ITGA2B / ITGB3 ‐Related Macrothrombocytopenia Associated With Gain‐of‐Function Mutations in ITGA2B or ITGB3 Genes
Year: 2026
Type: article
Abstract: Glanzmann thrombasthenia (GT) is an inherited hemorrhagic disorder characterised by impaired platelet functions, manifested clinically as spontaneous bleeding. It is usually inherited in an autosomal recessive manner. Platelet dysfunction in patients with GT is caused by quantitative and/or qualitative deficiencies in αIIbβ3, which result from mutations in the genes encoding αIIbβ3. These genetic alterations lead to platelet dysfunction characterised by impaired fibrinogen binding capacity upon agonist stimulation, defective aggregation and spreading. While classical GT typically exhibits normal platelet counts and morphology, very rare mutations in ITGA2B (encoding αIIb) and/or ITGB3 (encoding β3) cause macrothrombocytopenia or increased platelet anisotropy (heterogeneity of platelet size and morphology). This type of mutation mainly localises in the membrane-proximal region of αIIbβ3 and is inherited in an autosomal dominant manner. This particular type of disorder is called ITGA2B/ITGB3-related macrothrombocytopenia and has been considered a subset of congenital macrothrombocytopenia. Current research suggests that gain-of-function mutations in ITGA2B or ITGB3 underlie the pathogenesis of most ITGA2B/ITGB3-related macrothrombocytopenia and mechanistically distinguish it from classical GT. However, recent reports have documented non-activating ITGB3 mutations that also cause macrothrombocytopenia, presenting a profound challenge to the mechanistic understanding of ITGA2B/ITGB3-related macrothrombocytopenia. This review summarises the reported cases of gain-of-function mutations in ITGA2B and ITGB3 associated with ITGA2B/ITGB3-related macrothrombocytopenia hitherto and discusses the potential molecular pathways contributing to the unique phenotypes in ITGA2B/ITGB3-related macrothrombocytopenia.
DOI: 10.1111/jcmm.70988
Authors: Jiao Wu, Han Yan, Zijian Li, Yilin Zhu, Ruonan Shao, Honglei Xin, Tongyu Jia, Mengyu Ge, Lu Zhang, Suyu Jiang, Jianhua Mao, Jiansong Huang, Chao Fang, Xiaodong Xi, Xiaofeng Shi
Institutions: Second Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Chifeng Municipal Hospital, Shanghai Jiao Tong University, Ruijin Hospital, Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, First Affiliated Hospital Zhejiang University, Huazhong University of Science and Technology
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,210
OpenAlex ID: W7118727182