Thrombosis Caused by Factor XI Gly397Ser Mutation with Enhanced Procoagulant Activity

Yanyan Shao; Yang Xu; Min Xin; Qin Xu; Weizhi Chen; Wansheng Ren; Qian Liang; Lei Li; Xi Wu; Yu Liu; Guanqun Xu; Can Lou; Qiulan Ding; Wenman Wu; Xuefeng Wang; Jing Dai

doi:10.1055/a-2740-1731

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost
DOI: 10.1055/a-2740-1731

Original Article: Stroke, Systemic or Venous Thromboembolism

Thrombosis Caused by Factor XI Gly397Ser Mutation with Enhanced Procoagulant Activity

Autor*innen

Yanyan Shao‡^‡

¹Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

²Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Yang Xu‡^‡

¹Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

²Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Min Xin‡^‡

¹Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Qin Xu

³State Key Laboratory of Microbial Metabolism and Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
Weizhi Chen

³State Key Laboratory of Microbial Metabolism and Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
Wansheng Ren

³State Key Laboratory of Microbial Metabolism and Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China

⁴Chemistry and Material Science Faculty, Shandong Agricultural University, Taian, China
Qian Liang

¹Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

²Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Lei Li

¹Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Xi Wu

¹Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Yu Liu

¹Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Guanqun Xu

¹Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Can Lou

¹Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Qiulan Ding

¹Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

⁵Collaborative Innovation Center of Hematology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Wenman Wu

¹Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

⁵Collaborative Innovation Center of Hematology, Shanghai Jiao Tong University School of Medicine, Shanghai, China

⁶Faculty of Laboratory Medicine, Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
Xuefeng Wang

¹Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

⁵Collaborative Innovation Center of Hematology, Shanghai Jiao Tong University School of Medicine, Shanghai, China

⁶Faculty of Laboratory Medicine, Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
Jing Dai

¹Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

²Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

Abstract

Background

Elevated FXI levels are associated with increased risk of venous thromboembolism, yet genetic mutations contributing to elevated FXI levels have not been reported yet.

Material and Methods

We described a patient with a history of deep venous thrombosis (DVT) who tested negative on routine laboratory screening but was found to carry a novel pathogenic FXI mutation, Gly397Ser (G397S). FXI mutant protein was expressed, and functional assays were conducted in vitro to explore the underlying thrombotic mechanism.

Results and Conclusion

Consistent with FXI activity (FXI:C) and antigen (FXI:Ag) determined in the patient, the FXI G397S mutant exhibited a 2-fold increase of FXI:C/FXI:Ag. FXIa hydrolysis assay demonstrated that the Km value for G397S mutant was comparable to the wild-type FXIa (186.2~281.9 μM V.S. 141.6~242.6 μM), whereas the mutant FXIa displayed approximately 3-fold increases in kcat values. FXI activation by polyanions was more pronounced in the G397S mutant. Notably, this activation was more significant when triggered by thrombin compared with FXIIa in the presence of heparin. Otherwise, the G397S FXI mutant exhibited similar hydrolytic activity of FXIa against FIX, and equivalent inhibition of FXIa by Protease nexin 2 (PN2). Clot lysis assay revealed that the lysis time was longer in G397S mutant than the wild-type and the enhanced fibrinolytic resistance was thrombin-activatable fibrinolysis inhibitor-dependent. In summary, the FXI G397S mutation exhibited higher FXIa activity mainly because of the enhanced activation of FXI, which sustained thrombin generation and manifested resistance to fibrinolysis, ultimately leading to the development of DVT.

Keywords

gain of function - factor XI - deep vein thrombosis

Volltext

Referenzen

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