What is the management approach for an infant with hemophilia (Hemophilia A or B) presenting with intracranial bleeding and a normal activated partial thromboplastin time (aPTT)?

Management of Infant Hemophilia with Intracranial Bleeding and Normal aPTT

Immediately initiate factor replacement therapy or bypassing agents for any infant with suspected hemophilia presenting with intracranial hemorrhage, regardless of aPTT results, as a normal aPTT does not exclude hemophilia and intracranial bleeding carries 13.5% mortality and 39% permanent neurological sequelae risk.

Critical Diagnostic Considerations

Why aPTT May Be Normal in Hemophilia

• Moderate hemophilia (factor levels 1-5%) can present with normal or minimally prolonged aPTT, particularly in neonates where reference ranges differ from older children 1
• Factor VIII levels as low as 10% may show normal aPTT results, yet still cause life-threatening bleeding in the setting of trauma 1
• The diagnosis of hemophilia is frequently missed in infants with ICH when clinicians rely solely on aPTT screening 2, 1

Essential Immediate Testing

• Obtain specific factor VIII and factor IX assays immediately—do not wait for aPTT confirmation before treatment 2, 1
• Perform factor assays at higher serial dilutions if initial results are ambiguous, as this attenuates interference 3
• Consider that neonatal ICH occurs in 2-3% of severe hemophilia cases and represents the second most common initial hemorrhage manifestation 4, 5

Immediate Hemorrhage Management

First-Line Treatment for Intracranial Bleeding

Initiate factor replacement immediately upon clinical suspicion, even before confirmatory testing, as delays in treatment significantly worsen outcomes 2, 1

For Confirmed or Suspected Hemophilia A:

• Administer recombinant or plasma-derived factor VIII concentrate at loading dose to achieve 80-100% factor levels for intracranial hemorrhage 5
• Neonates may require higher doses than older children due to different pharmacokinetics 5
• Monitor factor levels closely as replacement therapy dosing must be individualized in neonates 5

For Hemophilia B:

• Administer factor IX concentrate with similar aggressive dosing strategy 5

If Bypassing Agents Are Needed:

• Recombinant activated factor VII (rFVIIa) at 90 μg/kg every 2-3 hours until hemostasis is achieved 3
• Activated prothrombin complex concentrates (aPCC) at 50-100 IU/kg every 8-12 hours (maximum 200 IU/kg/day) 3
• These agents are indicated when inhibitors develop or factor replacement fails 3

Surgical Management Considerations

• Administer prophylactic factor concentrate or fresh frozen plasma before any neurosurgical intervention, even if hemophilia diagnosis is not yet confirmed 1, 6
• One case series demonstrated that failure to provide prophylactic clotting therapy resulted in rebleeding requiring second surgery with poor outcome 1
• Neurosurgery can be performed safely under cover of highly potent factor concentrates 6

Prevention of Rebleeding

Duration of Factor Replacement

• Continue intensive factor replacement for minimum 10-14 days following intracranial hemorrhage 5
• Maintain factor levels >50% during acute phase, then >30% during recovery period 5
• 41% of neonatal ICH occurs within the first week of life, emphasizing need for sustained prophylaxis 4

Monitoring Strategy

• Cranial ultrasound is an excellent non-invasive screening method for ICH in newborns 5
• Serial imaging to assess for rebleeding or hydrocephalus development 6
• Hemoglobin/hematocrit monitoring is often more reliable than imaging for detecting ongoing bleeding 3

Special Considerations for Neonates

Inhibitor Development Risk

• Intensive early factor replacement carries risk of inhibitor formation (antibodies against factor VIII/IX) 4
• Despite this risk, immediate treatment of life-threatening ICH takes priority over inhibitor concerns 4, 5
• If inhibitors develop, switch to bypassing agents (rFVIIa or aPCC) as outlined above 3

Emicizumab Considerations

• Emicizumab should NOT be used as acute treatment for neonates with severe hemophilia A and active intracranial bleeding 5
• However, emicizumab prophylaxis initiated in the first days/weeks of life may prevent ICH in infants with severe hemophilia A 3
• The HAVEN 7 study showed no ICH in 55 infants treated with emicizumab, suggesting potential preventive benefit 3

Common Pitfalls to Avoid

• Never delay treatment waiting for factor assay results when ICH is clinically suspected 2, 1
• Do not assume normal aPTT excludes hemophilia in an infant with ICH and trauma history 1
• Do not attribute prolonged aPTT to other causes (such as DIC) without obtaining specific factor levels 2
• Avoid iatrogenic bleeding by minimizing invasive procedures and using prophylactic factor coverage when procedures are necessary 5
• Do not use emicizumab for acute bleeding management in neonates—it is not appropriate for active hemorrhage control 5

Risk Factors Requiring High Suspicion

• Male infant with ICH following traumatic delivery (forceps, vacuum, prolonged second stage labor) 2, 4
• ICH occurring within first week of life, even after seemingly minor trauma 4
• No family history does not exclude hemophilia—both reported cases with normal aPTT had no family history 1