What is the most likely diagnosis for a full-term neonate with spontaneous soft tissue bleeding, joint swelling, normal platelet count, normal prothrombin time (PT), but prolonged activated partial thromboplastin time (aPTT) that fails to correct with mixing study?

Diagnosis: Maternal Autoantibodies Leading to Acquired Hemophilia (Option D)

The most likely diagnosis is maternal autoantibodies causing acquired hemophilia A (Option D), as the failed mixing study correction definitively indicates an inhibitor rather than a simple factor deficiency, which is the hallmark distinguishing feature of acquired hemophilia from congenital hemophilia. 1

Diagnostic Reasoning

Why the Mixing Study is Critical

• A prolonged aPTT that fails to correct after mixing with normal plasma indicates the presence of an inhibitor (autoantibody) rather than simple factor deficiency. 1
• If this were a congenital factor deficiency (like Factor VIII deficiency/hemophilia A), the mixing study would correct immediately because the normal plasma would supply the missing factor. 1, 2
• The failure to correct with a Rosner index ≥11% specifically points to an inhibitory substance blocking factor activity. 2, 3

Clinical Presentation Supports Acquired Hemophilia

• The neonate presents with spontaneous soft tissue bleeding and hemarthrosis, which are classic manifestations of severe factor deficiency or inhibitor presence. 4
• Normal platelet count excludes Bernard-Soulier syndrome (Option B) and neonatal alloimmune thrombocytopenia (Option C), both of which are platelet disorders. 1
• Normal PT excludes extrinsic pathway defects and confirms the problem is isolated to the intrinsic pathway. 1

Transplacental Transfer of Maternal Autoantibodies

• In neonates, acquired hemophilia results from transplacental passage of maternal IgG autoantibodies against Factor VIII. 1
• This is distinct from congenital hemophilia A (Option A), which would show mixing study correction and would be inherited as an X-linked recessive disorder affecting males. 3
• The maternal autoantibodies create a temporary acquired inhibitor state in the neonate that typically resolves as maternal antibodies are cleared over weeks to months.

Why Other Options Are Incorrect

Factor VIII Deficiency (Option A) - Incorrect

• Congenital Factor VIII deficiency (hemophilia A) would show immediate correction on mixing studies because the normal plasma supplies the missing factor. 2, 3
• The failed mixing study correction definitively rules out simple factor deficiency. 1
• While the clinical presentation (bleeding, hemarthrosis) fits hemophilia A, the laboratory findings do not support congenital deficiency. 3

Bernard-Soulier Syndrome (Option B) - Incorrect

• This is a platelet function disorder that would present with thrombocytopenia and abnormal platelet morphology on blood smear. 1
• The normal platelet count in this case excludes this diagnosis entirely.
• Bernard-Soulier syndrome does not cause prolonged aPTT. 1

Neonatal Alloimmune Thrombocytopenia (Option C) - Incorrect

• This condition presents with severe thrombocytopenia (often platelet counts <50,000/mm³), not normal platelet counts. 1
• It does not cause prolonged aPTT or coagulation factor abnormalities.
• The normal platelet count excludes this diagnosis. 1

Immediate Next Steps

Confirmatory Testing Required

• Measure Factor VIII activity level immediately, which will be reduced in acquired hemophilia A. 1
• Perform Bethesda assay to quantify the Factor VIII inhibitor titer, though it may underestimate autoantibody potency due to type 2 kinetics. 1
• Consider Factor VIII antibody ELISA if results are ambiguous or to distinguish from lupus anticoagulant. 1
• Perform lupus anticoagulant testing to exclude this alternative cause of non-correcting mixing studies, though lupus anticoagulant rarely causes bleeding in neonates. 1, 2

Critical Management Considerations

• Immediate hemostatic control is the priority using bypassing agents (recombinant activated factor VII or activated prothrombin complex concentrate) if active bleeding is present. 1
• In neonates with transplacentally acquired maternal autoantibodies, the condition is typically self-limited as maternal IgG is cleared over 2-3 months.
• Avoid Factor VIII replacement therapy as it will be neutralized by the inhibitor and may boost antibody titers. 1

Common Pitfalls to Avoid

• Never assume immediate mixing study correction excludes all inhibitors—proceed with Factor VIII inhibitor testing if clinical bleeding is present regardless of mixing study results. 2, 3
• Do not delay treatment while awaiting confirmatory testing if life-threatening bleeding is present; initiate bypassing agents immediately. 1
• Do not confuse this with congenital hemophilia A based solely on clinical presentation; the mixing study result is the key distinguishing feature. 1, 2