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.

Monitoring of Antiplatelet Therapy in Children on Ventricular Assist Device Support: Comparison of Multiplate and Thromboelastography Platelet Mapping.

The optimal method for monitoring antiplatelet therapy in children supported with ventricular assist devices (VADs) is unknown. We conducted a retrospective study to compare Thromboelastography Platelet Mapping (TEG/PM) with multiple electrode platelet aggregometry (MEA) on a Multiplate analyzer (Roche Diagnostics, Mannheim, Germany). We analyzed data from 66 paired blood samples from 9 patients <16 years of age on VAD where platelet function was simultaneously measured with TEG/PM and MEA. Antiplatelet dose-response relationships and intraindividual variability during steady state therapy were determined. Agreement in determination of therapeutic antiplatelet therapy was poor (arachidonic acid, κ 0.23; adenosine diphosphate [ADP], κ 0.13). Rate of aspirin and clopidogrel resistance was much higher when determined using TEG/PM than MEA. In patients receiving ≥5 mg/kg/day aspirin, 72% of TEG/PM measurements showed subtherapeutic response compared with 11% of MEA measurements. There was evidence of a dose-response relationship with clopidogrel and MEA ADP-induced aggregation (R2 = 0.56; p < 0.0001); however, there was no association between dose and TEG/PM% ADP inhibition (p = 0.15). Intraindividual variability in platelet reactivity was far greater when measured by TEG/PM during steady state therapy. Multiple electrode platelet aggregometry appears to be more reliable than TEG/PM for monitoring antiplatelet therapy in children supported with VAD.

Myeloproliferative Neoplasms in Children and Adolescents and Thrombosis at Unusual Sites: The Role of Driver Mutations.

Myeloproliferative neoplasms (MPNs) in childhood and adolescence are rare and seldom complicated by thrombosis. We describe 3 cases of thrombosis at unusual sites in young patients with MPNs. In the pediatric MPN population, unlike in adult MPNs, a clonal mutation is identifiable in only a minority of cases (22% to 26%). All 3 of these individuals had JAK2 mutations driving the disease process. A literature search identified 19 cases of MPN-associated thrombosis in children. Seventeen of the 19 children (89.5%) had a driver mutation. These cases suggest that identifiable driver mutations may confer an increased thrombotic risk in children with MPNs.

Identifying Children with HEreditary Coagulation disorders (iCHEC): a protocol for a prospective cohort study.

INTRODUCTION: It is challenging to obtain a reliable bleeding history in children who are referred for a suspected inherited bleeding disorder. Bleeding symptoms may be subtle as children face fewer haemostatic challenges compared with adults. In order to standardise bleeding histories, questionnaires have been developed, called bleeding assessment tools (BATs). Although it has been shown that high bleeding scores are associated with the presence of a mucocutaneous bleeding disorder, these BATs lack sensitivity, efficiency and flexibility in the paediatric setting. We developed a new BAT (the iCHEC (identifying Children with HEreditary Coagulation disorders) BAT) to improve on these characteristics. We aim to evaluate the diagnostic accuracy of the iCHEC BAT as a screening tool for children who are suspected for having a bleeding disorder. METHODS AND ANALYSIS: This is a prospective cohort study. Children (age 0-18 years) suspected for a bleeding disorder who present at tertiary haematology clinics, and/or their parents/guardians, will be asked to complete the iCHEC BAT. Sensitivity was increased by inclusion of paediatric-specific bleeding symptoms and novel qualitative questions per bleeding symptom. Efficiency was improved by developing a self-administered (online) version of the questionnaire. Flexibility for changes in the bleeding phenotype of developing children was improved by including questions that define when the bleeding symptoms occurred in the past. The diagnostic accuracy of the specific bleeding items will be evaluated by receiver operator characteristic curves, using classification based on the results from laboratory assessment as the reference standard. Analysis of the discriminative power of individual bleeding symptoms will be assessed. ETHICS AND DISSEMINATION: The study has been approved by the medical ethics committees of all participating centres in the Netherlands, Canada and the UK. All paediatric subjects and/or their parents/guardians will provide written informed consent. Study results will be submitted for publication in peer-reviewed journals.

Association between CYP4F2 genotype and circulating plasma vitamin K concentration in children on chronic warfarin therapy: Possible long-term implications for bone development and vascular health.

Vitamin K is essential, for the activation of clotting proteins, as well as the biosynthesis of osteocalcin in bones and the activation of matrix-Gla protein needed in maintaining vasculature health. Cytochrome p450 4F2 (CYP4F2) enzyme is involved in vitamin K catabolism. Genetic polymorphism in CYP4F2 is thus likely to affect vitamin K systemic availability. We show that children on chronic warfarin therapy have low levels of vitamin K and vitamin K levels are linked to CYP4F2 genotype. Long-term low levels of vitamin K, influenced by CYP4F2 genotype, might affect bone development and vascular health in children on chronic warfarin therapy.

Strategies to Prevent and Manage Thrombotic Complications of Acute Lymphoblastic Leukemia in Children and Young People Vary Between Centers in the United Kingdom.

There is a lack of evidence-based guidance for the prevention and management of thrombosis in children and young people treated for acute lymphoblastic leukemia. To determine current UK practice, a survey was sent to 28 centers participating in the Medical Research Council UKALL 2011 trial. Marked variation in practice was noted. In total, 43% of centers defer central venous access device insertion until end of induction for treatment of low-risk disease. Central venous access devices are removed at the end of intensive blocks in 38% and end of treatment in 42%. Duration of anticoagulation for line-associated thrombosis is 6 weeks in 43% and 3 months in 33% and for cerebral sinovenous thrombosis is 3 months in 71% and 6 months in 24%. Platelet transfusion to maintain platelet count >50×10/L, in preference to interrupting therapeutic anticoagulation, is used by 50% for line-associated thrombosis and 73% for cerebral sinovenous thrombosis. Conformity of practice was seen in some areas. In total, 70% treat thrombosis with twice-daily low-molecular weight heparin and 86% monitor antifactor Xa activity levels. In total, 91% reexpose individuals to asparaginase following a thrombotic event. Given this variation in practice, in the absence of high-quality evidence, consensus guidelines may be helpful.

Venous thromboembolism occurring during adolescence.

OBJECTIVE: Risk assessment for venous thromboembolism (VTE) and thromboprophylaxis in those with risk factors is established in adult practice. Evidence to support efficacy and safety of this approach in adolescents is lacking. We aimed to describe thrombotic risk factors and to determine the proportion of potentially preventable events in a retrospective cohort study of adolescents with VTE. DESIGN, SETTING AND PATIENTS: Data were collected between 2008 and 2014 from eight tertiary UK centres. Qualifying events were radiologically confirmed VTE in subjects aged 12-17 years. Central venous line-related upper venous system events were excluded. RESULTS: 76 cases were identified, 41 males, median age 15 years. Frequent risk factors were: reduced mobility, 45%; thrombophilia, 24%; malignancy, 20%; surgery, 18%; combined oral contraceptive pill, 12%; congenital venous anomaly, 5%. 28 (37%) had no significant underlying diagnosis and no provoking event/hospitalisation, presenting as outpatients with VTE which was considered 'unpreventable'. Of 48 where there had been opportunity for risk assessment, chemical thromboprophylaxis was not indicated in 26 and was contraindicated in 8. 14/76 (18%) had an indication to consider thromboprophylaxis and no contraindication. Of these, four had cerebral palsy, five malignancy and two inflammatory bowel disease. All had reduced mobility with recent surgery in eight. Four received chemical thromboprophylaxis prior to presentation. CONCLUSIONS: Among a cohort of adolescents with VTE, a small proportion (13%) had an indication to consider chemical thromboprophylaxis but did not receive it. VTE risk assessment and prevention should focus on adolescents with immobility or surgery, particularly in those with malignancy.

The use of elastic compression stockings for post-thrombotic syndrome in a child.

Post-thrombotic syndrome (PTS) is a potential complication following deep vein thrombosis (DVT) in children. Guidelines for management of PTS in children are non-existent. The absence of guidelines may limit the use of elastic compression stockings (ECS), offered for prevention and treatment of PTS in adults. We report the case of a 6-year-old, who developed PTS following a presumed line-related lower limb DVT, with dramatic improvement in functional status with ECS use. The presented case highlights the subtle nature of symptoms, potential benefits and limitations of ECS use for PTS, and current lack of evidence in children.

Clinical features and outcome of pulmonary embolism in children.

Pulmonary embolism (PE) is rare in childhood but evidence suggests it is under-recognised. Children diagnosed with PE at a large tertiary centre over an 8-year period were retrospectively reviewed. Fifty-six children with radiologically proven PE were identified, 31 males and 25 females, median age 12 years. Eighty-four per cent had symptoms of PE. Risk factors for thromboembolism were present in 54 patients (96.4%); most commonly immobility (58.9%), central venous line (35.7%) and recent surgery (28.6%). Investigation revealed a thrombophilic abnormality in 14/40 patients (35%). Concurrent deep vein thrombosis was confirmed in 31 patients (55.4%), predominantly lower limb. D dimer was elevated at presentation in 26/30 patients (86.7%). Eight patients underwent systemic thrombolysis. An inferior vena cava filter was placed in five patients. Therapy was complicated by major haemorrhage in 12 patients (21.4%). The majority (82.1%) had complete or partial resolution of PE following a median of 3 months anticoagulation. Seven patients had a recurrent thromboembolic event and 12 patients died (mortality 21.4%); five due to thromboembolism (8.9%) and two due to haemorrhage. Risk factors for PE in children are distinct from adults and morbidity and mortality is significant. Multicentre prospective studies are required to determine optimal treatment and long-term outcome of childhood PE.