The Israeli National Hemophilia Center and Thrombosis Institute, Sheba Medical Center, Tel Hashomer, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
The Israeli National Hemophilia Center and Thrombosis Institute, Sheba Medical Center, Tel Hashomer, Israel.
Blood Cells Mol Dis. 2021 Jul;89:102560. doi: 10.1016/j.bcmd.2021.102560. Epub 2021 Mar 4.
Glanzmann thrombasthenia (GT) is a severe inherited platelet function disorder (IPFD), presenting with bleeding diathesis and impaired platelet aggregation, is caused by mutations in the genes ITGA2B or ITGB3.
We aimed to study the genetic cause of IPFD mimicking GT.
During 2017-2019, 16 patients were referred to our tertiary center with bleeding symptoms, impaired platelet aggregation and normal platelet count and size.
Using flow cytometry, 13/16 patients were diagnosed with GT, yet three patients displayed normal surface expression of the integrins αIIbβ3 and αvβ3, as well as normal integrin αIIbβ3 activation following incubation with the activating monoclonal antibody anti-LIBS6, while platelet activation following ADP or epinephrine was impaired. Whole exome sequencing detected 2 variants in RASGRP2 gene in all 3 patients.
Both RASGRP2 mutations predicted frameshift, premature stop codon (p. I427Mfs92 and p. R494Afs54, respectively) and truncated calcium-sensing guanine nucleotide exchange factor [CalDAG-GEFI]- the major signaling molecule that regulates integrin-mediated aggregation and granule secretion, causing IPFD-18.
Patients who suffer from bleeding diathesis without immune dysregulation, may be mistakenly diagnosed as GT. Further studies are required to confirm the diagnosis of specific IPFD.
Glanzmann 血小板无力症（GT）是一种严重的遗传性血小板功能障碍（IPFD），表现为出血倾向和血小板聚集受损，是由 ITGA2B 或 ITGB3 基因突变引起的。
我们旨在研究模仿 GT 的 IPFD 的遗传原因。
在 2017-2019 年期间，有 16 名患者因出血症状、血小板聚集受损和正常血小板计数和大小而被转诊到我们的三级中心。
通过流式细胞术，13/16 例患者被诊断为 GT，但有 3 例患者的整合素 αIIbβ3 和 αvβ3 表面表达正常，以及在用激活单克隆抗体抗 LIBS6 孵育后整合素 αIIbβ3 的激活正常，而 ADP 或肾上腺素诱导的血小板激活受损。全外显子组测序在所有 3 例患者中均检测到 RASGRP2 基因中的 2 个变异。
两种 RASGRP2 突变均预测移码，导致提前终止密码子（p. I427Mfs92 和 p. R494Afs54）和截短钙感应鸟嘌呤核苷酸交换因子[CalDAG-GEFI]-调节整合素介导的聚集和颗粒分泌的主要信号分子，导致 IPFD-18。
患有出血倾向而无免疫失调的患者可能被误诊为 GT。需要进一步研究来确认特定 IPFD 的诊断。
