Recombinant factor VIII Fc fusion protein for first-time immune tolerance induction: final results of the verITI-8 study.

Inhibitor development remains a major challenge in factor VIII (FVIII) replacement therapy. verITI-8 is the first prospective study of a recombinant FVIII Fc fusion protein (rFVIIIFc; efmoroctocog alfa) for first-time immune tolerance induction (ITI) in males with severe hemophilia A and high-titer inhibitors (historical peak ≥5 Bethesda units [BU]/mL). In this single-arm, open-label, multicenter study, screening was followed by ITI (rFVIIIFc 200 IU/kg per day until tolerization or maximum of 48 weeks). Those who achieved ITI success entered a tapering period, returning to standard prophylaxis, and then entered follow-up. Primary end point was time to tolerization with rFVIIIFc defined by inhibitor titer <0.6 BU/mL, incremental recovery (IR) ≥66% of expected IR (IR ≥1.32 IU/dL per IU/kg), and half-life (t½) ≥7 hours within 48 weeks. Sixteen patients received ≥1 rFVIIIFc dose. Twelve (75%), 11 (69%), and 10 patients (63%), respectively, achieved negative inhibitor titers, an IR ≥66%, and a t½ ≥7 hours (ie, tolerance) within 48 weeks. Median times in weeks to achieve these markers of success were 7.4 (interquartile range [IQR], 2.2-17.8), 6.8 (IQR, 5.4-22.4), and 11.7 (IQR, 9.8-26.2), respectively. All patients experienced ≥1 treatment-emergent adverse event (TEAE), and 1 reported ≥1 related TEAE (injection site pain). Nine patients experienced ≥1 treatment-emergent serious AE. No thrombotic events, discontinuations because of AEs, or deaths were reported during the study. As the first extended half-life rFVIII with prospective data in ITI, rFVIIIFc offered short time to tolerization with durable responses in almost two-thirds of patients and was well tolerated. This trial was registered at www.clinicaltrials.gov as #NCT03093480.

Canadian clinical experience on switching from standard half-life recombinant factor VIII (rFVIII), octocog alfa, to extended half-life rFVIII, damoctocog alfa pegol, in persons with haemophilia A ≥ 12 years followed in a Comprehensive Hemophilia Care Program in Canada.

INTRODUCTION: Damoctocog alfa pegol (BAY 94-9027, Jivi®) is an extended half-life recombinant factor (F)VIII replacement, indicated for the treatment of haemophilia A in patients aged ≥12 years. Following introduction of damoctocog alfa pegol in Canada in 2020, there have been no reports on routine clinical effectiveness and satisfaction, when switching from a previous FVIII product in Canada. AIM: To report changes in pharmacokinetics, effectiveness, utilization and patient satisfaction when switching to damoctocog alfa pegol prophylaxis from previous standard half-life octocog alfa (BAY 81-8973, Kovaltry®) treatment. METHODS: A single-centre, intra-patient comparison of pharmacokinetics and clinical outcomes was performed. Blood samples drawn once pre-dose and ≥2 times post-dose were measured by a one-stage assay to assess pharmacokinetic parameters including area under the curve (AUC, primary endpoint). Patient-reported outcomes data were collected using the Patient-Reported Outcomes, Burdens and Experiences questionnaire (PROBE). Clinical outcomes included annualized bleeding rate (ABR) and factor utilization. RESULTS: Dose-normalized AUC was significantly increased after switch to damoctocog alfa pegol from octocog alfa. Median (quartile [Q]1; Q3) annualized bleeding rates were 0.67 (0.00; 1.33) with damoctocog alfa pegol and 1.33 (0.00; 2.67) with octocog alfa. Half of the patients receiving damoctocog alfa pegol prophylaxis experienced zero bleeds (n = 9, 50.0%) versus 38.9% (n = 7) of patients treated with octocog alfa. Patients' good quality of life was maintained. CONCLUSION: This study provides routine clinical evidence supporting the benefits of switching from octocog alfa to damoctocog alfa pegol for patients with severe haemophilia A.

Development and validation of thromboembolism diagnostic algorithms in children with cancer from real-world data.

OBJECTIVE: To evaluate the accuracy of diagnostic algorithms developed using the International Classification of Diseases (ICD-9-CM and ICD-10-CA) diagnostic codes and physician billing codes for thromboembolism (TE) from health administrative data compared to chart review diagnoses of TE in children with cancer. METHODS: Using data linkage between the Pediatric Oncology Group of Ontario Network Information System (Ontario pediatric cancer registry) and various administrative data housed at ICES, eight algorithms were developed including a single reference to one of the billing codes, multiple references with varying time intervals, and combinations of various billing codes during primary cancer therapy for the whole cohort and, for early (<04/2002) and later (≥04/2002, solely ICD-10 codes) periods. Reference standard was chart review data from prior studies (from 1990 to 2016) among children (≤19 years) with cancer and radiologically confirmed TE. RESULTS: Records of 2056 patients diagnosed with cancer at two participating sites during study period were reviewed; 112 had radiologically confirmed TE. The algorithm with addition of anticoagulation utilization codes was the best performing algorithm (sensitivity = 0.76;specificity = 0.85). With use of ICD-10 only codes, sensitivity of the same algorithm improved to 0.84 with specificity of 0.80. CONCLUSION: This study provides a valid approach for ascertaining pediatric TE using real-world data. IMPACT: Research in pediatric thrombosis, especially cancer-related thrombosis, is limited mainly due to small-sized studies. Real-world data provide ready access to large and diverse populations. However, there are no validated algorithms for identifying thrombosis in real-world data for children. An algorithm based on combination of thrombosis and anticoagulation utilization codes had 76% sensitivity and 85% specificity to identify diagnosis of thrombosis in children in administrative data. This study provides a valid approach for ascertaining pediatric thrombosis using real-world data and offers a good avenue to advance pediatric thrombosis research.

Availability of Safe and Effective Therapeutic Options to Pregnant and Lactating Individuals Following the United States Food and Drug Administration Pregnancy and Lactation Labeling Rule.

OBJECTIVE: To explore the extent and type of pregnancy and lactation data of newly approved prescription drugs and assess whether the presented recommendations are data-driven, as required by the US Food and Drug Administration Pregnancy and Lactation Labeling Rule implemented in 2015. STUDY DESIGN: In this descriptive analysis, we reviewed pregnancy and lactation data of all new molecular entities approved between 2001 and 2020 in their most updated labeling. Information was collected regarding the pregnancy and lactation risk statements, the source of pregnancy and lactation data, and the design and methods of pregnancy and lactation studies in the labeling. RESULTS: Of the 422 new molecular entities, the key advisory statement for use of 133 (32%) drugs in pregnancy and 194 (46%) drugs in lactation were classified as "against use." Less than 2% of all drugs had a key advisory statement that supported their use during pregnancy or lactation. The sources of data regarding use in pregnancy were studies in human and animals in 46 (11%) and 348 (82%) drugs, respectively. For use during lactation, data included studies in human and animals in 23 (5%) and 251 (59%) drugs, respectively. The key advisory recommendation was consistent with the available human information in 4 (8%) drugs in pregnancy and 3 (13%) drugs in lactation. Prescription drug labeling contains limited data to support informed decision-making for the use of prescription drugs during pregnancy/lactation. Close collaboration among stakeholders is required to enhance the availability of data in this population.

Long-term immunogenicity, efficacy and tolerability of simoctocog alfa in patients with severe haemophilia A who had completed the NuProtect study in previously untreated patients.

BACKGROUND: The NuProtect study reported data on the immunogenicity, efficacy and tolerability of simoctocog alfa (Nuwiq® ) in 108 previously untreated patients with severe haemophilia A planned to be treated for ≥100 exposure days or up to 5 years. The NuProtect-Extension study collected long-term prophylaxis data in children with severe haemophilia A. METHODS: Patients who completed the NuProtect study according to the protocol were eligible for the NuProtect-Extension study, a prospective, multinational, non-controlled, Phase 3b study. RESULTS: Of 48 patients who entered the extension study, 47 (median age 2.8 years) received prophylaxis with simoctocog alfa for a median of 24 months, with 82%-88% on a twice-weekly or less regimen. No patient developed FVIII inhibitors during the extension study. The median (IQR) annualized bleeding rate (ABR) during prophylaxis was 0 (0-0.5) for spontaneous bleeding episodes (BEs) and 1.00 (0-1.95) for all BEs. ABRs estimated using a negative binomial model were .28 (95% CI: .15, .53) for spontaneous and 1.62 (95% CI: 1.09, 2.42) for all BEs. During the median follow-up of 24 months, 34 (72%) patients had zero spontaneous BEs and 46 (98%) had zero spontaneous joint BEs. Efficacy in treating BEs was excellent or good for 78.2% of rated BEs, and efficacy of surgical prophylaxis was excellent for two rated surgeries. No treatment-related adverse events were reported. CONCLUSION: No FVIII inhibitors developed during long-term prophylaxis in the NuProtect-Extension study. Prophylaxis with simoctocog alfa was efficacious and well-tolerated, and is therefore an attractive long-term option for children with severe haemophilia A.

Childhood nephrotic syndrome and the clinical profile of thromboembolism: a systematic review and meta-analysis.

Nephrotic syndrome (NS) is a common kidney disease of childhood, affecting 2-7 children per 100,000. A potentially life-threatening complication affecting children with NS is thromboembolism (TE). However, there remains a paucity of information regarding the burden of TE and its associated risk factors in this population. A systematic review was performed on observational studies examining TE events in children with NS, published in Medline, Embase, CINAHL, and CENTRAL, until May 2021. Meta-analyses were separately conducted on the prevalence of TE within articles exclusively studying children with congenital NS and among articles including all forms of NS. Out of 13,626 articles, 22 were included (14,290 children). The pooled prevalence of symptomatic TE among articles including patients with all forms of NS was 3.60% (95% CI 1.95-5.63), which increased to 8.70% (95% CI 5.11-12.96) in articles with exclusively congenital NS patients. Children with steroid-resistant NS were at a higher risk of TE compared to steroid-sensitive children (OR 4.40, 95% CI 1.34-15.59, p = 0.013). Focal segmental glomerulosclerosis was the most common histology present in patients with TE (51.2%). Children diagnosed with NS have a significant risk of TE, particularly in patients with congenital NS and steroid resistance. IMPACT: The prevalence of symptomatic thromboembolic (TE) events in children with nephrotic syndrome (NS) was 3.60% (95% CI 1.95-5.63), which increased more than two-fold in children with congenital NS to 8.70% (95% CI 5.11-12.96). Potential risk factors for TE events in this population include congenital forms of NS and steroid resistance. This review provides a better estimate of the prevalence of TE in children with NS, while identifying potentially higher-risk populations who may benefit from TE screening and thromboprophylaxis.

Simoctocog alfa (Nuwiq®) in previously untreated patients with severe haemophilia A-Final efficacy and safety results from the NuProtect study.

INTRODUCTION: Simoctocog alfa (Nuwiq®) is a 4th generation recombinant FVIII with proven efficacy for the prevention and treatment of bleeding episodes (BEs) in previously treated patients with severe haemophilia A. The NuProtect study assessed the immunogenicity, efficacy and safety of simoctocog alfa in 108 previously untreated patients (PUPs). The incidence of high-titre inhibitors was 16.2% and no patients with non-null F8 mutations developed inhibitors. AIM: To report the efficacy and safety results from the NuProtect study. METHODS: PUPs received simoctocog alfa for prophylaxis, treatment of BEs, or as surgical prophylaxis. The efficacy of prophylaxis (during inhibitor-free periods) was assessed using annualised bleeding rates (ABRs). The efficacy in treating BEs and in surgical prophylaxis was assessed using a 4-point scale. Adverse events were recorded throughout the study. RESULTS: Of 108 PUPs treated with simoctocog alfa, 103 received at least one prophylactic dose and 50 received continuous prophylaxis for at least 24 weeks. In patients on continuous prophylaxis, the median ABR was 0 (mean 0.5) for spontaneous BEs and 2.5 (mean 3.6) for all BEs. In 85 patients who had BEs, efficacy of BE treatment was excellent or good for 92.9% (747/804) of rated BEs; 92.3% of BEs were treated with 1 or 2 infusions. The efficacy of surgical prophylaxis was excellent or good for 94.7% (18/19) of rated procedures. There were no safety concerns and no thromboembolic events. CONCLUSION: Simoctocog alfa was efficacious and well tolerated as prophylaxis, surgical prophylaxis and for the treatment of BEs in PUPs with severe haemophilia A.

Do Children With an Allergic Transfusion Reaction Require Premedication For All Blood Products?

BACKGROUND: Children with a history of allergic transfusion reactions (ATRs) receive antihistamine premedication with or without hydrocortisone to prevent subsequent reactions. We aim to examine the frequency of developing ATRs to subsequent different blood product type transfusions. METHODS: A retrospective chart review of children who received blood product transfusions (packed red blood cells, platelets, frozen plasma, intravenous immunoglobin, albumin, and cryoprecipitate) and developed ATRs. Cases were identified through Transfusion Transmitted Injuries Surveillance System- Ontario database with a complementary chart review. Demographics and subsequent transfusions records were described. RESULTS: During this period, 35,925 blood products were transfused to 4153 patients. Thirty-eight ATRs were reported in 30 patients. All ATRs were minor except 1 anaphylaxis to albumin transfusion. Seven patients (23%) developed multiple ATRs, and all of them were of the same blood product type. A total of 60 subsequent different blood product types were transfused to the 7 patients who had multiple ATRs; none of those transfusions caused ATR. CONCLUSION: In children with a history of ATR, developing a reaction to a different blood product type is rare. Hence, premedicating those transfusions is not warranted.

Management of Colorectal Cancer with Synchronous Liver Metastases: An Inception Cohort Study (CoSMIC).

BACKGROUND: Approximately one-fifth of patients with colorectal cancer present with hepatic metastases. There are limited prospective data on the outcomes of synchronous combined liver and bowel surgery and liver-first or bowel-first routes where contemporary chemo(radio)therapy is integrated into management. METHODS: Between 1 April 2014 and 31 March 2017, 125 patients with colorectal cancer and synchronous liver metastases were recruited. Data are reported on pathway-specific outcomes, including perioperative complications, treatment completion, and overall and disease-free survival. The study was registered with ClinicalTrials.gov (NCT02456285). RESULTS: There was no difference in age, body mass index, or Charlson score between surgical groups. Neoadjuvant chemotherapy was used in 50 (40%) patients for a mean duration of 4.6 months (standard deviation [SD] 5.4), and mean time from completion of chemotherapy to surgery was 2.6 months (SD 1.9). Complications were similar between patients completing the synchronous and staged pathways (p = 0.66). Mean total inpatient stay was 16.5 days (SD 8.1) for staged surgery compared with 16.8 days (SD 10.3) for the synchronous group (t-test; p = 0.91). There was no difference in time to treatment completion between pathways. Thirty six (35%) patients were disease-free at 12 months, with no significant difference between groups (Chi-square, p = 0.448). Quality of life was similar in all surgical groups. CONCLUSIONS: Perioperative complications and oncological and healthcare occupancy outcomes are equivalent between patients completing staged and synchronous pathways for the management of patients with colorectal cancer and synchronous liver metastases. Future studies should focus on optimizing the criteria for pathway selection, incorporation of cancer genomics data, and patient (user) preferences.

Risk factors for neonatal thrombosis: A retrospective study conducted in a single Canadian intensive care unit.

Among children, neonates have the highest incidence of thrombosis. We conducted a retrospective review of neonatal thrombosis, in a single intensive care unit (ICU) over 4.5 years. Among 4860 ICU admissions to our center, identified through the Canadian Neonatal Network database, 186 were associated with arterial and venous thrombosis involving 195 thrombotic sites. The neonatal thrombosis incidence was 38 per 1000 neonatal ICU admissions. We assessed patient characteristics and compared the association between risk factors and thrombosis. In the multivariate analysis, central venous catheters, sepsis, and respiratory distress syndrome were significant predictors of neonatal thrombosis.

Successful Use of Thrombolysis in an Extremely Low Birth Weight, Premature Infant With Aortic Thrombosis.

BACKGROUND: Severe neonatal aortic thrombosis is rare but can lead to significant morbidity or death if inadequately treated. Thrombolytic therapy is indicated for thrombi which are life-threatening, organ-threatening, or limb-threatening, but dosing consensus has not been established. OBSERVATION: We report a case of a 700 g preterm neonate with spontaneous intestinal perforation who developed an occlusive aortic thrombus with signs of limb ischemia. He was treated successfully with tissue plasminogen activator without hemorrhagic complications. He was started at a dose of 0.06 mg/kg/h and received a maximum dose of 0.3 mg/kg/h. Long-term follow-up at 3 years and 3 months showed no negative sequelae. CONCLUSION: Alteplase may be considered in premature, extremely low-birth weight infants with careful assessment of risk and benefits, along with frequent surveillance and supportive care.

A retrospective cohort study examining health care utilization patterns in individuals diagnosed with an eating disorder in childhood and/or adolescence.

OBJECTIVE: This study examined a 2-year period following an eating disorder (ED) diagnosis in order to determine patterns of health care utilization. METHOD: We conducted a retrospective cohort study of children (n = 1560) diagnosed with an ED between 2000 and 2017. The ED diagnosis was made at a tertiary level hospital for children and adolescents presenting for outpatient assessment by specialist adolescent medicine physicians and recorded in a program database over this period of time. We then created three sex- and age-matched comparison cohorts using provincial health administrative databases including: a general population cohort, a diabetes cohort (to compare nonmental health care utilization) and a mood disorder cohort (to compare mental health care utilization). Outcomes included hospitalizations, emergency department visits, as well as general practitioner, psychiatrist, and pediatrician visits. Odds ratios (dichotomous outcomes) and rate ratios (continuous outcomes) were calculated. RESULTS: Compared to the general population cohort, the ED cohort had higher odds and rates of all types of health care utilization. Compared to the diabetes cohort, the ED cohort had higher odds of nonmental health-related admissions (OR 1.45, 95% CI 1.09-1.95) and higher rates of nonmental health-related emergency department visits (RR 1.59, 95% CI 1.18-2.13). Compared to the mood disorder cohort, the ED cohort had higher rates of pediatrician visits, which were mental health-related (RR 14.88, 95% CI 10.64-20.82), however most other types of mental health service utilization were lower. DISCUSSION: These patterns indicate that the service needs of young people diagnosed with EDs are higher than those with diabetes with respect to nonmental health admissions and emergency department visits, while in terms of mental health service utilization, there appears to be a lack of use of mental health services compared to youth with mood disorders with the exception of pediatrician mental health visits. These findings must be interpreted in the context of under-detection and under-treatment of EDs. PUBLIC SIGNIFICANCE STATEMENT: Our study found that the health service needs of young people with EDs are higher than those with diabetes with respect to admissions and emergency department visits, while there appears to be a lack of use of mental health services compared to youth with mood disorders with the exception of pediatrician mental health visits.

Cord-Blood High-Sensitivity Troponin-I Reference Interval and Association with Early Neonatal Outcomes.

OBJECTIVE: This study was aimed to establish a reference interval for high-sensitivity cardiac troponin I (hs-cTnI) in umbilical cord blood of infants and to assess its association with the risk of predetermined early neonatal outcomes in a high-acuity tertiary care hospital. STUDY DESIGN: Umbilical cord-blood samples were collected and hs-cTnI was measured in all infants born between August 2015 and September 2015 at McMaster Children's Hospital (n = 256). Gestational age, birth weight, Apgar's scores, age in days at which feeding was established, neonatal intensive care unit (NICU) admission, and discharge in days after birth were recorded. RESULTS: The 90th, 95th, and 99th percentiles for the term infant subcohort were 19.75, 41.45, and 166.30 ng/L, respectively. We observed decreased mean gestational ages and birth weights in both the 90th (37.7 weeks; 2,961.4 g) and 95th percentiles (37.1 weeks; 2,709.9 g) when compared with the remaining infants. Moreover, levels of hs-cTnI were significantly higher in infants with respiratory distress requiring intervention (p < 0.05), low birth weight infants (p < 0.01), preterm infants (p < 0.001), and those requiring NICU admission (p < 0.01). Multiple linear regression of the recorded demographic factors revealed prematurity (gestational age <35 weeks: coefficient 0.346 ± 0.160, p < 0.05; gestational age <37 weeks: coefficient 0.253 ± 0.105, p < 0.05) and male sex (coefficient 0.138 ± 0.047; p < 0.01) to be most predictive of log-hs-cTnI levels. CONCLUSION: This study establishes the reference values for cord-blood hs-cTnI in infants at a tertiary care center. Premature and sick infants requiring NICU admission had significantly higher levels of hs-cTnI. KEY POINTS: · Established the 90th, 95th, and 99th percentiles of neonatal cord-blood hs-cTnI in term infants as 19.75, 41.45, and 166.30 ng/L, respectively.. · Infants with hs-cTnI levels exceeding the 90th percentile had lower gestational ages and birth weights with higher rates of NICU admissions.. · Infants with respiratory distress or requiring NICU admission were found to have higher levels of hs-cTnI..

Management of Anticoagulation Therapy in Patients With Thromboembolism in the Context of Renal Dysfunction: Challenging Cases and Practical Algorithms.

BACKGROUND: Low-molecular-weight heparin is cleared through the kidneys and is commonly used for anticoagulation in the pediatric population. OBSERVATION: We present 3 challenging cases of children requiring anticoagulation in the context of acute kidney injury, nephrotic syndrome, and hemodialysis. CONCLUSIONS: A significant change in anti-factor Xa (anti-Xa) levels-used for drug monitoring-should prompt an assessment of renal function. In nephrotic syndrome, anti-Xa levels should be closely monitored when there is a change in the status of nephrotic disease activity. In hemodialysis patients, enoxaparin at once daily reduced dosing should be considered with trough and peak anti-Xa levels monitoring.

Central venous catheters are an important factor in paediatric thrombosis.

AIM: To establish the incidence and characteristics of paediatric thrombosis (PT) in a Canadian tertiary care centre during the era of low molecular weight heparin (LMWH). METHODS: A retrospective observational case study of all patients <18 years of age evaluated for arterial and venous thrombosis from May 2008 to July 2018 at McMaster Children's Hospital was conducted through the electronic medical record. RESULTS: The incidence of PT was 52.2 per 10 000 hospital admissions (n = 477/91 462). Provoked thrombosis was more prevalent (88.9%, n = 424/477) than unprovoked (2.9%, n = 14/477) or idiopathic thrombosis (4%, n = 19/477). Half of PT were in children <2 years (51.2%, n = 244/477). Central vascular catheterisation was a contributory factor in more than half of thrombotic events (56.2%, n = 268/477), while trauma (1.1%, n = 5/477), oral contraceptives (4%, n = 19/477), infection (4%, n = 19/477), surgery (6.9%, n = 33/477) and malignancy (8.4%, n = 40/477) were also risk factors. Arterial ischaemic stroke was diagnosed in 11.1% of cases (n = 53/477), while pulmonary embolism was identified in 7.1% (n = 34/477) and 1.7% of cases were fatal (n = 8/477). LMWH was the first-line therapeutic of choice (47.8%, n = 228/477), with 28.1% (n = 134/477) requiring no intervention. CONCLUSION: These data reiterate the elevated thrombosis risk to which infants and children with central vascular access are exposed.

Heparin-Induced Thrombocytopenia in a Pediatric Population: Implications for Clinical Probability Scores and Testing.

OBJECTIVES: To determine the applicability of the 4Ts score and the Heparin-Induced Thrombocytopenia (HIT) Expert Probability (HEP) score in children with suspected HIT and to estimate the number of children potentially at risk of HIT. STUDY DESIGN: We retrospectively estimated 4Ts and HEP scores in a cohort of 50 children referred for laboratory screening with enzyme immunoassay. In addition, minor modifications were introduced to the 4Ts score (modified 4Ts score) to adapt it for use in the pediatric setting. All patients with positive enzyme immunoassays were tested with serotonin release assay. We also extracted the number of patients started on heparins in a similar period of time. RESULTS: The median age at the time of testing was 4 years (25th-75th percentile, 8.7 months to 13.5 years); 78% of patients had low and 22% had intermediate risk pretest probability scores using the original 4Ts score; 86% had low risk and 14% had intermediate risk scores using the modified 4Ts score; 54% of children had a HEP score of ≥2. Six patients (12%) had a positive (≥0.40 optical density units) enzyme immunoassay, but none had a positive serotonin release assay. Based on anticoagulation dose, there were 1-2 new daily potentially high-risk exposures to heparinoids at our institution. CONCLUSIONS: The modified 4Ts and original 4Ts scores may be more adequate than the HEP score to determine HIT pretest probability in children. Despite the number of patients potentially at risk, HIT is rare in pediatrics.

Feasibility and safety of delivering full-dose anticoagulation therapy in children treated according to Dana-Farber Cancer Institute acute lymphoblastic leukemia consortium therapy protocols.

BACKGROUND: The literature is void of an evidence-based anticoagulation therapy (ACT) management strategy in the context of thrombocytopenia. We examined the impact of thrombocytopenia on low-molecular-weight heparin (LMWH) dosing and incidence of bleeding in children with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) who developed thromboembolism (TE) during therapy according to DFCI ALL protocols. PROCEDURE: Patient records from our tertiary care center were reviewed for demographics, details of diagnoses and therapy of ALL/LL and TE diagnoses, platelet counts during ACT, LMWH dosing, and bleeding episodes. RESULTS: Thirty-nine TEs were diagnosed in 33 patients [mean age 9 years (range, 2.5-18); 16 males and 31 with ALL] during the study period. A majority (85%) of patients were diagnosed with TE in the consolidation phase with mean time to TE 5.75 months from ALL/LL diagnosis. All patients received LMWH, and the median duration of ACT was 5.9 months (range, 1-11 months). Platelets were measured weekly. On 29 occasions, platelet nadir was <50 × 109 /L, and twice it was < 20 × 109 /L. One (3%) patient had major bleeding episode while on ACT. Platelet count at the time of bleeding was 222 × 109 /L. Ninety-two procedures [83 lumbar punctures (LPs), 9 central venous line (CVL) insertion/revision] were completed without bleeding complications. Asparaginase was held temporarily with TE diagnosis in 48% of patients; most (88%) patients completed all scheduled doses as per protocol. CONCLUSIONS: Ability to administer full-dose LMWH, expected bleeding rate, and completion of asparaginase doses while on ACT suggest full-dose ACT is feasible and safe in children with ALL/LL who develop TE during DFCI ALL consortium therapy protocols.

Outcomes following neonatal portal vein thrombosis: A descriptive, single-center study and review of anticoagulant therapy.

BACKGROUND: Neonatal portal vein thrombosis (PVT) is uncommon with potentially serious complications that may manifest in infancy and childhood. OBJECTIVE: The primary aim of our study was to describe the short-term and long-term outcomes of neonatal PVT. METHODS: A retrospective chart review was conducted from 2008 to 2016 of neonates diagnosed with PVT. A systematic review was also performed from 2000 to 2018 to evaluate anticoagulant therapy (ACT) in neonatal PVT. RESULTS: Forty-four premature and 30 term infants (mean gestational age 30.7 vs 39.1 weeks, respectively) had PVT. Sixty-eight involved the left portal vein, one involved only the main portal vein, and 5 involved ≥1 vein. PVT was catheter associated in 46 (62%); none of the 7 neonates tested had thrombophilia. Of 74 neonates, 19 (26%) received ACT and 55 (74%) were untreated. The mean follow-up duration was 16.6 months (SD = 17.62; range, 0-89.6); 59.5% were followed for ≥6 months. On last ultrasound examination, thrombus resolution was documented in treated (ACT; n = 19) and nontreated (n = 55) neonates: 12 (63%) versus 32 (58%) with complete resolution, 1 (5%) versus 6 (11%) partial, 0 versus 1 (2%) extension, and 6 (32%) versus 16 (29%) had nonprogressive lesions, respectively. Seventy-one (96%) had no complications. Seventy-one articles met inclusion criteria for the systematic review and 19 were retained for analysis after assessment. CONCLUSIONS: PVT resolution rate was similar to previous reports. Although a low complication rate was detected, longer follow-up is necessary to determine the need for early treatment and the precise incidence of outcomes such as portal hypertension.

Pediatric superior vena cava syndrome: An evidence-based systematic review of the literature.

Superior vena cava syndrome (SVCS) results in vascular, respiratory, and neurologic compromise. A systematic search was conducted to determine the prevalence of pediatric SVCS subtypes and identify clinical characteristics/treatment strategies that may influence overall outcomes. Data from 101 case reports/case series (142 patients) were analyzed. Morbidity (30%), mortality (18%), and acute complications (55%) were assessed as outcomes. Thrombosis was present in 36%, with multi-modal anticoagulation showing improved outcome by >50% (P = 0.004). Infant age (P = 0.04), lack of collaterals (P = 0.007), acute complications (P = 0.005), and clinical presentation may have prognostic utility that could influence clinical decisions and surveillance practices in pediatric SVCS.

Cerebral sinus venous thrombosis during childhood acute lymphoblastic leukemia therapy: Risk factors and management.

BACKGROUND: Cerebral sinus venous thrombosis (CSVT) is a rare but serious complication of childhood acute lymphoblastic leukemia (ALL) therapy. No available consensus exists regarding its risk factors and appropriate management due to the rarity of cases. PROCEDURES: Out of 209 ALL patients aged 1-21 years treated at the Children's Cancer Center of Lebanon between May 2002 and May 2015, 13 developed CSVT during therapy. Patient characteristics, clinical management, and outcomes were studied. RESULTS: The incidence of CSVT was 6.2% (95% confidence interval [CI]: 3.4-10.4). Using univariate analysis, increased risk of CSVT was observed with age >10 years (odds ratio [OR]: 3.56, 95% CI: 1.13-11.2), T-cell immunophenotype (OR: 4.14, 95% CI: 1.16-14.7), and intermediate/high risk disease (OR: 3.4, 95% CI: 1.03-11.7). The only statistically significant risk factor by multivariate analysis was the treatment as per the intermediate-/high-risk protocol (HR: 15.6, 95% CI: 1.43-171.3). Most cases (77%) occurred in the postinduction phases of treatment while receiving a combination of asparaginase and dexamethasone rather than prednisone. Treatment with low molecular weight heparin (LMWH) for a minimum of 3 months and until significant radiological improvement is observed resulted in 100% survival rate. All but one patient had complete neurological recovery. CONCLUSIONS: CSVT is an important complication of childhood ALL therapy. Postinduction combined asparaginase and dexamethasone intensive treatment for intermediate-/high-risk patients was the most important risk factor. Treatment with LMWH for a minimum of 3 months, and until asparginase therapy is over, with major radiological improvement seems to be effective and feasible.