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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:241.)
© 2007 American Heart Association, Inc.

Thrombosis

Decreased Thrombotic Tendency in Mouse Models of the Bernard-Soulier Syndrome

C. Strassel; C. Nonne; A. Eckly; T. David; C. Leon; M. Freund; J.-P. Cazenave; C. Gachet; F. Lanza

From INSERM U311, EFS-Alsace, ULP, Strasbourg, France.

Correspondence to François Lanza, INSERM U.311, Etablissement Français du Sang-Alsace, 10 rue Spielmann, BP 36, 67065 Strasbourg Cedex, France. E-mail francois.lanza{at}efs-alsace.fr

Objective— The platelet glycoprotein (GP)Ib-V-IX complex is a receptor required for normal hemostasis deficient in the Bernard-Soulier bleeding disorder. To evaluate the consequences of GPIb-V-IX deficiency in thrombosis we generated mouse models of the disease by targeting the GPIbß subunit.

Methods and Results— Complete deletion (GPIbß^–/–) or an intracellular truncation (GPIbßIC^–/–) reproduced typical and variant forms of Bernard-Soulier, with absent and partial (20%) expression of the complex on the platelet surface. Both strains exhibited thrombocytopenia and enlarged platelets with abnormal microtubular structures but normal granule composition. They exhibited prolonged tail bleeding times, which were less pronounced in GPIbßIC^–/–. Decreased thrombus formation was observed after blood perfusion over a collagen coated surface at high shear. Resistance to vascular occlusion and an abnormal thrombus composition were observed in a model of FeCl₃-induced lesion of carotid arteries. In a model of laser-induced lesion of mesenteric arterioles, thrombosis was strongly reduced in GPIbß^–/– mice, while a more modest effect was observed in GPIbßIC^–/– animals. Finally, the two strains were protected against death in a model of systemic thromboembolism.

Conclusions— This study provides in vivo evidence of a decreased thrombotic tendency linked to defective platelet GPIb-V-IX in mouse models of Bernard-Soulier syndrome.

Mouse models of Bernard-Soulier bleeding disorder were generated by targeting the GP GPIbß. These mice displayed, in addition to their defective hemostasis, decreased thrombotic responses in different models of arterial and systemic thrombosis.

Key Words: GPIb-V-IX complex • von Willebrand factor • knockout • thrombosis models • hemostasis

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