Article

Glanzmann thrombasthenia: A review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability, and mouse models

Centre de Référence des Pathologies Plaquettaires, Plateforme Technologique et d'Innovation Biomédicale, Hôpital Xavier Arnozan, Pessac, France. alan.nurden@cnrshl.u-bordeaux2
Blood (Impact Factor: 10.43). 09/2011; 118(23):5996-6005. DOI: 10.1182/blood-2011-07-365635
Source: PubMed

ABSTRACT Characterized by mucocutaneous bleeding arising from a lack of platelet aggregation to physiologic stimuli, Glanzmann thrombasthenia (GT) is the archetype-inherited disorder of platelets. Transmitted by autosomal recessive inheritance, platelets in GT have quantitative or qualitative deficiencies of the fibrinogen receptor, αIIbβ3, an integrin coded by the ITGA2B and ITGB3 genes. Despite advances in our understanding of the disease, extensive phenotypic variability with respect to severity and intensity of bleeding remains poorly understood. Importantly, genetic defects of ITGB3 also potentially affect other tissues, for β3 has a wide tissue distribution when present as αvβ3 (the vitronectin receptor). We now look at the repertoire of ITGA2B and ITGB3 gene defects, reexamine the relationship between phenotype and genotype, and review integrin structure in the many variant forms. Evidence for modifications in platelet production is assessed, as is the multifactorial etiology of the clinical expression of the disease. Reports of cardiovascular disease and deep vein thrombosis, cancer, brain disease, bone disorders, and pregnancy defects in GT are discussed in the context of the results obtained for mouse models where nonhemostatic defects of β3-deficiency or nonfunction are being increasingly described.

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    • "In turn, this knowledge has aided the development of the GPIIbIIIa blocking drugs that are widely used in the prevention of thrombosis during percutaneous coronary interventions (Bledzka et al, 2013). The mutations that give rise to GT are distributed throughout the ITGA2B and ITGB3 genes encoding the aIIb and b3 integrins, respectively (Nurden et al, 2011; Glanzmann Thrombasthenia Database; http://sinaicentral .mssm.edu/intranet/research/glanzmann/menu). Consanguinity contributes to a higher prevalence of the disorder and its association with specific mutations in certain ethnic groups (e.g. "
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    • "Integrin aIIbb3 plays essential roles in thrombosis and hemostasis as a platelet receptor for fibrinogen and von Willebrand factor, but its role for normal platelet production and morphology is still controversial. Glanzmann thrombasthenia (GT) is a congenital bleeding disorder due to qualitative or quantitative defects of aIIbb3, and platelet counts and morphology in GT are usually normal (Tomiyama 2000; Nurden et al. 2011a). Slight but not statistically significant decrease of platelet number with normal morphology was reported in b3-knockout mice (Hodivala-Dilke et al. 1999), whereas abnormalities in platelet counts and morphology have not been reported in aIIb-knockout mice or aIIbb3-deficient dogs (Lipscomb et al. 2000; Tronik-Le Roux et al. 2000). "
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