therapy. Elevated factor VIII levels, as can be seen in acute phase reaction, can normalize the aPTT and effectively reduce PC levels.⁶ PC levels can be falsely low in patients with the factor V_Leiden mutation. PC levels can become depleted as the result of activation of coagulation limiting the utility of testing for congenital PC deficiency during the immediate convalescent period after a thrombotic event.⁷ Heparin therapy up to 1 unit/mL does not affect PC levels.⁷ This test should not be used for patients receiving thrombin inhibitors such as hirudin and argatroban.⁶

PC antigen: enzyme immunoassay (EIA)

PC activity: A specific enzyme extracted from the venom of Agkistrodon c. contortrix is used to activate PC in the patient sample. All other factors required for normal aPTT are supplied in the reagent. The activated protein C inhibits factors V and VIII in the reagent and the resultant prolongation of the aPTT-based clotting time is proportional to plasma PC activity.

PC levels tend to be lower in newborns but typically reach adult ranges by six months of age.⁶ Levels in some children remain low until up to 16 years of age.⁶

Protein C (PC) is a vitamin K-dependent plasma protein that is synthesized by the liver as an inactive precursor.^7-9 This protein is then further transformed into activated PC by a complex of thrombin and the endothelial factor, thrombomodulin, that is bound to phospholipid membrane in a calcium-dependent manner. aPC regulates the coagulation process by inactivating factors Va and VIIIa. Protein S, another vitamin K-dependent protein, serves as an essential cofactor of aPC for the inactivation of factors Va and VIIIa. In inhibiting these factors, PC serves to limit thrombus extension, and thus acts as a major regulator of the coagulation process.

Congenital protein C deficiency: Congenital PC deficiency has been estimated to occur in approximately 3 out of 1000 individuals.^7,8 Between 2% and 5% of cases of recurrent venous thrombosis are related to congenital PC deficiency.⁷ Nearly 50% of individuals with heterozygous PC deficiency and 10% of their relatives experience thrombotic episodes by age 45. Initial thrombotic events frequently occur between 20 and 30 years of age. The probabilities of thrombosis or pulmonary emboli increase dramatically when PC activity levels fall to <50%.⁷ Thrombosis can sometime occur at unusual sites, including mesenteric and axillary veins. Recurrent thrombotic events are common.⁷ In the majority of cases, thrombosis can be linked to trauma, surgery, pregnancy oral contraceptive usage, or other risk factors. However, thrombosis can occur spontaneously with no precipitating events or other known risk factors in about 33% of cases.⁷

Congenital PC deficiency can be classified as either type I or type II.⁹ Type I deficiency results from a quantitative reduction in PC production, resulting in a simultaneous decrease of both the functional and antigenic levels of PC. In type II deficiency, PC antigen concentration is normal but its activity is diminished because the PC is dysfunctional due to genetic defect. This is reflected by a diminished PC activity in the context of normal PC antigen levels. Neonates born with homozygous or doubly heterozygous PC deficiency suffer from DIC or purpura fulminans of the newborn, devastating conditions requiring immediate treatment.⁸

Acquired protein C deficiency: Acquired PC deficiency occurs more frequently than congenital deficiency.⁷ PC levels can be transiently diminished after a thrombotic event or surgery. Oral anticoagulant therapy with warfarin will lower PC levels. Vitamin K deficiency, due to dietary insufficiency or malabsorption, will also lead to reduced PC levels. Acquired deficiency can be found in individuals with disseminated intravascular coagulation (DIC) and sepsis. Severe hepatic disorders (hepatitis, cirrhosis, etc), renal failure, malignancy, and inflammatory bowel disease can lead to diminished PC levels.⁷ Drug therapy with L-asparaginase or fluorouracil can also reduce PC levels.

In some cases, warfarin anticoagulation of thrombotic patients with heterozygous PC deficiency will induce skin necrosis due to the rapid drop in already low PC activity.^7,9