Differential Diagnosis and Workup for a 20-Year-Old with Recurrent Menorrhagia, Ecchymoses, and Prolonged PT/INR
This presentation strongly suggests an acquired coagulation factor deficiency, most likely acquired hemophilia A, which requires immediate hematologic evaluation with mixing studies and specific factor assays to prevent potentially fatal bleeding complications.
Differential Diagnosis
Primary Considerations
Acquired Hemophilia A: The combination of menorrhagia, ecchymoses, and prolonged PT/INR in a young woman is highly concerning for this rare but life-threatening condition, which has a 9-31% mortality rate from bleeding 1, 2. Postpartum women and young adults can develop autoantibodies against Factor VIII 3, 4.
Von Willebrand Disease (VWD): Affects 10-20% of women with documented menorrhagia and commonly presents with bleeding since menarche 5, 6. However, VWD typically does not prolong PT/INR, making this less likely as the sole diagnosis 7.
Factor VII Deficiency: An isolated prolonged PT/INR with normal aPTT suggests Factor VII deficiency, though this would be congenital rather than acquired 1.
Vitamin K Deficiency: Can occur with fat malabsorption or chronic cholestasis, causing prolonged PT/INR due to reduced production of Factors II, VII, IX, and X 1.
Liver Disease: Significant hepatic dysfunction (>70% loss of synthetic function) causes prolonged PT/INR, though this would be unusual in an otherwise healthy 20-year-old 1.
Less Likely but Important Considerations
Platelet Function Disorders: Can cause menorrhagia and ecchymoses but typically do not prolong PT/INR 8, 7.
Factor XI Deficiency: Causes bleeding symptoms but prolongs aPTT, not PT/INR 6.
Immediate Workup Plan
Step 1: Urgent Laboratory Assessment
Complete the following tests immediately:
Mixing Study (1:1 patient plasma with normal plasma): Perform immediately and after 2-hour incubation to distinguish factor deficiency from inhibitor presence 3, 4. Immediate correction indicates factor deficiency; failure to correct suggests an inhibitor (acquired hemophilia A) 3, 4.
Calculate Rosner Index: Values <11% support factor deficiency, while ≥11% indicate inhibitor presence 3, 4.
Specific Factor Assays: Measure Factor VIII activity level as the most critical diagnostic step 3, 4. Also measure Factor VII level given the isolated PT/INR prolongation 1.
Bethesda Assay: If Factor VIII is low with non-correcting mixing study, quantify inhibitor titer 1, 4.
Complete Blood Count: Assess for anemia (hemoglobin/hematocrit), thrombocytopenia 1, 5.
Iron Profile: Check ferritin to assess iron deficiency from chronic blood loss 5, 7.
Liver Function Tests: Including albumin, bilirubin, transaminases to exclude hepatic dysfunction 1.
Renal Function: Serum creatinine 7.
Thyroid Function: TSH level, as thyroid disorders can contribute to menorrhagia 7.
Step 2: Exclude Confounding Factors
Rule out heparin contamination: Check thrombin time or review medication history 3, 4.
Assess for warfarin effect: 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 3, 4.
Lupus anticoagulant testing: Perform even when mixing study corrects, as both conditions can coexist 3, 4.
Medication review: Assess for NSAIDs, antiplatelet agents, or other medications affecting hemostasis 1.
Step 3: Von Willebrand Disease Workup
If Factor VIII is isolated and low, distinguish between hemophilia A and VWD:
- VWF:RCo (Ristocetin Cofactor) 3, 7
- VWF:Ag (von Willebrand Factor Antigen) 3, 7
- Note: Patient stress, recent exercise, pregnancy, or inflammatory illness can falsely elevate Factor VIII and VWF levels, potentially masking mild deficiencies 3.
Step 4: Additional Hemostatic Studies
Platelet aggregation and release studies: If VWD workup is normal, as platelet function defects cause menorrhagia in a significant proportion of women 8, 7.
Euglobulin clot lysis time: To assess for fibrinolytic defects 7.
Factor XI level: Consider if bleeding history is significant 7.
Step 5: Gynecological Evaluation
Concurrent gynecological assessment is mandatory to exclude structural causes:
- Pelvic examination 1
- Transvaginal ultrasound (TVUS): First-line imaging to assess for polyps, leiomyomas, adenomyosis 1
- Endometrial biopsy: If indicated based on risk factors, though less likely in a 20-year-old 1
Step 6: Quantify Menstrual Blood Loss
- Pictorial Blood Assessment Chart (PBAC): Validated tool to objectively quantify menstrual blood loss 7. Look for clots ≥1 inch diameter, "flooding" (changing pad/tampon more frequently than hourly), and prolonged menses as predictors of underlying bleeding disorder 5.
Critical Pitfalls to Avoid
Never dismiss isolated prolonged PT/INR without bleeding as benign until acquired hemophilia A is definitively excluded, as bleeding can develop suddenly with high mortality 3, 2.
Do not assume immediate mixing study correction excludes all inhibitors—proceed with Factor VIII inhibitor testing (Bethesda assay) if clinical presentation suggests acquired hemophilia A with bleeding 3, 4.
Do not interpret low factor levels at face value if lupus anticoagulant is present, as this causes artifactual lowering through phospholipid inhibition in the assay; repeat at higher dilutions 3.
Do not start oral contraceptives before completing the hemostatic workup, as hormonally induced increases in Factor VIII and VWF may mask the diagnosis of VWD 6.
Immediate Management Considerations
If acquired hemophilia A is confirmed with active bleeding:
- Admit to hospital immediately 1, 4
- Hematology consultation 1, 4
- Initiate bypassing agents: Recombinant Factor VIIa (90 mcg/kg every 2-3 hours) or aPCCs (50-100 IU/kg every 8-12 hours, maximum 200 IU/kg/day) 1, 2
- High-dose corticosteroids: Prednisone 1-2 mg/kg/day 1, 2, 4
- Consider rituximab: 375 mg/m² weekly for 3-4 weeks as second-line therapy 1, 2, 4
The key is rapid diagnosis through mixing studies and specific factor assays, as acquired hemophilia A can be fatal if unrecognized, while VWD and other bleeding disorders require different management strategies but are less immediately life-threatening.