Laboratory Testing for Children of Parents with Protein C Deficiency
Order a protein C activity assay (chromogenic or clot-based method) as the primary screening test for the child, ideally after 6 months of age to avoid physiologically low neonatal levels. 1, 2
Primary Testing Approach
Initial Screening Test
- Protein C activity assay is the recommended first-line test, using either chromogenic or clot-based (coagulometric) methods 1, 2
- The chromogenic assay is most commonly used and detects the majority of protein C deficiencies 2
- Consider adding a coagulometric assay if chromogenic results are normal but clinical suspicion remains high, as rare qualitative defects may be missed by chromogenic methods alone 2
Optimal Timing for Testing
- Test after 6 months of age when possible, as protein C levels are physiologically low in neonates and gradually increase to adult levels 1
- If testing must be done earlier due to clinical concerns, interpret results cautiously and plan for repeat testing after 6 months 1
- Avoid testing during acute illness, as protein C is an acute phase reactant and levels can be transiently reduced 1
Sample Collection Requirements
Proper Specimen Handling
- Collect venous blood into 3.2% (0.105-0.109 mol/L) trisodium citrate at a 1:10 ratio 3
- Double-centrifuge to obtain platelet-poor plasma with residual platelet count <10.0 × 10⁹/L 3
- Test within 4 hours of collection, or freeze at -20°C for ≤2 weeks or -70°C for >2 weeks 3
- Rapidly thaw frozen samples in a 37°C waterbath and mix thoroughly before testing 3
Interpretation of Results
Expected Findings in Heterozygous Deficiency
- Heterozygous protein C deficiency typically shows levels between 35% and 65% of normal, while normal individuals have levels between 70% and 130% 4
- Both parents should be tested to confirm hereditary transmission if the child shows deficiency 5
Type Classification
- Type I deficiency: Both functional (activity) and antigenic (immunological) levels are reduced proportionally 4
- Type II deficiency: Antigenic levels are normal but functional activity is reduced (qualitative defect) 4
- Differentiation requires both functional and antigenic assays 4
Additional Considerations
Baseline Coagulation Screening
- Preliminary coagulation screening (PT/aPTT) is useful to detect previously unknown factor deficiencies that could interfere with protein C testing 6
- These routine tests will be normal in isolated protein C deficiency 1
Genetic Testing
- Genetic analysis of the PROC gene (chromosome 2q14.3) allows definitive diagnosis and confirms inherited versus acquired deficiency 1, 2
- Genetic testing is particularly valuable in families with severe protein C deficiency and can identify asymptomatic carriers 2
- Consider genetic testing if functional assays show deficiency, especially for family planning and counseling purposes 2
Critical Pitfalls to Avoid
Timing and Clinical Context
- Do not test during acute thrombotic events, as protein C levels may be consumed and falsely low 1
- Do not test while on anticoagulation (warfarin reduces protein C levels; heparin may interfere with assays) 1
- Do not rely solely on neonatal testing, as physiologically low levels in infants can lead to false-positive results 1
Assay Limitations
- Be aware that chromogenic assays may miss rare qualitative defects (Type II deficiency) that would be detected by coagulometric methods 2
- Icterus, hemolysis, and lipemia can interfere with coagulation assays, so ensure proper sample quality 3
Clinical Implications
- Asymptomatic heterozygous deficiency is common and does not automatically require prophylactic anticoagulation 4, 7
- Homozygous deficiency (extremely rare) presents in the neonatal period with purpura fulminans and requires immediate intervention 5
- Variable penetrance means not all individuals with protein C deficiency will develop thrombosis, even with very low levels 7