What is the approach to diagnose Bernard-Soulier syndrome?

Diagnostic Approach to Bernard-Soulier Syndrome

Bernard-Soulier Syndrome (BSS) should be diagnosed through a systematic approach beginning with clinical evaluation, followed by specific laboratory tests including complete blood count with peripheral blood smear, flow cytometry, and platelet aggregation studies.

Clinical Presentation and Initial Evaluation

• Key clinical features to identify:
  • Bleeding tendency (mucocutaneous bleeding, epistaxis, menorrhagia)
  • Family history of bleeding disorders (autosomal recessive inheritance)
  • Previous misdiagnosis as immune thrombocytopenia (ITP) resistant to steroid therapy 1

First-Line Diagnostic Tests

1. Complete Blood Count (CBC) with peripheral blood smear:

   • Look for thrombocytopenia (moderate, not severe)
   • Presence of giant platelets on peripheral smear (hallmark finding) 2

2. Platelet Function Testing:

   • Light Transmission Aggregometry (LTA):
     • Absent or severely reduced aggregation with ristocetin 2
     • Normal aggregation with other agonists (ADP, collagen) 3

3. Flow Cytometry:

   • Evaluate expression of GPIb/IX/V complex:
     • Reduced expression of GPIbα (typically <10% of normal) 4
     • Normal expression of GPIIb/IIIa (CD41/CD61) 2, 3

Second-Line Diagnostic Tests

1. Molecular Genetic Testing:

   • Direct sequencing of GP1BA, GP1BB, and GP9 genes 4, 5
   • Common mutations to screen for:
     • GPIX gene: Asn-45Ser mutation (particularly common in Caucasians) 1
     • Look for homozygous or compound heterozygous mutations 6

2. Additional Specialized Tests:

   • Whole blood platelet aggregation (electrical impedance method) 3
   • Radioimmunoassay of platelet glycoprotein expression 3
   • Western blotting for GPIb-IX complex 1

Diagnostic Algorithm

1. Initial screening:

   • CBC with peripheral blood smear showing thrombocytopenia and giant platelets
   • Bleeding assessment (using a standardized bleeding assessment tool) 2

2. Confirmatory testing:

   • Flow cytometry showing reduced GPIb/IX/V expression
   • Platelet aggregation studies showing absent ristocetin-induced aggregation but normal response to other agonists

3. Definitive diagnosis:

   • Genetic testing confirming biallelic pathogenic variants in GP1BA, GP1BB, or GP9 genes

Diagnostic Pitfalls and Considerations

• Common misdiagnosis: Often misdiagnosed as ITP, leading to ineffective steroid treatment 1
• Carrier detection: Heterozygous carriers may have normal platelet counts and function or subtle abnormalities 4
• Differential diagnosis:
  • Other macrothrombocytopenias (MYH9-related disorders, May-Hegglin anomaly)
  • Platelet-type von Willebrand disease (enhanced ristocetin response) 2
  • 22q11.2 deletion syndrome (can rarely lead to BSS if there is a pathogenic variant on the remaining GPIBB allele) 2

Clinical Implications

• Early and accurate diagnosis is crucial to avoid inappropriate treatments (such as steroids or splenectomy for presumed ITP)
• Genetic confirmation helps with family counseling and identification of carriers
• Diagnosis guides appropriate management of bleeding episodes and surgical planning

BSS is a rare but significant bleeding disorder that requires specific diagnostic testing. The combination of thrombocytopenia, giant platelets, and absent ristocetin-induced platelet aggregation with reduced GPIb/IX/V expression is diagnostic, with genetic testing providing definitive confirmation.