How I treat pediatric venous thromboembolism in the DOAC era.

ABSTRACT: The direct oral anticoagulants (DOACs) rivaroxaban and dabigatran are newly licensed for the treatment and prevention of venous thromboembolism (VTE) in children and mark a renaissance in pediatric anticoagulation management. They provide a convenient option over standard-of-care anticoagulants (heparins, fondaparinux, and vitamin K antagonists) because of their oral route of administration, child-friendly formulations, and significant reduction in monitoring. However, limitations related to therapeutic monitoring when needed and the lack of approved reversal agents for DOACs in children raise some safety concerns. There is accumulating experience of safety and efficacy of DOACs in adults for a broad scope of indications; however, the cumulative experience of using DOACs in pediatrics, specifically for those with coexisting chronic illnesses, is sparse. Consequently, clinicians must often rely on their experience for treating VTE and extrapolate from data in adults while using DOACs in children. In this article, the authors share their experience of managing 4 scenarios that hematologists are likely to encounter in their day-to-day practice. Topics addressed include (1) appropriateness of indication; (2) use for special populations of children; (3) considerations for laboratory monitoring; (4) transition between anticoagulants; (5) major drug interactions; (6) perioperative management; and (7) anticoagulation reversal.

Intravenous fluid therapy and hospital outcomes for vaso-occlusive episodes in children, adolescents, and young adults with sickle cell disease.

BACKGROUND: While intravenous fluid (IVF) therapy in patients with sickle cell disease (SCD) admitted for a vaso-occlusive episode (VOE) can help reduce red blood cell sickling, clinical practice varies across institutions. We examined the relationship between IVF therapy and hospital length of stay (HLOS), as well as adverse events, such as acute chest syndrome (ACS), pediatric intensive care unit (PICU) transfer, and 28-day re-admission. METHODS: This is a single-center retrospective analysis of SCD VOE hospitalizations between January 2015 and April 2020. Patients with SCD, age 0-30, with consecutive hospitalizations for VOE were included. For the first 3 days of each admission, an "IVF ratio" was calculated by dividing actual IVF rate administered by weight-based maintenance IVF (mIVF) rate. RESULTS: A total of 617 hospitalizations for 161 patients were included. Mean HLOS was 5.7 days, (SD 3.9), and mean IVF volume over the first 3 days of admission was 139.6 mL/kg/day (SD 57.8). Multivariate analysis showed that for each additional 0.5 times the mIVF rate, HLOS increased by 0.53 day (p < .001; 95% confidence interval [CI]: 0.609-0.989), but there was no significant association between IVF therapy and adverse events. History of chronic pain was associated with increased odds of re-admission (OR 6.4; 95% CI: 3.93-10.52). CONCLUSIONS: Despite the theoretical potential for IVF therapy to slow down the sickling process, our findings suggest that increased IVF therapy was associated with prolonged HLOS, which places a burden on patients, families, and the health system.

Factors associated with thrombotic and hemorrhagic complications in pediatric liver transplant: A multi-center analysis from the Starzl Network for Excellence in Pediatric Transplantation.

BACKGROUND: Survival after pediatric liver transplantation (PLT) is negatively impacted by thrombotic and hemorrhagic complications. Limited data exists regarding factors associated with these complications and utilization of anticoagulation. METHODS: Retrospective review of donor, recipient variables and outcomes from four centers participating in the Starzl Network for Excellence in Pediatric Transplantation. RESULTS: 76 PLT included 39 (51%) technical variant transplants, with mean follow-up 628 ± 193.6 days. Median age/weight at transplant were 59.3 ± 53.8 months and 19.6 ± 17.2 kg. Seven (9.2%) transplants experienced intraoperative hepatic artery thrombosis (iHAT), all successfully corrected. Four HAT recurred postoperatively on POD 1,7,8 and 616. All three portal vein thromboses (PVT) occurred on POD1. Anticoagulation protocols were initiated intraoperatively in 50 and postoperatively in 66 and were active for all thrombotic and hemorrhagic events. Two patients were re-transplanted for HAT. Two patients died without having thrombotic or hemorrhagic complications. iHAT and post-operative HAT were associated with lower hepatic arterial flows. iHAT was associated with donor variant anatomy, reduced allografts and intraoperative blood loss. Intraoperative ultrasound could not predict post-operative HAT nor PVT. Surgeon pre-operative concern regarding the native portal vein correlated with postoperative PVT. Lower hepatic arterial and portal flows, higher estimated blood losses, higher prothrombin time and use of arterial interposition grafts were associated with postoperative hemorrhagic complications. CONCLUSIONS: Thrombotic and hemorrhagic complications after pediatric liver transplant remain rare but significant events. Their occurrence can be predicted with pre-operative assessment of donor and recipient vascular anatomy and direct flow measurement but may not be predicted with ultrasound evaluation nor prevented with anticoagulation.

Perioperative management in chronically anticoagulated children undergoing tonsillectomy.

BACKGROUND: When undergoing tonsillectomy, patients at high risk of thrombosis who require chronic anticoagulation therapy pose a special challenge as bleeding may occur up to 2 weeks after surgery. Because of a lack of evidence-based data, there is no consensus on the best management for such patients. The objective of our study was to review perioperative anticoagulation bridging strategies in children undergoing tonsillectomy. METHODS: The study group were a retrospective series of patients on chronic anticoagulation therapy at high risk of a thromboembolic event, who underwent tonsillectomy from 2010 to 2021. Patients whose anticoagulation treatment was discontinued because of a low risk of thromboembolic events were excluded. RESULTS: Four patients met the inclusion criteria (age range, 1.5-16.1 years). All patients were admitted prior to surgery for bridging therapy with intravenous unfractionated heparin (UFH), drip-titrated to a therapeutic dose until 4-6 h prior to surgery. The estimated blood loss during surgery was minimal in all surgeries. Unfractionated heparin was readministered according to the hospital protocol on the night of surgery and titrated to a therapeutic dose. Warfarin was restarted within 2 days postsurgery for all patients. High-risk patients were kept in hospital until postoperative day 6-8 because of concern for delayed bleeding. One patient was noticed to have blood-tinged sputum requiring no intervention; none of the patients developed early or delayed hematemesis. CONCLUSIONS: Our data show that bridging therapy with UFH has been successful in chronically anticoagulated patients undergoing tonsillectomy. These patients require multidisciplinary care for the management of their pre- and postoperative course.

Early thrombotic and hemorrhagic complications associated with a risk-adjusted postoperative anticoagulation protocol after pediatric liver transplantation.

BACKGROUND: Systemic anticoagulation after pediatric liver transplantation (pLT) is believed to reduce the incidence of vascular thrombosis, but it may also cause an increase in hemorrhagic complications. PROCEDURE: A 5-year retrospective review of pLT done at our institution was performed (2014-2018). The occurrence of early hemorrhagic and thrombotic complications was compared when using low-dose or high-dose anticoagulation after transplant (p < .05 considered significant). RESULTS: Sixty-nine patients received 73 transplants during the study period. Median age at transplant was 2.3 years (40 days to 18.5 years). Low-dose anticoagulation was utilized in 71% cases. Additionally, six patients were converted from low-dose to high-dose anticoagulation because of a thrombotic event or concerns for suboptimal vascular inflow. Postoperative anticoagulation was discontinued in 18 occurrences due to bleeding (low dose 19%, high dose 47% vs. low dose to high dose 17%, p = .085). Surgical take back for bleeding occurred in 17 occasions (low dose 13.5%, high dose 53% vs. low dose to high dose 33%, p = .005). The overall incidence of hepatic artery thrombosis (HAT) and portal vein thrombosis were each 5.5%, respectively. While patient survival was not statistically different between groups, graft survival was significantly lower in the high-dose group (low dose 93%, high dose 73% vs. low dose to high dose 100%, p = .046). However, graft losses from HAT were similar between groups (low dose 2%, high dose 7% vs. low dose to high dose 0%, p = .56). CONCLUSION: The use of a standardized risk-adjusted anticoagulation protocol after pLT is associated with a low occurrence of thrombotic and hemorrhagic complications. High-dose anticoagulation leads to more bleeding, but those risks outweigh the risks of possible graft loss.

Hemostasis in Pediatric Extracorporeal Life Support: Overview and Challenges.

Extracorporeal membrane oxygenation (ECMO) and ventricular assist devices (VADs) are increasingly used in critically ill children. Despite improvements in mechanical design and clinical management, thromboembolic and hemorrhagic events remain significant causes of morbidity and mortality related to the use of both devices. Choice of anticoagulant agents and assays for monitoring continue to present challenges in management. In this review, we describe the incidence and risk factors for thrombosis and hemorrhage, the different types of anticoagulants currently in use, the assays available for monitoring anticoagulation, and management of thromboembolic and bleeding complications in children on mechanical circulatory support (MCS). We conclude by emphasizing the areas that need further study to minimize the risk for thrombosis and hemorrhage in the use of ECMO and VAD in children.

Enoxaparin Thromboprophylaxis in Children Hospitalized for COVID-19: A Phase 2 Trial.

BACKGROUND: Evidence regarding the safety and efficacy of anticoagulant thromboprophylaxis among pediatric patients hospitalized for coronavirus disease 2019 (COVID-19) is limited. We sought to evaluate safety, dose-finding, and preliminary efficacy of twice-daily enoxaparin as primary thromboprophylaxis among children hospitalized for symptomatic COVID-19, including primary respiratory infection and multisystem inflammatory syndrome in children (MISC). METHODS: We performed a phase 2, multicenter, prospective, open-label, single-arm clinical trial of twice-daily enoxaparin (initial dose: 0.5mg/kg per dose; max: 60mg; target anti-Xa activity: 0.20-0.49IU/mL) as primary thromboprophylaxis for children <18 years of age hospitalized for symptomatic COVID-19. Study endpoints included: cumulative incidence of International Society of Thrombosis and Haemostasis-defined clinically relevant bleeding; enoxaparin dose-requirements; and cumulative incidence of venous thromboembolism within 30-days of hospital discharge. Descriptive statistics summarized endpoint estimates that were further evaluated by participant age (±12 years) and clinical presentation. RESULTS: Forty children were enrolled and 38 met analyses criteria. None experienced clinically relevant bleeding. Median (interquartile range) dose to achieve target anti-Xa levels was 0.5 mg/kg (0.48-0.54). Dose-requirement did not differ by age (0.5 [0.46-0.52] mg/kg for age ≥12 years versus 0.52 [0.49-0.55] mg/kg for age <12 years, P = .51) but was greater for participants with MISC (0.52 [0.5-0.61] mg/kg) as compared with primary COVID-19 (0.48 [0.39-0.51] mg/kg, P = .010). Two children (5.3%) developed central-venous catheter-related venous thromboembolism. No serious adverse events were related to trial intervention. CONCLUSIONS: Among children hospitalized for COVID-19, thromboprophylaxis with twice-daily enoxaparin appears safe and warrants further investigation to assess efficacy.

Risk factors associated with venous and arterial neonatal thrombosis in the intensive care unit: a multicentre case-control study.

BACKGROUND: Critically ill infants are susceptible to thrombosis due to several risk factors. The aim of this study was to identify risk factors associated with venous and arterial thrombosis in neonates admitted to the neonatal intensive care unit (NICU) and to identify differences in risk factors for venous versus arterial thrombosis. METHODS: We conducted a case-control study at 31 level IV NICUs using the Children's Hospital Neonatal Database between Jan 1, 2010, and Dec 13, 2016, in the USA. Cases were identified on the basis of having an outcome of venous or arterial thrombosis. Controls were matched by gestational age, presence of a central access device (CAD), hospital, and admission year. Four controls per case (1:4) were randomly selected. Bivariable and multivariable regression analyses were performed to examine the associations between potential risk factors and venous or arterial thrombosis. CAD-related risk factors were analysed in the subset of neonates with a CAD. FINDINGS: We identified 118 952 new admissions to 31 NICUs. The overall thrombosis incidence was 15·5 per 1000 NICU admissions (95% CI 14·8-16·2). After exclusion of patients with a length of hospitalisation longer than 3 days or heart disease, the study included 1326 thrombosis cases (1022 with venous thrombosis and 362 with arterial thrombosis; 58 patients had both types of thrombosis and are included within both of these numbers) and 5304 randomly selected controls. Venous thrombosis was independently associated with bloodstream infection (odds ratio 2·07, 95% CI 1·72-2·49; p<0·0001), maternal diabetes (1·62, 1·30-2·03; p<0·0001), abdominal or gastrointestinal surgery (1·36, 1·17-1·58; p<0·0001), thrombocytopenia (2·44, 2·02-2·94; p<0·0001), prolonged mechanical ventilation (1·27, 1·10-1·46; p=0·0014), and age 7 days or older at admission (1·49, 1·28-1·74; p<0·0001). Arterial thrombosis was independently associated with maternal hypertension (1·42, 1·05-1·91; p=0·030), thrombocytopenia (2·20, 1·59-3·06; p<0·0001), prolonged mechanical ventilation (1·58, 1·24-2·01; p=0·0002), age 7 days or older at admission (1·35, 1·05-1·74; p=0·0018), and small for gestational age (1·56, 1·13-2·16; p=0·0003). In the CAD subset analysis, CAD duration of 21 days or longer (venous thrombosis: 1·52, 1·15-2·01, p=0·0034; arterial thrombosis: 1·98, 1·25-3·14, p=0·035) and CAD in both the upper and lower body (venous thrombosis: 2·43, 1·92-3·08, p<0·0001; arterial thrombosis: 1·58, 1·02-2·45, p=0·040) were associated with higher odds of thrombosis. INTERPRETATION: Identification of thrombosis-associated risk factors will be useful in developing a risk prediction model to prevent thrombosis and in improving outcomes. The study results add to the knowledge of the differences in risk factors for venous versus arterial thrombosis in neonates and to the understanding of the associations of CAD characteristics with neonatal thrombosis. FUNDING: Bristol-Myers Squibb-Pfizer Alliance.

Molecular and phenotypic diversity of CBL-mutated juvenile myelomonocytic leukemia.

Mutations in the gene CBL were first identified in adults with various myeloid malignancies. Some patients with juvenile myelomonocytic leukemia (JMML) were also noted to harbor mutations in CBL, but were found to have generally less aggressive disease courses compared to other forms of Ras pathway-mutant JMML. Importantly, and in contrast to most reports in adults, the majority of CBL mutations in JMML patients are germline with acquired uniparental disomy occurring in affected marrow cells. Here, we systematically studied a large cohort of 33 JMML patients with CBL mutations and found this disease to be highly diverse in presentation and overall outcome. Moreover, we discovered somatically-acquired CBL mutations in 15% of pediatric patients who presented with more aggressive disease. Neither clinical features nor methylation profiling were able to distinguish somatic CBL patients from germline CBL patients, highlighting the need for germline testing. Overall, we demonstrate that disease courses are quite heterogeneous even among germline CBL patients. Prospective clinical trials are warranted to find ideal treatment strategies for this diverse cohort of patients.

Morphologic and Immunophenotypic Differences in Juvenile Myelomonocytic Leukemias With CBL and Other Canonical RAS-pathway Gene Mutations: A Single Institutional Experience.

The diagnostic criteria for juvenile myelomonocytic leukemia have recently been revised to include clinical findings and RAS-pathway gene mutations per the 2016 World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissues. Differing clinical behaviors have been observed in cases with CBL versus other RAS-pathway gene (RAS-p) mutations, notably the patients with CBL mutations can be self-limiting with spontaneous resolution. Additional clinical characteristics and histopathologic findings between these subsets are less well-described. We performed a retrospective search and identified cases with either CBL or RAS-p mutations, as per targeted and/or massively parallel sequencing. Eight patients had sufficient material for review, including cytogenetic studies and peripheral blood, bone marrow aspirate, and/or biopsy with flow cytometry analyses. Three patients showed CBL mutations and lower percentages of hemoglobin F and peripheral blood absolute monocyte counts, lesser degrees of leukocytosis compared with the RAS-p cohort, and normal megakaryocyte morphology and myeloblast immunophenotypes. Two of these patients were managed with observation only and experienced resolution of their disease. The patients with RAS-p mutations had severe thrombocytopenia, moderate to severe anemia, and experienced variable clinical outcomes. Abnormal megakaryocyte morphology and decreased numbers of megakaryocytes were seen in cases with RAS-p mutations. In addition, 3 of 4 cases with flow cytometry data demonstrated aberrant CD7 expression in myeloblasts. Our study is the first to identify morphologic and immunophenotypic differences between juvenile myelomonocytic leukemia cases with CBL or RAS-p mutations, and further supports previous reports of significantly different clinical behaviors between these subsets of patients.

Quality of life is an important indication for second-line treatment in children with immune thrombocytopenia.

BACKGROUND: The decision to initiate second-line treatment in children with immune thrombocytopenia (ITP) is complex and involves many different factors. METHODS: In this prospective, observational, longitudinal cohort study of 120 children from 21 centers, the factors contributing to the decision to start second-line treatments for ITP were captured. At study entry, clinicians were given a curated list of 12 potential reasons the patient required a second-line treatment. Clinicians selected all that applied and ranked the top three reasons. RESULTS: Quality of life (QOL) was the most frequently cited reason for starting a second-line therapy. Clinicians chose it as a reason to treat in 88/120 (73%) patients, as among the top three reasons in 68/120 (57%), and as the top reason in 32/120 (27%). Additional factors ranked as the top reason to start second-line treatment included severity of bleeding (22/120, 18%), frequency of bleeding (19/120, 16%), and severity of thrombocytopenia (18/120, 15%). Patients for whom QOL (p = .006) or sports participation (p = .02) were ranked reasons were more likely to have chronic ITP, whereas those for whom severity (p = .003) or frequency (p = .005) of bleeding were ranked reasons were more likely to have newly diagnosed or persistent ITP. Parental anxiety, though rarely the primary impetus for treatment, was frequently cited (70/120, 58%) as a contributing factor. CONCLUSION: Perceived QOL is the most frequently selected reason pediatric patients start second-line therapies for ITP. It is critical that studies of treatments for childhood ITP include assessments of their effects on QOL.

Novel compound heterozygous variants of TBXAS1 presenting with Ghosal hematodiaphyseal dysplasia treated with steroids.

BACKGROUND: Homozygous or compound heterozygous pathogenic variants in the thromboxane A synthase 1 (TBXAS1) gene are associated with Ghosal hematodiaphyseal dysplasia (GHDD) which is characterized by defective hematopoiesis and increased bone density of long bones. METHODS: Patients 1 and 2 are identical twins, who presented with red blood cell transfusion-dependent normocytic anemia and thrombocytopenia with bone marrow fibrosis and cortical bone thickening of long bones on plain radiograph. To clarify the etiology of their anemia and thrombocytopenia, whole blood was used for the DNA extraction and analyzed using next-generation sequencing (NGS) on an in-house bone marrow failure syndrome panel. RESULTS: The NGS results indicated that these two patients carried two heterozygous variants in TBXAS1, exon7, c.583_584del, p.Ala195Leufs*12, and exon12, c.1420G>T, p.Gly474Trp, which were inherited from their mother and father, respectively. Patients 1 and 2 have been on chronic oral steroids with normalization of hemoglobin and platelet count after steroid initiation. Patient 3 is their sister who has normal blood counts but also has the same variants in TBXAS1 as her brothers. Radiographs showed cortical bone thickening and she has not required any treatment or transfusion. CONCLUSION: We report three Caucasian siblings from non-consanguineous parents with novel compound heterozygous variants of TBXAS1 presenting with the phenotypes of GHDD. These three cases illustrate the variable clinical expressivity of the GHDD from two-compound heterozygous pathogenic variants of TBXAS1.

Safety and efficacy of rivaroxaban in pediatric cerebral venous thrombosis (EINSTEIN-Jr CVT).

Anticoagulant treatment of pediatric cerebral venous thrombosis has not been evaluated in randomized trials. We evaluated the safety and efficacy of rivaroxaban and standard anticoagulants in the predefined subgroup of children with cerebral venous thrombosis (CVT) who participated in the EINSTEIN-Jr trial. Children with CVT were randomized (2:1), after initial heparinization, to treatment with rivaroxaban or standard anticoagulants (continued on heparin or switched to vitamin K antagonist). The main treatment period was 3 months. The primary efficacy outcome, symptomatic recurrent venous thromboembolism (VTE), and principal safety outcome, major or clinically relevant nonmajor bleeding,were centrally evaluated by blinded investigators. Sinus recanalization on repeat brain imaging was a secondary outcome. Statistical analyses were exploratory. In total, 114 children with confirmed CVT were randomized. All children completed the follow-up. None of the 73 rivaroxaban recipients and 1 (2.4%; CVT) of the 41 standard anticoagulant recipients had symptomatic, recurrent VTE after 3 months (absolute difference, 2.4%; 95% confidence interval [CI], -2.6% to 13.5%). Clinically relevant bleeding occurred in 5 (6.8%; all nonmajor and noncerebral) rivaroxaban recipients and in 1 (2.5%; major [subdural] bleeding) standard anticoagulant recipient (absolute difference, 4.4%; 95% CI, -6.7% to 13.4%). Complete or partial sinus recanalization occurred in 18 (25%) and 39 (53%) rivaroxaban recipients and in 6 (15%) and 24 (59%) standard anticoagulant recipients, respectively. In summary, in this substudy of a randomized trial with a limited sample size, children with CVT treated with rivaroxaban or standard anticoagulation had a low risk of recurrent VTE and clinically relevant bleeding. This trial was registered at clinicaltrials.gov as #NCT02234843.

Implementation of automatic data extraction from an enterprise database warehouse (EDW) for validating pediatric VTE decision rule: a prospective observational study in a critical care population.

Multiple clinical risk prediction tools for hospital acquired venous thromboembolism (HA-VTE) have been developed. The objectives of this study were to develop and assess the feasibility of data extraction from Electronic Medical Records (EMR) from an enterprise database warehouse (EDW) and to test the validity of a previously developed Pediatric Clot Decision Rule (PCDR). This single-center prospective observational cohort study was conducted between March 2016 and March 2017 and included eligible patients admitted to the intensive care units. Risk score was calculated using the PCDR tool. Sensitivity, specificity, positive and negative predicted value (PPV and NPV) were calculated based on a cut-point of 3. A total of 2822 children were eligible for analysis and 5.1% (95% CI 4.2-6.2) children had a PCDR score of 3. Children with PCDR score of ≥ 3 had a 3 times higher odd of developing VTE compared to those with scores < 3 (OR 3.1; 95% CI 1.93-4.80; p < 0.001). The model performance showed that at the cutoff point of ≥ 3, both the specificity and sensitivity of the PCDR in predicting VTE was 69% and NPV of 98%. We successfully demonstrated using our EDW to populate a research database using an automatic data import. A PCDR score of ≥ 3 was associated with VTE. Collaboration through large registries will be useful in informing practices and guidelines for rare disorders such as pediatric VTE.

Fatigue in children and adolescents with immune thrombocytopenia.

Immune thrombocytopenia (ITP), an acquired autoimmune disorder of low platelets and risk of bleeding, has a substantial impact on health-related quality of life (HRQoL). Patients with ITP often report significant fatigue, although the pathophysiology of this is poorly understood. In this observational cohort of 120 children receiving second-line therapies for ITP, we assessed reports of fatigue using the Hockenberry Fatigue Scale. Children and adolescents with ITP reported a similarly high level of fatigue with 54% (29/54) of children and 62% (26/42) of adolescents reporting moderate-to-severe fatigue. There was no correlation between fatigue and age or gender. Adolescents with newly diagnosed and persistent ITP had higher mean fatigue scores than those with chronic ITP (P = 0·03). Fatigue significantly improved in children and adolescents by 1 month after starting second-line treatments, and this improvement continued to be present at 12 months after starting treatment. Fatigue scores at all time-points correlated with general HRQoL using the Kids ITP Tool, but did not correlate with bleeding symptoms, platelet count, or platelet response to treatment. Fatigue is common in children and adolescents with ITP and may benefit from ITP-directed treatment even in the absence of bleeding symptoms.

Anticoagulation in preterm and term neonates: Why are they special?

The preterm and term neonatal population is most at risk for thrombotic complications in pediatrics. Among various treatment modalities, anticoagulation is primarily used in the management of thrombosis. Developmental differences in preterm and term infants compared to older infants and children and limitations of anticoagulation agents currently used are important considerations for treatment. Additionally, dosages and durations of anticoagulant treatment are widely variable across countries. This article will highlight the differences in anticoagulation in neonates compared to other populations due to developmental hemostatic changes, epidemiology of neonatal thrombosis, pharmacokinetic and pharmacodynamic properties of drugs used and presence of neonatal co-morbidities.