Which lab tests (PT [prothrombin time] with INR [international normalized ratio], aPTT [activated partial thromboplastin time], and specific Factor VII and protein C activity assays) should be ordered to evaluate a patient with suspected combined Factor VII and protein C deficiency?

Laboratory Testing for Combined Factor VII and Protein C Deficiency

Order PT with INR, aPTT, and specific Factor VII and Protein C activity assays as your initial panel when evaluating suspected combined Factor VII and protein C deficiency. 1

Initial Screening Tests

Start with these four tests simultaneously:

• PT with INR - screens for Factor VII deficiency (extrinsic pathway) 1
• aPTT - screens for protein C pathway abnormalities and other intrinsic pathway defects 1
• Complete blood count (CBC) - rules out thrombocytopenia as a bleeding cause 2, 1
• Fibrinogen level (Clauss method) - identifies consumptive coagulopathies 1

Interpreting Initial Results

Expected Pattern for Combined Deficiency

• Prolonged PT indicates Factor VII deficiency affecting the extrinsic pathway 2
• Normal or mildly prolonged aPTT may occur since Factor VII does not affect the intrinsic pathway 2
• Protein C deficiency alone does not prolong PT or aPTT in standard screening tests 2

Critical Next Step: Mixing Study

Perform a 50:50 mixing study with normal plasma if PT or aPTT is prolonged 1:

• Complete correction indicates factor deficiency rather than an inhibitor 1, 3
• Incomplete correction suggests presence of an inhibitor requiring different evaluation 3

Specific Factor Assays

Once screening tests suggest deficiency, order these confirmatory tests:

For Factor VII Deficiency

• Factor VII activity assay using one-stage PT-based clotting method 1
• Severity classification: severe <10 IU/dL, moderate 10-30 IU/dL, mild 30-50 IU/dL 1
• Factor activity <20% correlates with bleeding risk 1

For Protein C Deficiency

• Protein C activity assay (functional assay preferred over antigen) 2
• Protein C levels <50% suggest deficiency 2
• Severe deficiency presents with levels <20% 4

Critical Timing Considerations

Avoid Testing During Anticoagulation

Do not interpret protein C levels in patients on warfarin or vitamin K antagonists - both Factor VII and protein C are vitamin K-dependent and will be artificially low 2, 5:

• Warfarin causes parallel reduction in both proteins 5
• Use protein C:Factor VII ratio (normal ~1.12) if testing cannot be delayed - ratio <0.63 suggests true protein C deficiency 5
• Ideally, wait until anticoagulation is discontinued before definitive testing 2

Acute Phase Reactants

• Factor VIII (not Factor VII) can be elevated during acute illness 2
• Repeat abnormal results to confirm diagnosis, as some factors vary with clinical status 2

Special Clinical Scenarios

Newborns with Bleeding

If evaluating a bleeding newborn with hepatomegaly:

• Consider vitamin K deficiency first - causes combined prolongation of PT and aPTT affecting Factors II, VII, IX, and X 2, 6
• Measure PIVKA-II (proteins induced by vitamin K absence) if vitamin K or FFP already given 2, 6
• Homozygous protein C deficiency presents with purpura fulminans in the newborn period 2, 6

Liver Disease Patients

• INR is unreliable in cirrhosis - does not account for reduced anticoagulant factors like protein C 2
• Both procoagulant (Factor VII) and anticoagulant (protein C) factors are reduced, creating a rebalanced but precarious hemostatic state 2
• Standard coagulation tests do not predict bleeding risk accurately in this population 2

Diagnostic Algorithm

1. Order initial panel: PT/INR, aPTT, CBC, fibrinogen 1

2. If PT prolonged: Perform 50:50 mixing study 1

3. If mixing study corrects: Order Factor VII activity assay 1

4. Simultaneously order: Protein C activity assay regardless of aPTT result, since protein C deficiency does not reliably prolong screening tests 2

5. Confirm diagnosis: Repeat testing showing Factor VII activity <50% and/or protein C activity <50% 1, 4

6. If both deficiencies confirmed: Consider genetic testing and family screening, as combined deficiency may represent distinct genetic syndrome 7, 8

Common Pitfalls to Avoid

• Do not rely on aPTT alone to screen for protein C deficiency - it is typically normal 2
• Do not test during acute illness without recognizing that results may be transiently abnormal 2
• Do not interpret isolated low protein C in patients on warfarin as diagnostic without calculating protein C:Factor VII ratio 5
• Do not assume bleeding risk from Factor VII levels alone - clinical severity does not correlate reliably with factor levels, especially between 2-10% activity 9
• Do not forget vitamin K deficiency in the differential, particularly in newborns or patients with malabsorption 2, 6