Anemia and Associated Risk Factors in Pediatric Patients.

Anemia is the most common hematologic abnormality identified in children and represents a major global health problem. A delay in diagnosis and treatment might place patients with anemia at risk for the development of rare but serious complications, including chronic and irreversible cognitive impairment. Identified risk factors contributing to the development of anemia in children include the presence of nutritional deficiencies, environmental factors, chronic comorbidities, and congenital disorders of hemoglobin or red blood cells. Pediatricians, especially those in the primary care setting, serve a particularly critical role in the identification and care of those children affected by anemia. Prompt recognition of these risk factors is crucial for developing appropriate and timely therapeutic interventions and prevention strategies.

Acute Thrombotic Events in Association With Coronavirus Disease of 2019 Immunization as Initial Presentation of Congenital Factor VII Deficiency.

Coagulation factor VII (FVII) deficiency is a congenital disorder with heterogeneous clinical phenotypes ranging from asymptomatic to life-threatening bleeding and/or thrombotic events. We present the case of an adolescent male who developed acute deep and superficial venous thromboses of the upper extremities in the setting of multiple peripheral venous line insertions and shortly after receiving his second coronavirus disease of 2019 immunization dose. A hemostatic work-up revealed low FVII activity levels associated with 4 different FVII genetic variants. We highlight the need to better understand the pathophysiologic mechanisms behind FVII deficiency-associated prothrombotic risk and the role that specific FVII genetic variants may play in the clinical presentation of these patients.

High Prevalence of Congenital Factor VII (FVII) Deficiency in Adolescent Females with Heavy Menstrual Bleeding and Iron Deficiency Anemia.

STUDY OBJECTIVE: To examine the clinical characteristics and prevalence of congenital bleeding disorders (CBDs), with emphasis on congenital factor VII (FVII) deficiency and other rare bleeding disorders, in adolescent and young adult females referred to a hemophilia treatment center (HTC) for evaluation and management of heavy menstrual bleeding (HMB) and iron deficiency anemia (IDA) DESIGN: In this single-center retrospective study, we reviewed the clinical characteristics and prevalence of CBDs in postmenarchal females, younger than 22 years of age, referred to an HTC from 2015 to 2021 for evaluation of HMB with or without IDA. RESULTS: One hundred females, with a mean age of 15 years (range 9-20 years), met initial study criteria, and 95 were included in the final analysis. Forty-five (47%) females were ultimately diagnosed with a CBD. The most prevalent diagnoses were FVII deficiency and type 1 von Willebrand disease (VWD) (42.3%, n = 19 each). Forty-two percent of patients with FVII deficiency had a low-for-age FVII activity level, 21.1% were only positive for the FVII R353Q variant associated with borderline FVII levels, whereas 36.8% had both a low-for-age FVII activity level and a positive R353Q variant. Eighty percent of patients with a CBD were found to have relatives with abnormal bleeding symptoms. CONCLUSION: Congenital FVII deficiency is prevalent among female adolescents experiencing HMB with or without IDA. In addition to VWD, evaluation for this specific factor deficiency should be considered as part of the initial CBD workup. Presence of abnormal bleeding history in the family could also help to predict presence of a CBD.

Eptacog beta efficacy and safety in the treatment and control of bleeding in paediatric subjects (<12 years) with haemophilia A or B with inhibitors.

INTRODUCTION: Eptacog beta is a new recombinant activated human factor VII bypassing agent approved in the United States for the treatment and control of bleeding in patients with haemophilia A or B with inhibitors 12 years of age or older. AIM: To prospectively assess in a phase 3 clinical trial (PERSEPT 2) eptacog beta efficacy and safety for treatment of bleeding in children <12 years of age with haemophilia A or B with inhibitors. METHODS: Using a randomised crossover design, subjects received initial doses of 75 or 225 µg/kg eptacog beta followed by 75 µg/kg dosing at predefined intervals (as determined by clinical response) to treat bleeding episodes (BEs). Treatment success criteria included a haemostasis evaluation of 'excellent' or 'good' without use of additional eptacog beta, alternative haemostatic agent or blood product, and no increase in pain following the first 'excellent' or 'good' assessment. RESULTS: Treatment success proportions in 25 subjects (1-11 years) who experienced 546 mild or moderate BEs were 65% in the 75 µg/kg initial dose regimen (IDR) and 60% in the 225 µg/kg IDR 12 h following initial eptacog beta infusion. By 24 h, the treatment success proportions were 97% for the 75 µg/kg IDR and 98% for the 225 µg/kg IDR. No thrombotic events, allergic reactions, neutralising antibodies or treatment-related adverse events were reported. CONCLUSION: Both 75 and 225 µg/kg eptacog beta IDRs provided safe and effective treatment and control of bleeding in children <12 years of age.

Clinical Implications of Hematologic and Hemostatic Abnormalities in Children With COVID-19.

Leukopenia, thrombocytopenia, elevated D-dimer, and prolonged prothrombin time are considered poor prognostic factors in adults with acute Coronavirus Disease 2019. The prognostic significance of these abnormalities among pediatric patients remains underreported in the literature. This retrospective cohort study evaluates the prognostic implications of hematologic and hemostatic derangements in patients younger than 22-years-of-age who were admitted to a tertiary-care referral institution for management of acute Coronavirus Disease 2019 infection. Leukopenia and thrombocytopenia were identified as independent prognostic factors of disease severity. Although the majority of children, with available results, had elevated D-dimer or prolonged prothrombin time upon initial presentation, these markers were not found to be associated with the development of severe clinical complications.

Neonatal hip ultrasound: tangent to lateral roof angle correlates better with stability than alpha angle according to Graf or percentage femoral head coverage.

The aim of this study was to determine the relationship of tangent to the lateral roof angle (TLRA), Graf's alpha angle and percentage femoral head cover (PHC) and to observed stability, and to establish intraobserver and interobserver errors for measurement of alpha angle and TLRA. In total, 2235 babies referred to the hip review clinic over a period of 8 years. Intraobserver and interobserver errors were calculated from readings of 383 hip images by an experienced paediatric radiologist and a trainee. Taking TLRA <70° as abnormal resulted in sensitivity for unstable right hips of 88% compared with 77% for alpha angle <60° (P = 0.002) and 81% for PHC <60% (P = 0.028) and specificity of TLRA 89%, alpha angle 90% (P = 0.07) and PHC 83% (P < 0.001). Corresponding figures for left hips are sensitivity of TLRA 99%, alpha angle 91% (P < 0.001) and PHC 96% (P = 0.013), and specificity TLRA 86%, alpha angle 83% (P = 0.001) and PHC 67% (P < 0.001). Mean intraobserver errors for alpha angle were 1.85° and 1.81° for consultant and trainee compared to 2.54 and 2.55 for TLRA. Mean interobserver errors were 2.22 for alpha angle and 3.42 for TLRA. TLRA, a new parameter, correlated better with observed stability with significant improvement in sensitivity in both hips and specificity in left hips compared with Graf's alpha angle, and significantly improved sensitivity and specificity in both hips compared with percentage femoral head cover.

Barriers and challenges for the fast treatment of bleeds in the non-haemophilia treatment centre hospital setting.

INTRODUCTION: Early treatment for acute bleeds in patients with haemophilia and inhibitors is feasible when patients are managed in haemophilia treatment centres (HTCs). Patients may need to attend non-HTCs for out-of-hours emergency care, especially if HTCs are not local and/or transport is difficult. AIM: We evaluated the barriers to the fast treatment of bleeds in patients with haemophilia and inhibitors presenting at non-HTCs. METHODS: Healthcare professionals (HCPs) from non-HTCs in the United States (n = 218) and Germany (n = 98) were selected from validated online panels and invited to participate in a survey (October-November 2017). RESULTS: A mean of 6 (US) and 5 (German) patients with haemophilia and inhibitors were managed for bleeds by these HCPs over 12 months; patient characteristics were similar in both countries. The main HCPs involved in treating bleeds were emergency room specialists (94%) and haematologists (91%) (US); haematologists (79%) and anaesthesiologists (59%) (Germany). Only 26% (US) and 28% (Germany) of HCPs had access to treatment guidelines for these patients; access to bypassing agents was similarly limited: 44% (US) and 38% (Germany) of HCPs reported their institution did not stock these agents. In both countries, key reasons for delaying treatment were lack of bypassing agent availability, HCP experience/education of bleed disorders and internal process time. CONCLUSION: Barriers to fast treatment of bleeds in patients with haemophilia and inhibitors were identified in non-HTCs in the United States and Germany. These could be reduced by improving the availability of treatment guidelines, bypassing agents and HCP education/training.

Use of a multiagency approach to eradicate New World screwworm flies from Big Pine Key, Florida, following an outbreak of screwworm infestation (September 2016-March 2017).

On September 30, 2016, the US National Veterinary Services Laboratory confirmed an autochthonous case of New World screwworm infestation in a Key deer (Odocoileus virginianus clavium) from Big Pine Key, Fla. This case marked the first identification of a sustained and reproducing population of New World screwworm flies in the United States since 1966. Multiple federal, state, and local government agencies collaborated to initiate a response to the outbreak. Efforts were successful in eradicating the flies from Florida.

Systematic review and analysis of efficacy of recombinant factor IX products for prophylactic treatment of hemophilia B in comparison with rIX-FP.

Aims: Prophylaxis with standard-acting recombinant factor IX (rFIX) in hemophilia B patients requires frequent injections. Extended half-life (EHL) products allow for prolonged dosing intervals, and so reduce this treatment burden. Three technologies are employed to extend the half-life of FIX; glycopegylation, Fc-fusion, and albumin fusion. rIX-FP is a novel albumin fusion protein, which allows for a prolonged dosing interval of up to 14 days. A systematic review and indirect statistical comparison was performed to evaluate the efficacy of both EHL and standard-acting rFIX products compared with rIX-FP in Phase III trials for prophylaxis in adult hemophilia B patients. Materials and methods: A systematic search was conducted in both EMBASE and PubMed to identify Phase III trials of prophylactic rFIX treatment in previously treated hemophilia B patients aged ≥12 years (FIX ≤2%). Annualized bleeding rate (ABR), spontaneous ABR (AsBR), and joint ABR (AjBR) data were extracted from each study. A z-test was performed using the mean of each parameter, and the mean difference in outcome between studies was calculated. Results: Seven articles investigating six rFIX products were identified. Median ABR, AsBR, and AjBR ranged from 0-3.0, 0-1.0, and 0-1.1 (means = 0.8-4.26, 0.13-2.6, and 0.34-2.85), respectively. rIX-FP achieved the lowest median and mean values in all three parameters. Z-tests showed that mean ABR was significantly lower for rIX-FP 7-day prophylaxis compared with the majority of standard-acting and other EHL rFIX products. Limitations: The low number of appropriate trials available for comparison limits the quantity of data available for comparison, and restricts the use of methods of adjustment for variance in study design or patient characteristics. However, these limitations are shared with similar analyses published in this field. Conclusion: This indirect comparison of Phase III trials indicates that rIX-FP efficacy compares favorably vs other rFIX products for prophylaxis in hemophilia B.

Focusing in on use of pharmacokinetic profiles in routine hemophilia care.

BACKGROUND: Emergence of population pharmacokinetic models for prediction of individual pharmacokinetic (PK) profiles facilitates individualization of prescribed prophylactic therapy for patients with hemophilia A and B and may have a favorable impact on clinical outcomes and annual factor utilization. How providers approach the integration and application of these data into routine clinical practice is not clear. OBJECTIVE: To explore the potential application of and barriers to incorporating PK profiles into current hemophilia prophylaxis decision making. METHODS: A facilitated group discussion of hematologists practicing within the federally-supported United States Hemophilia Treatment Center Network was conducted. Separately, a group of parents of patients with severe hemophilia less than 18 years of age participated in a focus group on individualizing prophylactic factor regimens with the use of PK data. RESULTS: Physician participants constructed a conceptual model for factors that determined their selection of hemophilia prophylaxis. These factors clustered in five groupings. When charged with creating a prophylaxis regimen for a specific clinical case including PK data, eight of nine providers generated a unique regimen. Parent focus group supported PK data use as they preferred data driven treatment decisions. CONCLUSIONS: Clinician application of PK data for prophylaxis decision making is heterogeneous. Prospective evaluation of the use of PK-tailored prophylaxis in routine care and its impact on patient outcomes is needed. Parents perceived that, while obtaining blood draws could be challenging, images of factor activity decay informed their decisions about physical activity timing and provided an opportunity for partnership and shared decision making with their provider.

Cattle Assessment On-Site During Emergencies.

Veterinary assessment of the condition and needs of livestock and their owners in an emergency is an essential element of the disaster response. The emergency response for livestock has 4 critical components: assessing the need for and attending to the immediate medical needs of injured or affected livestock, determining the resources available to meet the needs, including feed and facilities, identifying any ongoing threats or potential hazards to livestock health and welfare, and appropriate documentation of damages and actions by responders. Information gathered from cattle assessments by veterinarians is used to prioritize resources and plan for anticipated needs.

Prevalence of Hypertension (HTN) and Cardiovascular Risk Factors in a Hospitalized Pediatric Hemophilia Population.

Improved life expectancy in hemophilia has led to a greater interest in age-related disorders. Hypertension (HTN) as well as cardiovascular disease have been increasingly reported in hemophilic adults but there is currently very limited data in the pediatric population. We conducted a cross-sectional study using data from the 2012 National Health Cost and Utilization Project database to determine the prevalence of HTN and associated cardiovascular risk factors in a hospitalized pediatric hemophilia population, between the ages of 0 to 21 years, in comparison with the general pediatric population. The prevalence of HTN was significantly higher in children with hemophilia (CWH) in comparison with the general pediatric population (1.71% vs. 1.02%, P-value=0.005). When adjusting the analysis for sex, the prevalence of HTN in the hemophilia cohort remained higher, although not statistically significant (1.52% vs. 1.22%, P-value=0.2568). When examining the concomitant presence of ≥1 cardiovascular risk factors in the hypertensive subgroups, CWH had a higher prevalence of obesity (2.64% vs. 1.32%, P-value <0.0001). Interestingly, diabetes mellitus was more prevalent in nonhemophilic children (1.47% vs. 0.56%, P-value=0.0015). These data suggest that cardiovascular risk factors need to be closely monitored in CWH, and a better preventive strategy is likely needed to identify those hemophilic patients at higher risk of developing cardiovascular disease in adulthood.

Evaluation of optimal extracellular vesicle small RNA isolation and qRT-PCR normalisation for serum and urine.

MicroRNAs are small regulatory molecules that demonstrate useful biomarker potential. They have been recognised in biofluids, where they are protected from degradation by encapsulation into extracellular vesicles (EVs). A number of commercial products are available for the isolation of EVs and their RNA content; however, extensive protocol comparisons are lacking. Furthermore, robust qRT-PCR assessment of microRNA expression within EVs is problematic, as endogenous controls (ECs) previously used in cellular samples may not be present. This study compares EV isolation and RNA extraction methods (EV precipitation reagents, RNA isolation kits and ultracentrifugation) from serum or urine samples and evaluates suitable ECs for incorporation into qRT-PCR analysis. Results were assessed by electron microscopy, nanoparticle tracking analysis and bioanalyzer concentrations. The stability of 8 ECs was compared for both serum and urine EV RNA and retrospectively validated in independent cohorts (serum n=55, urine n=50). The Life Technologies precipitation reagent gave superior serum EV recovery compared to SBI reagent, as assessed by NTA size distribution, increased RNA concentration, and lower small RNA Ct values. Similarly, the Norgen Biotek Urine Exosome RNA Isolation Kit gave improved results for urine EV isolation compared to ultracentrifugation, when determined by the same parameters. The Qiagen miRNeasy™ RNA isolation kit gave suitable serum EV RNA concentrations compared to other kits, as assessed by Bioanalyzer and small RNA qRT-PCR. Small RNAs HY3 (S.D=1.77, CoV=6.2%) and U6 (S.D=2.14, CoV=8.6%) were selected as optimal ECs for serum EV microRNA expression analysis, while HY3 (S.D=1.67, CoV=6.5%) and RNU48 (S.D=1.85, CoV=5.3%) were identified as suitable for urine studies. In conclusion, this study identifies optimal methods for isolation of serum and urine EV RNA, and suitable ECs for normalisation of qRT-PCR studies. Such reports should aid in the standardisation of EV microRNA data, particularly for biomarker studies.

Hemophilic Pseudotumor: An Important Differential Diagnosis of an Intracranial Mass.

Hemophilic pseudotumor is a rare complication of hemophilia. We present the case of a male toddler with moderate hemophilia A and cranial hemophilic pseudotumor managed with factor VIII infusions. We also provide a review of the literature. Recognition of this rare manifestation of this complication of hemophilia is important to provide correct treatment and avoid unnecessary investigations, particularly biopsy, which is contraindicated in this condition.

Extensive juvenile xanthogranuloma involving the orbit, sinuses, brain, and subtemporal fossa in a newborn.

A 6-week-old-boy presented with a 3-week history of right axial proptosis. Vision, motility, anterior segment, and fundus examinations were normal in both eyes. Imaging revealed a multicystic right orbital lesion with extensive involvement of the infratemporal fossa and paranasal sinuses with intracranial extension. Systemic workup was negative, and he showed no functional deficits. Histopathology revealed a tumor rich in histiocytes, and immunohistochemistry indicated a juvenile xanthogranuloma. He did well with observation, and the tumor partially involuted after 18 months of follow-up.

Cold infusion for salvage partial hilar nephrectomy in patient with bilateral wilms tumor.

We describe the use of an ice-cold solution of Ringer's lactate with additives to ameliorate ischemia-reperfusion injury and avoid renal failure in a child with bilateral Wilms tumor requiring nonanatomic, hilar resection that would leave the patient with marginal renal parenchyma postoperatively. The adequate renal function afforded by the procedure avoided the possible need for dialysis and allowed the resection area to be irradiated to prevent tumor recurrence before eventual renal transplantation.

Older people awaken more frequently but fall back asleep at the same rate as younger people.

STUDY OBJECTIVES: To determine whether the increased wake within a bedrest episode in healthy older people is due to an increased number and/or increased duration of awakenings by evaluating the rates of transition between sleep and wake bouts within a bedrest episode. DESIGN: Analysis of previously reported polysomnographic data from 13 older and 11 younger healthy individuals scheduled to sleep at many different phases of the endogenous circadian cycle during conditions of forced desynchrony (18.7 hours wake: 9.3 hours bedrest) of the circadian and wake-bedrest cycles. SETTING: General clinical research center PATIENTS OR PARTICIPANTS: None. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Older subjects had an approximately 2.7-fold increased rate of awakening from sleep but the same rate of falling back asleep as younger subjects. These differences between young and older individuals were observed at most circadian phases and throughout the bedrest episodes. In addition, the circadian variation in transition rates was greater in younger than older subjects. CONCLUSIONS: These results suggest that the reduced consolidation of sleep within a bedrest episode is due to difficulties remaining asleep, rather than falling asleep once awake, and is a primary change in sleep with aging.