Thromboprophylaxis In Children Research Articles

Enoxaparin thromboprophylaxis in hospitalized obese pediatric patients.

Enoxaparin is an anticoagulant used for pharmacologic thromboprophylaxis in pediatrics. Enoxaparin pharmacokinetics can be altered in the setting of obesity. Optimal enoxaparin dosing for thromboprophylaxis in children with obesity remains unclear. A retrospective review was conducted of pediatric patients who weighed ≥60kg with BMI≥95th percentile, received enoxaparin for thromboprophylaxis, and had at least one appropriately drawn anti-factor Xa(anti-Xa) from 2013 to 2022. Anti-Xa levels were reviewed for patients initially treated with enoxaparin 30mg every 12h. The average daily enoxaparin dose required to achieve an anti-Xa of 0.2-0.4 unit/mL, which was stratified by BMI percentile and weight, was calculated. Of 116 patients (median age 15.8 years) included for analysis, 106 patients were initially treated with enoxaparin 30mg every 12h. Anti-Xa levels were<0.2 unit/mL in 53% of patients with BMI>99th percentile and 54% of patients>100kg. Ninety-one patients had at least one anti-Xa 0.2-0.4unit/mL with an average daily enoxaparin dosing of 66mg. When stratified by severity of obesity, higher doses were required to attain an anti-Xa 0.2-0.4 unit/mL in patients with BMI>99th percentile compared with those with 95th-99th percentile (67.8±15.7 vs. 62±5.6mg/day, p=.01). Patients>100kg required significantly higher dose than those ≤100kg (69.1±15.5 vs 61.2±7.3mg/day, p=.002). Increased initial dosing and/or anti-Xa level monitoring should be considered in adolescents with severe obesity receiving enoxaparin thromboprophylaxis.

Edoxaban for Thromboembolism Prevention in Pediatric Patients With Cardiac Disease

BackgroundStandard of care (SOC) anticoagulation for thromboembolism (TE) prevention in children with cardiac disease includes low molecular weight heparins or vitamin K antagonists. Limited data exists for alternate use of direct oral anticoagulants in children. ObjectivesThe investigators aimed to obtain safety and efficacy data for edoxaban in children. MethodsWe performed a phase 3, multinational, prospective, randomized, open-label, blinded-endpoint trial in patients <18 years of age with cardiac disease (ENNOBLE-ATE [Edoxaban for Prevention of Blood Vessels Being Blocked by Clots (Thrombotic Events) in Children at Risk Because of Cardiac Disease] trial). Patients were randomized 2:1 to age- and weight-based oral edoxaban once daily vs SOC for 3 months (main study period), stratified by cardiac diagnosis. Both groups could continue in an open-label edoxaban extension arm through 1 year. The primary endpoint was adjudicated clinically relevant bleeding (CRB). The main secondary endpoint was symptomatic TE or asymptomatic intracardiac thrombosis. ResultsThe modified intention-to-treat cohort included 167 children. One patient per group experienced a nonmajor CRB in the main period. Treatment-emergent adverse events occurred in 46.8% (51 of 109) with edoxaban and 41.4% (24 of 58) with SOC. One SOC patient experienced 2 TE events (DVT with PE). Among 147 children in the extension, 1 CRB event (0.7%) and 4 TEs occurred (2.8%; 2 strokes and 2 of 33 Kawasaki disease patients with coronary artery thromboses and/or myocardial infarctions). ConclusionsEdoxaban is a potential alternative mode of thromboprophylaxis in children with cardiac disease showing low rates of CRB and TEs with advantages of once daily dosing and infrequent monitoring requirement. (ENNOBLE-ATE [Edoxaban for Prevention of Blood Vessels Being Blocked by Clots] (Thrombotic Events) in Children at Risk Because of Cardiac Disease trial; NCT03395639).

Multisystem inflammatory syndrome, probably associated with SARS-CoV-2, complicated by thrombus in the right atrium, in a child

Aim. Clinical case report of multisystem inflammatory syndrome, probably associated with COVID-19 and complicated by large thrombus in the right atrium in a child highlights the problems of monitoring, treatment, and the possibility of their solution. Presentation of a clinical case. We demonstrate one of the cases of multisystem inflammatory syndrome (MIS-C), which meets WHO criteria. In a child with a severe course of the disease and symptoms of hyperinflammation, on the 16th day from the onset of the disease, a positive effect was registered on the introduction of human normal immunoglobulin for intravenous administration and glucocorticosteroids. But on the day 27 of the disease, despite administration of anticoagulant therapy, a large blood clot was found in the right atrium cavity. Operation was performed with removal of the thrombus from the right atrium under artificial blood circulation and the child was discharged in satisfactory condition to continue treatment in an outpatient setting on the day 56 of the disease. Conclusions. Timely diagnosis of MIS-C in children with fever, signs of inflammation and organ dysfunction during the pandemic spread of COVID-19 and reasonable administration of intravenous immunoglobulin and steroids may reduce the inflammatory response and improve the prognosis. It is also important to conduct population-based prospective studies to optimize thromboprophylaxis in children with COVID-19 and MIS-C.

Thromboprophylaxis for children hospitalized with COVID‐19 and MIS‐C

BackgroundLimited data exist about effective regimens for pharmacological thromboprophylaxis in children with acute coronavirus disease 2019 (COVID‐19) and multisystem inflammatory syndrome in children (MIS‐C). ObjectivesStudy the outcomes of institutional thromboprophylaxis protocol for primary venous thromboembolism (VTE) prevention in children hospitalized with acute COVID‐19/MIS‐C. MethodsThis single‐center retrospective cohort study included consecutive children (aged less than 21 years) with COVID‐19/MIS‐C who received tailored intensity thromboprophylaxis, primarily with low‐molecular‐weight heparin, from April 2020 through October 2021. Thromboprophylaxis was given to those with moderate to severe disease based on the World Health Organization scale and exposure to two or more VTE risk factors. Therapeutic intensity was considered for severe illness. Clinical recovery along with D‐dimer improvement determined thromboprophylaxis duration. Outcomes were incident VTEs, bleeding, and mortality. ResultsAmong 211 hospitalizations, 45 (21.3%) received thromboprophylaxis (COVID‐19, 16; MIS‐C, 29). Median age was 14.8 years (interquartile range [IQR], 8.9–16.1). Among 35 (77.8%) with severe illness, 27 (60.0%) required respiratory support, and 19 (42.2%) required an intensive care unit stay. Median hospitalization was 6 days (IQR, 5.0–10.5). Median thromboprophylaxis duration was 19 days (IQR, 6.0–31.0) with therapeutic intensity in 24 (53.3%) and prophylactic in 21 (46.7%). Outcomes were as follows: VTE, 1 (2.2%); death, 1 (2.2%, unrelated to bleeding/thrombosis); major/clinically relevant nonmajor bleeding, 0; and minor bleeding, 7 (15.5%). D‐dimer was elevated in a majority at diagnosis (median, 2.3; IQR, 1.2–3.3 mg/ml fibrinogen‐equivalent units) and was noninformative in assessing disease severity. D‐dimer normalized at thromboprophylaxis discontinuation. ConclusionsOur experience of using clinically directed thromboprophylaxis with tailored intensity approach for children hospitalized with COVID‐19 and MIS‐C favors its inclusion in current standard of care. The role of D‐dimer in directing thromboprophylaxis management deserves further evaluation.

Prophylaxis of Venous Thromboembolism in Children: A Systematic Review.

Venous thromboembolism (VTE) in children is a rare but serious event. Current guidance on pharmacological thromboprophylaxis in children is mostly based on adult studies and expert opinions. The aim of this systematic review was to examine under which conditions children (age ≤ 18 years) would benefit from pharmacological thromboprophylaxis with low molecular weight heparin or unfractionated heparin. Eligible studies included children, who did not receive pharmacological thromboprophylaxis as comparator, and VTE events were radiologically verified. MEDLINE and Embase were searched up to October 3, 2021. Ten studies were included presenting data for 976 children receiving pharmacological thromboprophylaxis. We divided the studies into three categories based on the population studied: children in the intensive care unit (n = 2), children with fractures and/or undergoing surgery (n = 5), and children with systemic disease (n = 3). A lower incidence of VTE was found when pharmacological thromboprophylaxis was used compared with no prophylaxis in children in intensive care unit with central venous catheter and mechanical ventilation (7/27 vs. 13/24), children in the intensive care unit admitted after trauma with a very high risk of VTE based on several risk factors (0/21 vs. 13/96), and children with acute lymphoblastic leukemia treated with L-asparaginase concomitant with steroid and presence of central venous catheter (0/82 vs. 8/121). Pharmacological thromboprophylaxis was not associated with an increased bleeding risk. In conclusion, pharmacological thromboprophylaxis in children is sparsely investigated. Only children with several risk factors for VTE are likely to benefit from pharmacological thromboprophylaxis.

Venous thromboembolism in pediatric patients with acute lymphoblastic leukemia under chemotherapy treatment. Risk factors and usefulness of thromboprophylaxis. Results of LAL‐SEHOP‐PETHEMA‐2013

IntroductionSymptomatic venous thromboembolism (VTE) is diagnosed in 3%–14% of patients during pediatric acute lymphoblastic leukemia (ALL) therapy. There are well‐known risk factors, but the role of others as inherited thrombophilia is still controversial. Prophylaxis with low molecular weight heparin (LMWH) has been described, but its use is not globally accepted. MethodsA retrospective multicentric study in ALL patients 1–18 years old following SEHOP‐PETHEMA‐2013 treatment guideline was performed to evaluate VTE rate, anticoagulant treatment, outcome, risk factors, and safety and usefulness of LMWH administration as primary thromboprophylaxis in children with inherited thrombophilia. ResultsA total of 652 patients were included in the study. VTE incidence was 8.7%. Most of the cases occurred during induction therapy associated with central venous catheter. Univariant analysis showed that family history of thrombosis, presence of mediastinal mass, high‐risk treatment group, and inherited thrombophilia were statistically significant risk factors. LMWH administration seemed to decrease VTE rate in patients with inherited thrombophilia and those with T‐cell ALL phenotype. ConclusionMost of the VTE cases occurred in patients without inherited thrombophilia, but when it is present, the VTE risk is higher. LMWH administration was useful to decrease VTE in these patients.

Safety of Venous Thromboprophylaxis With Low-molecular-weight Heparin in Children With Ulcerative Colitis.

To evaluate for increased rectal bleeding following enoxaparin thromboprophylaxis in children hospitalized for ulcerative colitis (UC). Retrospective cohort study (2007--2016) of 218 inpatients with active UC. Patients receiving enoxaparin were compared with a nonenoxaparin-treated patient group. Severity of UC was determined using the Pediatric Ulcerative Colitis Activity Index (PUCAI). Hemoglobin (Hb) values and packed red blood cell (pRBC) transfusions were reviewed for a 7-day period following hospital admission. A linear mixed effect model was used to compare change in Hb values between the groups. Risk of pRBC transfusion was compared using a log-rank test and Cox proportional hazard regression. A sub-analysis was also conducted restricting to patients with severe UC to provide more generalizable insight into safety profile of enoxaparin. Children hospitalized for UC and receiving enoxaparin were more likely to have severe disease, received infliximab therapy and be admitted after 2010. Use of enoxaparin showed there was not a difference (P = 0.60) in the fall of Hb detected among those with acute severe colitis (initial PUCAI ≥65) during the week following admission. Moreover, there was no difference in the risk of requiring a pRBC transfusion with enoxaparin use (log-rank test all patients: P = 0.80; severe UC: P = 0.88; Cox proportional hazard regression all patients: P = 0.72; severe UC: 0.85). There was no difference in Hb levels or need for blood transfusions in children hospitalized for severe UC (PUCAI ≥65) whether or not they received enoxaparin for thromboembolism prophylaxis.

Venous Thromboembolism Prophylaxis Practices for Patients with Sickle Cell Disease Pre and during the COVID-19 Pandemic

Background: The coronavirus disease pandemic of 2019 (COVID-19) has been associated with coagulopathy and an increased rate of thrombosis in adults. Medical practitioners have been prompted to consider prophylactic anticoagulation in special populations diagnosed with COVID-19. Patients with sickle cell disease (SCD) are predisposed to a hypercoagulable state. Despite the concern for development of venous thromboembolism (VTE) in these patients, there are no standardized guidelines for routine thromboprophylaxis in either adults or children with SCD. Thus, VTE management options are often extrapolated from guidelines for the general population.Methods: A cross-sectional electronic survey was distributed to pediatric and adult hematology oncology practitioners through 7 SCD specific interest groups. Pediatric and adult practitioners were defined as those who medically manage patients 0-21 years of age and >21 years of age respectively. We examined responses to survey questions focused on routine thromboprophylaxis practices in children and adults with SCD prior to the pandemic and in patients with SCD admitted with COVID-19. Chi-square analyses or Fisher’s exact tests for small samples were used to compare proportions as needed.Results: The survey was distributed to approximately 2,550 providers. Of 93 total responses, 14% (N=13) only treat patients >21yo; 38.7% (N=36) only treat patients 0-21yo and 47.3% (N=44) treat both. Nearly all adult practitioners (96.6%) would recommend pharmacologic prophylaxis, mechanical prophylaxis or both for hospitalized adults, but only 76% of pediatric treaters would recommend any prophylaxis (PPX) in hospitalized children (p<0.0001, Figure 1). Only 16% would recommend pharmacologic PPX only for patients 0-21yo, with 36% preferring non-pharmacologic only methods and 24% preferring both forms. In contrast, for the >21yo patients, 51% preferred to use both pharmacologic and non-pharmacologic PPX, 25% preferred pharmacologic alone, with just 5.3% preferring non-pharmacologic PPX only. Enoxaparin was the most frequently used anticoagulant among both pediatric and adult practitioners [78% vs 89% respectively] (Figure 2). Direct oral anticoagulants (DOACS) were infrequently recommended (3.8% for SCD children and 10.9% for adults); of these, rivaroxaban was used most often. The most common indication for starting thromboprophylaxis for both 0-21yo and >21yo patients was history of prior VTE [81% and 81% respectively], followed by hip replacement [57% and 75% respectively].In patients admitted with COVID-19, prophylactic anticoagulation was recommended for adults by 94% of treaters. There was a significant increase in the use of prophylactic anticoagulation in children with COVID-19 vs. those without (84% vs. 40%; p=.0001). Figure 3 shows extended thromboprophylaxis practices upon discharge for COVID related admissions. Almost half of respondents (46%) would not recommend any thromboprophylaxis for children on discharge; 37% would recommend either 2-4 weeks or >4weeks of post-discharge PPX. The majority of adult providers would recommend discharge thromboprophylaxis for adults with 2 weeks post discharge (33%), and 2-4 weeks (30%) being the most common regimens.Conclusion:This pilot survey describes the thromboprophylaxis practices used for adult and pediatric SCD patients by specialty practitioners. In general, practitioners were likely to prescribe pharmacologic thromboprophylaxis for adults while mechanical PPX was preferred for children. However, in the high-risk setting of COVID-19 infection, pediatric practitioners would modify their practice to include pharmacologic thromboprophylaxis. Interestingly, despite the long-term availability of direct oral anticoagulants in adults, and recent completion of pediatric studies, the most commonly used pharmacologic agent pre-COVID in adults and children was enoxaparin. Of note, this survey was conducted prior to release of the International Society on Thrombosis and Haemostasis guidelines regarding discharge PPX in COVID-19. (Spyropoulos AC, J Thromb Haemost, 2020)These results highlight the influence of COVID-19 on the use of pharmacologic thromboprophylaxis, specifically in the pediatric population. Due to frequent hospitalization, studies are needed to guide decision making surrounding VTE PPX for the adult and pediatric inpatient SCD population.DisclosuresDavila:Spire Learning: Speakers Bureau; ATHN: Other: Grant Funding. Minniti:Bluebird bio: Consultancy, Research Funding; TauTona: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Emmaus: Consultancy, Research Funding; CLS Bering: Consultancy; Novartis: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding. Desai:Pfizer, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; GBT, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ironwood Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Rockpointe Continuing Medical Education Company: Consultancy. O'Brien:Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees.OffLabel Disclosure:Enoxaparin used as a form of thromboprophylaxis in children.

Provider Practices Regarding Prophylactic Anticoagulation in Children with Leukemia

Venous thromboembolism (VTE) is a known complication in children with leukemia, with prevalence in acute lymphoblastic leukemia (ALL) reported as high as 37% (Mitchell, et al, Cancer, 2003). Indwelling catheters, hyperviscosity, mediastinal masses, and medications such as asparaginase, can all contribute to increased VTE risk. In addition to national interest in preventing VTE in hospitalized children, decreasing risk of VTE in children with cancer is of great importance to pediatric hematologist/oncologists. The International Society of Hemostasis and Thrombosis released a guidance statement (Tullius, et al, JTH, 2017) that suggested considering thromboprophylaxis on a case-by-case basis for children with cancer and multiple VTE risk factors, and suggested discontinuing anticoagulant prophylaxis when predisposing conditions resolve. Children with leukemia certainly may have multiple risk factors and therefore deserve consideration for prophylaxis. The Children's Oncology Group is currently conducting a clinical trial studying thromboprophylaxis during induction for ALL. Given the importance of reducing VTE and the interest in thromboprophylaxis, we sought to assess practitioners' practices regarding thromboprophylaxis in children with leukemia. We performed a cross sectional, anonymous survey of pediatric members of VENUS (the VTE Network of the Hemostasis and Thrombosis Research Society) and ASH (the American Society of Hematology) using Qualtrics, a secure online survey tool. Responses were excluded if physicians answered no to either of 2 screening questions (related to clinical practice and board certification/eligibility), or if no questions were answered after screening. A gift card incentive was offered anonymously. Institutional IRBs approved this study. 870 surveys were distributed, with a response rate of 17.7%; after exclusions, a total of 142 surveys were included. Demographics were well balanced regarding size of program and years in practice. When asked about which anticoagulant agents may be used for thromboprophylaxis (n=36), 92% of those responding reported using enoxaparin (Table 1). In addition, 36% use Apixaban and 14% use Rivaroxaban. When asked if they ever provide primary VTE prophylaxis to children with leukemia (n=127), 71% said no, while 29% answered yes (Table 1). When asked in what scenarios primary prophylaxis was used, the most common answer was in leukemia patients with a known inherited thrombophilia (57%). Also common were children with mediastinal masses with vessel compression, and children enrolled on the COG prophylaxis study. Some additional scenarios offered were AYA patients, and those with additional risk factors, such as obesity and immobility. When asked about duration of primary prophylaxis (n=36), the most common times for discontinuing therapy were resolution of mediastinal mass and/or vessel compression (58%), end of all asparaginase therapy (50%), and until the central line is removed (42%). A smaller number of physicians (22%) would consider continuing anticoagulant prophylaxis until the end of all cancer chemotherapy. When questioned about secondary prophylaxis following VTE (n=127), 8% of respondents never provide post-VTE prophylaxis, 11% always give post-VTE prophylaxis, and 81% used post-VTE prophylaxis in certain cases (Table 1.) The most common stopping point for secondary prophylaxis (n=116) was after central line removal (55%), followed by completion of all asparaginase therapy (41%). Our study is limited by a low response rate. Due to technical issues, we had missing data for many questions and could not obtain free-text answers for some of the prophylaxis questions, limiting full data acquisition. Despite these issues, our results provide some insights into current practices of pediatric hematologist/oncologists. This study shows that many physicians are not utilizing primary anticoagulant prophylaxis in their pediatric leukemia patients, despite the high-risk nature of these patients, possibly trying to balance bleeding risk due to thrombocytopenia. Duration of anticoagulant therapy varies, and it is likely that there are no clear definitions regarding resolution of predisposing factors. Given their unique set of risk factors, and the potential morbidity associated with VTE, further study of VTE prophylaxis is essential for development of pediatric leukemia-specific guidelines. Disclosures Cooley: off-label: Other: drug use. Acharya:Bayer Pharmaceuticals, LLC: Research Funding; Novonordisk: Membership on an entity's Board of Directors or advisory committees; BioProducts Laboratory: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: We surveyed physicians on which anticoagulants they use in their pediatric leukemia patients and the majority of drugs offered as answer choices are technically off-label.

Effectiveness and Safety of Primary Thromboprophylaxis in Children with Cancer: A Systematic Review of the Literature and Network Meta-Analysis.

Thromboembolism (TE) is a well-recognized complication of pediatric cancer and can lead to mortality and excess morbidity. There is conflicting evidence about the effectiveness and safety of thromboprophylaxis in children. We conducted a systematic literature review and network meta-analysis of primary pharmacological thromboprophylaxis in children and adolescents (0-21 years) with cancer. The primary outcomes were objectively proven TE and major bleeding. The network meta-analysis included comparisons of multiple alternatives simultaneously: antithrombin (AT) replacement, low molecular weight heparin (LMWH), vitamin K antagonists (VKAs), and standard of care (SOC) defined as no thromboprophylaxis or low-dose heparin for catheter patency. Six articles describing 1,318 patients were included (mean age: 6.7 years, 56.7% male). Acute lymphoblastic leukemia was the underlying diagnosis in 97.5% of patients. All studies were considered at moderate or high risk of bias. LMWH was the only agent associated with lower odds of TE compared with SOC (odds ratio [OR]: 0.23, 95% confidence interval [CI]: 0.06-0.81). No statistically significant difference was detected between other thromboprophylaxis modalities and SOC. Tau2 and I 2 suggested a high degree of heterogeneity. No statistically significant differences in the odds of major bleeding were found between AT replacement, LMWH, VKA, and SOC. Current evidence suggests that low-dose LMWH is effective and safe to prevent TE in children with cancer but is insufficient to conclude if AT replacement or VKA are effective thromboprophylaxis options. Further research, notably randomized controlled trials enrolling children with diverse types of cancer, is crucially needed.

Prevention of perioperative venous thromboembolism in pediatric patients: Guidelines from the Association of Paediatric Anaesthetists of Great Britain and Ireland (APAGBI).

The Association of Paediatric Anaesthetists of Great Britain and Ireland (APAGBI) Guidelines Working Group on Thromboprophylaxis in Children has reviewed the literature and where possible provided advice on the care of children in the perioperative period. Areas reviewed include the incidence of perioperative venous thromboembolism (VTE), risk factors, evidence for mechanical and chemical prophylaxis, and complications. Safe practice of regional anesthesia with anticoagulant prophylaxis is detailed. In summary, there are few areas of strong evidence. Routine prophylaxis cannot be recommended for young children. Postpubertal adolescents (approximately 13 years and over) are at a slightly increased risk of VTE and should be assessed for prophylaxis and may warrant intervention if other risk factors are present. However, the incidence of VTE is significantly lower than in the adult population. This special interest review presents a summary and discussion of the key recommendations, a decision-making algorithm and a risk assessment chart. For the full guideline, go to www.apagbi.org.uk/publications/apa-guidelines.

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

BackgroundVenous 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/DesignThromboprophylaxis 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.DiscussionThis 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 registrationNederlands Trial Register NTR4707. Registered 30 July 2014.

Clinical Predictors of Venous Thromboembolism during Therapy for Childhood Acute Lymphoblastic Leukemia

Venous thromboembolism (VTE) is an unpredictable and life-threatening toxicity that occurs early in acute lymphoblastic leukemia (ALL) therapy. The incidence is approximately 5% in children diagnosed with ALL [Caruso et al. Blood. 2006;108(7):2216-22], which is higher than in other pediatric cancer types [Athale et al. Pediatric Blood & Cancer. 2008;51(6):792-7]. Clinical risk factors for VTE in children during ALL therapy include older age and the use of asparaginase. We hypothesized that there may be additional risk factors that can modify VTE risk, beyond those previously reported [Mitchell et al. Blood. 2010;115(24):4999-5004]. We sought to define early predictive clinical factors that could select a group of children at highest risk of VTE, with possible utility in an interventional trial of prophylactic anticoagulation.We conducted a retrospective study of 1021 Australian children, aged 1-18 years, treated between 1998-2013 on successive BFM-based ALL therapies. Patient records were reviewed to ascertain incidence of VTE; and to systematically document clinical variables present at diagnosis and during induction/consolidation phases of therapy. The CTCAE v4.03 system was used for grading of VTE events. Multivariate logistic and cox regression were used to determine significant clinical risk factors associated with VTE (SPSS v23.0). All P values were 2-tailed, significance level <.05.The incidence of on-treatment VTE was 5.09% [96% ≥Grade 2 (CTCAE v4.0)]. Age ≥10 years [P =.048, HR 1.96 (95% confidence interval= 1.01-3.82)], positive blood culture in induction/consolidation [ P =.009, HR 2.35 (1.24-4.46)], extreme weight at diagnosis <5th or >95th centile [ P =.028, HR 2.14 (1.09-4.20)] and elevated peak gamma-glutamyl transferase (GGT) >5 x upper limit normal in induction/consolidation [ P =.018, HR 2.24 (1.15-4.36)] were significantly associated with VTE in multivariate cox regression modeling. The cumulative incidence of VTE, if all 4 clinical risk factors in our model were present, was 33.33%, which is significantly greater than the incidence of VTE for a patient without any risk factors (1.62%, P <.001).These 4 clinical factors could be used as a basis for assigning thromboprophylaxis in children with ALL. Our model detected 80% (42/52) of all VTE events by incorporating one or more risk factors. An equal proportion of patients eventually developing VTE could be predicted by weight and age ≥10 years; or later bacteremia and elevated GGT. Bacteremia, when present as a risk factor, preceded VTE in 80% of cases (20/25 cases) at a median of 29 days before VTE (range 3-668 days).The negative predictive value (NPV), specificity and sensitivity for the 4 risk factor model were 98.38%, 98.70% and 28.57% respectively.If 3 specified risk factors were included in the algorithm, such as 2 baseline and one treatment-related variable, the incidence of VTE was ≥25%, NPV 98.38%, specificity ≥96.19% and sensitivity 80%. The high NPV and high specificity mean the model can successfully exclude children who are not at increased risk of VTE. The challenge is to balance unnecessary exposure to anticoagulation against the risk of development of VTE.We have identified novel clinical risk factors in induction/consolidation - positive blood culture, hepatic enzymatic elevation and extreme weight at diagnosis- that may highlight risk mechanisms related to VTE pathogenesis. Our predictive model can define a group at highest risk of VTE who may benefit from randomized trials of prophylactic anticoagulation in childhood ALL therapy.Acknowledgments: The authors acknowledge support from the Kids Cancer Alliance (a Translational Cancer Research Centre of Cancer Institute NSW), Cancer Institute New South Wales, Royal Australasian College of Physicians - Kids Cancer Project Research Entry Scholarship, Cancer Therapeutics CRC (CTx) PhD Clinician Research Top-Up Scholarship, The Kids Cancer Project, Australian and New Zealand Children's Haematology Oncology Group, ASSET study members, data managers and clinical research associates at each site. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

THROMBOEMBOLIC DISEASE IN CHILDREN (EPIDEMIOLOGY, ETIOPATHOGENY AND DIAGNOSIS) (I)

Thrombosis is the result of an imbalance between two complex systems: hemostasis and fibrinolysis. Although the incidence of thromboembolism is lower in children than in adults, the associated morbidity is clinically relevant. This paper summarizes the main risk factors – important in defining effective strategies for primary thrombo-prophylaxis in children at risk, the diagnostic criteria and the optimal therapeutic approach, which have mostly been extrapolated from the adult’s recommendations until now.

Central venous catheter‐related thrombosis and thromboprophylaxis in children: a systematic review and meta‐analysis

In preparation for a pediatric randomized controlled trial on thromboprophylaxis, we determined the frequency of catheter-related thrombosis in children. We also systematically reviewed the pediatric trials on thromboprophylaxis to evaluate its efficacy and to identify possible pitfalls in the conduct of these trials. We searched MEDLINE, EMBASE, Web of Science and the Cochrane Central Register for Controlled Trials for articles published until December 2013. We included cohort studies and trials on patients aged 0-18years with central venous catheters who underwent active surveillance for thrombosis with radiologic imaging. We estimated the pooled frequency of thrombosis and the pooled risk ratio (RR) with thromboprophylaxis by using a random effects model. From 2651 articles identified, we analyzed 37 articles with 3128 patients. The pooled frequency of thrombosis was 0.20 (95% confidence interval [CI]0.16-0.24). In 10 trials, we did not find evidence that heparin-bonded catheters (RR0.34; 95%CI0.01-7.68), unfractionated heparin (RR0.93; 95%CI0.57-1.51), low molecular weight heparin (RR1.13; 95%CI0.51-2.50), warfarin (RR0.85; 95%CI0.34-2.17), antithrombin concentrate (RR0.76; 95%CI0.38-1.55) or nitroglycerin (RR1.53; 95%CI0.57-4.10) reduced the risk of thrombosis. Most of the trials were either not powered for thrombosis or were powered to detect large, probably unachievable, reductions in thrombosis. Missing data on thrombosis also limited these trials. Catheter-related thrombosis is common in children. An adequately powered multicenter trial that can detect a modest, clinically significant reduction in thrombosis is critically needed. Missing outcome data should be minimized in this trial.

Supportive Care in Pediatric Cancer: The Road to Prevention of Thrombosis

The survival rate of children with cancer has increased impressively to almost 80% over the last decades as a result of improved diagnostic procedures and multimodal treatment strategies. Therefore, it becomes more and more important to prevent mortality and morbidity of treatment-associated complications, including venous thromboembolism (VTE). VTE occurs predominantly in children with acute lymphoblastic leukemia, lymphoma, and sarcoma. Pathogenesis of thrombosis in children with cancer is multifactorial. Thrombosis develops due to a combination of the primary disease itself, chemotherapy and supportive care, associated complications, and inherited prothrombotic risk factors probably contributed to the development of thrombosis in these children. Mortality as a result of VTE is low, but both symptomatic and asymptomatic thrombosis cause significant morbidity to justify primary thromboprophylaxis in children with cancer. Identification of risk factors is important to develop predictive models to identify patients at highest risk of thrombosis. Due to variations in risk factors, these models should be tailored to treatment protocols and patient populations. Multicenter studies are needed to investigate which prophylactic strategies are effective and safe to prevent thrombosis in children with cancer.

Venous thromboembolism in children with cancer – A population-based cohort study

IntroductionCancer is a known risk factor for venous thromboembolism (VTE) in adults, but population-based data in children are scarce.Materials and methodsWe conducted a cohort study utilising linkage of the Clinical Practice Research Database (primary care), Hospital Episodes Statistics (secondary care), UK Cancer Registry data and Office for National Statistics cause of death data. From these databases, we selected 498 children with cancer diagnosed between 1997 and 2006 and 20,810 controls without cancer. We calculated VTE incidence rates in children with cancer vs. controls, and hazard ratios (HRs) using Cox regression.ResultsWe identified four VTE events in children with cancer compared with four events in the larger control population corresponding to absolute risks of 1.52 and 0.06 per 1000 person-years respectively. The four children with VTE and cancer were diagnosed with hematological, bone or non-specified cancer. Childhood cancer was hence associated with a highly increased risk of VTE (HR adjusted for age and sex: 28.3; 95%CI = 7.0-114.5).ConclusionsChildren with cancer are at increased relative risk of VTE compared to those without cancer. Physicians could consider thromboprophylaxis in children with cancer to reduce their excess risk of VTE however the absolute risk is extremely small and the benefit gained therefore would need to be balanced against the risk invoked of implementing such a strategy.Novelty & Impact StatementsWhile there is a reasonable level of knowledge about the risk of VTE in adult populations, it is not well known whether this risk is reflected in paediatric patients. We found a substantial increase in risk of VTE in children with cancer compared to a child population without cancer. While this finding is important, the absolute risk of VTE is still low and must be balanced with the risks of anticoagulation.

Venous Thromboembolism in Children

The term venous thromboembolism (VTE) includes deep venous thrombosis of the extremity and pulmonary embolism, a potentially fatal clinical entity. Although the prevalence of VTE may be lower in children compared with adults, recent reports suggest a possible rise in this diagnosis among pediatric patients, especially in association with certain risk factors. We assessed the clinical experience and practice of members of the Pediatric Orthopaedic Society of North America (POSNA) related to VTE among their pediatric patients. A 36-question online survey was sent to all 636 active POSNA members. The proportion of surgeons who had encountered at least 1 child with VTE and the respondents' practice of using thromboprophylaxis in children (<18 y old) was assessed. The relationship of responders' experience with VTE among pediatric patients with various practice characteristics was evaluated. The response rate was 56% (354/636). More than half (55%) [95% confidence interval (CI), 50%-60%] of the respondents could recall at least 1 (median, 2 cases/member) pediatric patient with deep venous thrombosis and 29% (95% CI, 24%-34%) could recall ≥1 child with pulmonary embolism. Approximately one quarter (23%) (95% CI, 18%-27%) of all respondents reported never using mechanical prophylaxis and almost one half (45%) (95% CI, 40%-50%) of respondents reported never using pharmacologic prophylaxis against VTE in children. Only 16% (95% CI, 12%-20%) of the respondents had a thromboprophylaxis protocol for pediatric patients. Respondent characteristics such as being in clinical practice <5 years (P=0.01) and having a surgical volume of <100 cases/y (P=0.03) were associated with a lower likelihood of encountering a pediatric patient with VTE. More than half of responding active POSNA members reported having come across at least 1 case of VTE among pediatric patients during their practice. The routine use of VTE prophylaxis for children is uncommon among pediatric orthopaedists. Further studies aimed at determining the prevalence of VTE and developing specific guidelines for prophylaxis among pediatric patients seeking orthopaedic care are warranted. IV.

G184(P) Thrombophilia Testing in Children; Three Case Vignettes

AimAn increasing number of children are being tested for inherited thrombophilias. We present three cases of children known to our centre, who were tested for and found to have a...

Natural Health Product Utilization in Warfarinized Children; Prevalence and Knowledge

Background:The need for long-term thromboprophylaxis in children using warfarin therapy is increasing. Natural health products (NHPs) are administered to children by parents who perceive them to be useful and acceptable adjuncts or alternatives to conventional therapies. Interactions of NHPs with prescribed therapies may result in serious adverse events. NHP usage is underevaluated in children and there are no studies evaluating NHP usage in warfarinized children.Objectives:To explore NHP use in warfarinized children and their siblings to determine the prevalence, varieties, and reasons for NHP usage, as well as the potential effect on warfarinization (eg, time in therapeutic range [TTR]).Methods:This is a 3-phase cross-sectional cohort study that includes the (1) prevalence (2) NHP education and knowledge assessment, and (3) the follow-up NHP utilization phase.Results:Forty-six percent of warfarinized children consumed NHPs, with time in therapeutic range of 74%. The mean score for baseline knowledge of NHPs and warfarin following the education phase was 67%. Follow-up NHP use was 30%, and increased consistency of utilization with TTR was 83% (p &lt; 0.05), consistent with education provided.Conclusions:The consistent prevalence rates over time of NHP usage in warfarinized children indicate the need for future studies. Education remains vital to combat the potential risks of NHP-warfarin interaction, encouraging patient disclosure and consistency.