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Scenario-Based Question: Bernard-Soulier Syndrome

Clinical Scenario

A 9-year-old girl is brought to the pediatric hematology clinic by her parents who report that she has had recurrent nosebleeds since infancy, easy bruising after minor bumps, and prolonged bleeding after a tooth extraction last year. Her parents are first cousins. There is no family history of hemophilia. Physical examination shows petechiae on her lower limbs. No hepatosplenomegaly is noted.

Laboratory investigations:

Test	Patient Result	Reference Range
Platelet count	65,000/µL	1,50,000-4,00,000/µL
Peripheral smear	Giant platelets, reduced in number	Normal
Bleeding time	Prolonged	2-7 min
PT	Normal	Normal
aPTT	Normal	Normal
Platelet aggregation with ADP	Normal aggregation	Normal
Platelet aggregation with collagen	Normal aggregation	Normal
Platelet aggregation with ristocetin	Absent/markedly reduced	Normal
Platelet aggregation with ristocetin + normal plasma	No correction	Corrects in vWD
vWF antigen level	Normal	Normal

Questions

Q1. What is the most likely diagnosis?

A. Von Willebrand disease type 1 B. Glanzmann thrombasthenia C. Bernard-Soulier syndrome D. Immune thrombocytopenic purpura

Answer: C - Bernard-Soulier syndrome

Explanation: BSS is an autosomal recessive disorder caused by deficiency or dysfunction of the GPIb-IX-V complex on the platelet surface. GPIb is the receptor for von Willebrand factor (vWF), so platelets cannot adhere to damaged subendothelium. The classic triad is:

Thrombocytopenia with giant platelets on peripheral smear
Absent aggregation with ristocetin only (ADP, collagen, epinephrine are normal)
Failure to correct with addition of normal plasma (distinguishes it from vWD, where normal plasma corrects the ristocetin response because it supplies functional vWF)

(Goldman-Cecil Medicine, Platelet Receptor Defects; Quick Compendium of Clinical Pathology 5th ed., §5.2.12.1)

Q2. What is the inheritance pattern, and what clue in this case supports it?

A. X-linked recessive - affects males predominantly B. Autosomal dominant - one parent must be affected C. Autosomal recessive - consanguinity in parents D. Mitochondrial - maternal transmission

Answer: C - Autosomal recessive; consanguineous parents (first cousins)

Explanation: BSS is autosomal recessive, caused by mutations in GPIBA, GPIBB, or GP9 genes. Consanguinity (parents being first cousins) significantly increases the likelihood of inheriting two defective copies of the same recessive gene. The heterozygous carrier state may manifest only as mild macrothrombocytopenia (Mediterranean macrothrombocytopenia), seen in southern Europe. (Quick Compendium of Clinical Pathology 5th ed., §5.2.12.1; Goldman-Cecil Medicine)

Q3. The key test that distinguishes Bernard-Soulier syndrome from von Willebrand disease is:

A. Bleeding time B. Platelet count C. Ristocetin aggregation corrected by normal plasma D. Platelet morphology on peripheral smear

Answer: C - Ristocetin aggregation corrected by normal plasma

Explanation: Both BSS and vWD show absent/reduced ristocetin-induced platelet aggregation. The critical distinguishing test is the mixing study:

In vWD: adding normal plasma (which contains functional vWF) corrects ristocetin aggregation, because the problem is in the plasma (absent/dysfunctional vWF).
In BSS: adding normal plasma does NOT correct ristocetin aggregation, because the defect is in the platelet receptor (GPIb-IX-V) itself - there is no GPIb to bind even normal vWF.

(Quick Compendium of Clinical Pathology 5th ed., §5.2.12.1)

Q4. How does the aggregation pattern of BSS differ from Glanzmann thrombasthenia?

Feature	Bernard-Soulier Syndrome	Glanzmann Thrombasthenia
Deficient receptor	GPIb-IX-V	GPIIb-IIIa
Platelet size	Giant (macro)	Normal to small
Platelet count	Low (thrombocytopenic)	Normal
Ristocetin	Absent	Normal
ADP, collagen, epinephrine	Normal	Absent
Clot retraction	Normal	Abnormal

Explanation: In BSS, ristocetin alone fails because GPIb (the vWF receptor for adhesion) is absent. In Glanzmann thrombasthenia, GPIIb-IIIa (the fibrinogen receptor for aggregation) is absent, so all agonists except ristocetin fail. (Goldman-Cecil Medicine; Quick Compendium of Clinical Pathology 5th ed.)

Q5. The patient develops heavy menstrual bleeding at age 13 and requires intervention. What is the most appropriate management?

A. Fresh frozen plasma infusion B. Platelet transfusion and/or recombinant activated factor VII (rFVIIa) C. Intravenous immunoglobulin (IVIG) D. Desmopressin (DDAVP)

Answer: B - Platelet transfusion and/or rFVIIa

Explanation: Since BSS is a platelet membrane receptor defect, DDAVP (which works by releasing vWF from endothelium) and FFP are ineffective. The mainstay of treatment during bleeding episodes is:

Platelet transfusion - provides functional GPIb-expressing platelets (risk: patients may develop alloantibodies against GPIb with repeated transfusions, making future transfusions ineffective)
Recombinant FVIIa (rFVIIa) - used when platelet transfusions are contraindicated or alloantibodies are present
Antifibrinolytics (tranexamic acid) can help for mucosal bleeding

(Goldman-Cecil Medicine, Platelet Receptor Defects; Quick Compendium of Clinical Pathology §5.2.12.1)

Q6. Flow cytometry of the patient's platelets would most likely show:

A. Absent CD41/CD61 (GPIIb-IIIa) B. Absent CD42b (GPIbα) C. Absent CD62P (P-selectin) D. Elevated CD36 expression

Answer: B - Absent CD42b (GPIbα)

Explanation: CD42b is the flow cytometry marker for GPIbα, the main component of the GPIb-IX-V complex. Its absence (or severely reduced expression) on flow cytometry confirms BSS. This is also the standard confirmatory test when genetic testing is not immediately available. CD41/CD61 (GPIIb-IIIa) would be absent in Glanzmann thrombasthenia, not BSS. (Goldman-Cecil Medicine - "Flow cytometry usually confirms the absence of the receptor on the platelet surface")

Summary Table: BSS at a Glance

Feature	Detail
Defect	GPIb-IX-V complex (GPIbα is vWF receptor)
Genes	GPIBA, GPIBB, GP9
Inheritance	Autosomal recessive
Platelet count	Low (thrombocytopenia)
Platelet size	Giant (macro) on smear
Bleeding time	Prolonged
Ristocetin aggregation	Absent - NOT corrected by normal plasma
ADP/collagen/epinephrine	Normal
Clot retraction	Normal
Confirmatory test	Flow cytometry (absent CD42b) or genetic testing
Treatment	Platelet transfusion, rFVIIa, antifibrinolytics

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