Extracorporeal membrane oxygenation (ECMO) is a critical intervention for patients with severe respiratory or cardiac failure, requiring careful management of anticoagulation to prevent thromboembolic complications. This review examines current practices and challenges in ECMO anticoagulation, focusing on strategies, agents, and emerging insights. Unfractionated heparin (UFH) remains the most commonly used anticoagulant, monitored via activated partial thromboplastin time (aPTT) or activated clotting time (ACT). Increasing attention is given to alternative tools like anti-Xa and viscoelastic assays (VEA), which offer potentially more reliable results. Supplementation with antithrombin should be considered if levels fall below 50%-70% to optimize heparin efficacy. Low molecular weight heparin (LMWH) is occasionally used due to its predictable pharmacokinetics, though challenges in dosing and reversal limit its application. Direct thrombin inhibitors, such as bivalirudin, are valuable alternatives, particularly for patients with heparin-induced thrombocytopenia (HIT), though their cost and availability remain barriers. Anticoagulation in ECMO patients is complex, balancing the risks of thrombosis and bleeding. Factors such as patient age, underlying conditions, and ECMO-induced coagulopathies complicate management. Personalized anticoagulation protocols and point-of-care VEA are emerging as effective tools for improving therapy. Routine no-anticoagulation strategies are not recommended unless there are significant bleeding complications. Ongoing research into novel anticoagulants and the long-term impact of anticoagulation on ECMO outcomes is critical. Anticoagulation management in ECMO continues to evolve, focusing on individualized approaches, improved monitoring, and better outcomes. Standardized protocols and further research are essential for optimizing care in this high-risk population.

IntroductionBleeding and thrombotic complications are common in extracorporeal membrane oxygenation (ECMO) patients and are associated with increased mortality and morbidity. The optimal anticoagulation monitoring protocol in these patients is unknown. This study aims to compare the incidence of thrombotic and hemorrhagic complications before and after a protocol change. In addition, the association between hemostatic complications, coagulation tests and risk factors is evaluated.MethodsThis is a retrospective single center cohort study of adult ECMO patients. We collected demographics, ECMO parameters and coagulation test results. Outcomes of the aPTT guided and multimodal protocol, including aPTT, anti-Xa assay and rotational thromboelastometry were compared and the association between coagulation tests, risk factors and hemostatic complications was determined using a logistic regression analysis for repeated measurements.ResultsIn total, 250 patients were included, 138 in the aPTT protocol and 112 in the multimodal protocol. The incidence of thrombosis (aPTT: 14%; multimodal: 12%) and bleeding (aPTT: 36%; multimodal: 40%), did not significantly differ between protocols. In the aPTT guided protocol, the aPTT was associated with thrombosis (Odds Ratio [OR] 1.015; 95% confidence interval [CI] 1.004-1.027). In both protocols, surgical interventions were risk factors for bleeding and thrombotic complications (aPTT: OR 93.2, CI 39.9-217.6; multimodal OR 17.5, CI 6.5-46.9).DiscussionThe incidence of hemostatic complications was similar between both protocols and surgical interventions were a risk factor for hemostatic complications. Results from this study help to elucidate the role of coagulation tests and risk factors in predicting hemostatic complications in patients undergoing ECMO support.

Over 10% of children develop thrombosis after cardiac surgery for congenital heart disease. Children with a single ventricle physiology have the highest risk of thrombosis associated with increased length of the postoperative stay, neurologic complications, and mortality. To decrease these complications, research is needed to understand the mechanisms that promote cardiopulmonary bypass (CPB) surgery-induced thrombin generation and clot formation.

The objective of this pilot observational study was to measure the generation of prothrombotic microvesicles (MVs) and thrombin generation in 21 children collected 5 minutes after initiation of CPB, at the end of CPB, upon arrival in the pediatric congenital cardiac unit (PCCU), and 20 to 24 hours after arrival in the PCCU.

An observational pilot study measured platelet and leukocyte MV, platelet aggregation, coagulation, and thrombin generation in 21 children undergoing CPB surgery. The study setting was a tertiary pediatric hospital. Inclusion criteria included age between birth to 5 years and weight on the day of surgery greater than three kilograms.

Bleeding outcomes were measured by chest tube output and thrombotic outcomes were measured by surveillance ultrasound. Laboratory outcomes of prothrombotic MVs and thrombin generation were measured by high-resolution flow cytometry and calibrated automated thrombogram, respectively.

Time on CPB correlated with a significant increase in WBCs and phosphatidylserine-expressing MVs. Children with single ventricle physiology had increased levels of prothrombotic MVs (p = 0.017), platelet aggregation, peak thrombin (p = 0.019), and d-dimer (p = 0.029) upon arrival to the ICU compared with children with a dual ventricle. Only single ventricle children had a positive correlation between generation of platelet MV with peak thrombin (p = 0.010).

Larger prospective studies are needed to determine if prothrombotic MVs can predict children with congenital heart disease at risk for thrombotic events.

Children assisted with mechanical circulatory support experience bleeding and thrombotic complications that may depend upon anticoagulation strategies. The primary aim of this study was to compare the incidence of thrombotic events in pediatric heart failure patients assisted with mechanical circulatory support with the use of bivalirudin versus heparin anticoagulation. A secondary aim was to compare the percentage of out-of-range partial thromboplastin time values between these anticoagulants.

Retrospective cohort study.

Tertiary pediatric cardiac intensive care unit.

Pediatric patients undergoing mechanical circulatory support for cardiac failure.

None.

A total of 36 pediatric patients on mechanical support treated with either heparin (n.18) or bivalirudin (n.18) during the first 30 days of intensive care unit admission were compared. Bivalirudin group data were retrieved from February 2018 to August 2020 while data on the heparin group were extrapolated from 2015 to 2017. A comparison of anticoagulation was conducted specifically in EXCOR Berlin Heart and extracorporeal membrane oxygenation patients. Berlin Heart patients showed 1 (12.5%) versus 8 (80%) thrombotic episodes in the bivalirudin and heparin groups, respectively (p = 0.005), 0 and 3 (30%) cerebrovascular events, and 0 versus 3 (30%) death episodes, respectively (p = 0.054). In extracorporeal membrane oxygenation patients, the bivalirudin and heparin groups showed 0 versus 1 (8.3%) patient with a thrombosis episode (p = 0.40), 0 and 0 cerebrovascular events, and 5 (50%) versus 3 (25%) death episodes, respectively (p = 0.169). The number of out-of-range partial thromboplastin time values was higher in the heparin group both in Berlin Heart and extracorporeal membrane oxygenation patients (p < 0.0001).

In a cohort of children with heart failure, bivalirudin use was associated with a reduction in thrombotic events in Berlin Heart patients compared with heparin over a period of 30 days.

Thrombosis associated with implants can severely impact therapeutic outcomes and lead to increased morbidity and mortality. Thus, developing blood-contacting materials with superior anticoagulant properties is essential to prevent and mitigate device-related thrombosis. Herein, we propose a novel single-molecule multi-functional strategy for creating blood-compatible surfaces. The synthesized azide-modified Cu-DOTA-(Lys)3 molecule, which possesses both NO release and fibrinolysis functions, was immobilized on material surfaces via click chemistry. Due to the specificity, rapidity, and completeness of click chemistry, the firmly grafted Cu-DOTA-(Lys)3 endows the modified material with excellent antithrombotic properties of vascular endothelium and thrombolytic properties of fibrinolytic system. This surface effectively prevented thrombus formation in both in vitro and in vivo experiments, owing to the synergistic effect of anticoagulation and thrombolysis. Moreover, the modified material maintained its functional efficacy after one month of PBS immersion, demonstrating excellent stability. Overall, this single-molecule multifunctional strategy may become a promising surface engineering technique for blood-contacting materials.

To test feasibility of a randomized controlled trial (RCT) with an endpoint of time at goal anticoagulation in children on extracorporeal membrane oxygenation (ECMO) randomized to receive bivalirudin vs. unfractionated heparin.

Open-label pilot RCT (NCT03318393) carried out 2018-2021.

Single-center quaternary U.S. pediatric hospital.

Children 0 days to younger than 18 years old supported with ECMO in the PICU or cardiovascular ICU.

Randomization to bivalirudin vs. unfractionated heparin while on ECMO.

Sixteen patients were randomized to bivalirudin, and 14 patients were randomized to heparin. There was no difference in the primary outcome, time spent at goal anticoagulation, for patients randomized to bivalirudin compared with those randomized to heparin. While hemorrhagic complications were similar between study groups, thrombotic complications were higher with six of 16 patients in the bivalirudin group having one or more circuit changes compared with 0 of 14 patients in heparin group (mean difference, 37.5% [95% CI, 8.7-61.4%]; p = 0.02). Patients in the bivalirudin group received less packed RBC transfusions vs. those receiving heparin (median [interquartile range], 6.3 mL/kg/d [2.5-8.4 mL/kg/d] vs. 12.2 mL/kg/d [5.5-14.5 mL/kg/d]; p = 0.02).

In this single-center pilot RCT carried out 2018-2021, we found that the test of anticoagulation therapy of bivalirudin vs. heparin during ECMO was feasible. Larger multicenter studies are required to further assess the safety and efficacy of bivalirudin for pediatric ECMO.

With the shift in donor lung allocation from blood type and waiting order to the use of the lung allocation score (LAS) system, there are increasingly more cases of ECMO bridging lung transplantation. However, there are still some problems in case selection, implementation, and management.

We analyzed and summarized a series of data on ECMO bridging lung transplantation through an extensive literature review.

The improvement of the lung transplant allocation system and the progress of ECMO technology have made the ECMO bridge to lung transplant more widely used in clinical practice. The selection of bridge patients is a crucial link in the success of transplantation, and accurate assessment of the patient before transplantation is necessary. The advantages and disadvantages of different bridge strategies exist, and the appropriate bridge strategy should be selected based on the patient's situation. Bleeding and thrombosis complications often occur during ECMO circulation, and there is currently no optimal anticoagulation strategy. The predictive score for bridge post-outcome is still subject to certain limitations.

ECMO bridging lung transplantation is suitable for patients waiting for lung transplantation when other respiratory support is ineffective or when hemodynamic instability occurs the disease is severe and the donor organ is easily obtainable. Patients aged 65 years or older, or have reversible multiple organ dysfunction should not be included as contraindications for ECMO bridging lung transplantation.

Should we rely on anticoagulation monitoring in ECMO patients or simply flip a coin? The increasing use of anti-factor Xa activity to monitor the effect of UFH appears appropriate, given its moderate correlation with the UFH infusion rates, and it may play a role in preventing thromboembolic events. However, to avoid bleeding complications, more sophisticated tools, and careful clinical decision-making remain essential.

Extracorporeal Membrane Oxygenation (ECMO) has become an essential lifesaving intervention for individuals with severe cardiovascular and respiratory failure. Its application is expanding across several therapeutic contexts, surpassing conventional indications. The COVID-19 pandemic has significantly stressed worldwide health systems to manage acute respiratory failure. ECMO has been employed as a vital intervention, particularly for patients with severe COVID-19-induced acute respiratory distress syndrome (ARDS). ECMO is applicable throughout pregnancy. The principal indications for ECMO in pregnant women align with those in the general population. However, pregnancy complicates issues, necessitating consideration of both mother's and infant's well-being. Patients with systemic rheumatic diseases are prone to experience life-threatening complications. While a majority of these patients respond to immunosuppressive drugs, a small percentage suffer organ failure and may benefit from ECMO as a bridge to recovery. The article addresses coagulation therapies, highlighting the necessity of precise anticoagulation to avert both bleeding and thrombosis, particularly in patients requiring extended ECMO support. Additionally, the pharmacokinetics of antibiotics in ECMO patients are summarized, including the influence of the ECMO circuit on drug metabolism. Survey-based research offers valuable insights into ECMO use, procedures, and challenges. The paper evaluates current survey-based research and ECMO guidelines, highlighting clinical practice, training, and resource availability discrepancies across ECMO centers globally. Particular focus is placed on the rehabilitation requirements of ECMO survivors, acknowledging the importance of early mobilization and post-discharge care in improving long-term outcomes and quality of life.

Extracorporeal membrane oxygenation (ECMO) requires systemic anticoagulation to reduce the risk of thromboembolic events. Despite its historic role, activated clotting time (ACT) remains a widely used heparin monitoring method. Systematic evidence on the association of ACT-guided monitoring with hemorrhagic or thromboembolic complications does not exist.

Systematic literature review and meta-analysis (Scopus and PubMed, July 2023).

All cohort studies.

Patients receiving ECMO support.

Anticoagulation monitoring with ACT.

We identified 3,177 publications, with 8 studies reporting the average ACT values for patients with and without bleeding. Meta-analysis revealed no significant difference in the compared groups (SMD = 0.69; 95% CI -0.05 to 1.43, p = 0.069; I2 = 87.4%). Three studies (n = 117 patients) reported on the average ACT values for patients with thrombosis, without significant differences in ACT between patients with and without thrombosis (SMD = 0.47; 95% CI -0.50 to 1.44, p = 0.342; I2 = 81.1%).

Even though ACT is a widely used heparin monitoring tool, the evidence on its association with hemorrhagic or thromboembolic events is still controversial and limited. Further studies are essential to elucidate the role of ACT in anticoagulation monitoring during ECMO support.

Extracorporeal membrane oxygenation (ECMO) is mainly used for support of patients with cardiopulmonary collapse. The increasing use of ECMO has shown promising outcomes; however, it still carries the risk of significant complications. Inferior vena cava (IVC) thrombosis is an underestimated complication.

We described a series of 5 ECMO patients diagnosed with IVC thrombosis in our institution. An electronic literature search of the PubMed, Cochrane Library and Web of Science databases. A total of 12 cases were identified.

The occurrence of IVC thrombosis in ECMO patients is not uncommon. In our case series, elevated CRP and PCT levels and activated partial thromboplastin times (aPTT) of less than 50 s during ECMO operation were observed. In the literature review, a higher proportion of veno-arterial (VA) ECMO application (67%; 8/12) was presented in patients with IVC thrombosis. Eight patients (73%; 8/11) were monitored for anticoagulation using either aPTT or a combination of aPTT and ACT, with all aPTT measurements achieving the target range for anticoagulation. The mainstay of treatment for IVC thrombosis was anticoagulation alone (75%; 9/12). After the treatment, IVC thrombosis disappeared in the majority of patients (75%; 9/12) and there was no thrombosis-related mortality.

Factors such as elevated CRP and PCT levels, low aPTT levels, and the use of VA ECMO may contribute to the development of ECMO-related IVC thrombosis. Monitoring of anticoagulation with aPTT alone or in combination with ACT during ECMO may have inherent limitations. Anticoagulation alone may be an effective treatment for IVC thrombosis.

Extracorporeal membrane oxygenation (ECMO) support of critically ill pediatric patients is associated with increased risk of thromboembolic events, and unfractionated heparin is used commonly for anticoagulation. Given reports of acquired antithrombin (AT) deficiency in this patient population and associated concern for heparin resistance, AT activity measurement and off-label AT replacement have become common in pediatric ECMO centers despite limited optimal dosing regimens. We conducted a retrospective cohort study of pediatric ECMO patients (0 to <18 years) at a single academic center to characterize the pharmacokinetics (PK) of human plasma-derived AT. We demonstrated that a two-compartment turnover model appropriately described the PK of AT, and the parameter estimates for clearance, central volume, intercompartmental clearance, peripheral volume, and basal AT input under non-ECMO conditions were 0.338 dL/h/70 kg, 38.5 dL/70 kg, 1.16 dL/h/70 kg, 40.0 dL/70 kg, and 30.4 units/h/70 kg, respectively. Also, ECMO could reduce bioavailable AT by 50% resulting in 2-fold increase of clearance and volume of distribution. To prevent AT activity from falling below predetermined thresholds of 50% activity in neonates and 80% activity in older infants and children, we proposed potential replacement regimens for each age group, accompanied by therapeutic drug monitoring.

Despite the advancements in extracorporeal membrane oxygenation (ECMO) technology, balancing the prevention of thrombosis and the risk of bleeding in patients on ECMO is still a significant challenge for physicians. This systematic review and meta-analysis aimed to assess the efficacy and safety of viscoelastic point-of-care (POC)-guided coagulation management in adult patients on ECMO.

PubMed Medline, Embase, Scopus, Web of Science, and Cochrane Library databases were searched. After quality assessment, meta-analysis was carried out using random effects model, heterogeneity using I2 and publication bias using Doi and Funnel plots.

A total of 1718 records were retrieved from the searches. Fifteen studies that enrolled a total of 583 participants met the inclusion criteria. Of those, 3 studies enrolling 181 subjects were eligible for meta-analysis. In patients managed with POC-guided algorithms, the odds were coherently lower for bleeding (OR 0.71, 95%CI 0.36-1.42), thrombosis (OR 0.91, 95%CI 0.32-2.60), and in-hospital mortality (OR 0.54, 95%CI 0.29-1.03), but not for circuit change or failure (OR 1.50, 95%CI 0.59-3.83). However, the differences were not statistically significant due to wide 95%CIs.

Viscoelastic POC monitoring demonstrates potential benefits for coagulation management in ECMO patients. Future research should focus on standardizing evidence to improve clinical decision-making.

The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) with registration ID CRD42023486294.

Extracorporeal membrane oxygenation (ECMO) has been widely used as a life support for different kinds of acute cardiopulmonary dysfunction. The present study aimed at presenting the global trend of the top 100 cited original studies related to ECMO.

Bibliometric analysis was the primary methodology for this study. Literature data were collected from Web of Science Core Collection (WoSCC). Indicators were analyzed and visualized by Excel and VOSviewer, the study design, study population, study topic, journal impact factor (IF), Category Rank and Category Quartile, author, country, journal and keywords were included.

The top 100 cited articles were published between 1979 and 2021. With 19 publications, 2020 was the most prolific year. High-income countries or regions, such as the United States of America (USA), France and Canada owned a majority of the articles. Seventeen studies were randomized trials, 52 were finished in single center, and 53 focused on adults. The 100 articles were documented by 31 different journals. The journals were well recognized, with a mean IF2022 of 28.77, a median of 8.8, and a range of 1.6-168.9. The major diseases were viral infection of respiratory system, acute respiratory distress syndrome (ARDS) or respiratory failure, pulmonary hypertension of infants, heart failure/cardiogenic shock, diaphragmatic hernia and cardiac arrest. Specifically, coronavirus disease 2019 (COVID-19) accounted for 72.7% of viral infections. The disease spectrum changed from congenital cardiopulmonary dysfunction to cardiac arrest, ARDS and cardiopulmonary failure, and to severe COVID infection cases. Another fresh hotspot is immune dysfunction.

This bibliometric analysis identified 100 most frequently cited original studies on ECMO and described their characteristics, which may help with further investigations.

Extracorporeal membrane oxygenation (ECMO), as an extracorporeal life support technique, can save the lives of reversible critically ill patients when conventional treatments fail. However, ECMO-related acute organ injury is a common complication that increases the risk of death in critically ill patients, including acute kidney injury, acute brain injury, acute lung injury, and so on. In ECMO supported patients, an increasing number of studies have shown that activation of the inflammatory response plays an important role in the development of acute organ injury. Cross-cascade activation of the complement system, the contact system, and the coagulation system, as well as the mechanical forces of the circuitry are very important pathophysiological mechanisms, likely leading to neutrophil activation and the production of neutrophil extracellular traps (NETs). NETs may have the potential to cause organ damage, generating interest in their study as potential therapeutic targets for ECMO-related acute organ injury. Therefore, this article comprehensively summarized the mechanism of neutrophils activation and NETs formation following ECMO treatment and their actions on acute organ injury.

This study aimed to investigate the relationship between acquired antithrombin deficiency in patients undergoing postcardiotomy extracorporeal membrane oxygenation (PC-ECMO) and thromboembolic or haemorrhagic events such as bleeding, peripheral arterial thromboembolism, and ischemic cerebrovascular events.

The study was designed as a single-center, prospective study and conducted at our hospital between November 2019 and June 2021. 50 patients who underwent ECMO due to postcardiotomy cardiogenic shock were included in the study. Antithrombin (AT) activity testing was performed immediately after ECMO placement and continued for 5 days. The total of haemorrhagic or thromboembolic events was defined as morbidity. The entire patient population was assessed daily for AT measurements according to morbidity status, and ROC analysis was applied to determine the cut-off point. The correlation between clinical outcomes and morbidities with antithrombin levels was analysed.

In our study, we identified a cut-off for AT levels on the first postoperative day. The risk of both bleeding (p = .006) and thromboembolism (p = .012) was significantly higher in patients below the 48.9% cut-off value. AT levels were compared with data on separation from PC-ECMO. The rate of separation from ECMO was 7.969 times higher in cases with AT levels above 51.8 on the third postoperative day and 5.6 times higher in cases with AT levels above 47.5 on the fourth postoperative day.

Acquired antithrombin deficiency may develop in adults undergoing PC-ECMO. In our study, we demonstrated that in patients with low antithrombin levels, the risk of bleeding and thromboembolism increased. Additionally, since AT levels were higher in survivors, this can be considered an indicator of severity. This study is the first prospective study related to determining target antithrombin levels in adult patients undergoing PC-ECMO.

Use of extracorporeal membrane oxygenation (ECMO) for cardiorespiratory failure remains complicated by blood clot formation (thrombosis), triggered by biomaterial surfaces and flow conditions. Thrombosis may result in ECMO circuit changes, cause red blood cell hemolysis, and thromboembolic events. Medical device thrombosis is potentiated by the interplay between biomaterial properties, hemodynamic flow conditions and patient pathology, however, the contribution and importance of these factors are poorly understood because many in vitro models lack the capability to customize material and flow conditions to investigate thrombosis under clinically relevant medical device conditions. Therefore, an ECMO thrombosis-on-a-chip model is developed that enables highly customizable biomaterial and flow combinations to evaluate ECMO thrombosis in real-time with low blood volume. It is observed that low flow rates, decelerating conditions, and flow stasis significantly increased platelet adhesion, correlating with clinical thrombus formation. For the first time, it is found that tubing material, polyvinyl chloride, caused increased platelet P-selectin activation compared to connector material, polycarbonate. This ECMO thrombosis-on-a-chip model can be used to guide ECMO operation, inform medical device design, investigate embolism, occlusion and platelet activation mechanisms, and develop anti-thrombotic biomaterials to ultimately reduce medical device thrombosis, anti-thrombotic drug use and therefore bleeding complications, leading to safer blood-contacting medical devices.

Extracorporeal membrane oxygenation (ECMO) is a type of circulatory life support for patients with severe lung failure. The use of ECMO has increased worldwide since the pandemic of H1N1 in 2009 and more recently SARS-CoV-2 in 2020 both of which caused severe respiratory failure. ECMO patients experience both increased risk of bleeding and thrombosis. This is due to the pathological insult that damages the lungs, the ECMO circuit, coagulopathy, inflammation and anticoagulation. ECMO presents unique demands on the coagulation laboratory both in tests required to manage the patients and result interpretation. This is a personal opinion of 20 years ECMO experience as a clinical scientist and a short current review of the literature. It will focus on the laboratory coagulation tests used to manage ECMO patients, including different anticoagulants used, testing frequency and interpretation of the results.

The initiation of extracorporeal membrane oxygenation (ECMO) triggers complex coagulation processes necessitating systemic anticoagulation. Therefore, anticoagulation monitoring is crucial to avoid adverse events such as thrombosis and hemorrhage. The main aim of this work was to analyze the association between anti-Xa levels and thrombosis occurrence during ECMO support.

Systematic literature review and meta-analysis (Scopus and PubMed, up to July 29, 2023).

All retrospective and prospective studies.

Patients receiving ECMO support.

Anticoagulation monitoring during ECMO support.

A total of 16 articles with 1,968 patients were included in the review and 7 studies in the meta-analysis (n = 374). Patients with thrombosis had significantly lower mean anti-Xa values (standardized mean difference -0.36, 95% confidence interval [CI] -0.62 to -0.11, p < 0.01). Furthermore, a positive correlation was observed between unfractionated heparin infusion and anti-Xa levels (pooled estimate of correlation coefficients 0.31, 95% CI 0.19 to 0.43, p < 0.001). The most common adverse events were major bleeding (42%) and any kind of hemorrhage (36%), followed by thromboembolic events (30%) and circuit or oxygenator membrane thrombosis (19%). More than half of the patients did not survive to discharge (52%).

This work revealed significantly lower levels of anti-Xa in patients experiencing thromboembolic events and a positive correlation between anti-Xa and unfractionated heparin infusion. Considering the contemplative limitations of conventional monitoring tools, further research on the role of anti-Xa is warranted. New trials should be encouraged to confirm these findings and determine the most suitable monitoring strategy for patients receiving ECMO support.

Cardiopulmonary bypass and extracorporeal membrane oxygenation have many similarities, but there are significant differences in managing hemostasis. Cardiopulmonary bypass includes shorter mechanical circulatory support times, blood stasis, higher flows, and an increased blood-air interface. These factors cause differences in the risk of coagulopathy, management of anticoagulation, monitoring of the hemostatic system, and management of coagulopathy. This article aims to identify these key differences in the hemostatic system between patients on cardiopulmonary bypass and those on extracorporeal membrane oxygenation.

To derive systematic-review informed, modified Delphi consensus regarding the medications used for anticoagulation for pediatric extracorporeal membrane oxygenation (ECMO) for the Pediatric ECMO Anticoagulation CollaborativE (PEACE).

A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021.

Included studies assessed anticoagulation used in pediatric ECMO.

Two authors reviewed all citations independently, with a third reviewer adjudicating any conflicts. Eighteen references were used for data extraction as well as for creation of recommendations. Evidence tables were constructed using a standardized data extraction form.

Risk of bias was assessed using the Quality in Prognosis Studies tool. The evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation system. Forty-eight experts met over 2 years to develop evidence-informed recommendations and, when evidence was lacking, expert-based consensus statements, or good practice statements for anticoagulation during pediatric ECMO. A web-based modified Delphi process was used to build consensus via the Research and Development/University of California Appropriateness Method. Consensus was based on a modified Delphi process with agreement defined as greater than 80%. Two recommendations, two consensus statements, and one good practice statement were developed, and, in all, agreement greater than 80% was reached.

There is insufficient evidence to formulate optimal anticoagulation therapy during pediatric ECMO. Additional high-quality research is needed to inform evidence-based practice for anticoagulation during pediatric ECMO.

Bleeding and thrombotic complications compromise outcomes in patients undergoing percutaneous mechanical circulatory support (pMCS) with veno-arterial extracorporeal membrane oxygenation (V-A ECMO) and/or microaxial flow pumps like Impella™. Antithrombotic practices are an important determinant of the coagulopathic risk, but standardization in the antithrombotic management during pMCS is lacking. This survey outlines European practices in antithrombotic management in adults on pMCS, making an initial effort to standardize practices, inform future trials, and enhance outcomes.

This online cross-sectional survey was distributed through digital newsletters and social media platforms by the Association of Acute Cardiovascular Care and the European branch of the Extracorporeal Life Support Organization. The survey was available from 17 April 2023 to 23 May 2023. The target population were European clinicians involved in care for adults on pMCS. We included 105 responses from 26 European countries. Notably, 72.4% of the respondents adhered to locally established anticoagulation protocols, with unfractionated heparin (UFH) being the predominant anticoagulant (Impella™: 97.0% and V-A ECMO: 96.1%). A minority of the respondents, 10.8 and 14.5%, respectively, utilized the anti-factor-Xa assay in parallel with activated partial thromboplastin time for UFH monitoring during Impella™ and V-A ECMO support. Anticoagulant targets varied across institutions. Following acute coronary syndrome without percutaneous coronary intervention (PCI), 54.0 and 42.7% were administered dual antiplatelet therapy during Impella™ and V-A ECMO support, increasing to 93.7 and 84.0% after PCI.

Substantial heterogeneity in antithrombotic practices emerged from participants' responses, potentially contributing to variable device-associated bleeding and thrombotic complications.

The use of extracorporeal membrane oxygenation (ECMO) is associated with complex hemostatic changes. Systemic anticoagulation is initiated to prevent clotting in the ECMO system, but this comes with an increased risk of bleeding. Evidence on the use of anti-Xa-guided monitoring to prevent bleeding during ECMO support is limited. Therefore, we aimed to analyze the association between anti-factor Xa-guided anticoagulation and hemorrhage during ECMO.

A systematic review and meta-analysis was performed (up to August 2023).

CRD42023448888.

Twenty-six studies comprising 2293 patients were included in the analysis, with six works being part of the meta-analysis. The mean anti-Xa values did not show a significant difference between patients with and without hemorrhage (standardized mean difference -0.05; 95% confidence interval [CI]: -0.19; 0.28, p = .69). We found a positive correlation between anti-Xa levels and unfractionated heparin dose (UFH; pooled estimate of correlation coefficients 0.44; 95% CI: 0.33; 0.55, p < .001). The most frequent complications were any type of hemorrhage (pooled 36%) and thrombosis (33%). Nearly half of the critically ill patients did not survive to hospital discharge (47%).

The most appropriate tool for anticoagulation monitoring in ECMO patients is uncertain. Our analysis did not reveal a significant difference in anti-Xa levels in patients with and without hemorrhagic events. However, we found a moderate correlation between anti-Xa and the UFH dose, supporting its utilization in monitoring UFH anticoagulation. Given the limitations of time-guided monitoring methods, the role of anti-Xa is promising and further research is warranted.

Direct thrombin inhibitors, including argatroban, are increasingly used for anticoagulation during venovenous extracorporeal membrane oxygenation (VV ECMO). In many centers activated partial thromboplastin time (aPTT) is used for monitoring, but it can be affected by several confounders. The aim of this study was to evaluate the safety and efficacy of anticoagulation with argatroban titrated according to diluted thrombin time targets (hemoclot™ assay) compared to anti-Xa guided anticoagulation with unfractionated heparin (UFH).

This cohort study included adults at two tertiary care centers who required VV ECMO for severe COVID-19-related acute respiratory distress syndrome (CARDS). Patients received center-dependent argatroban or UFH for anticoagulation during ECMO. Argatroban was guided following a hemoclot™ target range of 0.4-0.6 μg/ml. UFH was guided by anti-factor Xa (antiXa) levels (0.2-0.3 IU/ml). The primary outcome was safety of argatroban compared to UFH, assessed by time to first clinically relevant bleeding event or death during ECMO. Secondary outcomes included efficacy (time to thromboembolism) and feasibility (proportion of anticoagulation targets within range).

From 2019 to 2021 57 patients were included in the study with 27 patients (47 %) receiving argatroban and 30 patients (53 %) receiving UFH. The time to the first clinically relevant bleeding or death during ECMO was similar between groups (HR (argatroban vs. UFH): 1.012, 95 % CI 0.44-2.35, p = 0.978). Argatroban was associated with a decreased risk for thromboembolism compared to UFH (HR 0.494 (95 % CI 0.26-0.95; p = 0.034)). The overall proportion of anticoagulation within target ranges was not different between groups (46 % (23-54 %) vs. 46 % (37 %-57 %), p = 0.45).

Anticoagulation with argatroban according to hemoclot™ targets (0.4-0.6 μg/ml) compared to antiXa guided UFH (0.2-0.3 IU/ml) is safe and may prolong thromboembolism-free time in patients with severe ARDS requiring VV ECMO.

Extracorporeal membrane oxygenation (ECMO) serves as cardiopulmonary therapy in critically ill patients with respiratory/heart failure and often necessitates multiple blood product transfusions. The administration of platelet transfusions during ECMO is triggered by the presence or risk of significant bleeding. Most paediatric ECMO programmes follow guidelines that recommend a platelet transfusion threshold of 80-100 × 109/L. To reduce exposure to platelets, we developed a practice to dynamically lower the threshold to ~20 × 109/L. We describe our experience with patient-tailored platelet thresholds and related bleeding outcomes.

We retrospectively evaluated our platelet transfusion policy, bleeding complications and patient outcome in 229 ECMO-supported paediatric patients in our unit.

We found that more than 97.4% of patients had a platelet count <100 × 109/L at some point during their ECMO course. Platelets were transfused only on 28.5% of ECMO days; and 19.2% of patients never required a platelet transfusion. The median lowest platelet count in children who had bleeding events was 25 × 109/L as compared to 33 × 109/L in children who did not bleed (p < 0.001). Our patients received fewer platelet transfusions and did not require more red blood cell transfusions, nor did they experience more haemorrhagic complications.

We have shown that a restrictive, 'patient-tailored' rather than 'goal-directed' platelet transfusion policy is feasible and safe, which can greatly reduce the use of platelet products. Although there was a difference in the lowest platelet counts in children who bled versus those who did not, the median counts were much lower than current recommendations.

Due to the risk of thrombosis, nearly all children supported by extracorporeal membrane oxygenation (ECMO) receive systemic anticoagulation. While heparin has traditionally been used, there are reports of increased use of direct thrombin inhibitors. We sought to describe the use of anticoagulation in children supported by ECMO in the United States using a large administrative database.

We performed a retrospective cohort study of children supported by ECMO within the Pediatric Health Information System (PHIS) database. Pediatric encounters involving ECMO from 2012 to 2020 were identified. Data regarding demographics, diagnoses, anticoagulation, complications, and outcomes were extracted for eligible encounters.

Eleven thousand five hundred ninety-five encounters that involved ECMO were identified. Fifty-four percent were male with an age range of 0-17 years and a median (IQR) age of 0 (0-2) years. Unfractionated heparin (UFH) only was used in 94% (95% CI: 93.6-94.5%) of encounters and UFH followed by bivalirudin in 5% (95% CI: 4.3-5.1%) of cases. There was a significant difference in the use of bivalirudin from 2012 to 2020 (p < 0.001). Differences in anticoagulation regimens were observed between infants and children (p = 0.004) and between those with and without cardiac indications for ECMO (p < 0.001). Four percent (95% CI: 4.1-4.8%) of encounters were associated with diagnostic coding for thrombosis and differences in occurrence of thrombosis were observed between different anticoagulant regimens (p < 0.001).

Though the majority of children on ECMO in the United States receive heparin anticoagulation, there is an increase in use of direct thrombin inhibitors. Prospective studies must evaluate the efficacy of different anticoagulants in this patient population.

To evaluate a restrictive transfusion policy of red blood cells (RBC) and platelets in pediatric patients submitted to extracorporeal membrane oxygenation (ECMO).

Retrospective descriptive study of pediatric patients supported with ECMO, from January 2010 to December 2019. Hemoglobin, platelet, lactate and mixed venous oxygen saturation (SvO2) values of each patient while on ECMO, were collected. Transfusion efficiency and tissue oxygenation were statistically evaluated comparing pre-transfusion hemoglobin, lactate and SvO2 with post-transfusion values. Ranges of hemoglobin and platelets were established, and the number of transfusions registered. The bleeding complications and outcome were documented.

Of a total of 1016 hemoglobin values, the mean value before transfusion was 8.6 g/dl. Hemoglobin and SvO2 increased significantly post-transfusion. Red blood cell transfusion varied with hemoglobin values: when hemoglobin value was less than 7 g/dl, 89% (41/46) were transfused but just 23% (181/794) when greater or equal to 7 g/dl. In the presence of active bleeding, the frequency of RBC transfusion increased from 32% to 62%, with hemoglobin between 7 g/dl and 8 g/dl.The mean value for platelet transfusion was 32 x 109/L. Thirty-eight (43%) platelet values between 20 x 109/L and 30x109/L, and 31 (40%) between 30 x 109/L and 40 x 109/L led to platelet transfusion; between 40 x 109/L and 50 x 109/L, only 7 (9%) prompted platelet transfusion.Comparing the 2010-2015 to 2016-2019 periods there was a decrease in RBC and platelet transfusion threshold with similar survival (p = .528). Survival to discharge was 68%.

Using a restrictive RBC and platelet transfusion policy was safe and allowed a good outcome in this case series. The presence of active bleeding was an important decision factor when hemoglobin was above 7 g/dl and platelets were above 30 x 109/L.

Extracorporeal Membrane Oxygenation (ECMO) is an important tool for managing critically ill neonates. Bleeding and thrombotic complications are common and significant. An understanding of ECMO physiology, its interactions with the unique neonatal hemostatic pathways, and appreciation for the distinctive risks and benefits of neonatal transfusion as it applies to ECMO are required. Currently, there is variability regarding transfusion practices, related to changing norms and a lack of high-quality literature and trials. This review provides an analysis of the neonatal ECMO transfusion literature and summarizes available best practice guidelines.

Since its first success in 1975, extracorporeal membrane oxygenation (ECMO) has been used with increasing frequency for pulmonary and cardiopulmonary bypass. Use in adults has increased exponentially since the early 2000s, but despite thousands of international cannulations using both veno-arterial (VA) and veno-venous (VV) ECMO, there are still significant hemocompatibility-related adverse events. Current management of anticoagulation has been based on the Extracorporeal Life Support Organization guidance published in 2014 with recent updates published in 2022. Despite this guidance, there is still limited international consensus on how to manage anticoagulation in ECMO. For this review, we completed a comprehensive search of multiple electronic databases to identify studies pertaining to anticoagulation of adult patients on VV or VA-ECMO. The highest priority was given to sources that were prospective, randomized, controlled studies, but in the absence of such resources, observational studies, retrospective uncontrolled studies, and case series/reports were considered for inclusion. This document serves to provide a comprehensive review of the current understanding of management pertaining to anticoagulation relating to ECMO.

Extracorporeal membrane oxygenation (ECMO) is a vital technique for severe respiratory or heart failure patients. Bleeding and thrombotic events are common during ECMO and negatively impact patient outcomes. Unfractionated heparin is the primary anticoagulant, but its adverse effects limit its use, necessitating alternative anticoagulants.

Review available alternative anticoagulants for adult ECMO patients. Explore potential novel anticoagulants for future ECMO use. Aim to reduce complications (bleeding and thrombosis) and improve safety and efficacy for critically ill ECMO patients.

Comprehensive literature review of existing and emerging anticoagulants for ECMO.

Identified a range of alternative anticoagulants beyond unfractionated heparin. Evaluated their potential utility in mitigating ECMO-related complications.

Diverse anticoagulant options are available and under investigation for ECMO. These alternatives may enhance patient safety and outcomes during ECMO support. Further research and clinical studies are warranted to determine their effectiveness and safety profiles.

The optimal method for monitoring of anticoagulation in patients on extracorporeal life support (ECLS) is unknown. The objective of this study was to assess the relationship between anti-factor Xa level (anti-Xa; IU/mL) and activated partial thromboplastin time (aPTT; seconds) for monitoring intravenous unfractionated heparin anticoagulation in adult ECLS patients.

Charts of all adult patients cannulated for ECLS from 2015 through 2017 were reviewed and laboratory and heparin infusion data were extracted for analysis. Time matched pairs of anti-Xa and aPTT were considered concordant if both laboratory values were within the same clinically utilized range. A hierarchical logistic regression model was used to determine factors associated with discordance while accounting for patient level effects.

A total of 1016 paired anti-Xa and aPTT values from 65 patients were evaluated. 500 (49.2%) paired samples were discordant with a degree of variability on linear regression (r2 = 0.315). The aPTT fell into a higher therapeutic range compared to the anti-Xa in 31.6% and lower in 17.3%. Logistic regression demonstrated that discordance was independently associated with time from initiation of ECLS (OR 1.17 per day, p < 0.001), average heparin infusion rate (OR 1.25 per U/kg/hr, p < 0.001), and INR (OR 3.22, p < 0.001).

Nearly half of all aPTT and anti-Xa values were in discordant ranges and discordance is more likely as the time on ECLS and the INR level increase. The use of either assay in isolation to guide heparin anticoagulation may lead to misestimation of the degree of anticoagulation in complex ECLS patients.

Extracorporeal membrane oxygenation (ECMO) is used in children with cardiopulmonary failure. While the majority of ECMO centers use unfractionated heparin, other anticoagulants, including factor XI and factor XII inhibitors are emerging, which may prove suitable for ECMO patients. However, before these anticoagulants can be applied in these patients, baseline data of FXI and FXII changes need to be acquired.

This study aimed to describe the longitudinal profile of FXI and FXII antigenic levels and function before, during, and after ECMO in children.

This is a prospective observational study in neonatal and pediatric patients with ECMO (<18 years). All patients with venoarterial ECMO and with sufficient plasma volume collected before ECMO, on day 1 and day 3, and 24 hours postdecannulation were included. Antigenic levels and functional activity of FXI and FXII were determined in these samples. Longitudinal profiles of these values were created using a linear mixed model.

Sixteen patients were included in this study. Mean FXI and FXII antigenic levels (U/mL) changed from 7.9 and 53.2 before ECMO to 6.0 and 34.5 on day 3 and they recovered to 8.8 and 39.4, respectively, after stopping ECMO. Function (%) of FXI and FXII decreased from 59.1 and 59.0 to 49.0 and 50.7 on day 3 and recovered to 66.0 and 54.4, respectively.

This study provides the first insights into changes of the contact pathway in children undergoing ECMO. FXI and FXII antigen and function change during ECMO. Results from this study can be used as starting point for future contact pathway anticoagulant studies in pediatric patients with ECMO.

Heparin resistance is a common complication of surgical patients requiring anticoagulation, such as those undergoing cardiopulmonary bypass (CPB). Treatments to address heparin resistance include supplementation of antithrombin (AT) or fresh frozen plasma (FFP). This retrospective database analysis compared key outcomes in suspected heparin-resistant patients undergoing CPB treated with AT or FFP.

De-identified United States electronic health records (Cerner Health Facts®) were queried. International Classification of Diseases (ICD-9/10) codes were used to determine CPB procedures and FFP administration. AT administration was identified using medication data, while a combination of lab and medication data examining activated clotting times detected heparin resistance in FFP patients. Adult inpatients (≥18 years old) seen between 2001 and 2018 were included. Differences in mortality, intensive care unit (ICU) length of stay (LOS), and hospital-free days (using a 30-day post-discharge period) were assessed with univariate models as well as adjusted logistic regression models controlling for patient characteristics and Charlson Comorbidity Index (CCI) scores.

Of the 502 patients identified, 247 received AT and 255 received FFP. The FFP cohort was associated with a higher CCI compared to the AT cohort (3.3 ± 2.4 vs. 2.3 ± 2.0, P < .001). The AT cohort was associated with a 71% (Odds Ratio [OR]: 0.29, 95% Confidence Interval [CI]: P = .003) and 66% (OR: 0.34, 95% CI: P = .01) reduction in mortality when compared to FFP using univariate and adjusted logistic regression models, respectively. Similarly, use of AT also showed a 22% shorter ICU LOS (P = .02) and 10% more hospital-free days in the 30 days following discharge (P = .004) according to the univariate models, though statistical significance was absent within adjusted models in both ICU LOS (P = .08) and hospital-free days (P = .53).

Compared to FFP, AT use suggests a reduction in the odds of mortality in suspected heparin-resistant patients undergoing CPB, though larger prospective studies are necessary to elucidate potential differences in hospital-free days or ICU LOS across treatment modalities.

To achieve optimal hemostatic balance in patients on extracorporeal membrane oxygenation (ECMO), a liberal transfusion practice is currently applied despite clear evidence. We aimed to give an overview of the current use of plasma, fibrinogen concentrate, tranexamic acid (TXA), and prothrombin complex concentrate (PCC) in patients on ECMO.

A prespecified subanalysis of a multicenter retrospective study. Venovenous (VV)-ECMO and venoarterial (VA)-ECMO are analyzed as separate populations, comparing patients with and without bleeding and with and without thrombotic complications.

Sixteen international ICUs.

Adult patients on VA-ECMO or VV-ECMO.

None.

Of 420 VA-ECMO patients, 59% (n = 247) received plasma, 20% (n = 82) received fibrinogen concentrate, 17% (n = 70) received TXA, and 7% of patients (n = 28) received PCC. Fifty percent of patients (n = 208) suffered bleeding complications and 27% (n = 112) suffered thrombotic complications. More patients with bleeding complications than patients without bleeding complications received plasma (77% vs. 41%, p < 0.001), fibrinogen concentrate (28% vs 11%, p < 0.001), and TXA (23% vs 10%, p < 0.001). More patients with than without thrombotic complications received TXA (24% vs 14%, p = 0.02, odds ratio 1.75) in VA-ECMO, where no difference was seen in VV-ECMO. Of 205 VV-ECMO patients, 40% (n = 81) received plasma, 6% (n = 12) fibrinogen concentrate, 7% (n = 14) TXA, and 5% (n = 10) PCC. Thirty-nine percent (n = 80) of VV-ECMO patients suffered bleeding complications and 23% (n = 48) of patients suffered thrombotic complications. More patients with than without bleeding complications received plasma (58% vs 28%, p < 0.001), fibrinogen concentrate (13% vs 2%, p < 0.01), and TXA (11% vs 2%, p < 0.01).

The majority of patients on ECMO receive transfusions of plasma, procoagulant products, or antifibrinolytics. In a significant part of the plasma transfused patients, this was in the absence of bleeding or prolonged international normalized ratio. This poses the question if these plasma transfusions were administered for another indication or could have been avoided.

Pediatric extracorporeal membrane oxygenation is an increasingly utilized, life-saving technology with high mortality and morbidity. A complex technology employed urgently or emergently for some of the sickest children in the hospital by a large multidisciplinary team, ECMO is an ideal area for using quality improvement strategies to reduce the variability in care and improve patient outcomes. We review critical concepts from quality improvement and apply them to patient selection and management, staffing, credentialing and continuing education, and the variability of management among providers and institutions.

Low-molecular-weight heparin (LMWH) is an anticoagulant used to prevent clotting during blood purification treatments. This study aimed to evaluate the clinical use of the anti-factor Xa level (anti-Xa) for monitoring LMWH anticoagulant levels during intermittent venovenous hemofiltration (IVVHF). This prospective observational study enrolled patients who required IVVHF for renal failure in Beijing Hospital between May 2019 and February 2021. The LMWH anticoagulation was assessed by the coagulation grade of the filter and line. One hundred and ten participants were included. There were 90 patients with a filter and line coagulation grade of ≤ 1 and 20 patients with grade > 1. The anti-Xa level of 0.2 IU/mL was a critical value. The multivariable logistic regression analysis showed that anti-Xa level > 0.2 IU/mL (odd ratio [OR] = 2.263; 95% CI: 1.290-4.871, P = 0.034) and cardiovascular disease (OR = 10.028; 95% CI: 1.204-83.488; P = 0.033) were independently associated with the coagulation grade of the filter and line. Anti-Xa level could monitor LMWH anticoagulation during IVVHF.