Protein C
Function of Protein C
Protein C is a member of the Vitamin K-dependent coagulation factor family. Unlike its procoagulant relatives, Factors II, VII, IX and X, Protein C acts as a natural anticoagulant by downregulating thrombin generation after coagulation has been initiated.
Protein C is activated by thrombin bound to thrombomodulin on the endothelial cell surface .Activated Protein C (APC) then combines with its cofactor, Protein S, on the surface of the platelet where it can degrade and inactivate factor Va and factor VIIIa. In the absence of Protein C, thrombin generation goes relatively unchecked and a hypercoagulable state ensues.
Protein C Deficiency
Congenital Protein C deficiency was first described in 1981. In its heterozygous form, it is associated with a significantly increased risk of venous thrombosis. Homozygous Protein C deficiency may be associated with purpura fulminans at birth and may be fatal if untreated. Congenital Protein C deficiency is classified into two types:
Type I Protein C deficiency is a quantitative defect and is associated with a decrease in the total amount of Protein C in the plasma . Although the Protein C molecule in Type 1 patients functions normally, the amount is insufficient to adequately regulate thrombin generation.
Type II Protein C deficiency is a qualitative defect, and is characterized by the presence of defective Protein C molecules. The total amount of Protein C present may be normal, but it is unable to function normally. Numerous qualitative defects in the Protein C molecule have been described. These may alter the ability of Protein C to interact with thrombomodulin, phospholipids, factor Va or factor VIIIa.
Laboratory Diagnosis
Diagnosis of Protein C deficiency requires specific assay of the functional Protein C activity in the patient's plasma.
In the Hemostasis and Thrombosis Laboratory, the normal range for Protein C activity is 70 - 130% and Protein C antigen is 53 - 152%.
If the Protein C level is <40%, we will perform an assay for Factor VII. This protein is also Vitamin K-dependent and has a short plasma half life similar to that of Protein C. If Factor VII is also decreased, the low Protein C activity is most likely due to hepatic insufficiency or Vitamin K absence or antagonism. It is not unusual for blood for hypercoagulabilitystudies to be drawn after oral anticoagulant therapy has been initiated and Protein C levels will fall within a few hours of the first dose.
Low levels of Protein C activity should always be checked on a second plasma sample. The level of Protein C antigen should also be measured in order to classify the deficiency as Type 1 or Type 2. It may be necessary to wait until the patient has discontinued oral anticoagulants before confirming the diagnosis.
Treatment of Protein C Deficiency
Treatment of the patient with Protein C deficiency depends upon the individual patient's overall thrombotic risk. Initial treatment of a venous thrombosis will comprise heparin, followed by an oral anticoagulant for 3-6 months. Patients that have had multiple thromboembolic episodes or are at high risk of further episodes (e.g. those with multiple thrombotic risk factors) may be candidates for longer-term anticoagulation. Homozygous Protein C deficiency will require treatment with fresh frozen plasma or Protein C concentrate since the risk of overwhelming thrombosis is high.
