Enoxaparin treatment dosing for venous thromboembolism in pediatric patients with obesity.

BACKGROUND: The optimal enoxaparin dosing for treatment of venous thromboembolism (VTE) in pediatric patients with obesity remains uncertain. We described the mean enoxaparin dose required to attain anti-factor Xa (anti-Xa) levels of 0.5-1 unit/mL in pediatric patients with obesity. METHODS: Pediatric patients with obesity (body mass index [BMI] ≥95th percentile) who received treatment dose of enoxaparin from 2013 to 2022 and had at least one appropriately timed anti-Xa level were retrospectively evaluated. Daily enoxaparin dose required to achieve an anti-Xa level of 0.5-1 unit/mL was reviewed and compared by the severity of obesity. The correlation coefficients between enoxaparin dose requirement and BMI, BMI percentile, and weight were measured by Spearman's rank correlation coefficient. RESULTS: Pediatric patients with obesity (n = 89) required a mean enoxaparin dose of 0.8 ± 0.18 mg/kg twice daily to attain a therapeutic anti-Xa level. Children with BMI 95th-99th percentile and weight ≤100 kg achieved the target level on a significantly higher weight-based enoxaparin dose compared to BMI greater than 99th percentile (0.95 ± 0.15 vs. 0.75 ± 0.15 mg/kg twice daily; p < .001) and weight greater than 100 kg (0.95 ± 0.14 vs. 0.7 ± 0.12 mg/kg twice daily; p < .001). BMI, BMI percentile, and weight showed a moderate to strong negative correlation with enoxaparin dose requirement. CONCLUSIONS: Pediatric patients with obesity required a lower weight-based dose of enoxaparin to achieve a therapeutic anti-Xa than the recommended starting dose of 1 mg/kg twice daily for treatment of VTE. Among obesity indices, weight showed the strongest negative correlation with total daily enoxaparin requirement.

Enoxaparin thromboprophylaxis in hospitalized obese pediatric patients.

BACKGROUND: 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. PROCEDURE: A retrospective review was conducted of pediatric patients who weighed ≥60 kg 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 30 mg every 12 h. 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. RESULTS: Of 116 patients (median age 15.8 years) included for analysis, 106 patients were initially treated with enoxaparin 30 mg every 12 h. Anti-Xa levels were <0.2 unit/mL in 53% of patients with BMI > 99th percentile and 54% of patients >100 kg. Ninety-one patients had at least one anti-Xa 0.2-0.4 unit/mL with an average daily enoxaparin dosing of 66 mg. 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 ± 5.6 mg/day, p = .01). Patients > 100 kg required significantly higher dose than those ≤100 kg (69.1 ± 15.5 vs 61.2 ± 7.3 mg/day, p = .002). CONCLUSIONS: Increased initial dosing and/or anti-Xa level monitoring should be considered in adolescents with severe obesity receiving enoxaparin thromboprophylaxis.

A review of the perioperative management of direct oral anticoagulants for pediatric anesthesiologists.

BACKGROUND: Although direct oral anticoagulants (DOACs) have been used in the adult population for over a decade, DOACs use has begun to rise in pediatric populations since FDA approval of rivaroxaban and dabigatran, DOACs offer several advantages for pediatric patients, to other anticoagulants, including a similar safety profile, minimal lab monitoring, and ease of administration. The rise in DOAC use has led to an increasing number of pediatric patients managed on DOACs presenting for elective and urgent procedures. Perioperative management of anticoagulation is often challenging for providers due to the lack of expert consensus guidelines and the difficulty in balancing a patient's thrombotic risk with bleeding risk for a given procedure. AIMS: Using the most up to date literature, we provide a focused review on the perioperative management of DOACs in pediatric patients. CONCLUSIONS: This work presents a focused review for pediatric anesthesiologists on clinically available DOACs, perioperative monitoring and management of DOACs, as well as options and indications for reversal. While consensus expert practice guidelines are still needed, we hope this work will familiarize perioperative physicians with these agents, recommended uses, and potential perioperative management.

Successful Perioperative Management of Orthotopic Cardiac Transplantation in a Pediatric Patient With Concurrent Congenital von Willebrand Disease and Acquired von Willebrand Syndrome Using Recombinant von Willebrand Factor.

Von Willebrand disease (VWD) is the most common bleeding disorder and reportedly affects 1:1,000 of the world's population. There are three subtypes of VWD characterized by a quantitative defect (types 1 and 3 VWD) or a qualitative defect (type 2 VWD). Type 1 VWD results in a partial deficiency of von Willebrand factor (VWF) and affects approximately 75% of individuals with VWD, whereas type 3 VWD results in a severe or complete deficiency of VWF. Individuals with type 2 VWD subtypes (types 2A, 2B, 2M, and 2N VWD) express a dysfunctional VWF protein that has impaired interactions with platelets or factor VIII. The majority of individuals with VWD have mild type 1 VWD and occasionally require bolus infusions of VWF for severe bleeding or major surgery. A subset of patients, especially those with type 2A or 3 VWD, may require more frequent VWF replacement or prophylaxis for refractory bleeding or bleeding prevention, respectively. Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder that primarily occurs as a result of an underlying disease or other pathologic mechanism. Cases of AVWS associated with heart valve defects, left ventricular assist devices, or congenital cardiac disease result from high shear stress in the circulation that induces VWF unfolding and subsequent proteolysis of high-molecular-weight multimers by ADAMTS-13. In rare instances, plasma-derived factor VIII-containing VWF concentrates have been administered to individuals with AVWS for persistent or challenging bleeding events. In this case report, the hemostatic challenges and the perioperative management of cardiac transplantation surgery using a novel recombinant VWF product in a pediatric patient diagnosed with AVWS concomitant with congenital type 1 VWD are described. Written informed consent was obtained from the patient's mother for this case report. The diagnosis of congenital VWD remains a challenge because of multiple potential modifiers that can alter VWF laboratory results. Concurrent conditions, such as congenital heart disease and the rare secondary condition of AVWS, in addition to congenital VWD, can further affect interpretation of coagulation studies. This can result in delays in diagnosis, increase severity of the bleeding phenotype, and complicate hemostatic management in individuals at risk for bleeding and thrombosis. A multidisciplinary approach, including anesthesiologists, cardiologists, cardiovascular surgeons, hematologists, and pharmacists, is critical to achieving optimal patient outcomes, as highlighted in this case report. As diagnostic capabilities and understanding of VWD broaden, future studies evaluating alternative treatment approaches for individuals with various types of VWD would be of great benefit to the medical community.

Impact of erythrocytapheresis on natural anticoagulant levels in children with sickle cell disease: A pilot study.

Venous thromboembolism (VTE) is being increasingly recognized in children with sickle cell disease (SCD). In a retrospective cohort study, we identified bilateral central venous catheter (CVC) placement as an independent risk factor for VTE. At our institution, the only indication for bilateral CVC placement in children with SCD is erythrocytapheresis. To investigate the impact of erythrocytapheresis on coagulation, we measured levels of natural anticoagulants in 11 patients with SCD on chronic erythrocytapheresis, immediately before and after apheresis. We demonstrated a statistically significant reduction in most parameters. Additional studies are needed to further investigate the exact etiology and clinical impact of this acute decrease.

Variation in Platelet Delta Granules Over Time in Young Women Undergoing Evaluation for Heavy Menstrual Bleeding.

Delta-granule platelet storage pool deficiency (δ-PSPD) is a qualitative platelet function defect associated with variable bleeding phenotypes. Platelet electron microscopy (EM) is commonly utilized to evaluate for δ-PSPD, but intrapatient variability in platelet δ-granule numbers by EM is currently unknown. Fifteen young women aged 11 to 17 years presenting to a young women's hematology clinic for the evaluation of heavy menstrual bleeding underwent platelet EM testing at their initial hematology clinic visit and at 1 and 3 months later. Platelet aggregation of platelet-rich plasma by light transmission was also performed on all patients at their initial visit. Eight patients had average δ-granules per platelet consistently ≥2. Three patients were found to have average δ-granules per platelet <2 on initial testing, 2 of which reverted to ≥2 on subsequent testing. When initial average δ-granules per platelet was ≥2, initial repeat testing remained so in 83% (95% confidence interval [CI], 52%-98%) of cases and subsequent repeat testing remained so in 75% (95% CI, 43%-95%) of the cases. Platelet aggregation testing was abnormal in 53% of patients, and there was no apparent correlation between platelet EM findings and platelet aggregation testing. In this small group of young women presenting for the evaluation of bleeding symptoms, we found that almost half of the patients had substantial variability in platelet EM results. Given other identified limitations in platelet EM testing, and the intrapatient variability identified in this study, providers should use caution in utilizing EM in isolation to diagnose δ-PSPD.

Venous Thromboembolism in Children with Sickle Cell Disease: A Retrospective Cohort Study.

OBJECTIVES: To describe the cumulative incidence of venous thromboembolism (VTE) in children with sickle cell disease (SCD) followed at a single institution and report on the risk factors associated with VTE development. STUDY DESIGN: Charts for all patients with SCD, aged 0-21 years, followed at Nationwide Children's Hospital over a 6-year period (January 1, 2009, to January 31, 2015) were reviewed. Data on VTE diagnosis, sex, body mass index/weight-for-length, SCD genotype, SCD clinical complications, central venous catheter (CVC) placement, and thrombophilia testing were collected. RESULTS: Cumulative incidence of VTE in children with SCD followed at a single tertiary care institution was found to be 2.9% (12/414). Nine of the 12 VTE were CVC-associated. On univariate analysis, hemoglobin SS genotype (OR 10.7, 95% CI 1.4-83.5), CVC presence (OR 34.4, 95% CI 8.9-134.6), central nervous system vasculopathy (OR 19.4, 95% CI 5.6-63.4), chronic transfusion therapy (OR 30.6, 95% CI 8.9-122.2), and older age (P = .03) were associated with VTE. However, presence of CVC was the only independent risk factor identified on multivariable logistic regression analysis (OR 33.8, 95% CI 8.7-130.9). CONCLUSION: In our institution, nearly 3% of children with SCD had a history of VTE. CVC is an independent predictor of VTE in children with SCD.

Single-shot terahertz time-domain spectroscopy in pulsed high magnetic fields.

We have developed a single-shot terahertz time-domain spectrometer to perform optical-pump/terahertz-probe experiments in pulsed, high magnetic fields up to 30 T. The single-shot detection scheme for measuring a terahertz waveform incorporates a reflective echelon to create time-delayed beamlets across the intensity profile of the optical gate beam before it spatially and temporally overlaps with the terahertz radiation in a ZnTe detection crystal. After imaging the gate beam onto a camera, we can retrieve the terahertz time-domain waveform by analyzing the resulting image. To demonstrate the utility of our technique, we measured cyclotron resonance absorption of optically excited carriers in the terahertz frequency range in intrinsic silicon at high magnetic fields, with results that agree well with published values.

Light Transmission Aggregometry Does Not Correlate With the Severity of δ-Granule Platelet Storage Pool Deficiency.

Delta-granule platelet storage pool deficiency (δ-PSPD) is a poorly studied bleeding diathesis resulting from either decreased granule content or decreased average number of platelet δ-granules. Light transmission aggregometry (LTA) is commonly used to evaluate for δ-PSPD and platelet electron microscopy (EM) is used to confirm the diagnosis. Currently, little data exist examining the relationship between the likelihood of abnormal platelet aggregation findings, severity of δ-granule deficiency on platelet EM, and severity of bleeding symptoms in patients with δ-PSPD. Patients diagnosed with δ-PSPD by platelet EM who also underwent LTA testing were identified at a single institution for correlation between severity of bleeding, average number of platelet δ-granules, and number of agonist abnormalities on LTA. No statistically significant association was identified between the average number of δ-granules per platelet and likelihood of an abnormal LTA. LTA abnormalities were quite varied and only 50% diagnosed with δ-PSPD on EM had abnormal aggregation testing. Also, no correlation was seen between the number of clinical bleeding symptoms, number of average δ-granules per platelet, and the number of LTA agonist abnormalities. Our findings highlight the difficulties inherent in the laboratory evaluation of platelet function.

Radiation therapy may increase metastatic potential in alveolar rhabdomyosarcoma.

BACKGROUND: We previously determined that radiation could be safely administered using a mouse-flank in vivo model to both alveolar (Rh30) and embryonal (Rh18) rhabdomyosarcoma xenografts. Mice from both tumor lines in this experiment developed metastases, an event not previously described with these models. We sought to determine if radiation-induced changes in gene expression underlie an increase in the metastatic behavior of these tumor models. PROCEDURE: Parental Rh18 and Rh30 xenografts, as well as tumor that recurred locally after radiotherapy (Rh18RT and Rh30RT), were grown subcutaneously in the flanks of SCID mice and then subjected to either fractionated radiotherapy or survival surgery alone. Metastasis formation was monitored and recorded. Gene expression profiling was also performed on RNA extracted from parental, recurrent, and metastatic tissue of both tumor lines. RESULTS: Rh30 and Rh30RT xenografts demonstrated metastases only if they were exposed to fractionated radiotherapy, whereas Rh18 and Rh18RT xenografts experienced significantly fewer metastatic events when treated with fractionated radiotherapy compared to survival surgery alone. Mean time to metastasis formation was 40 days in the recurrent tumors and 73 days in the parental xenografts. Gene expression profiling noted clustering of Rh30 recurrent and metastatic tissue that was independent of the parental Rh30 tissue. Rh18RT xenografts lost radiosensitivity compared to parental Rh18. CONCLUSION: Radiation therapy can significantly decrease the formation of metastases in radio-sensitive tumors (Rh18) and may induce a more pro-metastatic phenotype in radio-resistant lines (Rh30).

Reduced intensity transplantation for congenital amegakaryocytic thrombocytopenia: report of a case and review of the literature.

CAMT is a bone marrow failure syndrome that usually presents with isolated thrombocytopenia soon after birth. HSCT is curative, and MAC is associated with increased transplant-related morbidity and mortality, especially in the unrelated setting. We used a RIC regimen with alemtuzumab, fludarabine, and melphalan in a seven-month-old patient with CAMT who underwent a MUD HSCT. The transplant was well tolerated with few complications. Neutrophil and platelet engraftment occurred on day +12 and +29, respectively, and she had 100% donor chimerisms on days +19.

Rapid scanning terahertz time-domain magnetospectroscopy with a table-top repetitive pulsed magnet.

We have performed terahertz time-domain magnetospectroscopy by combining a rapid scanning terahertz time-domain spectrometer based on the electronically controlled optical sampling method with a table-top minicoil pulsed magnet capable of producing magnetic fields up to 30 T. We demonstrate the capability of this system by measuring coherent cyclotron resonance oscillations in a high-mobility two-dimensional electron gas in GaAs and interference-induced terahertz transmittance modifications in a magnetoplasma in lightly doped n-InSb.

Technical Feasibility and Clinical Efficacy of Iliac Vein Stent Placement in Adolescents and Young Adults with May-Thurner Syndrome.

PURPOSE: To report technical feasibility and clinical efficacy of iliac vein stent placement in adolescent patients with May-Thurner Syndrome (MTS). MATERIALS AND METHODS: Single-institution retrospective review of the medical record between 2014 and 2021 found 63 symptomatic patients (F = 40/63; mean age 16.1 years, 12-20 years) who underwent left common iliac vein (LCIV) stent placement for treatment of LCIV compression from an overriding right common iliac artery, or equivalent (n = 1, left IVC). 32/63 (50.7%) patients presented with non-thrombotic iliac vein lesions (NIVL). 31/63 (49.2%) patients presented with deep vein thrombosis of the lower extremity and required catheter-directed thrombolysis after stent placement (tMTS). Outcomes include technically successful stent placement with resolution of anatomic compression and symptom improvement. Stent patency was monitored with Kaplan-Meier analysis at 3, 6, 12, 24, and 36 months. Anticoagulation and antiplatelet (AC/AP) regimens were reported. RESULTS: Technical success rate was 98.4%. 74 bare-metal self-expanding stents were placed in 63 patients. Primary patency at 12, and 24-months was 93.5%, and 88.9% for the NIVL group and 84.4% and 84.4% for the tMTS group for the same period. Overall patency for the same time intervals was 100%, and 95.4% for the NIVL group and 96.9%, and 96.9% for the tMTS group. Procedural complication rate was 3.2% (2/63) with no thrombolysis-related bleeding complications. Clinical success was achieved in 30/32 (93.8%) and 29/31 (93.5%) patients with tMTS and NIVL groups, respectively. CONCLUSION: CIV stent placement in the setting of tMTS and NIVL is technically feasible and clinically efficacious in young patients with excellent patency rates and a favorable safety profile.

Outcomes in Children with Provoked Venous Thrombosis and Antiphospholipid Antibodies: Findings from the Kids-DOTT Trial.

Few studies have prospectively evaluated the incidence and outcomes in children with provoked venous thromboembolism (VTE) and transient or persistent antiphospholipid antibodies (aPL). We compared outcomes of patients <21 years old with a first-episode acute provoked VTE and positive aPL at diagnosis enrolled in the Kids-DOTT trial. aPL were tested at enrollment and, when positive, repeated at 6 weeks post-VTE. Subsequent testing was performed at discretion of the treating hematologist. Of 524 patients, 116 (22%) had positive aPL at enrollment. At follow-up, 70 (60%) had transient (n=66) or low titer aPL (n=4), 11 (10%) had persistent aPL meeting criteria for antiphospholipid syndrome (APS), and 35 (30%) had no repeat testing. Patients with APS were older (15.8 vs. 9.9 years, p=.014), and had a statistically significant higher risk of symptomatic recurrent VTE (18% vs. 1%, OR: 12.2 [1.4 - 108], p= .025), and a statistically non-significant but clinically meaningful difference in the risk of anticoagulant-related clinically-relevant bleeding (9% vs. 0%, OR: 20.1 [0.7 - 558], p=0.077) compared to those in the transient or low titer aPL group. In conclusion, aPL are common in young patients with acute provoked VTE and are mostly transitory and clinically insignificant. Patients with APS and provoked VTE appear to have an increased risk of recurrent VTE compared to patients with transitory or low titer aPL. Future collaborative studies should investigate the optimal VTE management of children with provoked VTE who meet criteria for APS.

Novel Dosing and Monitoring of Aspirin in Infants With Systemic-to-Pulmonary Artery Shunt Physiology: the SOPRANO Study.

OBJECTIVES: Provision of pulmonary blood flow with a systemic-to-pulmonary artery shunt is essential in some patients with cyanotic congenital heart disease. Traditionally, aspirin (ASA) has been used to prevent thrombosis. We evaluated ASA dosing with 2 separate antiplatelet monitoring tests for accuracy and reliability. METHODS: This is a retrospective, pre-post intervention single center study. Two cohorts were evaluated; the pre-intervention group used thromboelastography platelet mapping (TPM) and post-intervention used VerifyNow aspirin reactivity unit (ARU) monitoring. The primary endpoint was to compare therapeutic effect of TPM and ARU with regard to platelet inhibition. Inadequate platelet inhibition was defined as TPM <50% inhibition and ARU >550. RESULTS: Data from 49 patients were analyzed: 25 in the TPM group and 24 in the ARU group. Baseline characteristics were similar amongst the cohorts. The TPM group had significantly more patients with inadequate platelet inhibition (14 [56%] vs 2 [8%]; p = 0.0006) and required escalation with additional thromboprophylaxis (15 [60%] vs 5 [21%]). There was no difference in shunt thrombosis (1 [2%] vs 0 [0%]; p = 0.32), cyanosis requiring early re-intervention (9 [36%] vs 14 [58%]; p = 0.11), or bleeding (15 [60%] vs 14 [58%]; p = 0.66). CONCLUSION: With similar cohorts and the same ASA-dosing nomogram, ARU monitoring resulted in a reduced need for escalation of care and concomitant thromboprophylaxis with no difference in adverse outcomes. Our study suggests ARU monitoring compared with TPM may be a more reliable therapeutic platelet inhibition test for determining ASA sensitivity in children with congenital heart disease requiring systemic-to-pulmonary artery shunt.

Successful Medical-Surgical Management of Intracardiac Thrombosis and Pulmonary Pseudoaneurysms in an Adolescent With Hughes-Stovin Syndrome.

We present an adolescent male with a single intracardiac mass and pulmonary emboli, complicated by peripheral venous thrombosis and subsequent development of pulmonary pseudoaneurysms, leading to diagnosis of Hughes-Stovin syndrome. Remission was achieved with cyclophosphamide, corticosteroids, and pseudoaneurysm resection and maintained with infliximab and methotrexate.

Practical considerations and consensus opinion for children's hospital-based inpatient hemostasis and thrombosis (HAT) consultative services: Communication from the ISTH SSC Subcommittee on Pediatric/Neonatal Thrombosis and Hemostasis.

Caring for children and adolescents with disorders of hemostasis and thrombosis (HAT) has become more specialized and requires a unique skill set that many providers are not able to obtain in standard pediatric hematology/oncology/bone marrow transplant fellowship training programs. The influx of numerous therapeutic advances and increasing medical complexity has expanded the need for experienced HAT providers and subspecialty collaboration in the inpatient setting due to the nuances in the management of patients with HAT complications and concerns. While there are data highlighting the benefits of an inpatient hemostasis, thrombosis, and anticoagulation management service in adult hospitals, there are limited pediatric data supporting such programs. In this article, we summarize the current practices of various pediatric institutions in the inpatient management of HAT patients and provide a consensus opinion for the development of a pediatric inpatient HAT service at tertiary care referral centers.