Glanzmann Thrombasthenia: State of the Art and Future Directions

Alan T. Nurden; Xavier Pillois; David A. Wilcox

doi:10.1055/s-0033-1353393

Seminars in Thrombosis and Hemostasis, Inhaltsverzeichnis

Semin Thromb Hemost 2013; 39(06): 642-655
DOI: 10.1055/s-0033-1353393

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Glanzmann Thrombasthenia: State of the Art and Future Directions

Alan T. Nurden

¹Plateforme Technologique et d'Innovation Biomédicale, Hôpital Xavier Arnozan, Pessac, France

,

Xavier Pillois

¹Plateforme Technologique et d'Innovation Biomédicale, Hôpital Xavier Arnozan, Pessac, France

²Unité1034 INSERM, Hôpital Haut-Lévêque, Pessac, France

,

David A. Wilcox

³Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin

⁴Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin

› Institutsangaben

Abstract

Glanzmann thrombasthenia (GT) is the principal inherited disease of platelets and the most commonly encountered disorder of an integrin. GT is characterized by spontaneous mucocutaneous bleeding and an exaggerated response to trauma caused by platelets that fail to aggregate when stimulated by physiologic agonists. GT is caused by quantitative or qualitative deficiencies of α_IIbβ₃, an integrin coded by the ITGA2B and ITGB3 genes and which by binding fibrinogen and other adhesive proteins joins platelets together in the aggregate. Widespread genotyping has revealed that mutations spread across both genes, yet the reason for the extensive variation in both the severity and intensity of bleeding between affected individuals remains poorly understood. Furthermore, although genetic defects of ITGB3 affect other tissues with β₃ present as α_vβ₃ (the vitronectin receptor), the bleeding phenotype continues to dominate. Here, we look in detail at mutations that affect (i) the β-propeller region of the α_IIb head domain and (ii) the membrane proximal disulfide-rich epidermal growth factor (EGF) domains of β₃ and which often result in spontaneous integrin activation. We also examine deep vein thrombosis as an unexpected complication of GT and look at curative procedures for the diseases, including allogeneic stem cell transfer and the potential for gene therapy.

Keywords

Glanzmann thrombasthenia - α_IIbβ₃ integrin - platelet aggregation - mutation analysis - gene therapy

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Referenzen

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