The relationship between antithrombin administration and inflammation during veno-venous ECMO

Panigada, Mauro; Spinelli, Elena; Falco, Stefano De; Consonni, Dario; Novembrino, Cristina; Anzoletti, Massimo Boscolo; Panarello, Giovanna; Occhipinti, Giovanna; Santos, Claudia C Dos; Artigas, Antonio; Grasselli, Giacomo

doi:10.1038/s41598-022-17227-7

Cited by 9 publications

(8 citation statements)

References 28 publications

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“…Some adult studies also suggest that AT3 could reduce inflammation. 28 Further studies in children are needed to evaluate the potential benefits of AT3 supplementation. 13,16,19 While the clinical benefits of AT3 administration are unclear, the financial costs are evident.…”

Section: Resultsmentioning

confidence: 99%

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Antithrombin III supplementation during neonatal and pediatric extracorporeal membrane oxygenation

Meshulami,

Green,

Kaushik

2023

Artificial Organs

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BackgroundBleeding and thrombosis are common extracorporeal membrane oxygenation (ECMO) complications associated with increased mortality. Heparin is the most commonly used ECMO anticoagulant, employed in 94% of cases. Reduced antithrombin III (AT3) levels could decrease heparin effectiveness. Neonates have inherently lower levels of AT3 than adults, and pediatric patients on ECMO can develop AT3 deficiency. One potential approach for patients on ECMO with AT3 deficiency is exogenous AT3 supplementation. However, there is conflicting data concerning the use of AT3 for pediatric and neonatal patients on ECMO.MethodsWe analyzed the Bleeding and Thrombosis during ECMO database of 514 neonatal and pediatric patients on ECMO. We constructed daily regression models to determine the association between AT3 supplementation and rates of bleeding and thrombosis. Given the physiological differences between pediatric patients and neonates, we constructed separate models for each.ResultsAT3 administration was associated with increased rates of daily bleeding among pediatric (adjusted odds ratio [aOR] 1.59, p < 0.01) and neonatal (aOR 1.37, p = 0.04) patients. AT3 supplementation did not reduce the rate of thrombosis for either pediatric or neonatal patients.ConclusionAT3 administration was associated with increased rates of daily bleeding, a hypothesized potential complication of AT3 supplementation. In addition, AT3 supplementation did not result in lower rates of thrombosis. We recommend clinicians utilize caution when considering supplementing patients on ECMO with exogenous AT3.

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Section: Resultsmentioning

confidence: 99%

“…It is possible that once a validated age‐specific AT3 target is identified (e.g., ≥50%), AT3 supplementation could improve patient outcomes. Some adult studies also suggest that AT3 could reduce inflammation 28 . Further studies in children are needed to evaluate the potential benefits of AT3 supplementation 13,16,19 …”

Section: Discussionmentioning

confidence: 99%

Antithrombin III supplementation during neonatal and pediatric extracorporeal membrane oxygenation

Meshulami,

Green,

Kaushik

2023

Artificial Organs

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“…Primary outcome results have not yet been published, but a pre-specified ancillary study showed a correlation between AT therapy and a decrease in inflammatory cytokines. 83 Overall, prevention of thrombosis must be balanced with efforts to minimize risks of bleeding, which can be particularly high in neonatal and pediatric patients. In both pediatric and adult patients undergoing ECMO or similar mechanical circulatory support such as a ventricular assist device, it can be a challenge to achieve appropriate titration of anticoagulation to prevent hemorrhagic and/or thrombotic complications, especially as substantial variability exists in the approach to management of anticoagulation and antiplatelet therapy.…”

Section: Patients Undergoing Ecmomentioning

confidence: 99%

“…Primary outcome results have not yet been published, but a pre-specified ancillary study showed a correlation between AT therapy and a decrease in inflammatory cytokines. 83…”

Section: Additional Patient Populations and Use Cases Where At Therap...mentioning

confidence: 99%

Antithrombin Therapy: Current State and Future Outlook

Rodgers,

Mahajerin

2023

Clin Appl Thromb Hemost

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Antithrombin (AT) is a natural anticoagulant pivotal in inactivating serine protease enzymes in the coagulation cascade, making it a potent inhibitor of blood clot formation. AT also possesses anti-inflammatory properties by influencing anticoagulation and directly interacting with endothelial cells. Hereditary AT deficiency is one of the most severe inherited thrombophilias, with up to 85% lifetime risk of venous thromboembolism. Acquired AT deficiency arises during heparin therapy or states of hypercoagulability like sepsis and premature infancy. Optimization of AT levels in individuals with AT deficiency is an important treatment consideration, particularly during high-risk situations such as surgery, trauma, pregnancy, and postpartum. Here, we integrate the existing evidence surrounding the approved uses of AT therapy, as well as potential additional patient populations where AT therapy has been considered by the medical community, including any available consensus statements and guidelines. We also describe current knowledge regarding cost-effectiveness of AT concentrate in different contexts. Future work should seek to identify specific patient populations for whom targeted AT therapy is likely to provide the strongest clinical benefit.

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“…In a recent sub-study of a multicenter randomized trial assessing the effect of antithrombin (AT) supplementation during vv-ECMO, 3 we observed that AT administration was associated with reduced plasmatic levels of pro-inflammatory cytokine. 14 This suggests that AT does not only play as the serine-protease cofactor of heparin for its anticoagulant properties, but it also deploys anti-inflammatory and anti-microbial properties. 15,16 The effects of circulating inflammatory cytokines on viscoelastic test parameters during vv-ECMO are unknown.…”

Section: Introductionmentioning

confidence: 99%

The role of inflammation and antithrombin supplementation on thromboelastographic parameters during veno-venous ECMO for respiratory failure

Meli,

De Falco,

Novembrino

et al. 2024

Perfusion

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Introduction Extracorporeal membrane oxygenation (ECMO) may act as a driver or propagator of systemic inflammation. In turn, cytokine release can modify thromboelastographic (TEG) tests which are commonly used for anticoagulation monitoring. In this context, antithrombin (AT) supplementation might further modify TEG. Methods This is a pre-specified sub-study of the “Randomized Controlled Trial of Antithrombin Supplementation During Extracorporeal Membrane Oxygenation” study (investigator-initiated, randomized, single-blind, two-arm trial) conducted in two Italian ECMO referral ICUs. Adult patients requiring vv-ECMO for respiratory failure and undergoing unfractioned heparin (UFH) administration were enrolled and randomized whether to receive AT supplementation. Plasma samples for cytokine assay (IL-8, IL-10, IL-6, IL-1β, TNF-α and Pro-ADM) and heparinase TEG were collected from every patient before ECMO start, 24 h and 72 h after ECMO start, before ECMO removal, and 7 days after ECMO removal or upon ICU discharge whichever happened first. AT concentration, coagulation and clinical data were collected before ECMO start and at pre-fixed time points. Results Thirty-nine patients were enrolled (21 treatments, 18 controls). TEG-R had a weak-to-moderate positive correlation with IL-8, IL-6, IL-10 and TNF-α and a moderate positive correlation with Pro-ADM. TEG-ANG showed a weak negative correlation with IL-8, IL-6 and TNF-α, while TEG-MA negatively correlated with IL-8, TNF-α and Pro-ADM. AT supplementation seemed to modify the association between TEG-MA and IL-8, IL-10 and Pro-ADM; conversely, AT did not affect the relationship among TEG-R or TEG-ANG and the studied cytokines. Conclusions High concentrations of systemic cytokines correlated with longer reaction times and decreased angle and amplitude at TEG, suggesting that an increase in inflammation is related with hypocoagulability as revealed by thromboelastography.

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The relationship between antithrombin administration and inflammation during veno-venous ECMO

Cited by 9 publications

References 28 publications

Antithrombin III supplementation during neonatal and pediatric extracorporeal membrane oxygenation

Antithrombin III supplementation during neonatal and pediatric extracorporeal membrane oxygenation

Antithrombin Therapy: Current State and Future Outlook

The role of inflammation and antithrombin supplementation on thromboelastographic parameters during veno-venous ECMO for respiratory failure

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