Inherited thrombophilia in a Han Chinese family caused by prothrombin Ile441Met mutation

Inherited thrombophilia (IT) is a genetically determined predisposition to thromboembolic events. Beyond the well-known G20210A mutation, there has been limited research on other prothrombin mutations in the Chinese population.

This study aimed to identify and characterize a novel prothrombin mutation in a Han Chinese family with IT.

Clinical information was collected from the proband and his related family members. Coagulation tests, including protein S, plasminogen, protein C, and antithrombin Ⅲ activities, were conducted. Whole-genome sequencing was conducted on the proband and his mother to identify the causative mutation, and suspected mutations were verified in other family members using whole-exon sequencing. Thrombin generation assay was performed to evaluate hypercoagulable states.

Among the 53 family members, 11 individuals had a history of venous thromboembolism (VTE). Genetic analysis of 9 family members identified a novel heterozygous prothrombin mutation, p.Ile441Met (c.1323A>G), in 6 individuals with VTE history. These mutation carriers exhibited various forms of VTE, predominantly pulmonary embolism and lower-limb deep vein thrombosis. Routine coagulation tests showed no significant abnormalities in prothrombin time and activated partial thromboplastin time, while 5 carriers exhibited decreased protein S activity. Thrombin generation assay revealed a hypercoagulable state, characterized by shortened lag time, increased thrombin peak, and elevated endogenous thrombin potential.

The Ile441Met mutation is a novel prothrombin mutation associated with IT in the Han Chinese population, which induces a hypercoagulable state, leading to various forms of VTE. Further studies are needed to validate these findings and investigate the underlying pathogenic mechanisms.