Predictive value for increased activated factor XI activity in acute venous thromboembolism.

BACKGROUND

Venous thromboembolism (VTE) is associated with excessive coagulation activity, which in part can be attributed to activation of contact system. However, the knowledge regarding the impact of contact activation in acute VTE is limited.

OBJECTIVE

To unravel the involvement of contact activation in acute VTE.

METHODS

Contact activation was investigated in patients with acute VTE (n = 321) and population controls without a history of VTE (n = 300). For comparison, Factor XI(a) levels, activity, and plasma kallikrein (PKa) activity were determined in plasma samples with an activated partial thromboplastin time- or thrombin generation-based assay (free FXI concentration [FXI:c] and calibrated automated thrombogram:FXIa, respectively) and with enzyme-linked immunosorbent assays for enzyme-inhibitor complexes (FXIa:alpha-1-antitrypsin [α1AT], FXIa:antithrombin [AT], FXIa:C1-inhibitor [C1Inh], and PKa:C1-inh).

RESULTS

In patients with VTE, higher FXI:c levels (124 ± 37% vs 114 ± 28%), but lower calibrated automated thrombogram:FXIa levels were apparent. This was accompanied by increased FXIa:α1AT, FXIa:AT, and PKa:C1-inh levels in patients compared with controls (312pM [238-424] vs 203pM [144-288]; 29pM [23-38] vs 23pM [20-30]; 1.9nM [1.2-4.7] vs 1.4nM [0.7-3.5], respectively), whereas FXIa:C1-inh levels did not differ. Logistic regression models showed good discriminatory values for FXI:c and FXIa:α1AT (area under the curve = 0.64 [0.6/0.69] and 0.73 [0.69/0.77], respectively). After a 2-year follow-up, 81 recurrent VTE events or deaths occurred in the patient cohort, for which the baseline levels of FXIa:α1AT and FXIa:C1Inh had a significant prognostic value (Hazard ratios per SD [95% CI], 1.26 [1.10-1.45]; p =.0012 and 1.19 [1.05-1.36]; p =.0082, respectively).

CONCLUSION

Our study revealed elevated FXIa levels and activity in acute VTE, which was also associated with recurrent VTE, suggesting an important risk contribution of FXI activation to VTE. The evidence provided by this study supports the utility of FXIa inhibition in the setting of acute VTE.

Informations de copyright

Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interests T.K. receives consulting fees as biomarker consultant from Bayer AG, outside the submitted work. H.t.C. received fees for consultation or advisory boards from Pfizer, Leo, Alexion/Astra Zeneca, Galapagos, and Alveron; research support from Bayer; shareholder Coagulation Profile; all unrelated to the present work; all revenues were transferred to the Cardiovascular Research Institute Maastricht institute for support of own research. P.S.W. receives work grants from Bayer AG, nonfinancial grants from Philips Medical Systems, grants, and consulting fees from Boehringer Ingelheim, grants and consulting fees from Novartis Pharma, grants and consulting fees from Sanofi-Aventis, grants, consulting and lecturing fees from Bayer Health Care, grants from Daiichi Sankyo Europe, consulting fees from Astra Zeneca, consulting fees and nonfinancial support from Diasorin and nonfinancial support from I.E.M., outside the submitted work. S.H. and S.S. are employees of Bayer AG. H.M.H.S. is a shareholder of the Coagulation Profile. All other authors report no conflicts of interest.