Anticoagulation strategy in veno-arterial extracorporeal membrane oxygenation in lung transplantation

Introduction

Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) in the perioperative period of lung transplantation presents a number of poignant discussion points, due to the unique challenges facing this complex patient population. Not least of which is the topic of anticoagulation utilisation to support VA-ECMO in lung transplant patients, given the potential bleeding risks and an association of blood transfusion with primary graft dysfunction (1).

Anticoagulation plays a role in balancing the potentially catastrophic risks of bleeding and thrombosis, and has traditionally been a mainstay of the ECMO armamentarium. This practice, however, was initially extrapolated from work in the cardiac bypass setting (2), and has since largely been investigated via small retrospective studies. Due to a lack of definitive evidence, several pertinent questions remain, such as whether anticoagulation is necessary, the intensity of anticoagulation if it is required, and the best way to monitor anticoagulation.

Attempts to avoid blood transfusion in lung transplant patients have prompted investigation of the feasibility of conducting ECMO with low-dose anticoagulation. Chan et al. (3) have recently published their experience with a low-dose heparin protocol for lung transplant recipients who received central VA-ECMO intraoperatively in the Journal of Thoracic and Cardiovascular Surgery.

This retrospective study reviewed 116 patients, 46 of whom received a low heparin protocol, with the remaining 70 receiving a standard heparin protocol. All patients underwent central aortic cannulation. The ECMO blood flow rates were 50% of cardiac output in the low heparin group and 100% of cardiac output in the standard anticoagulation group. The low heparin protocol consisted of an initial bolus of 75 units per kilogram followed by a bolus of 20 units per kilogram if an activated clotting time (ACT) of 180 s is not achieved, with no further heparin once an ACT of 180 s is achieved. The standard protocol had 1,000 units of heparin added to the ECMO circuit, a bolus of 200 units per kilogram to start with, and further boluses given as required for an ACT of 180–250 s (3). Additionally, the low-heparin protocol patients received a tranexamic acid infusion, whereas the standard protocol group did not. The standard protocol group was reversed with protamine at the end of the case, whereas the low-heparin protocol group was not (3). The results were favourable for the low heparin protocol group, with significant reductions in total blood products including packed red blood cells, platelets, fresh frozen plasma and cryoprecipitate, postoperative blood products and total surgical time (3).

VA-ECMO in the lung transplant setting

The use of VA-ECMO carries several benefits in the lung transplantation population. Overall, an approach to intraoperative mechanical circulatory support that favours VA-ECMO over cardiopulmonary bypass and is able to limit blood product transfusion aims to mitigate potential modifiable risk factors for the development of primary graft dysfunction. Compared to cardiopulmonary bypass, which requires high-dose anticoagulation, VA-ECMO can provide the benefits of allowing controlled reperfusion of the lungs with a lower dose of anticoagulation. An analysis of the Extracorporeal Life Support in Lung Transplant Registry demonstrated that severe primary graft dysfunction (PGD) occurred with an odds ratio of 1.89 for cardiopulmonary bypass (CPB) compared to VA-ECMO (4). The ECMO circuit also has theoretical advantages to reduce systemic inflammation compared to cardiopulmonary bypass, including the absence of a blood air interface (5). Retrospective studies have demonstrated benefits in intraoperative ECMO over cardiopulmonary bypass, including reduced intensive care and hospital length of stay (6), mechanical ventilation duration (6), blood product utilisation (6,7), requirement for dialysis (7), and mortality (7). A recent meta-analysis has also summarised benefits of ECMO compared to CPB, including a lower platelet transfusion requirement, reduced ICU stay, need for tracheostomy, renal impairment and need for subsequent surgical interventions (8). The meta-analysis findings, however, did not demonstrate a reduction in mortality, primary graft dysfunction, or use of packed red blood cells and fresh frozen plasma (8).

Several small studies have explored low-dose anticoagulation for intraoperative ECMO use in the lung transplant setting. These studies have demonstrated favourable results in terms of rates of PGD and safety with respect to thrombotic events. A case study from 2017 by Bharat et al. (9) demonstrated success in performing a single lung transplant using VA-ECMO, with heparin only used when ECMO flows were reduced to de-air the allograft. In 2020, a single-centre observational prospective study by Hoetzenecker et al. (10) examined the routine utilisation of ECMO in the lung transplantation setting and demonstrated very low rates of primary graft dysfunction; 7.5% and 1.3% of patients had severe PGD at 2 and 72 hours following ICU admission, respectively. Of note in this study, the intraoperative anticoagulation strategy was a single dose of 40 units of heparin per kilogram without ongoing anticoagulation or monitoring of anticoagulation. The authors of this study reported no thromboembolic events. More recently, Vajter et al. (11) published a single-centre retrospective observational study which compared patients on intraoperative ECMO support for their lung transplant who received a total intraoperative dose of 60 units or less per kilogram of unfractionated heparin to patients who received 61 units or more per kilogram. They demonstrated significantly reduced utilisation of packed red blood cells, fresh frozen plasma transfusions and bleeding complications in the group with a lower dose of heparin. There was a reduction noted in severe primary graft dysfunction, but not in short- or long-term mortality. Neither group experienced thrombotic complications. When comparing these two studies there appears to be a difference in the amount of blood products utilised; Hoetzenecker et al. (10) report a mean of 4.2 units of packed red blood cells and 9.5 units of fresh frozen plasma, compared to Vajter et al. (11), who respectively in the high and low heparin groups report 1.908 and 0.5581 units of packed red blood cells and 1.628 and 0.4186 units of fresh frozen plasma. Specific triggers, if any, for instituting a transfusion were not defined and overall blood loss in the study by Hoetzenecker et al. (10) was not reported.

Anticoagulation in ECMO

The exposure of blood to an extracorporeal circuit is known to initiate numerous pro-coagulant processes, which can exacerbate the risk of thrombosis in patients already at risk of this complication from critical illness. Kumar et al. (12) and Frantzeskaki et al. (13) summarise these in their review articles and they include coagulation factor activation complement system activation and platelet adhesion and activation. In light of these prothrombotic processes, ECMO is typically delivered with anticoagulation with the aim of preventing the clinical consequences of thrombotic events. As these events can be catastrophic, leading to death or severe disability, anticoagulation has been a longstanding element in the delivery of ECMO.

It is generally accepted that a condition of no or low anticoagulation is that a certain level of ECMO flow should be maintained to help prevent circuit thrombosis, but at present, it is not known which ECMO flows are optimal for maintaining adequate support and preventing complications. There are, however, some ex-vivo data that contradict the notion that lower flows necessarily promote coagulation, with reduced RISTO-induced platelet aggregation, increased haemolysis, loss of high molecular weight von Willebrand multimers, reduced maximum clot firmness and increased clotting times seen in a low flow circuit of 1.5 L/minute compared to circuits operating at 4 L/minute (14). On the other hand, it should also be considered that higher ECMO flows will approach full cardiopulmonary bypass. In the setting of lung transplantation, transpulmonary blood flow should be maintained to help prevent graft ischaemia and minimise the risk of pulmonary artery thrombosis, as well as left ventricular thrombosis in the setting of marginal left ventricular function.

Bleeding complications associated with ECMO are frequently encountered in clinical practice. There is evidence that ECMO patients who experience a bleeding event have a stronger association with mortality than patients who experience a thrombotic event (15,16). Patients who require ECMO can become prone to haemorrhagic complications due to the underlying pathology that is being managed or as a result of ECMO itself. This may include the development of disseminated intravascular coagulation (13), exhaustion of the coagulation system (17), thrombocytopaenia, platelet dysfunction, acquired von Willebrand syndrome or due to inadvertent excess anticoagulant medication (18).

Advances in circuit technology may also obviate the need for significant levels of anticoagulation to prevent thrombus formation. These include the use of centrifugal pumps as well as biocompatible ECMO circuits (19).

Society guidelines and current evidence

Regarding the patient group specifically investigated in the work of Chan et al. (3), a consensus statement from the International Society for Heart and Lung Transplantation recommends that a low-dose heparin strategy could be considered in using intraoperative VA-ECMO for lung transplantation (20). The American Association of Thoracic Surgery further qualifies this consideration by suggesting that low or no heparin strategies may be considered specifically in the subset of patients with prominent adhesions or coagulopathy (21). In the broader perioperative setting, the Society of Cardiovascular Anesthesiologists Guidelines for the Intraoperative Management of Adult Patients on Extracorporeal Membrane Oxygenation recommend that systemic anticoagulation should be used in patients who are not actively bleeding or thought to be at high risk of bleeding (22).

Discussion

The work of Chan et al. (3) adds compelling evidence to support a burgeoning move to transition to less aggressive anticoagulation strategies in ECMO. They crucially address this question in a patient population that, in particular, stands to benefit from limiting transfusion requirements. Their single shot protocol led to no blood transfusions being required for the patients who received this strategy. Whilst there was no reduction in the rates of severe primary graft dysfunction, it is unlikely that the study was powered to detect this. This question certainly warrants further study to elucidate this relationship; however, it is notable that the low heparin strategy appears to reduce the use of blood products, which are a limited resource known to carry a well-established profile of side effects.

The significant concern of a low or no anticoagulation strategy in ECMO is thrombosis formation, and whilst this study reports there was no significant difference in the rate of deep vein thrombosis, there was no report of complications related to other thrombotic events such as any need for circuit exchange or formation of intracardiac thrombi. This is an important safety outcome in adopting a low anticoagulation dose strategy, and would need to be further elucidated to promote adoption of this approach. It should also be noted that the duration of ECMO in this study was relatively short and the approach to ongoing anticoagulation in the event that ECMO needs to continue postoperatively would need to be considered. Other studies, albeit small, have not reported significant issues with thrombotic complications in the lung transplantation setting (10,11).

As the authors acknowledge in their discussion, there were other aspects to the study protocol that differed between the two groups that may have impacted the outcome; namely the use of a continuous tranexamic acid infusion and restriction of crystalloid usage. The difference in tranexamic acid usage may reduce the propensity for bleeding and therefore influence the primary outcome of transfusion requirements. Importantly, the impact on any adverse outcomes, including thrombus formation and neurological sequelae, would need to be considered in recommending tranexamic acid as a part of this overall protocol; outcomes which are difficult to fully appreciate in a study with small numbers. The potential dilutional effect of crystalloid could impact on the transfusion requirement as a haemoglobin target was mentioned as one of considerations when deciding to transfuse. The amount of crystalloid that each group received was not reported. It should also be noted that the starting haemoglobin level in the low-dose heparin group was significantly lower than the high-dose group, which may have led to earlier use of blood product transfusion.

Another important consideration in this paper is the decision-making approach in prescribing blood products. The decisions in this study were largely based on clinical parameters such as haemodynamic stability, active bleeding, signs of coagulopathy and haemoglobin targets (3). Work from Durila et al. (23) demonstrated that rotational thromboelastometry (ROTEM) reduced packed red blood cell and fresh frozen plasma transfusions in the perioperative management of lung transplant recipients. Part of this study protocol included using 5% albumin as the sole volume replacement fluid in the ROTEM group, compared to a combination of crystalloids and other non-albumin colloids. The contribution of each of these interventions to the outcomes could not be defined due to limitations of the study. Additionally, a secondary analysis of this randomised controlled trial by Vajter et al. (11) demonstrated a significantly improved PaO₂/FiO₂ ratio in the group that was managed with ROTEM and 5% albumin, as well as a reduction in vasopressor requirements. Over several time points within the first 72 hours, moderate to severe PGD rates were only significantly less in ROTEM and albumin group at the 72-hour time point. These studies raise another possible strategy that warrants further investigation, and could be considered amongst a range of strategies in addition to what Chan et al. (3) have used to help reduce blood product consumption and the possible sequelae of this.

A further consideration in adopting a low-dose anticoagulation strategy is that the impact of ECMO blood flow rate on haemostatic parameters and on the intensity of anticoagulation needed at different flow rates remains unclear, especially while using modern ECMO circuitry. Although ex vivo studies have shown variable impact of ECMO blood flow rates on haemostasis, patient-centred outcomes such as reported in this study are more meaningful for clinical practice. The study findings are reassuring that lower flows and lower intensity anticoagulation resulted in better outcomes. This is an area that warrants further research.

The guidelines relating specifically to intraoperative lung transplantation support have somewhat liberalised the recommendations by suggesting that a low heparin strategy may be viable, particularly in groups prone to bleeding, such as those with dense adhesions. Whilst a more robust evidence base is developed regarding the safety of this approach, this highlights that it is crucial to consider the individual circumstances of each patient, as thrombotic complications can carry devastating complications.

Conclusions

We commend Chan et al. (3) on this well-constructed study that has added valuable data to a dynamic evidence base in the management of anticoagulation of intraoperative ECMO support for lung transplantation patients, as well as the broader discussion on this topic in ECMO. They present a protocol which appears viable in the short-term ECMO support required during lung transplantation surgery. As the authors acknowledge though, there are some shortcomings, such as the retrospective nature, low patient numbers and the addition of several interventions in this study that limit the generalisability of these data. Further studies would be of value to elucidate further the relationship of anticoagulation strategy to blood transfusion requirement and subsequent primary graft dysfunction.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Current Challenges in Thoracic Surgery. The article has undergone external peer review.

Peer Review File: Available at https://ccts.amegroups.com/article/view/10.21037/ccts-25-7/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://ccts.amegroups.com/article/view/10.21037/ccts-25-7/coif). K.S. is a member of the Scientific Committee of the International ECMO Network and reports research support from Queensland Health. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Subramaniam K, Loor G, Chan EG, et al. Intraoperative Red Blood Cell Transfusion and Primary Graft Dysfunction After Lung Transplantation. Transplantation 2023;107:1573-9. [Crossref] [PubMed]
2. Seelhammer T, Ninan J, Nei S, et al. Anticoagulation during extracorporeal membrane oxygenation. Cochrane Database Syst Rev 2024;6:CD015685. [Crossref] [PubMed]
3. Chan EG, Deitz RL, Ryan JP, et al. Bloodless lung transplantation: Comparison between 2 central venoarterial extracorporeal membrane oxygenation anticoagulation strategies and their impact on lung transplant outcomes. J Thorac Cardiovasc Surg 2025;169:1620-8. [Crossref] [PubMed]
4. Loor G, Huddleston S, Hartwig M, et al. Effect of mode of intraoperative support on primary graft dysfunction after lung transplant. J Thorac Cardiovasc Surg 2022;164:1351-1361.e4. [Crossref] [PubMed]
5. Biscotti M, Yang J, Sonett J, et al. Comparison of extracorporeal membrane oxygenation versus cardiopulmonary bypass for lung transplantation. J Thorac Cardiovasc Surg 2014;148:2410-5. [Crossref] [PubMed]
6. Machuca TN, Collaud S, Mercier O, et al. Outcomes of intraoperative extracorporeal membrane oxygenation versus cardiopulmonary bypass for lung transplantation. J Thorac Cardiovasc Surg 2015;149:1152-7. [Crossref] [PubMed]
7. Ius F, Kuehn C, Tudorache I, et al. Lung transplantation on cardiopulmonary support: venoarterial extracorporeal membrane oxygenation outperformed cardiopulmonary bypass. J Thorac Cardiovasc Surg 2012;144:1510-6. [Crossref] [PubMed]
8. Ma Y, Geng Y, Wang D, et al. The efficacy and safety of ECMO and CPB in lung transplantation: A systematic review and meta-analysis. Asian J Surg. 2025;48:4115-22.
9. Bharat A, DeCamp MM. Veno-arterial extracorporeal membrane oxygenation without therapeutic anticoagulation for intra-operative cardiopulmonary support during lung transplantation. J Thorac Dis 2017;9:E629-31. [Crossref] [PubMed]
10. Hoetzenecker K, Benazzo A, Stork T, et al. Bilateral lung transplantation on intraoperative extracorporeal membrane oxygenator: An observational study. J Thorac Cardiovasc Surg 2020;160:320-327.e1. [Crossref] [PubMed]
11. Vajter J, Holubova G, Novysedlak R, et al. Anaesthesiologic Considerations for Intraoperative ECMO Anticoagulation During Lung Transplantation: A Single-Centre, Retrospective, Observational Study. Transpl Int 2024;37:12752. [Crossref] [PubMed]
12. Kumar G, Maskey A. Anticoagulation in ECMO patients: an overview. Indian J Thorac Cardiovasc Surg 2021;37:241-7. [Crossref] [PubMed]
13. Frantzeskaki F, Konstantonis D, Rizos M, et al. Extracorporeal Membrane Oxygenation (ECMO)-Associated Coagulopathy in Adults. Diagnostics (Basel) 2023;13:3496. [Crossref] [PubMed]
14. Ki KK, Passmore MR, Chan CHH, et al. Low flow rate alters haemostatic parameters in an ex-vivo extracorporeal membrane oxygenation circuit. Intensive Care Med Exp 2019;7:51. [Crossref] [PubMed]
15. Nunez JI, Gosling AF, O'Gara B, et al. Bleeding and thrombotic events in adults supported with venovenous extracorporeal membrane oxygenation: an ELSO registry analysis. Intensive Care Med 2022;48:213-24. [Crossref] [PubMed]
16. Mansour A, Flecher E, Schmidt M, et al. Bleeding and thrombotic events in patients with severe COVID-19 supported with extracorporeal membrane oxygenation: a nationwide cohort study. Intensive Care Med 2022;48:1039-52. [Crossref] [PubMed]
17. Šoltés J, Skribuckij M, Říha H, et al. Update on Anticoagulation Strategies in Patients with ECMO-A Narrative Review. J Clin Med 2023;12:6067. [Crossref] [PubMed]
18. Kanji R, Vandenbriele C, Arachchillage DRJ, et al. Optimal Tests to Minimise Bleeding and Ischaemic Complications in Patients on Extracorporeal Membrane Oxygenation. Thromb Haemost 2022;122:480-91. [Crossref] [PubMed]
19. Lv X, Deng M, Wang L, et al. Low vs standardized dose anticoagulation regimens for extracorporeal membrane oxygenation: A meta-analysis. PLoS One 2021;16:e0249854. [Crossref] [PubMed]
20. Martin AK, Mercier O, Fritz AV, et al. ISHLT consensus statement on the perioperative use of ECLS in lung transplantation: Part II: Intraoperative considerations. J Heart Lung Transplant 2024;S1053-2498(24)01830-8.
21. Expert Consensus Panel. The American Association for Thoracic Surgery (AATS) 2022 Expert Consensus Document: The use of mechanical circulatory support in lung transplantation. J Thorac Cardiovasc Surg 2023;165:301-26. [Crossref] [PubMed]
22. Mazzeffi MA, Rao VK, Dodd-O J, et al. Intraoperative Management of Adult Patients on Extracorporeal Membrane Oxygenation: An Expert Consensus Statement From the Society of Cardiovascular Anesthesiologists-Part II, Intraoperative Management and Troubleshooting. Anesth Analg 2021;133:1478-93. [Crossref] [PubMed]
23. Durila M, Vajter J, Garaj M, et al. Rotational thromboelastometry reduces blood loss and blood product usage after lung transplantation. J Heart Lung Transplant 2021;40:631-41. [Crossref] [PubMed]