A 28-year-old woman presents to the emergency department with severe epistaxis for 2 hours, unresponsive to topical epinephrine and nasal packing. She reports a lifelong history of easy bruising and menorrhagia requiring transfusion twice. Her mother and maternal grandmother had similar bleeding tendencies. Physical examination reveals petechiae on lower extremities and bleeding gums. Laboratory investigations: Hb 9.2 g/dL, platelet count 45,000/μL, PT 12 sec (control 12 sec), aPTT 28 sec (control 28 sec), bleeding time 8 minutes. Peripheral blood smear shows giant platelets. What is the most likely diagnosis?

Explanation

## Clinical Presentation & Key Findings **Key Point:** Bernard-Soulier syndrome (BSS) is an autosomal recessive inherited platelet disorder characterized by: (1) moderate thrombocytopenia, (2) giant platelets on blood smear, (3) markedly prolonged bleeding time, and (4) deficiency of the GPIb-IX-V complex (the von Willebrand factor receptor) [Harrison's Principles of Internal Medicine, 21e, Ch. 111]. ### Why Bernard-Soulier Syndrome? This patient presents with: - **Moderate thrombocytopenia** (45,000/μL) — typical range in BSS (20,000–100,000/μL) - **Giant platelets** on peripheral smear — hallmark finding in BSS - **Normal PT and aPTT** — confirms no coagulation factor defect; platelet-specific disorder - **Prolonged bleeding time** — reflects defective platelet adhesion to subendothelial collagen via vWF - **Lifelong bleeding history** — epistaxis, menorrhagia, petechiae, gum bleeding consistent with platelet-type bleeding - **Autosomal dominant-appearing family history** — BSS is classically AR, but heterozygous carriers can have mild thrombocytopenia and giant platelets; the family history here is consistent with an inherited platelet disorder ### Why NOT May-Hegglin Anomaly (Option D)? May-Hegglin anomaly (MYH9 mutation) also presents with giant platelets and mild thrombocytopenia, but: - **Bleeding is typically mild** — severe, transfusion-requiring menorrhagia and life-threatening epistaxis are NOT characteristic of May-Hegglin - **Döhle bodies in neutrophils** are the pathognomonic distinguishing feature — NOT mentioned in this stem - **Platelet function is relatively preserved** — bleeding time is usually only mildly prolonged, not markedly so - The severity of bleeding in this vignette (transfusion twice, unresponsive to packing) far exceeds what is expected in May-Hegglin anomaly ### Differential Diagnosis Table | Feature | Bernard-Soulier | May-Hegglin | Glanzmann | Wiskott-Aldrich | |---------|-----------------|-------------|-----------|------------------| | Platelet count | Moderate ↓ (20–100K) | Mild ↓ (20–100K) | Normal/mild ↓ | Moderate ↓ (20–50K) | | Platelet size | **Giant** | **Giant** | Normal | **Small** | | Bleeding time | **Markedly prolonged** | Mildly prolonged | Markedly prolonged | Prolonged | | Inheritance | **AR** | AD | AR | XR | | Döhle bodies | No | **Yes** | No | No | | GPIb/IX defect | **Yes (absent)** | No | No | No | | Bleeding severity | **Severe** | Mild–moderate | Severe | Moderate | | Gender | Both | Both | Both | Males only | ### Mechanism Bernard-Soulier syndrome results from mutations in GP1BA, GP1BB, or GP9 genes encoding the GPIb-IX-V complex. This leads to: 1. **Defective platelet adhesion** — GPIb-IX-V is the receptor for von Willebrand factor; without it, platelets cannot adhere to damaged subendothelium 2. **Giant platelet morphology** — GPIb-IX-V normally restrains platelet size; its absence leads to uncontrolled membrane expansion 3. **Thrombocytopenia** — reduced platelet survival due to cytoskeletal instability **High-Yield:** The triad of **giant platelets + moderate thrombocytopenia + severe mucocutaneous bleeding + normal PT/aPTT** in a patient with a lifelong bleeding history strongly points to Bernard-Soulier syndrome. Confirmation is by flow cytometry showing absent GPIb (CD42b) on platelet surface. **Clinical Pearl:** In BSS, platelet aggregation studies show normal response to ADP, collagen, and epinephrine, but **absent ristocetin-induced platelet aggregation** (unlike vWD, which corrects with addition of normal plasma). This distinguishes BSS from von Willebrand disease at the bench.