Evaluation of an aPTT guided versus a multimodal heparin monitoring approach in patients on extra corporeal membrane oxygenation: A retrospective cohort study.

INTRODUCTION: Bleeding 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. METHODS: This 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. RESULTS: In 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). DISCUSSION: The 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.

Acquired von Willebrand disease in children undergoing extracorporeal membrane oxygenation: a prospective observational study.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) provides cardiopulmonary support for children with severe cardiac and/or pulmonary failure. The incidence of bleeding complications during ECMO support is high. Acquired von Willebrand disease (AVWD) might contribute to the development of bleeding complications. OBJECTIVE: To study the incidence and longitudinal profile of AVWD during the first 14 days of ECMO support in children and to investigate the association between AVWD and bleeding complications. METHODS: This prospective observational study included pediatric patients (0-17 years) receiving ECMO. Blood was sampled prior to and after ECMO start, daily and 12 to 24 hours after stopping ECMO. von Willebrand factor (VWF) parameters and multimer patterns were determined. Clinical data were collected for each patient. AVWD was defined as loss of high-molecular weight multimers (ie, decreased compared with baseline) or a VWF:collagen binding/VWF: antigen (Ag) ratio or VWF:activity/VWF:Ag ratio below 0.7. RESULTS: All of 50 (100%) patients developed AVWD during ECMO. The VWF:collagen binding /VWF:Ag ratio, VWF:activity/VWF:Ag ratio, and high-molecular weight multimers decreased during the initial days and recovered to baseline level within 24 hours after stopping ECMO. The incidence and longitudinal profile of AVWD were similar in patients with and without major bleeding complications. CONCLUSION: Children receiving ECMO support commonly develop AVWD. AVWD develops rapidly after ECMO initiation and recovers quickly after ECMO cessation. Importantly, AVWD appears to be independent of major bleeding.

Bacteria in Extracorporeal Membrane Oxygenation Circuit Clots of a Patient With Persistent Bacteremia: A Case Report.

A neonate with pulmonary hypertension was supported with extracorporeal membrane oxygenation (ECMO). During ECMO support, the patient developed Enterococcus faecalis bacteremia, treated with targeted antibiotics. Despite the maximum dose of antibiotics, routine blood cultures remained positive throughout the ECMO treatment. A circuit change was performed due to buildup of thrombotic material and disseminated intravascular coagulation (DIC) inside the circuit. Thrombus formation was more extensive in the first than the second circuit. Gram-positive diplococci were present in all initial circuit clots and gram-positive masses surrounded by fibrin were found inside thrombi of the second circuit. Scanning electron microscopy (SEM) revealed a dense fibrin network with embedded red blood cells and bacteria in the first circuit. In the second circuit, SEM analysis revealed scattered micro thrombi. Polymerase chain reaction for identification of bacteria in the thrombus of the first circuit showed the same bacteria as found in blood cultures and did not achieve a sufficient signal in the second circuit. This case report shows that bacteria can nestle in thrombi of an ECMO circuit and that there is a rationale for a circuit change in a patient with persistent positive blood cultures and DIC.

Factors XI and XII in extracorporeal membrane oxygenation: longitudinal profile in children.

Background: 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. Objectives: This study aimed to describe the longitudinal profile of FXI and FXII antigenic levels and function before, during, and after ECMO in children. Methods: 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. Results: 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. Conclusion: 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.

Coagulation in pediatric extracorporeal membrane oxygenation: A systematic review of studies shows lack of standardized reporting.

Objectives: Extracorporeal membrane oxygenation (ECMO) involves complex coagulation management and frequent hemostatic complications. ECMO practice between centers is variable. To compare results between coagulation studies, standardized definitions and clear documentation of ECMO practice is essential. We assessed how study population, outcome definitions, and ECMO-, coagulation-, and transfusion-related parameters were described in pediatric ECMO studies. Data sources: Embase, Medline, Web of Science, Cochrane Library and Google Scholar. Study selection: English original studies of pediatric ECMO patients describing hemostatic tests or outcome. Data extraction: Eligibility was assessed following PRISMA guidelines. Study population, outcome and ECMO-, coagulation, and transfusion parameters were summarized. Data synthesis: A total of 107 of 1312 records were included. Study population parameters most frequently included (gestational) age (79%), gender (60%), and (birth) weight (59%). Outcomes, including definitions of bleeding (29%), thrombosis (15%), and survival (43%), were described using various definitions. Description of pump type, oxygenator and cannulation mode occurred in 49%, 45%, and 36% of studies, respectively. The main coagulation test (53%), its reference ranges (49%), and frequency of testing (24%) were the most prevalent reported coagulation parameters. The transfusion thresholds for platelets, red blood cells, and fibrinogen were described in 27%, 18%, and 18% of studies, respectively. Conclusions: This systematic review demonstrates a widespread lack of detail or standardization of several parameters in coagulation research of pediatric ECMO patients. We suggest several parameters that might be included in future coagulation studies. We encourage the ECMO community to adopt and refine this list of parameters and to use standardized definitions in future research.

Use of rotational thromboelastometry to predict hemostatic complications in pediatric patients undergoing extracorporeal membrane oxygenation: A retrospective cohort study.

BACKGROUND: The incidence of hemostatic complications in pediatric patients undergoing extracorporeal membrane oxygenation (ECMO) is high. The optimal anticoagulation strategy in children undergoing ECMO is unknown. OBJECTIVES: To study the association between hemostatic complications, coagulation tests, and clinical parameters in pediatric patients undergoing ECMO and their effect on survival. METHODS: We performed a retrospective cohort study of pediatric patients undergoing centrifugal pump ECMO. Collected data included patient characteristics, risk factors, and coagulation test results. Statistical analysis was done using logistic regression analysis for repeated measurements. Dependent variables were thrombosis and bleeding, independent variables were rotational thromboelastometry (ROTEM), activated partial thromboplastin time (aPTT) and antifactor-Xa assay (aXa) results, ECMO duration, age <29 days, sepsis and surgery. RESULTS: Seventy-three patients with 623 ECMO days were included. Cumulative incidences of thrombosis and bleeding were 43.5% (95% confidence interval [CI], 26.0%-59.8%) and 25.4% (95% CI, 13.4%-39.3%), respectively. A lower maximum clot firmness of intrinsic ROTEM (INTEM; odds ratio [OR], 0.946; 95% CI, 0.920-0.969), extrinsic ROTEM (OR, 0.945; 95% CI, 0.912-0.973), and INTEM with heparinase (OR, 0.936; 95% CI, 0.896-0.968); higher activated partial thromboplastin time aPTT; OR, 1.020; 95% CI, 1.006-1.024) and age <29 days (OR, 2.900; 95% CI, 1.282-6.694); surgery (OR, 4.426; 95% CI, 1.543-12.694); and longer ECMO duration (OR, 1.149; 95% CI, 1.022-1.292) significantly increased thrombotic risk. Surgery (OR, 2.698; 95% CI, 1.543-12.694) and age <29 days (OR 2.242, 95% CI 1.282-6.694) were significantly associated with major bleeding. Patients with hemostatic complications had significantly decreased survival to hospital discharge (P = .009). CONCLUSION: The results of this study help elucidate the role of ROTEM, aPTT, anti-factor Xa, and clinical risk factors in predicting hemostatic complications in pediatric patients undergoing ECMO.

Challenges in Maintaining the Hemostatic Balance in Children Undergoing Extracorporeal Membrane Oxygenation: A Systematic Literature Review.

Background: Despite advances in technology and clinical experience, the incidence of hemostatic complications, including bleeding and thrombosis, remains high in children supported with extracorporeal membrane oxygenation (ECMO). These hemostatic complications are important to prevent, since they are associated with increased morbidity and mortality. This systematic literature review aims to outline the most important risk factors for hemostatic complications in children undergoing ECMO treatment, to summarize the reported alternative anticoagulant drugs used in pediatric ECMO and to describe studied associations between coagulation tests and hemostatic complications. Methods: A literature search was performed in Embase, Medline, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, and Google Scholar in February 2020. Included studies were studies evaluating children (<18 years old) treated with ECMO, and studies evaluating risk factors for hemostatic complications, alternative anticoagulants, or the association between coagulation tests and hemostatic complications. Results: Out of 1,152 articles, 35 studies were included. Thirteen out of 49 risk factors were investigated in three or more studies. Most consistent results were found regarding ECMO duration and pH. However, evidence for risk factors was equivocal in the majority of studies, which is explained by the variability of populations studied, definitions of hemostatic complications, ECMO circuits, anticoagulation protocols, transfusion triggers and monitoring of anticoagulation. Five studies described alternative anticoagulants, including bivalirudin (n = 3), argatroban (n = 1) and FUT (n = 1). Higher anti-factor Xa levels were associated with less clotting events in one of nine studies, investigating the association between tests and hemostatic complications. Two studies revealed an association between anti-factor Xa assay-based protocols and a decreased number of transfusions, bleedings and need for circuit change. Conclusion: Studies regarding risk factors showed conflicting results and a few retrospective studies reported the use of new anticoagulants and data on coagulation tests in relation to hemostatic complications. To decrease hemostatic complications in ECMO children, prospective multicenter studies are needed with clear bleeding and thrombotic definitions, and the best possible standardization of ECMO circuits used, anticoagulation protocols, and transfusion triggers.