How to manage hemophilia with normal Activated Partial Thromboplastin Time (APTT) levels?

Hemophilia with Normal aPTT: Diagnostic Approach and Management

Initial Recognition and Repeat Testing

If hemophilia is suspected clinically but the aPTT is normal, immediately repeat the aPTT and perform additional coagulation studies, as acquired hemophilia A can initially present with normal aPTT values before becoming prolonged. 1

• Elderly patients presenting with spontaneous hemorrhaging (particularly intramuscular hematomas or soft tissue bleeding without hemarthrosis) require repeated aPTT testing even when initial values are normal 1
• The aPTT may normalize transiently in some cases of acquired hemophilia A, making serial testing essential 1
• Normal aPTT does not exclude hemophilia A in the acute setting, particularly in acquired cases 1

Diagnostic Workup When aPTT Becomes Prolonged

Mixing Study Protocol

• Perform a 1:1 mixing study (patient plasma with normal plasma) immediately and after 2-hour incubation to distinguish factor deficiency from inhibitor presence 2
• Immediate correction of aPTT indicates factor deficiency (congenital hemophilia A), while failure to correct suggests an inhibitor (acquired hemophilia A or lupus anticoagulant) 2, 3
• Calculate the Rosner index: values <11% support factor deficiency, while ≥11% indicate inhibitor presence 2, 4

Critical Caveat

Do not assume immediate mixing study correction completely excludes acquired hemophilia A—if clinical bleeding is present, proceed with inhibitor workup regardless of mixing study results. 2

Specific Factor Assays

• Measure Factor VIII activity level as the most critical diagnostic step 2, 3
• Factor VIII levels >5% in congenital hemophilia A may respond to desmopressin 5
• Factor VIII levels <5% require factor replacement therapy 5
• If Factor VIII is low with non-correcting mixing study, perform Bethesda assay to quantify inhibitor titer 4, 3

Exclude Confounding Factors

• Rule out heparin contamination by checking thrombin time or medication history 2
• If patient is on warfarin, defer testing until INR <1.5 or wait 1-2 weeks after discontinuation if INR is 1.5-3.0 2
• Perform lupus anticoagulant testing even when mixing study corrects, as both conditions can coexist 2, 4

Management Based on Diagnosis

Congenital Hemophilia A (Factor VIII >5%)

For patients with hemophilia A and Factor VIII levels >5%, desmopressin 0.3 mcg/kg IV administered 30 minutes prior to procedures or bleeding episodes is the first-line hemostatic agent. 5

• Desmopressin is indicated for hemophilia A patients with Factor VIII coagulant activity levels >5% 5
• Desmopressin will maintain hemostasis during surgical procedures and stop bleeding in spontaneous or trauma-induced injuries 5
• Patients with Factor VIII levels between 2-5% may be tried on desmopressin but require careful monitoring 5
• Desmopressin is contraindicated in hemophilia A with Factor VIII ≤5%, hemophilia B, or patients with Factor VIII antibodies 5

Congenital Hemophilia A (Factor VIII ≤5%)

• Factor VIII replacement therapy is required 5
• Desmopressin is not indicated 5

Acquired Hemophilia A (Inhibitor Present)

For acquired hemophilia A with severe bleeding (Factor VIII <1%), immediately discontinue any immune checkpoint inhibitors, admit the patient, and initiate bypassing agents (recombinant Factor VIIa or FEIBA) combined with high-dose corticosteroids (1-2 mg/kg/day) plus rituximab (375 mg/m² weekly for 3-4 weeks). 6, 3

Grading and Treatment Algorithm

Grade 1 (Mild: 5-40% Factor VIII activity):

• Hold immune checkpoint inhibitors if applicable 6
• Administer prednisone 0.5-1 mg/kg/day 6
• Provide transfusion support as required 6
• Hematology consultation for bleeding management 6

Grade 2 (Moderate: 1-5% Factor VIII activity):

• Hold immune checkpoint inhibitors 6
• Administer Factor VIII replacement (choice based on Bethesda unit titer) 6
• Prednisone 1 mg/kg/day plus rituximab 375 mg/m² weekly for 3-4 weeks and/or cyclophosphamide 1-2 mg/kg/day 6
• Continue immunosuppression for at least 5 weeks 6
• Transfusion support for bleeding episodes 6

Grade 3-4 (Severe: <1% Factor VIII activity):

• Permanently discontinue immune checkpoint inhibitors 6
• Immediate hospital admission 6
• Bypassing agents (recombinant Factor VIIa or FEIBA) with caution in elderly patients or those with coronary artery disease 6
• High-dose corticosteroids (1-2 mg/kg/day oral or IV) plus rituximab and/or cyclophosphamide 6
• If no improvement, add cyclosporine or additional immunosuppression 6

Common Pitfalls to Avoid

• Do not dismiss hemophilia based on a single normal aPTT—repeat testing is mandatory in patients with spontaneous bleeding 1
• Do not interpret low factor levels at face value if lupus anticoagulant is present—this causes artifactual lowering through phospholipid inhibition; repeat at higher dilutions 2
• Do not use desmopressin in patients with Factor VIII antibodies or inhibitors—it is contraindicated and ineffective 5
• Do not delay hematology consultation in suspected acquired hemophilia A—mortality exceeds 20% without prompt treatment 7
• Do not assume hemarthrosis will be present—acquired hemophilia A typically presents with soft tissue bleeding and muscle hematomas, not joint bleeding 7, 8