Targeting the contact system in a rabbit model of extracorporeal membrane oxygenation

Abstract

Previous studies suggested that contact pathway factors drive thrombosis in mechanical circulation. We used a rabbit model of veno-arterial extracorporeal circulation (VA-ECMO) to evaluate the role of factors XI and XII in ECMO-associated thrombosis and organ damage. Factors XI and XII were depleted using established antisense oligonucleotides (ASO) prior to placement on a blood-primed VA-ECMO circuit. Decreasing FXII or FXI to <5% of baseline activity significantly prolonged ECMO circuit lifespan, limited the development of coagulopathy, and prevented fibrinogen consumption. Histological analyses suggested that FXII depletion mitigated interstitial pulmonary edema and hemorrhage whereas heparin and FXI depletion did not. Neither FXI nor FXII depletion were associated with significant hemorrhage in other organs. In vitro analyses showed that membrane oxygenator fibers (MOFs) alone are capable of driving significant thrombin generation in a FXII and FXI-dependent manner. MOFs also augment thrombin generation triggered by low (1 pM) or high (5 pM) tissue factor (TF) concentrations. However, only FXI elimination completely prevented the increase in thrombin generation driven by MOFs, suggesting MOFs augment thrombin-mediated FXI activation. Together, these results suggest that therapies targeting FXII or FXI limit thromboembolic complications associated with ECMO. Further studies are needed to determine the contexts where targeting FXI and FXII, either alone or in combination, would be most beneficial in ECMO. Further studies are also needed to determine the potential mechanisms coupling FXII to end organ damage in ECMO.

Anticoagulation in the ICU: a future for contact pathway inhibition?

“…Likewise, in a recent study, Tweddell and colleagues showed that FXI-or FXI-depletion using ASOs prolonged ECMO lifespan, limited thrombotic complications and prevented fibrinogen consumption in a rabbit model. [16] Interestingly, in this study, FXII-depletion also appeared to mitigate lung edema and haemorrhage while FXI-depletion did not. This might be due to the particular position of FXII at a crossroads between haemostasis and inflammation as it also activates 4 prekallikrein into kallikrein, resulting in complement activation and activation of the bradykinin pathway.…”

Polyphosphate as an antithrombotic target and hemostatic agent

“…In sharp contrast to the unimportant role in hemostasis, the intrinsic coagulation has been reported to significantly contribute to the development of thrombosis and inflammation 3,[37][38][39] Studies on mice with FXI-deficiency or FXII/FXI-double-deficiency have shown suppressed thrombotic tendencies compared to wild-type mice. 40,41 However, in primate models, the inhibition of FXII has yielded conflicting results, with several studies showing suppression of thrombosis, 42,43 while others indicating a nonobvious antithrombotic effect. 44 PolyP, especially microbial lc-PolyP, is a powerful activator of the contact pathway.…”

Bivalirudin-hydrogel coatings of polyvinyl chloride on extracorporeal membrane oxygenation for anticoagulation

“…Rabbit blood was collected through the auricular vein after circulation for 4 h. The depletion of coagulation factors is a key issue in the long-term use of ECMO, the relevant important clotting factors (II, V, and X) (1,20) and blood coagulation (PT/ APTT) were also tested in the whole blood of rabbits.…”