Effect of α2-plasmin inhibitor heterogeneity on the risk of venous thromboembolism

Introduction: Alpha2-plasmin inhibitor (alpha 2-PI) has a heterogeneous composition in the plasma. Both N- and C-terminal cleavages occur that modify the function of the molecule. C-terminal cleavage converts the plasminogen-binding form (PB-alpha 2-PI) to a non-plasminogen-binding form (NPB-alpha 2-PI). N-terminal cleavage by soluble fibroblast activation protein (sFAP) results in a form shortened by 12 amino acids, which is more quickly cross-linked to fibrin. The p.Arg6Trp polymorphism of alpha 2-PI affects N-terminal cleavage. In this work, we aimed to investigate the association between alpha 2-PI heterogeneity and the risk of venous thromboembolism. Materials and methods: Two hundred and eighteen patients with venous thromboembolism (VTE) and the same number of age and sex-matched healthy controls were enrolled. Total-alpha 2-PI, PB-alpha 2-PI and NPB-alpha 2-PI antigen levels, alpha 2-PI activity, sFAP antigen levels and p.Arg6Trp polymorphism were investigated. Results: Total-alpha 2-PI and NPB-alpha 2-PI levels were significantly elevated in VTE patients, while PB-alpha 2-PI levels did not change. Elevated NPB-alpha 2-PI levels independently associated with VTE risk (adjusted OR: 9.868; CI: 4.095-23.783). Soluble FAP levels were significantly elevated in the VTE group, however, elevated sFAP levels did not show a significant association with VTE risk. The alpha 2-PI p.Arg6Trp polymorphism did not influence VTE risk, however, in the case of elevated sFAP levels the carriage of Trp6 allele associated with lower VTE risk. Conclusion: Our results showed that the elevation of total-alpha 2-PI levels in VTE is caused by the elevation of NPB-alpha 2-PI levels. Elevated sFAP level or p.Arg6Trp polymorphism alone did not influence VTE risk. However, an interaction can be detected between the polymorphism and high sFAP levels.