Activated Factor XI is Increased in Plasma in Response to Surgical Trauma but not to Recombinant Activated FVII-Induced Thrombin Formation.

Heiko Rühl, Anne M Friemann, Sara Reda, Nadine Schwarz, Franziska I Winterhagen, Christina Berens, Jens Müller, Johannes Oldenburg, Bernd Pötzsch

Journal of atherosclerosis and thrombosis 2022 Jan 01

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Feedback activation of factor XI (FXI) by thrombin is believed to play a critical role in the amplification phase of thrombin generation and to contribute to thrombosis development and hemostasis. However, the activation of FXI by thrombin has been shown in vitro to require a cofactor. In this study, the role of thrombin in activated FXI (FXIa) formation in vivo is investigated. The study population comprised probands in whom coagulation activation was triggered by low-dose (15 µg/kg) recombinant activated factor VII (rFVIIa, n=89), of whom 34 with (VTE+) and 45 without a history of venous thromboembolism (VTE-), and patients undergoing major orthopedic surgeries (n=45). FXIa was quantified via an enzyme capture assay using a monoclonal FXI-specific antibody. Thrombin formation was monitored using an oligonucleotide-based enzyme capture assay and the thrombin activation markers prothrombin fragment 1＋2 (F1＋2) and thrombin-antithrombin complex (TAT). In the rFVIIa cohort, FXIa and thrombin remained below their lower limit of quantification of 3.48 and 1.06 pmol/L, respectively. By contrast, during the surgeries, median FXIa levels increased from 3.69 pmol/L pre-operatively to 9.41 pmol/L mid-operatively (P=4·10-4) and remained significantly elevated 24 h thereafter, with 9.38 pmol/L (P=0.001). Peak levels of F1+2 were comparable in the VTE+, VTE-, and surgery cohort (235, 268, and 253 pmol/L), whereas peak TAT levels were higher in the surgery cohort (53.1, 33.9, and 147.6 pmol/L). Under in vivo conditions, the activation of FXI requires specific local features that are present at the wounded site including potential cofactors of thrombin.

Citation

Heiko Rühl, Anne M Friemann, Sara Reda, Nadine Schwarz, Franziska I Winterhagen, Christina Berens, Jens Müller, Johannes Oldenburg, Bernd Pötzsch. Activated Factor XI is Increased in Plasma in Response to Surgical Trauma but not to Recombinant Activated FVII-Induced Thrombin Formation. Journal of atherosclerosis and thrombosis. 2022 Jan 01;29(1):82-98