期刊
SEMINARS IN THROMBOSIS AND HEMOSTASIS
卷 39, 期 6, 页码 642-655出版社
THIEME MEDICAL PUBL INC
DOI: 10.1055/s-0033-1353393
关键词
Glanzmann thrombasthenia; alpha(IIb)beta(3) integrin; platelet aggregation; mutation analysis; gene therapy
资金
- INSERM [ANR-08-GENO-028-03]
- GIS Maladies Rares
- National Heart Lung and Blood Institute, National Institutes of Health [HL-68138]
- American Heart Association Award (Northland Affiliate) [BGIA 0160441Z, GIA 0755827Z]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL068138] Funding Source: NIH RePORTER
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 alpha(IIb)beta(3), 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 beta(3) present as alpha(v)beta(3) (the vitronectin receptor), the bleeding phenotype continues to dominate. Here, we look in detail at mutations that affect (i) the beta-propeller region of the alpha(IIb) head domain and (ii) the membrane proximal disulfide-rich epidermal growth factor (EGF) domains of beta(3) 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.
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