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Screening and functional exploration of prothrombin Arg596 related mutations in Chinese venous thromboembolism patients
  1. Xi Wu1,
  2. Lei Li2,
  3. Qiulan Ding1,
  4. Xuefeng Wang1,
  5. Fang Wu3,
  6. Wenman Wu1,4
  1. 1Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
  2. 2State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
  3. 3Department of Geriatrics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
  4. 4Faculty of Medical Laboratory Science, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
  1. Correspondence to Fang Wu, Department of Geriatrics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China; wufangrjh{at}163.com and Wenman Wu, Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China; wenmanwu{at}shsmu.edu.cn

Abstract

Aims Dysfunctional prothrombin residue Arg596 associated mutation has been found to precipitate venous thromboembolism (VTE). In the current study we investigated the prevalence of Arg596 associated mutations in Chinese patients with VTE and explored the functional impact of Arg596Gln mutation on coagulation function in affected patients.

Methods Prothrombin clotting activity was measured in 267 unrelated patients with unprovoked VTE. Patients with moderately decreased activities underwent further analysis of the F2 gene. Prothrombin amidolytic activity and antigen levels were detected in mutation carriers. Specific family members were investigated about their VTE histories and clinical phenotypes. The thrombin generation test (TGT) was used to evaluate thrombin function and antithrombin resistance assay was applied to assess the extent of impaired antithrombin inhibition of mutation carriers.

Results Two heterozygous mutation carriers of prothrombin Arg596Gln were identified, both of whom had moderately decreased clotting activities but normal amidolytic activities and antigen levels. Among the families of the two probands, nine out of 13 mutation carriers experienced episodes of VTE. TGTs showed that patients had elevated endogenous thrombin potential and prolonged start tail time. Thrombin generation could be inhibited in the presence of thrombomodulin. The thrombin Arg596Gln variant in patients’ plasma presented strong resistance to antithrombin inhibition.

Conclusion Prothrombin Arg596Gln mutation is a risk factor for Chinese patients with VTE due to its moderately decreased clotting activity but strong resistance to antithrombin inhibition. Prothrombin clotting activity screening and its encoding gene sequencing should be considered in patients with VTE when other established risk factors are absent.

  • prothrombin
  • genetics
  • venous thromboembolism

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Footnotes

  • Handling editor Mary Frances McMullin.

  • Contributors WW managed the project. QD and FW established the diagnosis of patients. XW and LL collected blood samples and performed function assays. XW and FW designed the experiments and analysed the data. XW and WW wrote the paper.

  • Funding This work was supported by the National Natural Science Foundation of China NSFC 81670130 (WW).

  • Competing interests None declared.

  • Ethics approval The Ethics Committee of Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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