What is the likely diagnosis and management for a family with iron deficiency anemia, intermittent thrombocytopenia, and normal factor eight levels?

Diagnosis and Management of Platelet-Type von Willebrand Disease (PT-VWD)

The most likely diagnosis for a family with iron deficiency anemia, intermittent thrombocytopenia, and normal factor VIII levels is Platelet-Type von Willebrand Disease (PT-VWD), also known as pseudo-von Willebrand disease. This condition requires comprehensive evaluation and targeted management to address both the bleeding tendency and associated hematologic abnormalities.

Diagnostic Features and Pathophysiology

Platelet-Type von Willebrand Disease is characterized by:

• Family history of bleeding disorder across multiple generations 1
• Intermittent thrombocytopenia
• Normal factor VIII levels (distinguishing it from true von Willebrand Disease)
• Iron deficiency anemia due to chronic blood loss
• Intrinsic platelet defect causing abnormal binding to von Willebrand factor

The key pathophysiologic mechanism involves:

• An intrinsic platelet abnormality that causes enhanced adsorption of high-molecular-weight von Willebrand factor multimers 1
• Platelets that can aggregate with unmodified human factor VIII/von Willebrand factor without requiring ristocetin
• Secondary depletion of plasma von Willebrand factor high-molecular-weight multimers

Diagnostic Algorithm

1. Confirm iron deficiency anemia:

   • Complete blood count showing low hemoglobin with microcytosis
   • Serum ferritin < 30 ng/mL (most powerful test for iron deficiency) 2
   • Transferrin saturation < 30% 2

2. Document thrombocytopenia pattern:

   • Intermittent nature of low platelet counts
   • Rule out other causes of thrombocytopenia
   • Note that iron deficiency itself can rarely cause thrombocytopenia 3, 4

3. Specialized hematologic testing:

   • Confirm normal factor VIII levels
   • Assess von Willebrand factor antigen and function
   • Evaluate platelet function with specialized testing 2
   • Ristocetin-induced platelet aggregation (may show increased response)
   • Analysis of von Willebrand factor multimers in plasma and platelets

4. Bleeding assessment:

   • Document bleeding history using a standardized bleeding assessment tool 2
   • Assess family history across multiple generations
   • Evaluate for hypermobility (Beighton score), which can be associated with bleeding symptoms 2

5. Exclude other causes:

   • Gastrointestinal evaluation for sources of blood loss 2
   • Upper GI endoscopy with small bowel biopsies (to rule out celiac disease) 2
   • Lower GI tract examination (colonoscopy or barium enema) 2

Management Approach

1. Iron replacement therapy:

   • First-line: Oral iron supplementation (ferrous sulfate 325 mg daily or on alternate days) 5
   • Continue for at least 3 months after normalization of hemoglobin to replenish stores 5
   • Target ferritin level of at least 100 ng/mL
   • For severe anemia or poor response: Consider IV iron therapy

2. Bleeding management:

   • Tranexamic acid (TXA) for minor and major procedures 2
   • Avoid aspirin and NSAIDs which can worsen bleeding tendency 2
   • For women with menorrhagia: Consider hormonal therapy to reduce menstrual blood loss

3. Monitoring:

   • Regular complete blood counts to track hemoglobin and platelet levels
   • Ferritin levels to assess iron stores
   • Bleeding symptoms assessment

4. Family screening:

   • Evaluate first-degree relatives for similar hematologic abnormalities
   • Genetic counseling when appropriate

Important Clinical Considerations

• Unlike typical iron deficiency where thrombocytosis is common, PT-VWD presents with thrombocytopenia 3, 4
• The combination of iron deficiency anemia and thrombocytopenia can be misdiagnosed as immune thrombocytopenia (ITP) 4
• Persistent or recurrent iron deficiency despite adequate supplementation suggests ongoing blood loss and requires thorough GI evaluation 2
• Mean platelet volume (MPV) may help differentiate from ITP (typically lower in PT-VWD than in ITP) 4
• Response to iron therapy is typically rapid, with platelet count normalization occurring within 4-39 days (median 6 days) 4

Pitfalls to Avoid

• Misdiagnosing as immune thrombocytopenia (ITP)
• Failing to investigate gastrointestinal sources of blood loss
• Discontinuing iron therapy too early before stores are replenished
• Overlooking the familial nature of the condition
• Missing the association between iron deficiency and thrombocytopenia

By following this diagnostic and management approach, patients with this rare condition can receive appropriate treatment to address both the bleeding tendency and associated hematologic abnormalities, improving their quality of life and reducing morbidity.