Protein C Deficiency Workup
- Author: Adam Cuker, MD, MS; Chief Editor: Perumal Thiagarajan, MD more...
A variety of immunologic and functional protein C assays are available.
Immunologic methods for the measurement of protein C antigen include enzyme-linked immunosorbent assays (ELISAs), radioimmunoassays (RIAs), and electroimmunoassays. Logarithms of protein C antigen levels in the healthy, nonpregnant, adult population show a Gaussian distribution. The protein C antigen reference range is defined as the mean +/- 2 standard deviations (SDs) of this distribution and approximates 70-140% of the protein C antigen level of normal pooled plasma. As noted earlier, neonates and infants have lower levels of protein C than their adult counterparts, and age-based normal ranges must therefore be derived separately for these populations.
Functional protein C assays make use of the venom of the southern copperhead snake (Agkistrodon contortrix), which activates the protein C zymogen to activated protein C (aPC). Activated protein C (aPC) activity can then be measured by means of a clotting assay or a chromogenic substrate. The adult reference range for protein C activity tends to be slightly lower than the immunologic normal range.
A decreased protein C activity level is required to make the diagnosis of protein C deficiency. However, owing to the broad normal ranges of protein C antigen and activity, diagnosis of heterozygous protein C deficiency can be challenging. Patients with levels less than 50% are likely to have a true hereditary deficiency, whereas levels between 55% and 65% may reflect heterozygous deficiency or the low end of the normal distribution. A functional protein C assay should be employed for screening purposes, as it will identify both type I and type II defects. In the event of a low protein C activity, a reflexive immunologic assay should be performed to distinguish between these types.
As described in Causes, above, there are a number of acquired causes of protein C deficiency. To the extent possible, laboratory testing should be performed in the absence of such causes to confirm that deficiency, when identified, is due to a genetic defect rather than an acquired cause. The timing of testing with respect to acute thrombosis and warfarin therapy deserves special mention.
The levels of protein C, protein S, and antithrombin are reduced in the setting of acute thrombosis. Therefore, these levels should generally not be assessed at the time of presentation with acute VTE. However, a normal protein C activity in this setting essentially rules out hereditary protein C deficiency.
Because protein C is a vitamin K – dependent protein, its levels are reduced with warfarin administration. Therefore, it is recommended that protein C testing not be performed unless the patient has been off vitamin K antagonist therapy for at least 2 weeks. If the patient has a severe thrombotic diathesis that does not permit discontinuation of anticoagulation, the patient may be temporarily transitioned to low molecular weight heparin (LMWH) for testing purposes or, alternatively, the diagnosis may be inferred through testing of family members.
Several investigators have developed ratio methods for diagnosing protein C deficiency in the context of warfarin therapy by comparing the protein C level with that of other vitamin K – dependent clotting factors.[59, 60] However, such methods have not been broadly validated.
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