Barriers to medication adherence in children, adolescents, and young adults prescribed anticoagulation.

Pediatric and adolescent and young adult (AYA) thromboembolism is treated with anticoagulation, but little is known about adherence. The aims of this study were to describe barriers to adherence among children and AYAs (ages 0-25 years) prescribed anticoagulants and to explore the relationship between barriers and self-reported adherence. Nearly 75% of patients and caregivers reported barriers, and a larger number of barriers was associated with missing at least one dose in the past month per both patient (rpb  = 0.48, p = .01) and caregiver (rpb  = 0.52, p = .01) report. Limitations, clinical implications, and future directions are discussed.

A systematic review of adherence to anticoagulation regimens in pediatric patients.

Thromboembolic disease rates are increasing in pediatric patients. Anticoagulation is prescribed for treatment and prevention of thromboembolic disease. While nonadherence to anticoagulation regimens predicts poor health outcomes in adults, data in anticoagulated pediatric patients are limited. We systematically reviewed the rates, outcomes, and predictors of anticoagulation nonadherence in the pediatric population. Out of a total of 3581 unique articles identified for review, 17 studies met inclusion criteria. These studies primarily evaluated patients with cardiac disease treated with vitamin K antagonists. Overall nonadherence rates varied from 3% to 42%, based upon population, definition of adherence, and measurement strategy. Patient age, goal international normalized ratio (INR), and number of concurrent potentially interacting medications correlated with nonadherence. Data examining the relationship between nonadherence and health outcomes were included in only two studies. Limitations of current literature, as well as critical knowledge gaps that require future study, are discussed.

Results of an international survey on adherence with anticoagulation in children, adolescents, and young adults: Communication from the ISTH SSC Subcommittee on Pediatric and Neonatal Thrombosis and Hemostasis.

BACKGROUND: The ISTH Scientific and Standardization Committee (SSC) Subcommittee on Pediatric/Neonatal Thrombosis and Hemostasis convened a working group on medication adherence to begin to understand the current state of clinical practice to inform priority areas for efforts to improve adherence for children, and adolescents and young adults (AYA) prescribed anticoagulants. OBJECTIVES: We sought to survey an international group of clinicians involved in anticoagulation management in children and/or AYA about perceptions of medication on health outcomes, clinical practice related to medication adherence, and barriers to assessing and improving medication adherence. METHODS: Clinicians involved in anticoagulation management in children and/or AYA were surveyed via REDCap® . Descriptive statistics were used to summarize demographic and clinical characteristics and responses to multiple choice and Likert-type questions. Free-text answers were coded based on the Behaviour Change Technique Taxonomy and the Expert Recommendations for Implement Change project. RESULTS AND CONCLUSIONS: There were 200 participants, 90% of whom were pediatric hematology/oncology physicians. Based on the results, which demonstrate that clinicians are concerned about impact of poor medication adherence and have limited resources to identify and improve adherence, the working group has identified next steps to further understand impact of medication adherence on anticoagulation-related health outcomes, address the need for validated measures to assess medication adherence for all anticoagulants prescribed to this population, and develop an intervention and implementation research agenda to improve outcomes.

The ASH-ASPHO Choosing Wisely Campaign: 5 hematologic tests and treatments to question.

Choosing Wisely is a medical stewardship and quality-improvement initiative led by the American Board of Internal Medicine Foundation in collaboration with leading medical societies in the United States. The American Society of Hematology (ASH) has been an active participant in the Choosing Wisely project. In 2019, ASH and the American Society of Pediatric Hematology/Oncology (ASPHO) formed a joint task force to solicit, evaluate, and select items for a pediatric-focused Choosing Wisely list. By using an iterative process and an evidence-based method, the ASH-ASPHO Task Force identified 5 hematologic tests and treatments that health care providers and patients should question because they are not supported by evidence, and/or they involve risks of medical and financial costs with low likelihood of benefit. The ASH-ASPHO Choosing Wisely recommendations are as follows: (1) avoid routine preoperative hemostatic testing in an otherwise healthy child with no previous personal or family history of bleeding, (2) avoid platelet transfusion in asymptomatic children with a platelet count >10 × 103/µL unless an invasive procedure is planned, (3) avoid thrombophilia testing in children with venous access-associated thrombosis and no positive family history, (4) avoid packed red blood cells transfusion for asymptomatic children with iron deficiency anemia and no active bleeding, and (5) avoid routine administration of granulocyte colony-stimulating factor for prophylaxis of children with asymptomatic autoimmune neutropenia and no history of recurrent or severe infections. We recommend that health care providers carefully consider the anticipated risks and benefits of these identified tests and treatments before performing them.

Urinary 11-dehydrothromboxane B2 aspirin efficacy testing is sensitive to perioperative inflammation in pediatric solid-organ transplant patients.

BACKGROUND: Evidence for aspirin efficacy testing in pediatrics is limited, especially outside of cardiology, yet thrombotic events have high morbidity in other areas such as pediatric transplant surgery. Debates about whether thromboembolic events while on aspirin represent "aspirin resistance" or "high on-treatment platelet reactivity" persist, given the poor intertest agreement between testing platforms. PROCEDURE: This prospective observational study involved measuring aspirin efficacy using ex vivo testing of platelet aggregation (VerifyNow-Aspirin, VN) and urine 11-dehydrothromboxane B2 (AsprinWorks, UTxB2) contemporaneously at up to three time points after major noncardiac organ transplant surgery. The collection days (CD) were the second and seventh days after stable aspirin dosing and then a convalescent time point 2-9 months later. RESULTS: Fifty-five participants (age range, 0-21 years) were enrolled, having undergone total pancreatectomy with islet autotransplantation (N = 36), orthotopic liver transplantation (N = 18), and combined liver-kidney transplantation (N = 1). Platelet reactivity measured by VN remained unchanged, whereas UTxB2, which was elevated postoperatively, decreased significantly from CD1 to CD2 and CD3. Discordance in therapeutic efficacy was noted per manufacturer cutoffs, with therapeutic VN results in 86% of tests, whereas 12% of UTxB2 were therapeutic. Age-based stratification of UTxB2 results using previously published pediatric median levels increased overall UTxB2 therapeutic rates (80%) and intertest concordance (67% vs 27% if using adult range). No thrombotic events were observed. CONCLUSIONS: Our data suggest that urine thromboxane production may be an underappreciated reflection of postoperative inflammation. Validation of pediatric normal ranges for UTxB2 is a critical next step.

The ASH-ASPHO Choosing Wisely Campaign: 5 hematologic tests and treatments to question.

Choosing Wisely is a medical stewardship and quality-improvement initiative led by the American Board of Internal Medicine Foundation in collaboration with leading medical societies in the United States. The American Society of Hematology (ASH) has been an active participant in the Choosing Wisely project. In 2019, ASH and the American Society of Pediatric Hematology/Oncology (ASPHO) formed a joint task force to solicit, evaluate, and select items for a pediatric-focused Choosing Wisely list. By using an iterative process and an evidence-based method, the ASH-ASPHO Task Force identified 5 hematologic tests and treatments that health care providers and patients should question because they are not supported by evidence, and/or they involve risks of medical and financial costs with low likelihood of benefit. The ASH-ASPHO Choosing Wisely recommendations are as follows: (1) avoid routine preoperative hemostatic testing in an otherwise healthy child with no previous personal or family history of bleeding, (2) avoid platelet transfusion in asymptomatic children with a platelet count 10 × 103 /µL unless an invasive procedure is planned, (3) avoid thrombophilia testing in children with venous access-associated thrombosis and no positive family history, (4) avoid packed red blood cells transfusion for asymptomatic children with iron deficiency anemia and no active bleeding, and (5) avoid routine administration of granulocyte colony-stimulating factor for prophylaxis of children with asymptomatic autoimmune neutropenia and no history of recurrent or severe infections. We recommend that health care providers carefully consider the anticipated risks and benefits of these identified tests and treatments before performing them.

Hydroxyurea Pharmacokinetics in Pediatric Patients After Total Pancreatectomy With Islet Autotransplantation.

Total pancreatectomy with islet autotransplantation is a complex surgical approach for acute recurrent or chronic pancreatitis that frequently triggers extreme thrombocytosis (platelets ≥ 1000 × 109 /L). Thrombocytosis can be prothrombotic, so cytoreductive hydroxyurea is often initiated after this surgery; however, optimal dosing strategy and efficacy are unknown. This prospective pilot study characterized the pharmacokinetics of hydroxyurea after this procedure in children. It also compared them with previously published pediatric parameters in sickle cell anemia (SCA), the disease in which pediatric hydroxyurea pharmacokinetics have primarily been studied. Plasma hydroxyurea levels were quantified in 14 participants aged 4-19 years using high-performance liquid chromatography. Blood collections were scheduled 20 minutes, 1 hour, and 4 hours after the first dose, on pharmacokinetic day 1 (PK1), and again 2-3 months later if still on hydroxyurea (PK2). Six participants had PK1 and PK2 data at all 3 postdose timed collections, 5 only had PK1 samples, and 3 only had PK2 samples. Total pancreatectomy with islet autotransplantation participants had reduced and delayed absorption compared with sickle cell anemia participant data from the Hydroxyurea Study of Long-Term Effects, regardless of timing or dosing methodology. Total pancreatectomy with islet autotransplantation participants had different pharmacokinetic profiles at PK1 versus PK2, with lower dose-normalized exposures than previously reported in sickle cell anemia. These results suggest variability exists in hydroxyurea absorption and bioavailability in total pancreatectomy with islet autotransplantation patients, suspected to be primarily because of Roux-en-Y reconstruction, and suggest that more pharmacokinetic data are needed for scenarios when hydroxyurea is prescribed to children without sickle cell anemia.

Impact of exogenous antithrombin on low molecular weight heparin anti-Xa activity assays in a pediatric and young adult leukemia and lymphoma cohort with variable antithrombin levels.

BACKGROUND: Low molecular weight heparin (LMWH) remains the most commonly prescribed pediatric anticoagulant. There is debate whether LMWH anti-Xa assays with or without exogenous antithrombin (AT) best reflect anticoagulation effect, and how much discrepancy exists between assay types. OBJECTIVES: We assessed the effect of variable AT activity on LMWH anti-Xa levels in plasma samples from anticoagulated pediatric and young adult acute lymphoblastic leukemia and lymphoma (ALL/L) patients, using two instruments and their commercial kits with and without exogenous AT (ie, four platforms). METHODS: We analyzed LMWH anti-Xa levels on 60 plasma samples with known AT activity from 12 enoxaparin-treated ALL/L patients, using four commercial kits from Siemens and Stago containing AT or not, on Siemens BCS and Stago STA R Max, respectively. RESULTS: Of 236/240 samples with interpretable results, mean AT activity was 80% (46-138%). Correlation was acceptable for published kit ranges of LMWH anti-Xa levels when comparing kits containing AT (r = 0.82, P < .0001), or not (r = 0.93, P < .0001), and within a manufacturer (Berichrom to Innovance, r = 0.92, P < .0001; Stachrom to STA-Liquid Anti-Xa r = 0.98, P < .0001). LMWH anti-Xa levels were lower in platforms without added AT (P < .0001). For Stago kits, this effect increased when AT < 70% (P = .001, n = 19, mean 56%). Assay variability, measured as mean percent difference, was less pronounced with Stago kits (14.7%, n = 49) than Siemens (41.9%, n = 50). CONCLUSIONS: Although LMWH levels from anti-Xa assays with added AT trend higher than in those without, correlation was fairly good between platforms in pediatric ALL/L plasmas, even when AT activity was <70%.

Extreme Thrombocytosis after Pediatric Pancreatectomy with Islet Autotransplantation Is Unique Compared to Other Postsplenectomy States.

BACKGROUND: Hematologic trends after pancreatectomy with islet autotransplantation (IAT), which involves splenectomy, have been rarely studied. Reactive thrombocytosis (RT, platelets ≥500 K/µL) often occurs postoperatively, similar to other postsplenectomy states, but the degree of similarities and true incidence are unknown. STUDY DESIGN: A single-site, retrospective, observational cohort study of patients who underwent total splenectomy between 2010 and 2018 was performed. Thrombocytosis incidence and pharmacologic management strategies were evaluated, including cohort-based analyses for IAT versus other splenectomy indications. RESULTS: Analyses included 112 patients overall, 42 of whom underwent IAT. RT occurred frequently (93.8%) despite most patients having normal preoperative platelet counts. IAT patients had significantly higher peak platelet counts compared to non-IAT patients and the rate of platelet rise for IAT patients was significantly faster. IAT was uniquely predictive of developing extreme thrombocytosis (ExT, platelets ≥1000 K/µL, 90% vs. 15.7%, risk ratio 4.11, P < 0.0001) despite standardized hydroxyurea use. Thrombotic events were infrequent and did not differ between groups. CONCLUSIONS: RT was common regardless of splenectomy indication but ExT was uniquely associated with IAT despite cytoreductive pharmacotherapy. These results strongly suggest that splenectomy is unlikely to be the sole contributor to post-IAT RT but further investigations into this phenomenon are needed. LEVEL-OF-EVIDENCE RATING: Treatment study, Level III (retrospective comparative study).

Thrombopoietin Contributes to Extreme Thrombocytosis After Pediatric Pancreatectomy With Islet Autotransplantation.

OBJECTIVE: This study aims to explore the role of thrombopoietin (TPO) production in extreme thrombocytosis that is often observed after pancreatectomy with islet autotransplantation (IAT) and the effectiveness of hydroxyurea in thrombocytosis management. METHODS: Retrospective chart review was performed for all patients who underwent pancreatectomy with IAT at our institution between April 1, 2015, and December 31, 2016. Data evaluated included demographics, platelet counts, TPO levels, and thrombocytosis management strategies. RESULTS: Twelve total and 1 subtotal pancreatectomy with IAT cases were reviewed. All operations included splenectomy. No major surgical or thrombotic complications occurred. Thrombopoietin levels, normal preoperatively, rose significantly (median, 219 pg/mL) soon after surgery, peaking on median postoperative day 3. Platelet counts, also normal preoperatively, increased within a week of surgery, with 92% over 1000 K/µL (median peak platelet count, 1403 K/µL). Platelet counts and TPO levels dropped after hydroxyurea initiation in most patients. CONCLUSIONS: After pancreatectomy with IAT, patients experienced marked TPO rise and subsequent thrombocytosis, and both decreased significantly after hydroxyurea initiation. These data suggest that TPO elevation and associated increased platelet production may be one driver of early extreme post-total pancreatectomy with islet autotransplantation thrombocytosis, and this process may be modulated by hydroxyurea.

Capped antithrombin III dosing is cost effective in the management of asparaginase-associated thrombosis.

Asparaginase therapy induces a transient antithrombin III (ATIII) deficiency, which contributes to the risk of asparaginase-induced thrombosis. At Cincinnati Children's Hospital Medical Center, management of asparaginase-induced thrombosis includes ATIII supplementation during therapeutic anticoagulation with enoxaparin. Due to the expense associated with ATIII, a capped dosing approach for ATIII was evaluated in this population. Peak ATIII levels were obtained following capped doses to evaluate response. In this pilot evaluation, 11 patients received a total of 138 capped doses for a total cost savings of $803 782. This pilot evaluation represents the first reported analysis of capped ATIII dosing in oncology patients.

Aspirin in childhood acute ischemic stroke: The evidence for treatment and efficacy testing.

Aspirin is the most commonly prescribed antiplatelet agent worldwide, but evidence supporting its use varies by age and disease process. Despite its frequent use in childhood acute ischemic stroke prevention and management, major knowledge gaps exist about optimal pediatric aspirin use, particularly in this setting, where high-quality clinical trials are urgently needed. This review focuses upon the evidence for aspirin use in childhood acute ischemic stroke, includes a summary of aspirin pharmacology to highlight misconceptions and common clinical situations which may limit its efficacy, and discusses the techniques and potential role of laboratory monitoring of aspirin efficacy in children.

Organ iron accumulation in chronically transfused children with sickle cell anaemia: baseline results from the TWiTCH trial.

Transcranial Doppler (TCD) With Transfusions Changing to Hydroxyurea (TWiTCH) trial is a randomized, open-label comparison of hydroxycarbamide (also termed hydroxyurea) versus continued chronic transfusion therapy for primary stroke prevention in patients with sickle cell anaemia (SCA) and abnormal TCD. Severity and location of iron overload is an important secondary outcome measure. We report the baseline findings of abdominal organ iron burden in 121 participants. At enrollment, patients were young (9·8 ± 2·9 years), predominantly female (60:40), and previously treated with transfusions (4·1 ± 2·4 years) and iron chelation (3·1 ± 2·1 years). Liver iron concentration (LIC; 9·0 ± 6·6 mg/g dry weight) and serum ferritin were moderately elevated (2696 ± 1678 µg/l), but transferrin was incompletely saturated (47·2 ± 23·6%). Spleen R2* was 509 ± 399 Hz (splenic iron ~13·9 mg/g) and correlated with LIC (r(2)  = 0·14, P = 0·0008). Pancreas R2* was increased in 38·3% of patients but not to levels associated with endocrine toxicity. Kidney R2* was increased in 80·7% of patients; renal iron correlated with markers of intravascular haemolysis and was elevated in patients with increased urine albumin-creatinine ratios. Extra-hepatic iron deposition is common among children with SCA who receive chronic transfusions, and could potentiate oxidative stress caused by reperfusion injury and decellularized haemoglobin.

Kaposiform lymphangiomatosis: unifying features of a heterogeneous disorder.

Kaposiform lymphangiomatosis (KLA) is a rare proliferation of abnormal lymphatic vessels often complicated by pleural/pericardial effusions and a consumptive coagulopathy that may lead to life threatening hemorrhage. Establishing the diagnosis is challenging due to the clinical heterogeneity and variable findings in laboratory values, radiographic features, and pathologic characteristics. We report three patients who had slowly progressive symptoms and presented with pleural or pericardial effusions, evidence of a consumptive coagulopathy and anemia. Despite being a rare and challenging diagnosis, KLA should be considered in patients presenting with non-specific indolent symptoms, pleural or pericardial effusions and laboratory evidence of a consumptive coagulopathy.

Abnormal pulmonary function and associated risk factors in children and adolescents with sickle cell anemia.

Obstructive and restrictive pulmonary changes develop in children with sickle cell disease, but reports conflict as to the type of change that predominates. We prospectively performed spirometry, plethysmography, and lung diffusing capacity in 146 children aged 7 to 20 years with hemoglobin SS or Sß(0)-thalassemia. Nineteen percent of the patients had obstructive physiology as defined according to guidelines of the American Thoracic Society. In addition, 9% had restrictive physiology and 11% had abnormal but not categorized physiology. Increasing age, patient-reported or family-reported history of asthma or wheezing, and higher lactate dehydrogenase concentration were independent predictors of obstruction as reflected in lower forced expiratory volume in the first second/forced vital capacity. In conclusion, abnormal pulmonary function, most often obstructive, is common in children with hemoglobin SS and Sß(0)-thalassemia. Full pulmonary function testing should be performed in children with hemoglobin SS or Sß(0)-thalassemia, especially with history of asthma or wheezing and accentuated elevations in hemolytic markers.

Hematological complications of neonatal lupus: case report and review of the literature.

Neonatal thrombocytopenia is a common clinical problem and may be a result of maternal and/or fetal conditions. We present a young patient with thrombocytopenia as a result of neonatal lupus, a passively acquired autoimmune disease. The diagnosis was suspected on the basis of the presence of a facial rash. This case highlights the characteristic eruption of neonatal lupus and an underappreciated cause of neonatal thrombocytopenia for the pediatric hematologist. We also review the hematological complications of neonatal lupus.