What is the management approach for a patient with hemophilia and a prolonged Partial Thromboplastin Time (PTT)?

Management of Prolonged PTT in Hemophilia

In patients with hemophilia presenting with a prolonged Partial Thromboplastin Time (PTT), management should focus on both treating acute bleeding episodes with bypassing agents such as recombinant Factor VIIa (rFVIIa) or activated prothrombin complex concentrates (aPCCs), while simultaneously initiating immunosuppressive therapy to eradicate inhibitors if present. 1

Diagnostic Approach

• A prolonged PTT in hemophilia patients may indicate factor deficiency or development of inhibitors (autoantibodies) against factor VIII 1
• Mixing tests should be performed to distinguish between factor deficiency and inhibitor presence - prolongation of PTT in a mixture of patient and normal plasma after 1-2 hours incubation compared to immediate mix suggests FVIII autoantibodies 1
• Specific factor assays (FVIII, IX, XI, XII) should be measured in parallel with mixing tests to facilitate early diagnosis 1
• The Bethesda assay should be used to quantify inhibitor titers, though it may not accurately estimate the true potency of autoantibodies due to their complex, non-linear type 2 kinetics 1

Management of Acute Bleeding

• Anti-hemorrhagic treatment should be initiated in patients with active severe bleeding symptoms regardless of inhibitor titer or residual FVIII activity 1
• First-line treatment options for severe bleeding include:
  • Recombinant Factor VIIa (rFVIIa): 90 μg/kg every 2-3 hours until hemostasis is achieved 1
  • Activated Prothrombin Complex Concentrates (aPCCs): 50-100 IU/kg every 8-12 hours to a maximum of 200 IU/kg/day 1
• Recombinant or plasma-derived human FVIII concentrates or desmopressin should only be used if bypassing therapy is unavailable 1
• Tranexamic acid can be used as an adjunctive therapy to reduce or prevent hemorrhage in hemophilia patients, particularly during procedures like tooth extraction 2

Inhibitor Eradication

• All patients diagnosed with acquired hemophilia A should receive immunosuppressive therapy immediately following diagnosis 1
• First-line immunosuppressive therapy includes:
  • Corticosteroids alone (1 mg/kg/day PO for 4-6 weeks) or
  • Corticosteroids in combination with cyclophosphamide (1.5-2 mg/kg/day for maximum six weeks) 1
• Second-line therapy with rituximab should be considered if first-line immunosuppressive therapy fails or is contraindicated 1
• Immunotolerance regimens with immunoabsorption should only be considered in life-threatening bleeds or in clinical research studies 1

Monitoring and Follow-up

• After complete sustained response, follow-up should include:
  • PTT and FVIII:C monitoring monthly during the first six months
  • Every 2-3 months up to 12 months
  • Every six months during the second year and beyond 1
• Thromboprophylaxis according to ACCP guidelines should be considered following inhibitor eradication in patients with very elevated FVIII:C levels 1

Special Considerations

• Lupus anticoagulant can also cause prolonged PTT that doesn't correct with normal plasma and may cause artefactual lowering of factor levels 1
• Specific tests for lupus anticoagulant should be performed to establish differential diagnosis 1
• In complex cases, a FVIII antibody ELISA may help distinguish between lupus anticoagulant and acquired FVIII inhibitor 1
• Prophylactic use of bypassing agents is recommended prior to minor or major invasive procedures 1

Pitfalls to Avoid

• Do not rely solely on inhibitor titer to guide treatment decisions, as there is poor correlation between inhibitor titer and bleeding phenotype 1
• Immediate correction of PTT with normal plasma does not exclude acquired hemophilia A - further investigation is still required if clinical presentation is suggestive 1
• Avoid concomitant use of Factor IX with tranexamic acid due to increased risk of thrombosis 2
• Do not use high-dose intravenous immunoglobulin for inhibitor eradication in patients with acquired hemophilia A 1