From the Guidelines
Testing for protein C deficiency should be performed using functional protein C assays that measure activity, followed by immunologic assays to determine protein C antigen levels if activity is low, as recommended by the most recent guidelines 1. When testing for protein C deficiency, it is essential to consider the clinical context and potential interferences. The test should be performed when the patient is not taking anticoagulants like warfarin and not during an acute thrombotic event, as these can temporarily lower protein C levels. Ideally, testing should occur at least 2 weeks after completing anticoagulation therapy.
Key Considerations
- The standard approach includes functional protein C assays that measure activity, followed by immunologic assays to determine protein C antigen levels if activity is low 1.
- Genetic testing may be recommended to confirm hereditary deficiency.
- Testing is indicated for patients with unexplained venous thromboembolism, especially if occurring at a young age, in unusual locations, or with family history of thrombosis.
- Family members of individuals with confirmed protein C deficiency should also be tested.
- Interpretation requires clinical context, as protein C levels can be affected by pregnancy, liver disease, vitamin K deficiency, and certain medications.
Assay Selection
- The choice of assay depends on the specific clinical scenario and the presence of potential interferences, such as factor deficiencies, protein S, or lupus anticoagulant 1.
- Predilution assays are recommended because of their high sensitivity and specificity for F5 mutations conferring APC-R.
- RVV-X–based assays with predilution have near 100% sensitivity and specificity for F5 mutations conferring APC-R, and discrimination between heterozygotes and homozygotes.
Clinical Implications
- Protein C deficiency is important to identify because it increases thrombosis risk, and diagnosis may influence decisions about anticoagulation duration after thrombotic events and prophylaxis during high-risk situations like surgery or pregnancy.
- The diagnosis of protein C deficiency should be made in the context of a comprehensive clinical evaluation, taking into account the patient's medical history, family history, and other risk factors for thrombosis.
From the Research
Testing for Protein C Deficiency
- Protein C deficiency can be diagnosed using a clotting (functional) assay or an antigenic (immunological) assay 2.
- The recommended initial test for protein C is an activity (functional) assay, which may be clotting time based or chromogenic 3.
- The chromogenic PC assay is commonly used to diagnose deficiency due to its good specificity, but it fails to detect the rare type 2b deficiency 4.
- The clotting-based assay of PC is capable of detecting type 2b deficiency but it has reduced specificity 4.
Interpretation of Test Results
- Protein C levels can vary with age, and adult reference ranges cannot be applied to babies or children 4.
- Pre-analytical variables in the specimen can affect measurement of PC, and can be assay-dependent 4.
- Direct oral anticoagulants can falsely raise PC level in the clotting-based assay, but the standard chromogenic assay is unaffected 4.
Clinical Implications
- Hereditary protein C deficiency is a hypercoagulable state associated with an increased risk for venous thrombosis 3.
- Inherited protein C deficiency increases risk of venous thromboembolism (VTE) by 5 to 10-fold in thrombosis-prone families 4.
- Homozygous or compound heterozygous PC deficiencies are rare and serious disorders, and affected infants are often in families with no history of PC deficiency or thrombosis 4.
- Factor V Leiden (FVL) increases the risk of thrombosis in PC-deficient type I families 5.