2. Academic Validation
  3. A novel GATA1 variant p.G229D causing the defect of procoagulant platelet formation

A novel GATA1 variant p.G229D causing the defect of procoagulant platelet formation

  • Thromb Res. 2024 Feb:234:39-50. doi: 10.1016/j.thromres.2023.12.015.
Biying Ding 1,  Yinqi Mao 1,  Yang Li 1,  Min Xin 2,  Shifeng Jiang 3,  Xiaobo Hu 4,  Qin Xu 5,  Qiulan Ding 6,  Xuefeng Wang 7
Affiliations

Affiliations

  • 1 Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 2 Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 3 State Key Laboratory of Microbial Metabolism & Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
  • 4 Department of Molecular Biology, Shanghai Center for Clinical Laboratory, Shanghai, China.
  • 5 State Key Laboratory of Microbial Metabolism & Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. Electronic address: [email protected].
  • 6 Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Collaborative Innovation Center of Hematology, Shanghai Jiaotong University School of Medicine, Shanghai, China. Electronic address: [email protected].
  • 7 Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Collaborative Innovation Center of Hematology, Shanghai Jiaotong University School of Medicine, Shanghai, China. Electronic address: [email protected].
PMID: 38159323 DOI: 10.1016/j.thromres.2023.12.015
Abstract

Introduction: GATA1 is one of the master transcription factors in hematopoietic lineages development which is crucial for megakaryocytic differentiation and maturation. Previous studies have shown that distinct GATA1 variants are associated with varying severities of macrothrombocytopenia and platelet dysfunction.

Objective: To determine the underlying pathological mechanisms of a novel GATA1 variant (c. 686G > A, p. G229D) in a patient with recurrent traumatic muscle hematomas.

Methods: Comprehensive phenotypic analysis of the patient platelets was performed. Procoagulant platelet formation and function were detected using flow cytometry assay and Thrombin generation test (TGT), respectively. The ANO6 expression was measured by qPCR and western blot. The intracellular supramaximal calcium flux was detected by Fluo-5N fluorescent assay.

Results: The patient displayed mild macrothrombocytopenia with defects of platelet granules, aggregation, and Integrin αIIbβ3 activation. The percentage of the procoagulant platelet formation of the patient upon the stimulation of Thrombin plus Collagen was lower than that of the healthy controls (40.9 % vs 49.0 % ± 5.1 %). The patient platelets exhibited a marked reduction of Thrombin generation in platelet rich plasma TGT compared to the healthy controls (peak value: ∼70 % of the healthy controls; the endogenous Thrombin potential: ∼40 % of the healthy controls). The expression of ANO6 and intracellular calcium flux were impaired, which together with abnormal granules of the patient platelets might contribute to defect of procoagulant platelet function.

Conclusions: The G229D variant could lead to a novel platelet phenotype characterized by defective procoagulant platelet formation and function, which extended the range of GATA1 variants associated platelet disorders.

Keywords

GATA1; Hematoma; Macrothrombocytopenia; Procoagulant platelet formation; Variant.

Figures
Products