What diagnostic tests are recommended for a patient with a history of significant bleeding episodes and a family history of bleeding disorders, with a bleeding assessment score of 10 and platelet levels ranging from 120 to 150?

Diagnostic Approach for Patient with Elevated Bleeding Assessment Score and History of Hemorrhages

The patient should undergo comprehensive testing for von Willebrand disease (VWD) and inherited platelet function disorders (IPFD) as the most likely diagnoses based on the elevated bleeding assessment score, family history, and history of significant hemorrhages.

Initial Assessment and Clinical Context

This patient presents with several concerning features:

• Elevated bleeding assessment score (BAS) of 10 (abnormal)
• Family history of elevated bleeding scores (mother 9, uncle 6)
• Borderline thrombocytopenia (platelet count 120-150 × 10⁹/L)
• Three significant hemorrhagic episodes (postpartum, post-gum graft, post-thyroidectomy)

The ISTH BAT score of 10 is significantly elevated, as normal reference ranges for adult females are typically <6 1. This, combined with the family history and bleeding episodes, strongly suggests an inherited bleeding disorder.

First-Line Testing

1. Complete Blood Count (CBC)

   • Already performed showing borderline thrombocytopenia
   • Should be repeated to confirm consistent findings

2. Coagulation Screening Tests

   • Prothrombin Time (PT)
   • Activated Partial Thromboplastin Time (aPTT)
   • Fibrinogen level

3. Von Willebrand Disease Testing (highest priority)

   • VWF antigen (VWF:Ag)
   • VWF ristocetin cofactor activity (VWF:RCo)
   • Factor VIII coagulant activity (FVIII:C)
   • VWF:RCo/VWF:Ag ratio (to distinguish VWD subtypes)
   • VWF multimer analysis

4. Platelet Function Testing

   • Light Transmission Aggregometry (LTA) with multiple agonists:
     • ADP
     • Collagen
     • Ristocetin
     • Arachidonic acid
     • Epinephrine

Second-Line Testing (if first-line tests are inconclusive)

1. Expanded Platelet Function Testing

   • Flow cytometry for platelet surface glycoproteins
   • Expanded LTA panel with additional agonists (α-thrombin, TRAP-6, U46619, CRP, convulxin) 1
   • Platelet secretion assays
   • Clot retraction test

2. Specialized VWD Testing

   • VWF collagen binding assay
   • VWF propeptide assay
   • Genetic testing for VWD mutations

3. Genetic Testing

   • Next-generation sequencing panel for inherited bleeding disorders
   • Specific gene testing based on phenotype findings

Interpretation and Diagnostic Considerations

1. Von Willebrand Disease

   • Most common inherited bleeding disorder 1
   • Consistent with the patient's mucocutaneous bleeding pattern
   • Family history supports autosomal inheritance pattern
   • May require repeated testing as VWF is an acute phase reactant 1

2. Inherited Platelet Function Disorder

   • Borderline thrombocytopenia suggests possible platelet disorder
   • Mucocutaneous bleeding pattern is consistent
   • May coexist with mild VWD 1

3. Combined Hemostatic Defect

   • The severity of bleeding may indicate multiple hemostatic defects
   • The International Society on Thrombosis and Haemostasis (ISTH) notes that bleeding severity increases substantially when multiple hemostatic defects coexist 1

Common Pitfalls to Avoid

1. Relying solely on platelet count

   • Normal platelet counts do not exclude platelet function disorders 2
   • Borderline counts (120-150 × 10⁹/L) can be seen in some IPFDs

2. Single VWD testing

   • VWF is an acute phase reactant and levels can vary
   • Testing may need to be repeated up to 3 times for reliable results 1

3. Medication effects

   • Ensure patient is not taking NSAIDs, aspirin, or other medications affecting platelet function for at least 10 days before testing 1

4. Preanalytical variables

   • Proper sample collection and handling is critical for accurate results
   • Time-sensitive tests must be processed promptly

5. Overlooking mild factor deficiencies

   • Testing for factor XI deficiency should be considered, especially in patients of Ashkenazi Jewish descent 1

Management Considerations

If VWD is diagnosed:

• Desmopressin (DDAVP) is first-line therapy for most Type 1 and some Type 2 VWD 3
• VWF-containing concentrates for more severe types or when DDAVP is contraindicated

If platelet function disorder is diagnosed:

• Treatment will depend on specific diagnosis
• May require platelet transfusions for severe bleeding episodes
• Antifibrinolytic agents (tranexamic acid) for minor bleeding

Referral

Given the complexity of the case and need for specialized testing, referral to a hematologist with expertise in bleeding disorders is strongly recommended for proper diagnosis and management.