A 25-year-old woman with inherited severe von Willebrand disease type 3 is being evaluated for surgery. Her ADAMTS13 level is normal. In which molecular step of primary hemostasis does von Willebrand factor deficiency most critically impair platelet function at sites of high shear stress?

• A VWF deficiency impairs ADP-mediated P2Y12 receptor signaling on platelets, reducing thromboxane A2 generation
• B VWF is required for Factor VIII export from endothelial cells; type 3 VWD causes FVIII deficiency by impairing FVIII secretion into plasma
• C VWF deficiency impairs platelet fibrinogen binding to GPIIb/IIIa after thrombin activation, preventing platelet aggregation regardless of shear rate
• D At high shear stress (arteries/arterioles), VWF unfolds and its A1 domain binds GPIb-IX-V on platelets, providing the primary tethering and rolling interaction that allows initial platelet adhesion to subendothelial collagen; VWF also bridges platelet GPIIb/IIIa to collagen at sites of injury. Without VWF, the brief platelet-vessel wall contact time at arterial shear rates is insufficient for GPIa/IIa (collagen receptor) alone to capture platelets, resulting in failure of the platelet plug ✓

Explanation

Von Willebrand factor plays a dual role in hemostasis. In primary hemostasis under high shear conditions (arteries), VWF undergoes shear-induced conformational change, exposing its A1 domain that binds GPIb-IX-V on resting platelets, initiating transient tethering and rolling. This overcomes the brief contact time at high shear, allowing collagen receptor GPIa/IIa (α2β1) to engage. Additionally, VWF bridges FVIII in circulation (VWF type 3 severely depletes FVIII), and platelet GPIIb/IIIa also binds VWF at collagen interfaces. In type 3 VWD (complete VWF absence), both mucocutaneous bleeding (platelet plug failure) and deep-tissue bleeding (secondary hemostasis impairment from FVIII deficiency) occur.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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