Epidemiology of clinically unsuspected venous thromboembolism in children with cancer: A population-based study from Maritimes, Canada.

Inconsistencies in the definition of clinically unsuspected venous thromboembolism (VTE) in pediatric patients recently led to the recommendation of standardizing this terminology. Clinically unsuspected VTE (cuVTE) is defined as the presence of VTE on diagnostic imaging performed for indications unrelated to VTE in a patient without symptoms or clinical history of VTE. The prevalence of cuVTE in pediatric cancer patients is unclear. Therefore, the main objective of our study was to determine the prevalence of cuVTE in pediatric cancer patients. All patients 0-18 years old, treated at the IWK in Halifax, Nova Scotia, from August 2005 through December 2019 with a known cancer diagnosis and at least one imaging study were eligible (n = 743). All radiology reports available for these patients were reviewed (n = 18,120). The VTE event was labeled a priori as cuVTE event for radiology reports that included descriptive texts indicating a diagnosis of thrombosis including thrombus, central venous catheter-related, thrombosed aneurysm, tumor thrombosis, non-occlusive thrombus, intraluminal filling defect, or small fragment clot for patients without documentation of clinical history and or signs of VTE. A total of 18,120 radiology reports were included in the review. The prevalence of cuVTE was 5.5% (41/743). Echocardiography and computed tomography had the highest rate of cuVTE detection, and the most common terminologies used to diagnose cuVTE were thrombus and non-occlusive thrombus. The diagnosis of cuVTE was not associated with age, sex, and type of cancer. Future efforts should focus on streamlining radiology reports to characterize thrombi. The clinical significance of these cuVTE findings and their application to management, post-thrombotic syndrome, and survival compared to cases with symptomatic VTE and patients without VTE should be further studied.

Romiplostim for Treatment of Children and Young Adults With Severe Aplastic Anemia and Myelodysplastic Syndrome.

Thrombopoietin receptor agonists (TPO-RAs) induce trilineage hematopoiesis under conditions with acquired hematopoietic failure. We evaluated safety, tolerability, and preliminary efficacy of a TPO-RA, romiplostim (Nplate), with or without standard-of-care immunosuppressive therapy (±IST) for children (ages < 21 y) with newly diagnosed and relapsed/refractory severe aplastic anemia (SAA) and myelodysplastic syndrome (MDS). Data were collected from an observational study and a single arm interventional pilot study. The safety outcome was treatment-related adverse events (AEs). Efficacy was evaluated by complete hematopoietic response (CHR) at week 24. Romiplostim was commenced at 5 µg/kg/week, with dose escalation of 2.5 µg/kg/week (maximum, 20 µg/kg/dose) based on platelet response. Romiplostim was continued until CHR was observed. Ten subjects (SAA, 9 [IST, 4; without IST, 5]; MDS, 1) completed the study (median age: 9.2 y). Median romiplostim dose was 10 µg/kg/week (range: 5 to 17.5 µg/kg/week). The cumulative incidence of CHR was 70.4% (95% CI, 20.2%-92.6%). Among 21 AEs (Grade 1 to 3), 3 were attributed to romiplostim. At a median posttherapy follow-up of 10.9 months (range: 0.7 to 77.5), no clonal evolution, bone marrow fibrosis or mortality was reported. This proof-of-concept study provides data about short-term safety, tolerability, and preliminary efficacy of romiplostim (±IST) for treatment of pediatric SAA/MDS.

Treatment of newly diagnosed severe aplastic anemia in children: Evidence-based recommendations.

Severe aplastic anemia (SAA) is a rare potentially fatal hematologic disorder. Although overall outcomes with treatment are excellent, there are variations in management approach, including differences in treatment between adult and pediatric patients. Certain aspects of treatment are under active investigation in clinical trials. Because of the rarity of the disease, some pediatric hematologists may have relatively limited experience with the complex management of SAA. The following recommendations reflect an up-to-date evidence-based approach to the treatment of children with newly diagnosed SAA.

Treatment of relapsed/refractory severe aplastic anemia in children: Evidence-based recommendations.

Severe aplastic anemia (SAA) is a rare potentially fatal hematologic disorder. Although overall outcomes with treatment are excellent, there are variations in management approach, including differences in treatment between adult and pediatric patients. Certain aspects of treatment are under active investigation in clinical trials. Because of the rarity of the disease, some pediatric hematologists may have relatively limited experience with the complex management of SAA. The following recommendations reflect an up-to-date evidence-based approach to the treatment of children with relapsed or refractory SAA.

COVID-19 outcomes in persons with hemophilia: results from a US-based national COVID-19 surveillance registry.

BACKGROUND: Hypercoagulable state contributing to thrombotic complications worsens COVID-19 severity and outcomes, whereas anticoagulation improves outcomes by alleviating hypercoagulability. OBJECTIVES: To examine whether hemophilia, an inherent hypocoagulable condition, offers protection against COVID-19 severity and reduces venous thromboembolism (VTE) risk in persons with hemophilia (PwH). METHODS: A 1:3 propensity score-matched retrospective cohort study used national COVID-19 registry data (January 2020 through January 2022) to compare outcomes between 300 male PwH and 900 matched controls without hemophilia. RESULTS: Analyses of PwH demonstrated that known risk factors (older age, heart failure, hypertension, cancer/malignancy, dementia, and renal and liver disease) contributed to severe COVID-19 and/or 30-day all-cause mortality. Non-central nervous system bleeding was an additional risk factor for poor outcomes in PwH. Odds of developing VTE with COVID-19 in PwH were associated with pre-COVID VTE diagnosis (odds ratio [OR], 51.9; 95% CI, 12.8-266; p < .001), anticoagulation therapy (OR, 12.7; 95% CI, 3.01-48.6; p < .001), and pulmonary disease (OR, 16.1; 95% CI, 10.4-25.4; p < .001). Thirty-day all-cause mortality (OR, 1.27; 95% CI, 0.75-2.11; p = .3) and VTE events (OR, 1.32; 95% CI, 0.64-2.73; p = .4) were not significantly different between the matched cohorts; however, hospitalizations (OR, 1.58; 95% CI, 1.20-2.10; p = .001) and non-central nervous system bleeding events (OR, 4.78; 95% CI, 2.98-7.48; p < .001) were increased in PwH. In multivariate analyses, hemophilia did not reduce adverse outcomes (OR, 1.32; 95% CI, 0.74-2.31; p = .2) or VTE (OR, 1.14; 95% CI, 0.44-2.67; p = .8) but increased bleeding risk (OR, 4.70; 95% CI, 2.98-7.48; p < .001). CONCLUSION: After adjusting for patient characteristics/comorbidities, hemophilia increased bleeding risk with COVID-19 but did not protect against severe disease and VTE.

Congenital Neutropenia with Specific Granulocyte Deficiency Caused by Novel Double Heterozygous SMARCD2 Mutations.

SMARCD2 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily D, member 2) is critical for myelopoiesis. Recently, bi-allelic SMARCD2 mutations have been reported in five children, causing autosomal recessive congenital neutropenia with specific granulocytes deficiency (CN-SGD); a syndrome resulting in G-CSF resistant neutropenia, recurrent infections, and dysplastic myelopoiesis. We report a new case with CN-SGD caused by two novel heterozygous pathogenic variants in the SMARCD2 gene (c.1081del (p.Gln361Argfs*15)), and (c.217C>T (p.Arg73*)). Treatment with the weekly dosing of thrombopoietin receptor agonist, Romiplostim, along with daily G-CSF transformed her clinical course, implying potential synergism. This report advances the understanding of CN-SGD caused by SMARCD2 mutations.

Thrombotic potential during pediatric acute lymphoblastic leukemia induction: Role of cell-free DNA.

BACKGROUND: Thromboembolism affects up to 30% of children undergoing treatment for acute lymphoblastic leukemia (ALL). Increased thrombin generation has been reported in ALL, but the mechanisms remain elusive. OBJECTIVE: We aimed to show that extracellular traps and cell-free DNA (cfDNA) promote thrombin generation in pediatric ALL. METHODS: In a longitudinal single-center study, we recruited 17 consecutive pediatric ALL patients. Serial blood samples were collected at diagnosis and weekly during the 4-week induction phase of antileukemic chemotherapy. Healthy children (n = 14) and children with deep vein thrombosis (DVT; n = 7) or sepsis (n = 5) were recruited as negative and positive controls, respectively. In plasma, we measured endogenous thrombin generation potential (ETP) and components of extracellular traps, including cfDNA. RESULTS: In patients with ALL, ETP was increased at baseline and remained significantly elevated throughout the induction therapy. Plasma levels of cfDNA were increased at baseline and during the first 3 weeks of induction therapy. The extent of enhancement of ETP and plasma cfDNA in patients with ALL was similar to that seen in patients with DVT or sepsis. Treatment of plasma with DNase 1 lowered ETP in patients with ALL at each time point but did not affect ETP in healthy controls. CONCLUSION: We conclude that childhood ALL is associated with a prothrombotic milieu at the time of diagnosis that continues during induction chemotherapy, and cfDNA contributes to increased thrombogenic potential.

Diagnostic work-up for severe aplastic anemia in children: Consensus of the North American Pediatric Aplastic Anemia Consortium.

The North American Pediatric Aplastic Anemia Consortium (NAPAAC) is a group of pediatric hematologist-oncologists, hematopathologists, and bone marrow transplant physicians from 46 institutions in North America with interest and expertise in aplastic anemia, inherited bone marrow failure syndromes, and myelodysplastic syndromes. The NAPAAC Bone Marrow Failure Diagnosis and Care Guidelines Working Group was established with the charge of harmonizing the approach to the diagnostic workup of aplastic anemia in an effort to standardize best practices in the field. This document outlines the rationale for initial evaluations in pediatric patients presenting with signs and symptoms concerning for severe aplastic anemia.

How we approach thrombosis risk in children with COVID-19 infection and MIS-C.

Thrombosis within the microvasculature and medium to large vessels is a serious and common complication among critically ill individuals with coronavirus disease 2019 (COVID-19). While children are markedly less likely to develop severe disease than adults, they remain at risk for thrombosis during acute infection and with the post-acute inflammatory illness termed multisystem inflammatory syndrome in children. Significant knowledge deficits in understanding COVID-19-associated coagulopathy and thrombotic risk pose clinical challenges for pediatric providers who must incorporate expert opinion and personal experience to manage individual patients. We discuss clinical scenarios to provide framework for characterizing thrombosis risk and thromboprophylaxis in children with COVID-19.

Up-front Treatment With Romiplostim in Children With Acquired Bone Marrow Failure: A Single Institutional Pediatric Case Series.

BACKGROUND: Thrombopoietin receptor agonists are emerging as a therapeutic option for patients with aplastic anemia (AA) and myelodysplastic syndrome (MDS). We report our experience of treating children with AA/MDS with romiplostim, thrombopoietin receptor agonist. OBSERVATIONS: Three children (AA, 2; MDS, 1) received romiplostim treatment at a median dose of 10 µg/kg/week (starting dose: 5 µg/kg/wk; 2.5 µg/kg/wk increment). Trilineage hematopoietic recovery occurred at a median of 13 weeks (range: 13 to 16 wk) without adverse events. Hematopoiesis continued to improve after therapy discontinuation (median follow-up: 2.8 y; range: 0.5 to 3.0). CONCLUSION: Our experience supports the short-term safety and efficacy of romiplostim in children with AA/MDS.

Epidemiology and outcomes of clinically unsuspected venous thromboembolism in children: A systematic review.

BACKGROUND: Clinically unsuspected venous thromboembolic events (uVTE) detected during routine imaging pose a management challenge due to limited knowledge about their clinical significance. Unsuspected VTE are often referred as "asymptomatic," "incidental," or "clinically silent/occult" VTE. OBJECTIVE: To understand the epidemiology, management, and outcomes of uVTE in children. METHODS: A systematic review was performed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The search criteria included controlled vocabulary and keywords for VTE, incidental findings, and children (ages ≤ 21 years). RESULTS: Among 10 875 articles, 51 studies (8354 children with 758 uVTE) were selected. The studies were heterogeneous, I2 96%; P < .0001. Unsuspected VTE were diagnosed in two settings: first, asymptomatic VTE (aVTE) diagnosed through surveillance imaging for VTE (46 studies; n = 5894; aVTE: 715, pooled frequency: 19%, 95% confidence interval [CI]: 13%-24%); second, incidental VTE (iVTE) diagnosed during imaging performed for indications without primary suspicion for VTE (6 studies; n = 2460; iVTE: 43). The majority (94%) of aVTE were associated with central venous lines (CVL). Non-CVL settings included post-spinal surgery, post-splenectomy, trauma, nephrotic syndrome, and newborns. In general, aVTE were reported to have a benign clinical course, were mostly transient, and resolved without intervention and with few immediate or long-term functional complications. Incidental VTE were primarily detected in children with cancer and ranged from tumor-associated thrombi to pulmonary embolism (PE) with insufficient evidence to draw meaningful conclusions about their management. CONCLUSION: Clinically uVTE were predominantly diagnosed with CVL and their outcomes were generally favorable implying limited benefit of routine surveillance and thromboprophylaxis. Prospective research is needed to clarify the optimal management of iVTE.

Nox2 NADPH oxidase is dispensable for platelet activation or arterial thrombosis in mice.

Deficiency of the Nox2 (gp91phox) catalytic subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is a genetic cause of X-linked chronic granulomatous disease, a condition in which patients are prone to infection resulting from the loss of oxidant production by neutrophils. Some studies have suggested a role for superoxide derived from Nox2 NADPH oxidase in platelet activation and thrombosis, but data are conflicting. Using a rigorous and comprehensive approach, we tested the hypothesis that genetic deficiency of Nox2 attenuates platelet activation and arterial thrombosis. Our study was designed to test the genotype differences within male and female mice. Using chloromethyl-dichlorodihydrofluorescein diacetate, a fluorescent dye, as well as high-performance liquid chromatography analysis with dihydroethidium as a probe to detect intracellular reactive oxygen species (ROS), we observed no genotype differences in ROS levels in platelets. Similarly, there were no genotype-dependent differences in levels of mitochondrial ROS. In addition, we did not observe any genotype-associated differences in platelet activation, adhesion, secretion, or aggregation in male or female mice. Platelets from chronic granulomatous disease patients exhibited similar adhesion and aggregation responses as platelets from healthy subjects. Susceptibility to carotid artery thrombosis in a photochemical injury model was similar in wild-type and Nox2-deficient male or female mice. Our findings indicate that Nox2 NADPH oxidase is not an essential source of platelet ROS or a mediator of platelet activation or arterial thrombosis in large vessels, such as the carotid artery.

Successful medical management of a neonate with spontaneous splenic rupture and severe hemophilia A.

Splenic rupture in neonates is a rare event, usually occurring in the setting of underlying predisposing conditions. Here, we present the case of a term neonate who presented with worsening anemia in the setting of known hemolytic disease during the newborn period and was later found to have a spontaneous splenic rupture. He was subsequently diagnosed with severe hemophilia A, and was managed medically with recombinant factor VIII replacement therapy without any surgical intervention. This is the first reported case of a neonate who had spontaneous splenic rupture and severe hemophilia A, and underwent successful medical treatment without any surgical intervention.

Current Practice of Pharmacological Thromboprophylaxis for Prevention of Venous Thromboembolism in Hospitalized Children: A Survey of Pediatric Hemostasis and Thrombosis Experts in North America.

Pharmacological thromboprophylaxis (pTP) is the most effective intervention to prevent venous thromboembolism (VTE) in hospitalized adults. High-quality studies investigating the role of pTP in children are lacking. The aim of this study is to understand pediatric hematologists' current practices of pTP prescription and to explore their opinion about universal adoption of pTP for high-risk hospitalized children. An electronic survey was sent to members of Hemostasis and Thrombosis Research Society of North America. The response rate was 47.3% (53/112). VTE was perceived as a major hospital acquired complication by all and 96% (51/53) prescribed pTP in select cases. Majority would consider prescribing pTP for personal history of thrombosis, inheritance of severe thrombophilic conditions, and teen age. The majority of respondents (55%, 29/53) were either not in support of or uncertain about the universal adoption of pTP policy for high-risk hospitalized children. In total, 62% of respondents (33/53) did not support the use of pTP for central venous lines. Respondents reported on the presence of pharmacological (32%, 17/53) and mechanical (45%, 24/53) thromboprophylaxis policies at their institutions. Pediatric hematologists considered pTP a useful intervention to prevent VTE and prescribed pTP in select cases. Universal adoption of pTP was not supported. Wide variability in clinical practice was observed.

Neonatal Compartment Syndrome Associated With Disseminated Intravascular Coagulation.

Neonatal compartment syndrome is a rare, but devastating limb-threatening condition that requires early recognition and timely surgical intervention. We discuss the clinical presentation and management challenges of a neonate with forearm compartment syndrome and disseminated intravascular coagulation.