In Bernard‑Soulier disease, the giant platelets that fail to aggregate with ristocetin are deficient in which of the following: glycoprotein Ib (GPIb) platelet receptor, dense granules, glycoprotein IIb/IIIa receptor, or alpha granules?

Bernard-Soulier Disease: Glycoprotein Ib Deficiency

The answer is A: Glycoprotein Ib platelet receptor. Bernard-Soulier syndrome is definitively characterized by deficiency or dysfunction of the GPIb-V-IX complex, which causes the characteristic failure of platelet aggregation with ristocetin and the presence of giant platelets 1.

Diagnostic Hallmarks

The pathognomonic laboratory findings in Bernard-Soulier syndrome are:

• Defective expression of GPIb/IX on flow cytometry - This is the definitive diagnostic test showing absent or markedly reduced GPIb (CD42b) and GPIb/IX (CD42a) expression 1
• Absent ristocetin-induced platelet aggregation - Platelets fail to aggregate with ristocetin because GPIb is the receptor that binds von Willebrand factor in the presence of ristocetin 1
• Giant platelets (macrothrombocytopenia) - Characteristically large platelets with thrombocytopenia 2, 3, 4, 5
• Normal aggregation to other agonists - Aggregation to ADP, collagen, and arachidonic acid remains normal, distinguishing it from Glanzmann thrombasthenia 6

Molecular Basis

The GPIb-V-IX complex is a multisubunit receptor composed of GPIbα (disulfide-linked to GPIbβ) and noncovalently associated with GPIX and GPV 5. Mutations have been identified in the genes encoding GPIbα (GP1BA on chromosome 17p12), GPIbβ (GP1BB on chromosome 22q11.2), and GPIX (GP9 on chromosome 3q21), but not in GPV 2, 4. These mutations either prevent surface expression of the complex or alter its functional conformation 7, 4.

Why Not the Other Options

Dense granules (Option B) and alpha granules (Option D) are NOT deficient in Bernard-Soulier syndrome:

• Dense granule deficiency characterizes δ-storage pool disease (δ-SPD), Hermansky-Pudlak syndrome, and Chediak-Higashi syndrome 1
• Alpha granule deficiency characterizes Grey Platelet Syndrome (GPS) 1
• Bernard-Soulier syndrome shows normal granule content and release 2, 3

Glycoprotein IIb/IIIa receptor (Option C) is NOT deficient in Bernard-Soulier syndrome:

• GPIIb/IIIa deficiency is the hallmark of Glanzmann thrombasthenia, not Bernard-Soulier syndrome 1, 6
• In Glanzmann thrombasthenia, platelets fail to aggregate with ALL agonists except ristocetin (the opposite pattern from Bernard-Soulier syndrome) 6
• Bernard-Soulier platelets have normal GPIIb/IIIa expression 3, 5

Clinical Pitfall

Do not confuse the ristocetin aggregation patterns:

• Bernard-Soulier syndrome: Absent ristocetin aggregation, normal aggregation to other agonists 1
• Glanzmann thrombasthenia: Normal ristocetin aggregation, absent aggregation to other agonists 6
• Platelet-type von Willebrand disease: Enhanced ristocetin aggregation at low concentrations 1