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.

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.

Are low-molecular-weight heparins safe and effective in children? A systematic review.

The incidence of venous thromboembolism (VTE) in children is rising. Hence, there is an increasing off-label use of low-molecular-weight heparin (LMWH). There is little data about therapeutic and prophylactic LWMH dosages, and their safety and efficacy. This systematic review provided an oversight of the therapeutic and prophylactic dosages of LMWH required to reach therapeutic and prophylactic target ranges. Furthermore, the safety and efficacy of LMWH, in terms of bleeding complications, achieving therapeutic and prophylactic anti-factor Xa levels, development of (recurrent) VTE and cloth resolution were reviewed. A total of 49 studies were included, encompassing 3101 patients. Initial weight-adjusted dosages to reach therapeutic or prophylactic target ranges decreased with age. In children with therapeutic use of LMWH, major bleeding complications occurred in 1.8% (95% CI: 1.1-2.5%) of the patients, a mean of 79.9% (95% CI: 77.5-82.3%) of the children achieved the target range with or without dosage adjustments, recurrent VTE occurred in 3.2% (95% CI: 2.1-4.3%) and thrombus resolution in 63.5% (96% CI: 60.2-66.8%) of the patients. In children with prophylactic LMWH, major bleedings occurred in 0.6% (95% CI: 0.2-1.0%) of the patients, a mean of 90.4% (95% CI: 84.6-96.2%) of the children achieved the target range, and 2.2% (95% CI: 1.3-3.1%) experienced a new VTE. In conclusion, a higher initial therapeutic dosage of LMWH was needed in comparison to advised dosages, to achieve target range, especially in neonates and children <5 years. LMWH appeared to be safe and effective for therapeutic and prophylactic treatment of VTE in children.

TropicALL study: Thromboprophylaxis in Children treated for Acute Lymphoblastic Leukemia with Low-molecular-weight heparin: a multicenter randomized controlled trial.

BACKGROUND: Venous thromboembolism (VTE) is a common and severe complication during treatment of acute lymphoblastic leukemia (ALL). An important cause is the intensive use of asparaginase. Prospective cohort studies in which prophylactic low-molecular-weight heparin (LMWH) was used to prevent VTE showed lower VTE risk than in historic control cohorts, with a negligible bleeding risk. However, the efficacy of thromboprophylaxis with LMWH during ALL treatment has never been investigated in a randomized design. Here, we present the protocol of a randomized controlled trial in which the efficacy and safety of thromboprophylaxis with high prophylactic dose LMWH versus no thromboprophylaxis will be assessed in children treated for primary ALL with asparaginase. METHODS/DESIGN: Thromboprophylaxis in Children treated for Acute Lymphoblastic Leukemia with Low-molecular-weight heparin (TropicALL) is a multicenter, randomized controlled open-label trial conducted in the Netherlands. Patients between 1 and 19 years of age with primary ALL, who are treated within the Dutch Childhood Oncology Group (DCOG) ALL-11 or 12 study will be randomized to thromboprophylaxis with LMWH once daily, (dose of 85 IU/kg (intervention arm A)), or to no thromboprophylaxis (arm B, standard of care) during asparaginase courses of ALL treatment. Primary efficacy endpoint is symptomatic objectified VTE during ALL treatment; secondary efficacy endpoints are overall survival and the composite of symptomatic and asymptomatic objectified VTE. Primary safety endpoints are major bleeding, clinically relevant non-major bleeding and minor bleeding. A total of 324 patients will be included to obtain a relative risk reduction of 75% with a power of 80%, using a two-sided test with significance level α = 0.05. DISCUSSION: This trial will be the first to assess efficacy and safety of thromboprophylaxis with LMWH during asparaginase treatment for ALL in children in a randomized design. TRAIL REGISTRATION: Nederlands Trial Register NTR4707 . Registered 30 July 2014.

Thrombophilia in childhood: to test or not to test.

Inherited thrombophilia is defined as a genetically determined tendency to develop venous thromboembolism. In children, inherited thrombophilia contributes to the development of pediatric thromboembolic disease. As a consequence, pediatric hematologists are increasingly requested to test thrombophilia in pediatric patients with thrombosis or asymptomatic children from thrombophilic families. This article reviews the benefits and limitations of testing for thrombophilic disorders, for example, factor V Leiden, prothrombin mutation, and deficiencies of antithrombin, protein C, or protein S in childhood.