Mona D. Shah

Flow cytometric measurement of microparticles: Pitfalls and protocol modifications

Upon activation, many cells shed components of their plasma membranes as microparticles. Depending on the methods of preparation and analyses, microparticle counts may vary significantly between laboratories, making data analyses and clinical correlations challenging. To assess how variations in sample preparation affect microparticle measurements, blood samples from 13 healthy, adult volunteers were labeled with Annexin V, cell-specific antibodies, and antibodies against tissue factor (TF). Data were acquired and analysed using an EPICS XL-MCL flow cytometer. Annexin V+ monocyte-, platelet-, endothelial-, or erythrocyte-derived microparticles accounted for 10.4%, 38.5%, 43.8%, and 7.3% of the total number of microparticles (13.7 ± 3.0 × 103/ml of whole blood), respectively. A similar distribution of cell types was seen for TF+ microparticles (6.3 ± 2.6 × 103/ml of whole blood). No statistical difference was noted in microparticle distribution using either 19- or 21-gauge needles. Elevated levels of platelet- and erythrocyte-derived microparticles were detected in heparin and PPACK-anticoagulated samples as compared to samples anticoagulated with ACD or sodium citrate (P < 0.05, students t-test). Additional centrifugation was critical for removing platelet contamination, which significantly affected microparticle counts. Finally, Annexin V+ and TF+ microparticles were significantly reduced upon sample storage at low temperatures. Microparticle levels are significantly affected by variations in sample preparation and storage. These results illustrate the need to standardize assay protocols in order to obtain consistent measurements. Our studies further optimize sample preparation for microparticle detection.

Risk factors and co-morbidities in adolescent thromboembolism are different than those in younger children

INTRODUCTION In adolescent thromboembolism (TE), multiple risk factors (RFs) and co-morbidities (CMs) are reported, though overall prevalence has not been evaluated. We hypothesized that the spectrum of RFs/CMs in adolescent TE differs from children overall and sought to review Texas Childrens Hospitals experience. PATIENTS/METHODS Medical records of adolescents aged 12-21years, diagnosed with arterial or venous TE (AT/DVT) from 2004 to 2014, were retrospectively reviewed and analyzed with IRB approval. RESULTS Sixty-four adolescents (median age 16, range 12-20years) met study criteria. Fifty-seven (89%) had DVT and six (9%) had AT. Associated RFs/CMs included obesity (47%), CVC (27%), infection (27%), surgery (27%), autoimmune disease (19%), immobility (22%), anatomical abnormality (20%), cancer (8%), estrogen therapy (6%), tobacco use (6%), trauma (3%), inherited thrombophilia (19%), and other medical conditions (11%). Fifty-two (81%) had ≥2 RFs/CMs. Therapy included anticoagulants, antiplatelet agents, and interventional therapy. Of those with follow-up imaging, 49 had complete or partial resolution, 5 had no change and 4 had progression. Fourteen (22%) had recurrent TE. The majority with recurrent TE (79%) had ≥2 RFs at initial diagnosis. Mean time to recurrence was 4.80years; time to recurrence was shorter for occlusive TE (p=0.026). CONCLUSION Adolescent TE is often multi-factorial with the majority having ≥2 RFs at diagnosis, suggesting the need for detailed evaluation for RFs in this population, which may enable optimal management including thromboprophylaxis, and institution of RF-modifying strategies to prevent occurrence/recurrence.

Platelet function defects in adolescents with heavy menstrual bleeding

Platelet function defects (PFD) are reported to occur frequently in adult women with heavy menstrual bleeding (HMB). Few studies on adolescent HMB report varying incidence rates (2–44%) for PFD. We reviewed our institutional experience in detecting and managing PFD in adolescent HMB. Postmenarchial girls and adolescents with HMB seen at our institution undergo a comprehensive bleeding disorder work‐up by paediatric haematology and paediatric gynaecology providers. Whole blood platelet aggregometry (WBPA) is performed as a second tier test after excluding thrombocytopaenia, coagulation factor deficiencies and Von Willebrand disease (VWD). We retrospectively reviewed the medical records of adolescents with HMB seen between June 2009 and November 2010, as approved by the Institutional Review Board. Patient demographics, clinical features, laboratory results, therapy details and patient outcome information were analysed. Overall, 114 postmenarchial girls and adolescents with HMB were evaluated; 68 patients (59%) had WBPA study performed. Nineteen patients (28%) had at least one aggregation or secretion defect; 12 (18%) had two or more such defects. Treatment included hormonal therapy (13/19; 68%), antifibrinolytic agents (8/19; 42%) and intra‐nasal DDAVP (3/19; 16%). Thirteen patients (81%) had improved outcome (median follow‐up – 15.6 months; range of 1–66 months). In this study, PFD were identified in nearly one‐third of girls with HMB, with the majority of these having two or more defects as identified by WBPA. Further prospective studies are needed to better define the prevalence and address appropriate management of HMB and other bleeding complications of PFD in adolescents.

Algorithm for analysis of administrative pediatric cancer hospitalization data according to indication for admission.

BackgroundChildhood cancer relies heavily on inpatient hospital services to deliver tumor-directed therapy and manage toxicities. Hospitalizations have increased over the past decade, though not uniformly across childhood cancer diagnoses. Analysis of the reasons for admission of children with cancer could enhance comparison of resource use between cancers, and allow clinical practice data to be interpreted more readily. Such comparisons using nationwide data sources are difficult because of numerous subdivisions in the International Classification of Diseases Clinical Modification (ICD-9) system and inherent complexities of treatments. This study aimed to develop a systematic approach to classifying cancer-related admissions in administrative data into categories that reflected clinical practice and predicted resource use.MethodsWe developed a multistep algorithm to stratify indications for childhood cancer admissions in the Kids Inpatient Databases from 2003, 2006 and 2009 into clinically meaningful categories. This algorithm assumed that primary discharge diagnoses of cancer or cytopenia were insufficient, and relied on procedure codes and secondary diagnoses in these scenarios. Clinical Classification Software developed by the Healthcare Cost and Utilization Project was first used to sort thousands of ICD-9 codes into 5 mutually exclusive diagnosis categories and 3 mutually exclusive procedure categories, and validation was performed by comparison with the ICD-9 codes in the final admission indication. Mean cost, length of stay, and costs per day were compared between categories of indication for admission.ResultsA cohort of 202,995 cancer-related admissions was grouped into four categories of indication for admission: chemotherapy (N=77,791, 38%), to undergo a procedure (N=30,858, 15%), treatment for infection (N=30,380, 15%), or treatment for other toxicities (N=43,408, 21.4%). The positive predictive value for the algorithm was >95% for each category. Admissions for procedures had higher mean hospital costs, longer hospital stays, and higher costs per day compared with other admission reasons (p<0.001).ConclusionsThis is the first description of a method for grouping indications for childhood cancer admission within an administrative dataset into clinically relevant categories. This algorithm provides a framework for more detailed analyses of pediatric hospitalization data by cancer type.

Navigating your career path in pediatric hematology/oncology: On and off the beaten track.

1Division of Pediatrics, UTM.D. AndersonCancerCenter, Children’s CancerHospital, Houston, Texas 2Department of Pediatrics, YaleUniversity School ofMedicine, NewHaven, Connecticut 3Division ofHematology/Oncology, Children’sHospital LosAngeles, California 4Department of Pediatrics, Pediatrics, University of FloridaCollege ofMedicine, Gainesville, Florida 5Division ofHematology/Oncology, LosAngelesMattel Children’s Hospital, University of California, California 6Department of Pediatrics, University ofNebraskaMedical Center, Omaha, Nebraska 7Division ofHematology/Oncology, DoernbecherChildren’sHospital, OregonHealth& ScienceUniversity, Portland,Oregon 8Division ofHematology/Oncology, Baylor College ofMedicine, TexasChildren’s Hospital, Houston, Texas 9Providence SacredHeartMedical Center andChildren’sHospital, Pediatrics, Spokane,Washington 10Department of Pediatrics, StanfordUniversity School ofMedicine, Stanford, California 11Amgen, ThousandOaks, California 12National Cancer Institute (NCI), Cancer Therapy Evaluation Program, Bethesda,Maryland 13Department of Pediatrics, University of Texas SouthwesternMedical Center, Dallas, Texas 14Children’s CancerCenter, Staten IslandUniversity Center atNorthwell Health, Staten Island, NewYork 15Division ofHematology/Oncology, Children’sHospital &ResearchCenter, Oakland, California 16Department of Pediatrics, University of Colorado, School ofMedicine, Aurora, Colorado Correspondence LindaStork,DepartmentofPediatrics,CDRCP,OHSU,3181SWSamJacksonParkRoad, Portland,OR97239. Email: storkl@ohsu.edu

Work efficiency improvement of >90% after implementation of an annual inpatient blood products administration consent form

Paediatric haematology, oncology and bone marrow transplant (BMT) patients frequently require transfusion of blood products. Our institution required a new transfusion consent be obtained every admission. The objectives of this project were to: revise inpatient blood products consent form to be valid for 1 year, decrease provider time spent consenting from 15 to <5 min per admission, and improve provider frustration with the consent process. Over 6 months, we determined the average number of hospitalisations requiring transfusions in a random sampling of haematology/oncology/BMT inpatients. We surveyed nurses and providers regarding frustration levels and contact required regarding consents. Four and 12 months after implementation of the annual consent, providers and nurses were resurveyed, and new inpatient cohorts were assessed. Comparison of preintervention and postintervention time data allowed calculation of provider time reduction, a surrogate measure of improved work efficiency. Prior to the annual consent, >33 hours were spent over 6 months obtaining consent on 40 patients, with >19 hours spent obtaining consent when no transfusions were administered during admission. Twelve months after annual consent implementation, 97.5% (39/40) of analysed patients had a completed annual blood products transfusion consent and provider work efficiency had improved by 94.6% (>30 hours). Although several surveyed variables improved following annual consent implementation, provider frustration with consent process remained 6 out of a max score of 10, the same level as prior to the intervention. Development of an annual inpatient blood products consent form decreased provider time from 15 to <1 min per admission, decreased consenting numbers and increased work efficiency by >90%.

Population Pharmacokinetics of Enoxaparin in Pediatric Patients

Background: There are no studies evaluating the pharmacokinetics of enoxaparin in the hospitalized pediatric patient population. Objective: To characterize the pharmacokinetics of enoxaparin in pediatric patients. Methods: A retrospective review of inpatients 1 to 18 years of age admitted to our institution who received enoxaparin with anti–factor Xa activity level monitoring was performed. Demographic variables, enoxaparin dosing, and anti–factor Xa activity levels were collected. Population pharmacokinetic analysis was performed with bootstrap analysis. Simulation (n = 10 000) was performed to determine the percentage who achieved targeted anti-Xa levels at various doses. Results: A total of 853 patients (male 52.1%, median age = 12.2 years; interquartile range [IQR] = 4.6-15.8 years) received a mean enoxaparin dose of 0.86 ± 0.31 mg/kg/dose. A median of 3 (IQR = 1-5) anti–factor Xa levels were sampled at 4.4 ± 1.3 hours after a dose, with a mean anti–factor Xa level of 0.52 ± 0.23 U/mL. A 1-compartment model best fit the data, and significant covariates included allometrically scaled weight, serum creatinine, and hematocrit on clearance, and platelets on volume of distribution. Simulations were run for patients both without and with reduced kidney function (creatinine clearance of ≤30 mL/min/1.73 m2). A dose of 1 mg/kg/dose every 12 hours had the highest probability (72.3%) of achieving an anti-Xa level within the target range (0.5-1 U/mL), whereas a dose reduction of ~30% achieved the same result in patients with reduced kidney function. Conclusions: Pediatric patients should initially be dosed at 1-mg/kg/dose subcutaneously every 12 hours for treatment of thromboembolism followed by anti-Xa activity monitoring. Dose reductions of ~30% for creatinine clearance ≤30 mL/min/1.73 m2 are required.

Hispanic ethnicity as a risk factor for requiring glucarpidase rescue in pediatric patients receiving high-dose methotrexate

Anjum B. Khan , Rachel Kesse-Adu, Cormac Breen, Patrick B. Murphy, John Chambers, Paul Holmes, Joanna Howard Department of Haematology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK Department of Nephrology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK Lane Fox Respiratory Unit, Guy’s and St Thomas’ NHS Foundation Trust, London, UK Division of Asthma Allergy and Lung Biology, King’s College London School of Medical Education, London, UK Department of Cardiology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK Cardiovascular Division, King’s College London, UK Department of Neurology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK

Association of outcomes and anti-Xa levels in the treatment of pediatric venous thromboembolism

There are few data in the pediatric population evaluating the relationship between measured anti‐Xa levels during enoxaparin therapy and thrombotic outcomes.

Sustainability and Spread

The sustainability and spread of quality improvement and/or patient safety innovations is often elusive, presenting continuous challenges to clinicians and healthcare leaders. Somewhere between 33 and 70% of all innovations are reportedly not sustained, and even fewer are spread beyond the original team, or to other units within an institution. In plain language, sustainability is defined as locking in progress, while continually building upon that foundation, while spread is the exchange of knowledge and experience on targeted work practices to achieve expected results. The literature supports the concept that sustainability is both multi-dimensional and multi-factorial and has several characteristics and pre-conditions. Two case studies are presented: one addressing the prevention of central line associated blood stream infections (CLABSIs) and the other dealing with recognition and treatment of febrile neutropenia (FN). Two key quality improvement tools, which assisted with the quality improvement efforts as well as the ultimate success of sustainability and spread, were the key driver diagrams and cascading responsibility charts. We recommend considering the characteristics and pre-conditions of sustainability and spread in advance of a quality improvement process rather than at the conclusion of the initial initiative.