Fibrinolysis as a Causative Mechanism for Bleeding Complications on Extracorporeal Membrane Oxygenation: A Pilot Observational Prospective Study

Abstract

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.

Upper gastrointestinal bleeding on veno-arterial extracorporeal membrane oxygenation support

“…Among the latter, external or internal bleedings may be favored by curative anticoagulation, acquired von Willebrand syndrome, thrombocytopenia, platelet dysfunction or hypofibrinogenemia [ 7 , 8 ]. An excessive endogenous fibrinolysis is also an emerging mechanism [ 9 , 10 ].…”