Fibrinolysis as a causative mechanism for bleeding complications on ECMO: a pilot observational prospective study.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is associated with a high risk of bleeding complications. The specific impact of ECMO on fibrinolysis remains unexplored. The objective of the current pilot observational prospective study was to investigate the longitudinal dynamics of fibrinolytic markers - i.e., changes over time - in the context of bleeding events in patients on ECMO. METHODS: Longitudinal dynamics of contact phase components (kininogen and bradykinin) and fibrinolysis markers (tissue-type plasminogen activator [t-PA], plasminogen activator inhibitor-1 [PAI-1], their complexes [t-PA•PAI-1], plasmin-antiplasmin complexes, plasminogen, and D-dimer) were measured in patients undergoing veno-venous and veno-arterial ECMO, before implantation, at 0, 6, and 12 hours post-implantation, and daily thereafter. RESULTS: The cohort consisted of 30 patients (214 ECMO-days). The concentrations of t-PA, D-dimer, plasmin-antiplasmin complexes, PAI-1 and t-PA•PAI-1 complexes were increased, whereas plasminogen decreased compared to normal values. A noteworthy divergence was observed between hemorrhagic and non-hemorrhagic patients: in bleeding patients, D-dimer, plasmin-antiplasmin, t-PA, PAI-1 and t-PA•PAI-1 followed an increasing kinetics before hemorrhage and then decreased to their baseline level; conversely non-bleeding patients showed a decreasing kinetics in these markers. Also, D-dimer and t-PA followed an increasing kinetics in bleeding patients compared to non-bleeding patients (median values for D-dimer dynamics: 1080 vs. -440 ng/mL, p=0.05; t-PA dynamics: 0.130 vs. 0.100 nM, p=0.038), and both markers significantly increased the day before hemorrhage. A t-PA concentration above 0.304 nM was associated with bleeding events (OR 4.92, 95% CI [1.01-24.08], p=0.049). CONCLUSION: Contact activation induces fibrinolysis in ECMO patients, especially in patients experiencing bleeding. This finding supports the role of this mechanism as a possible causal factor for hemorrhages during ECMO and open new avenues for novel therapeutic perspectives. WHAT WE ALREADY KNOW ABOUT THIS TOPIC: Extracorporeal membrane oxygenation (ECMO) is associated with a high risk of bleeding complications due to multiple factors. However, the role of the fibrinolytic system is not well understood in this setting. WHAT THIS ARTICLE TELLS US THAT IS NEW: In patients requiring cardiac and/or pulmonary support with ECMO, D-dimer and tissue plasminogen activator levels were increased with bleeding, findings consistent with fibrinolysis.Although there are multiple causes for fibrinolysis during ECMO, their study suggests that patients who bled had increased contact activation, and may benefit from novel therapeutic agents that inhibit hemostatic activation through this pathway.

Measuring residual anti-Xa activity of direct factor Xa inhibitors after reversal with andexanet alfa.

INTRODUCTION: Andexanet alfa (AnXa) was developed for anticoagulant effect reversal of direct factor Xa inhibitors (DXaI) (apixaban, rivaroxaban, edoxaban) in emergency situations. Regular anti-Xa assays are not suitable to evaluate anti-Xa activity after AnXa administration because of the high sample dilution resulting in the AnXa-DXaI dissociation which gives inaccurately high DXaI measured concentrations. This study aimed at developing dedicated STA-Liquid anti-Xa test set-ups for accurately measuring DXaI after reversal with AnXa. METHODS: Modified anti-Xa test set-ups, with reduced sample dilution, were developed to overcome regular assays limitations and to improve measured accuracy with results comparable to Portola microplate reference method used in clinical studies. Both regular and optimized assays were used to measure DXaI concentration in AnXa-containing samples. Quality controls, normal pooled plasma spiked with five DXaI and three AnXa concentrations, samples from DXaI-treated patients spiked with AnXa and ex vivo healthy volunteers having received both DXaI and AnXa were used. RESULTS: The lower limit of quantitation of optimized anti-Xa assays was <10 ng/mL with CVs ≤10%. DXaI samples containing 300 ng/mL and 1 µmol/L AnXa resulted in DXaI residual concentrations of 29-72 ng/mL depending on the DXaI (76%-90% reversal), compared to 20-28 ng/mL with reference method (92%-94% reversal) and 135-165 ng/mL with regular assays (about 50% reversal). CONCLUSION: Modified test set-ups are automated alternative to reference method with improved precision and reproducibility. They can be run in all laboratories where regular anti-Xa assays are performed using commercially available reagents.