Factor XII promotes the thromboinflammatory response in a rat model of veno-arterial extracorporeal membrane oxygenation.
Abstract
Objective
Factor XII (FXII) is a multifunctional protease capable of activating thrombotic and inflammatory pathways. FXII has been linked to thrombosis in extracorporeal membrane oxygenation (ECMO), but the role of FXII in ECMO-induced inflammatory complications has not been studied. We used novel gene-targeted FXII deficient rats to evaluate the role of FXII in ECMO-induced thromboinflammation.
Methods
FXII deficient (FXII-/-) Sprague-Dawley rats were generated using CRISPR/Cas9. We used a minimally invasive veno-arterial (VA) ECMO model to compare wild-type (WT) and FXII-/- rats in 2 separate experimental cohorts – rats placed on ECMO without pharmacological anticoagulation, and rats anticoagulated with argatroban. Rats were maintained on ECMO until circuit failure or 1 hour. Comparisons were made with unchallenged rats and rats that underwent a sham surgical procedure without ECMO.
Results
FXII-/- rats were maintained on ECMO without pharmacological anticoagulation with low resistance throughout a 1-hour experiment. In contrast, WT rats placed on ECMO without anticoagulation developed thrombotic circuit failure within 10 minutes. Argatroban provided a means to maintain WT and FXII-/- rats on ECMO for the 1-hour timeframe without thrombotic complications. Analyses of these rats demonstrated that ECMO resulted in an increase in neutrophil migration into the liver that was significantly blunted by FXII deficiency. ECMO also resulted in increases in high molecular weight kininogen cleavage and complement activation that were abrogated by genetic deletion of FXII.
Conclusion
FXII initiates hemostatic system activation and key inflammatory sequelae in ECMO, suggesting that therapies targeting FXII could limit both thromboembolism and inopportune inflammatory complications in this setting.