Next Step After Abnormal Rosner Index in Prolonged aPTT
When a mixing test shows an abnormal Rosner index (≥11%), indicating failure to correct and suggesting an inhibitor rather than factor deficiency, the next step is to perform specific factor VIII activity measurement and lupus anticoagulant testing to differentiate between acquired hemophilia A and antiphospholipid syndrome. 1, 2
Understanding the Rosner Index Result
- A Rosner index ≥11% indicates the presence of an inhibitor rather than simple factor deficiency, as factor deficiencies would correct when mixed with normal plasma 3, 4
- The mixing test failure distinguishes acquired hemophilia A from congenital hemophilia and confirms an inhibitory substance (autoantibody) is present 1
- However, a Rosner index between 5.0% and 9.1% represents an intermediate zone where additional 4:1 mixing studies may be needed for clarification 3
Immediate Diagnostic Testing Required
Primary Tests to Order
- Factor VIII activity level measurement is the most critical next step, as reduced Factor VIII with a non-correcting mixing study is the hallmark of acquired hemophilia A 1, 5
- Lupus anticoagulant testing must be performed to exclude antiphospholipid syndrome, which is the other major cause of non-correcting mixing studies 1, 2, 5
- Bethesda assay to quantify Factor VIII inhibitor titer if Factor VIII activity is low, though this may underestimate autoantibody potency due to type 2 kinetics 1, 5
Confirmatory and Supportive Tests
- Factor VIII antibody ELISA if results are ambiguous or to further distinguish from lupus anticoagulant 1
- PT, platelet count, and fibrinogen to exclude other coagulation abnormalities and ensure normal extrinsic pathway function 1
- Incubated mixing study (if not already performed) is crucial because Factor VIII autoantibodies are time and temperature-dependent, showing greater prolongation after incubation compared to immediate mixing 2
Clinical Context Considerations
Medication Review
- Exclude heparin contamination by checking thrombin time or reviewing clinical history, as heparin can interfere with aPTT interpretation 5
- If the patient is on warfarin with INR 1.5-3.0, interpretation becomes difficult and testing should ideally be performed when INR <1.5 or 1-2 weeks after discontinuation 5
- Low molecular weight heparin can be present up to 0.8 U/mL in some reagents with neutralizers, but may still affect results 5
Bleeding History Assessment
- The presence or absence of bleeding helps differentiate acquired hemophilia A (typically presents with bleeding) from lupus anticoagulant (typically no bleeding tendency) 5, 6
- Acquired hemophilia A patients often present with spontaneous bleeding into skin, muscles, or mucous membranes despite no prior bleeding history 5
Common Pitfalls to Avoid
- Do not assume immediate correction excludes all inhibitors - some inhibitors are time-dependent and only manifest after incubation 2
- Do not delay specific factor assays - regardless of mixing study results, specific factor assays should be performed to facilitate accurate diagnosis 2
- Do not misinterpret lupus anticoagulant - it can cause artifactual lowering of factor levels due to inhibition of phospholipid in the assay 2
- Avoid testing during acute thrombotic events when patients may be on full-dose anticoagulation or have elevated acute phase reactants like Factor VIII 5
Algorithmic Approach Based on Results
If Factor VIII is Low (<40% activity):
- Proceed immediately to Bethesda assay for inhibitor quantification 1, 5
- Initiate hematology consultation for potential acquired hemophilia A management 5
- Consider immediate hemostatic control with bypassing agents if bleeding is present 1
If Factor VIII is Normal and Lupus Anticoagulant is Positive:
- Perform confirmatory lupus anticoagulant testing with high phospholipid concentration (integrated tests) 5
- Check anticardiolipin and anti-β2-glycoprotein I antibodies for complete antiphospholipid antibody profile 5
- Assess for thrombotic risk rather than bleeding risk 5