The Changing Landscape of Anticoagulation in Pediatric Extracorporeal Membrane Oxygenation: Use of the Direct Thrombin Inhibitors.

Bleeding and thrombosis frequently occur in pediatric patients with extracorporeal membrane oxygenation (ECMO) therapy. Until now, most patients are anticoagulated with unfractionated heparin (UFH). However, heparin has many disadvantages, such as binding to other plasma proteins and endothelial cells in addition to antithrombin, causing an unpredictable response, challenging monitoring, development of heparin resistance, and risk of heparin-induced thrombocytopenia (HIT). Direct thrombin inhibitors (DTIs), such as bivalirudin and argatroban, might be a good alternative. This review will discuss the use of both UFH and DTIs in pediatric patients with ECMO therapy.

Effectiveness and Safety of Nadroparin Therapy in Preterm and Term Neonates with Venous Thromboembolism.

INTRODUCTION: Optimal neonatal nadroparin dosages to treat venous thromboembolism (VTE) are unknown. OBJECTIVE: To evaluate therapeutic nadroparin dosages to reach therapeutic target ranges (TTR: 0.5-1.0 International Unit (IU)/mL) and the effectiveness and safety of nadroparin in neonatal VTE. METHODS: Retrospective study including neonates with VTE on nadroparin in a tertiary center between 2007 and 2018. Two groups were distinguished: neonates before (group 1) and after (group 2) switch to higher starting dosages in 2014. RESULTS: Sixty-one neonates (44 preterm, 17 term) with 64 VTEs were included. TTR was reached in 32/64 (50%) VTEs (group 1: 35.7%; group 2: 61.1%). Median nadroparin dosage to reach TTR was 197 (97.9-330.3) IU/kg/12 h. No therapy-related deaths occurred. Recurrent VTE developed in 6 (9.8%) neonates. Complete clot resolution was observed in 31/41 (75.6%) VTEs. TTR was reached in 58.1% VTEs with complete clot resolution. No major bleeding occurred. Non-major clinically relevant bleedings occurred in 3/64 (4.7%) VTEs, consisting of large hematomas due to the use of subcutaneous catheters. CONCLUSIONS: High nadroparin dosages are needed to reach TTR in neonates, which seem to be safe. Clot resolution may occur without reaching TTR. Subcutaneous catheters may cause important bleeding complications.

Coagulation complications after conversion from roller to centrifugal pump in neonatal and pediatric extracorporeal membrane oxygenation.

BACKGROUND/PURPOSE: Coagulation complications are frequent, unwanted occurrences in extracorporeal membrane oxygenation (ECMO) treatment, possibly influenced by the pump in the ECMO-circuit. We hypothesized that fewer complications would occur with a smaller, heparin-coated ECMO system with a centrifugal pump (CP) than with one with a roller pump (RP) and that after conversion, complication rates would decrease over time. METHODS: This single-center, retrospective chart study included all first neonatal and pediatric ECMO runs between 2009 and 2015. Differences between groups were assessed with Mann-Whitney U tests and Kruskal-Wallis tests. Determinants of complication rates were evaluated through Poisson regression models. The CP group was divided into three consecutive groups to assess whether complication rates decreased over time. RESULTS: The RP group comprised 90 ECMO runs and the CP group 82. Hemorrhagic complication rates were significantly higher with the CP than with the RP, without serious therapeutic consequences, while thrombotic complications rates were unaffected. Intracranial hemorrhage rates and coagulation-related mortality rates were similar. Gained experience with the CP did not improve complication rates or survival over time. CONCLUSIONS: Although the CP seems safe, it does not seem beneficial over the RP. Further research is warranted on how pump type affects coagulation, taking into account the severity and implications of coagulation complications. LEVEL OF EVIDENCE: Level III.

The Edoxaban Hokusai VTE PEDIATRICS Study: An open-label, multicenter, randomized study of edoxaban for pediatric venous thromboembolic disease.

BACKGROUND: Little evidence is available for treatment of pediatric venous thromboembolism (VTE). Large randomized controlled trials are challenging in children. Current antithrombotic agents have many limitations, including nonoral administration and frequent monitoring. Edoxaban is an oral direct inhibitor of factor Xa without need of monitoring. In adults with VTE, edoxaban has shown to be effective and safe. OBJECTIVES: The Edoxaban Hokusai VTE PEDIATRICS Study is an open-label, randomized clinical trial to evaluate pharmacokinetics (PK) and pharmacodynamics (PD) of edoxaban and whether edoxaban is noninferior to standard of care in treatment of pediatric VTE. METHODS: A goal of 274 patients will be recruited in 5 age categories. A multidose PK/PD assessment on day 5 in the first 12 patients of each age group is incorporated into this study. The primary composite efficacy outcome comprises symptomatic recurrent VTE, death due to VTE, and no change or extension of thrombotic burden. The principal safety end point is a combination of major and clinically relevant nonmajor bleeding. PK end points include apparent systemic clearance and volume of distribution of edoxaban. PD end points include prothrombin time, activated partial thromboplastin time, and anti-factor Xa level for the edoxaban treatment arm. RESULTS: To increase feasibility, the multidose PK/PD study is integrated in the phase 3 trial. In addition, thrombotic burden, which is a prognostic factor for post thrombotic syndrome in children, is one of the components of the primary composite efficacy outcome. CONCLUSION: This study will increase the level of evidence for treatment in pediatric VTE.

Thrombosis after umbilical venous catheterisation: prospective study with serial ultrasound.

BACKGROUND: Umbilical venous catheters (UVCs) are associated with thrombus formation. Most studies on thrombosis in infants with UVCs focus on only one part of the route, and none assessed a control group of infants without UVCs. OBJECTIVE: To determine the incidence and location of thrombi in infants after umbilical catheterisation and compare this with a control group of infants without umbilical catheters. DESIGN: Prospective observational study with serial ultrasonography of the UVC route from the umbilico-portal confluence to the heart. Ultrasonography was performed until day 14 after catheterisation in cases and day 14 after birth in controls. RESULTS: Thrombi in the UVC route were detected in 75% (30/40) of infants with UVCs in the study group, whereas no thrombi were detected in the control group of infants without UVCs (0/20) (p<0.001). Six thrombi (20%) were located in the right atrium. Most of these were also partly present in the ductus venosus. Six thrombi (20%) were located in the ductus venosus only, and in 12 infants (40%), the thrombus was at least partly located in the umbilico-portal confluence. Thrombi persisted after UVC removal in 25/30 cases. Two infants with thrombotic events were treated with low-molecular-weight heparin and resolution was found. In the other 23 infants managed expectantly, 2 died due to necrotising enterocolitis, 1 was lost to follow-up and in 20 spontaneous regression was seen. CONCLUSIONS: Thrombotic events occur frequently in infants after umbilical catheterisation. Most thrombi were asymptomatic and regressed spontaneously with expectant management. Routine screening for thrombi in UVCs is therefore not advised.

Neonatal ECMO.

Extracorporeal membrane oxygenation (ECMO) is becoming increasingly utilized to manage neonates with cardiac and respiratory failure. The procedure involves extensive anticoagulation in a sick neonate with underlying disease pathology. In addition, the immature hemostatic system in the neonate adds to the complexity of titrating the necessary anticoagulation. This places the infant at greater risk for life threatening hemorrhage and thrombosis. Managing anticoagulation in these infants is extremely challenging and needs the expertise of a physician with a thorough knowledge of the intricacies of developmental hemostasis and limitations of the current laboratory techniques available to manage anticoagulation. This article provides a brief overview of the developing hemostatic system of the neonate and the challenges associated with managing anticoagulation in this vulnerable population of patients.