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.

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.

Clinical advances in hemophilia management.

Hemophilia is an excellent example in medicine where clinical translation of basic science discoveries has transformed the gloomy outlook of the disease. This review provides an overview of clinical advances in hemophilia management with a specific focus on the molecular heterogeneity of the disease and progress in management of patients with inhibitors. Novel therapeutics and the emerging ethical issues in the field of hemophilia are also discussed.

Proximal radio-ulnar synostosis with bone marrow failure syndrome in an infant without a HOXA11 mutation.

SUMMARY: This report summarizes the clinical management of an infant with a proximal radio-ulnar synostosis and inherited bone marrow failure syndrome (PRUS/IBMFS). Molecular studies were negative for the characteristic HOXA11 mutation described earlier. He was successfully treated with a non-myeloablative hematopoietic stem cell transplantation from an human leukocyte antigen-identical sibling donor at the age of 3 months. We reviewed the literature on PRUS/IBMFS with an emphasis on the current understanding of the molecular mechanisms involved in the disease pathogenesis. Absence of the HOXA11 mutation in this case implies that molecular mechanisms beyond the HOXA11 gene, yet to be discovered, may contribute for the development of PRUS/IBMFS.

Management of a child with renal artery stenosis and homozygous factor V Leiden mutation.

Presence of factor V Leiden mutation is a known risk factor for thrombosis. It contributes for premature occlusion of vascular anastomosis. This report describes the intraoperative and postoperative anticoagulation management of a girl with homozygous factor V Leiden mutation and renal artery stenosis after her renovascular reconstruction surgery. This report suggests that postoperative anticoagulation may be helpful for the successful maturation of vascular anastomoses in children with underlying acquired or hereditary risk factors for thrombosis including factor V Leiden mutation.