What is the management plan for a postpartum patient with acquired hemophilia A?

Postpartum Acquired Hemophilia A: Case Report and Management

Case Presentation

A 26-year-old primigravida presented 3 weeks postpartum with spontaneous bruising and left leg pain, representing the first documented case of postpartum acquired hemophilia A (AHA) in the Philippines. The patient underwent cesarean section on May 14,2025, and developed progressive ecchymoses and hematomas without trauma, along with severe anemia (hemoglobin 73 g/L) and markedly prolonged aPTT (108.9 seconds, ratio 3.30) with normal PT and platelet count 1.

Clinical Course

Initial Presentation (2 weeks postpartum):

• Spontaneous bruising on bilateral upper arms and lower extremities
• Left calf pain with swelling, no trauma history
• Progressive anemia requiring multiple transfusions
• Isolated aPTT prolongation (108.9 seconds) with normal PT (14.3 seconds) and platelets (409.50 × 10⁹/L) 1

Diagnostic Workup:

• Mixing studies demonstrated incomplete correction of aPTT (patient 141.6 sec → mixing 78.3 sec → 140.8 sec at 3 hours), confirming presence of inhibitor 1
• Bethesda assay revealed Factor VIII inhibitor titer of 69.79 BU (normal control 114) 1
• Factor VIII activity was severely reduced (<1% expected based on inhibitor titer) 2
• Autoimmune workup (ANA, anti-dsDNA) negative, excluding underlying autoimmune disease 3
• HIV, HBV, HCV screening negative 3

Pathophysiology of Postpartum Acquired Hemophilia A

Postpartum AHA results from development of IgG autoantibodies against Factor VIII, triggered by immune dysregulation following pregnancy 3. The pathophysiologic mechanism involves:

1. Immune Tolerance Breakdown: Pregnancy induces significant immunologic changes to maintain fetal tolerance. The postpartum period represents a critical window where restoration of normal immune function can trigger autoimmunity 3.

2. Autoantibody Formation: Unlike congenital hemophilia inhibitors, acquired Factor VIII autoantibodies demonstrate type 2 kinetics—they incompletely neutralize Factor VIII in a time- and temperature-dependent manner, explaining why residual Factor VIII activity may persist despite high inhibitor titers 1.

3. Hemorrhagic Manifestations: The autoantibodies cause bleeding through two mechanisms: (a) direct neutralization of Factor VIII coagulant activity, and (b) accelerated clearance of Factor VIII-antibody complexes 3. This results in spontaneous bleeding into soft tissues, muscles, and mucous membranes—distinct from the hemarthroses typical of congenital hemophilia 1.

4. Postpartum Timing: AHA typically manifests within 1-4 months postpartum, with median onset at 3 months. The postpartum period accounts for approximately 7-20% of all AHA cases in women of childbearing age 3.

Management Protocol

Acute Bleeding Control

This patient required bypassing agents for hemorrhage control given the high inhibitor titer (69.79 BU), but resource limitations necessitated alternative approaches 4.

Hemostatic Management Implemented:

• Fresh frozen plasma (FFP) 3 units every 12 hours for factor replacement—suboptimal but necessary given lack of bypassing agents 4
• Tranexamic acid 1 gram IV every 8 hours as antifibrinolytic therapy 5
• Packed red blood cell transfusions (total 6 units) to maintain hemoglobin >70 g/L 4

Optimal Hemostatic Management (per guidelines):

• For severe bleeding with inhibitor >5 BU: Recombinant Factor VIIa (rFVIIa) 90 μg/kg every 2-3 hours OR activated prothrombin complex concentrate (aPCC) 50-100 IU/kg every 8-12 hours (maximum 200 IU/kg/day) 1, 4
• Avoid Factor VIII concentrates when inhibitor titer exceeds 5 BU, as they are ineffective and may boost antibody response 4
• Tranexamic acid is appropriate as adjunctive therapy but should not replace bypassing agents in severe bleeding 5

Immunosuppressive Therapy for Inhibitor Eradication

All patients with AHA require immediate immunosuppressive therapy to eradicate the inhibitor, regardless of bleeding severity 1, 4.

First-Line Regimen (Implemented in this case):

• Corticosteroids: Prednisone 1 mg/kg/day (80 mg daily for this 60 kg patient) 4
• Cyclophosphamide: 1.5-2 mg/kg/day (150 mg daily = 3 tablets of 50 mg) added on day 10 when steroids alone showed insufficient response 4
• Duration: Minimum 5 weeks of combination therapy 4

Treatment Response Monitoring:

• aPTT improved from 141.6 seconds (ratio 3.98) to 82.7 seconds (ratio 2.5) after 3 weeks of therapy 1
• Hemoglobin stabilized at 107 g/L without further transfusions 1
• New hematoma formation ceased after 2 weeks of immunosuppression 1

Second-Line Options (if first-line fails):

• Rituximab 375 mg/m² weekly for 4 weeks should be added if no response after 3-5 weeks of steroids ± cyclophosphamide 4
• Recent evidence suggests rituximab may be considered earlier in postpartum cases given better safety profile compared to cyclophosphamide 6, 3

Prognostic Factors

This patient had poor prognostic indicators that predicted delayed remission:

• Factor VIII <1 IU/dL (implied by inhibitor titer 69.79 BU): Associated with longer time to remission (median 43 vs 24 days), lower remission rate (77% vs 89%), and decreased survival 2
• High inhibitor titer (>20 BU): Less likely to achieve rapid remission on steroids alone (odds ratio 0.09 for remission ≤21 days) 2

Expected outcomes based on prognostic data:

• Partial remission (FVIII >50 IU/dL, bleeding stopped) expected in 77% by median 43 days 2
• Complete remission (inhibitor undetectable, FVIII normalized) expected in 76% by median 44 weeks with delayed immunosuppression 6

Supportive Care and Monitoring

Infection Prophylaxis (Critical given immunosuppression):

• Trimethoprim-sulfamethoxazole 800/160 mg daily for Pneumocystis jirovecii prophylaxis 4
• Proton pump inhibitor (pantoprazole 40 mg daily) for GI protection on high-dose steroids [@case details@]

Monitoring Schedule:

• During active treatment: CBC, aPTT, Factor VIII activity weekly 1
• After complete remission: Monthly for 6 months, then every 2-3 months until 12 months, then every 6 months during year 2 1
• Relapse rate: Approximately 20% within first year, necessitating prolonged surveillance 3

Thromboprophylaxis Consideration:

• Once inhibitor eradicated and Factor VIII levels normalize, consider thromboprophylaxis per ACCP guidelines if Factor VIII becomes markedly elevated (>150 IU/dL), as this increases thrombotic risk 1

Novel Therapeutic Approaches

Emicizumab (not available in this case) represents a paradigm shift in AHA management:

• Bispecific antibody mimicking Factor VIII cofactor function, effective regardless of inhibitor presence 6, 3
• Recent GTH-AHA-EMI study demonstrated improved 2-year survival (82% vs 63%) and reduced infection-related mortality (4% vs 17%) when emicizumab allowed postponed immunosuppression compared to immediate IST 6
• Allows outpatient management with bleeding prophylaxis while awaiting spontaneous remission (occurs in 15% of cases) 6
• Consider emicizumab as first-line prophylaxis in postpartum AHA when available, particularly given younger age and desire to minimize immunosuppression exposure 6, 3

Critical Management Pitfalls to Avoid

1. Do not delay immunosuppression while awaiting confirmatory testing—start corticosteroids immediately when AHA is suspected based on clinical presentation and isolated aPTT prolongation 1, 4

2. Do not rely on inhibitor titer to guide bleeding management—poor correlation exists between titer and bleeding phenotype; clinical assessment determines need for bypassing agents 1, 2

3. Do not use Factor VIII concentrates empirically in patients with high-titer inhibitors (>5 BU)—they are ineffective and may boost antibody response 4

4. Do not discontinue immunosuppression prematurely—maintain therapy minimum 5 weeks even if bleeding resolves, as inhibitor eradication requires prolonged treatment 4

5. Do not overlook infection risk—infections are the leading cause of death in AHA (17% mortality in historic cohorts), necessitating aggressive prophylaxis and low threshold for empiric antibiotics 6

6. Do not assume normal aPTT excludes AHA—mixing studies must be performed with incubation (1-2 hours) as immediate mixing may show correction despite inhibitor presence 1

Outcome and Follow-Up

This patient achieved clinical remission with cessation of new bleeding by day 20 of immunosuppression, though complete inhibitor eradication required ongoing therapy [@case details@]. She was discharged on day 28 with:

• Prednisone 80 mg daily
• Cyclophosphamide 150 mg daily
• Trimethoprim-sulfamethoxazole prophylaxis
• Tranexamic acid for breakthrough bleeding

At 2-week outpatient follow-up (day 42 total), new hematomas developed, indicating incomplete remission and need for treatment intensification [@case details@]. This aligns with predicted delayed response given baseline Factor VIII <1 IU/dL 2. Addition of rituximab should be strongly considered at this juncture given inadequate response to 6 weeks of steroids plus cyclophosphamide 4.

This case represents a significant contribution to the medical literature as the first documented postpartum AHA in the Philippines, highlighting the need for increased awareness of this rare but life-threatening complication 3.