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Key Points How TPEx impacts rituximab effectiveness in iTTP patients is not fully understood. In iTTP patients on therapeutic plasma exchange, rituximab eliminates circulating CD20+ B and T cells in 24 hours for at least 1 week.

Vaso-occlusive pain events (VOE) are the leading cause of emergency department (ED) visits in sickle cell anemia (SCA). This study assessed the variability in use of intravenous fluids (IVFs), and the association of normal saline bolus (NSB), on pain and other clinical outcomes in children with SCA, presenting to pediatric emergency departments (PED) with VOE. Four-hundred charts of children age 3-21 years with SCA/VOE receiving parenteral opioids at 20 high-volume PEDs were evaluated in a retrospective study. Data on type and amount of IVFs used were collected. Patients were divided into two groups: those who received NSB and those who did not. The association of NSB use on change in pain scores and admission rates was evaluated. Among 400 children studied, 261 (65%) received a NSB. Mean age was 13.8 ± 4.9 years; 46% were male; 92% had hemoglobin-SS. The IVFs (bolus and/or maintenance) were used in 84% of patients. Eight different types of IVFs were utilized and IVF volume administered varied widely. Mean triage pain scores were similar between groups, but improvement in pain scores from presentation-to-ED-disposition was smaller in the NSB group (2.2 vs 3.0, P = .03), while admission rates were higher (71% vs 59%, P = .01). Use of NSB remained associated with poorer final pain scores and worse change in pain scores in our multivariable model. In conclusion, wide variations in practice utilizing IVFs are common. NSB is given to >50% of children with SCA/VOE, but is associated with poorer pain control; a controlled prospective trial is needed to determine causality.

Background Delayed hemolytic transfusion reactions (DHTRs) are serious complications of RBC transfusion that can occur in previously alloimmunized patients. Patients who require episodic transfusions during heightened inflammatory states, such as patients with sickle cell disease (SCD), are particularly prone to alloimmunization and developing DHTRs with hyperhemolysis. While efforts to mitigate these hemolytic episodes via immunosuppressive drugs can be employed, the relative efficacy of various treatment options remains incompletely understood. Case reports In this study, we explored five patients with SCD and multiple RBC alloantibodies who received various forms of immunosuppressive therapy in an attempt to prevent or treat severe DHTRs. Results The clinical course for these five patients provides insight into the difficulty of effectively treating and preventing DHTRs in patients with SCD with currently available immunosuppressive therapies. Conclusion Based on our experience, and the current literature, it is difficult to predict the potential impact of various immunosuppressive therapies when seeking to prevent or treat DHTRs. Future mechanistic studies are needed to identify the optimal treatment options for DHTRs in the presence or absence of distinct alloantibodies in patients with SCD.

Renal medullary carcinoma (RMC) is one of the most aggressive renal cell carcinomas. It predominantly afflicts young adults and adolescents with sickle cell trait and other sickle hemoglobinopathies, and is refractory to targeted and antiangiogenic therapies used in patients with clear-cell renal cell carcinoma. Platinum-based cytotoxic chemotherapy is the mainstay for RMC treatment. On the basis of recent advances in the diagnosis, management, and clinical trial development for RMC, a panel of experts met in October 2017 and developed updated consensus recommendations to inform clinicians, researchers, and patients. Because RMC often aggressively recurs while patients are still recovering from nephrectomy, upfront chemotherapy should be considered for most patients, including those with localized disease. After safety and dosing information has been established in adults, phase II and III trials enrolling patients with RMC should allow patients aged 12 years and older to be accrued. Patients with the very rare unclassified renal cell carcinoma with medullary phenotype variant should be included in RMC trials. Medical providers should be aware that RMC can afflict subjects of all races, and not only those of African descent, and that the presence of sickle cell trait, or of other sickle hemoglobinopathies, can affect drug responses and toxicity.

In patients with sickle cell disease (SCD) and diabetes mellitus (DM), hemoglobin A(1c) (HbA(1c)) is unreliable and the American Diabetes Association recommends monitoring long-term glycemia by measuring serum glucose, but use of serum fructosamine (SF), a measurement independent of red cell lifespan, has been reported. SF as a screen for DM in SCD, however, is not standardized and its relationship to serum glucose has not been validated. Further, screening for DM was not adequately addressed in the 2014 National Heart, Lung, and Blood Institute (NHLBI) guidelines for SCD management. Blood transfusions, an important treatment for some patients with SCD, can also impact HbA(1c). We present a case of a patient with SCD and cystic fibrosis-related diabetes on monthly chronic transfusions therapy (CTT) who had well-correlated “steady state” HbA(1c) and SF levels over time, suggesting for the first time these markers may actually be useful when following long-term glycemic control in patients with SCD on CTT programs.

Hemostasis encompasses an ensemble of interactions among platelets, coagulation factors, blood cells, endothelium, and hemodynamic forces, but current assays assess only isolated aspects of this complex process. Accordingly, here we develop a comprehensive in vitro mechanical injury bleeding model comprising an “endothelialized” microfluidic system coupled with a microengineered pneumatic valve that induces a vascular “injury”. With perfusion of whole blood, hemostatic plug formation is visualized and “in vitro bleeding time” is measured. We investigate the interaction of different components of hemostasis, gaining insight into several unresolved hematologic issues. Specifically, we visualize and quantitatively demonstrate: the effect of anti-platelet agent on clot contraction and hemostatic plug formation, that von Willebrand factor is essential for hemostasis at high shear, that hemophilia A blood confers unstable hemostatic plug formation and altered fibrin architecture, and the importance of endothelial phosphatidylserine in hemostasis. These results establish the versatility and clinical utility of our microfluidic bleeding model., Hemostasis is a complex ensemble of events, but current bleeding assays only analyze single components like coagulation or platelet function. Here the authors present a comprehensive vascularized microfluidic mechanical injury bleeding model that addresses different aspects of the hemostatic process.

Introduction Individuals with sickle cell disease (SCD) in resource-rich countries are now living longer due to the implementation of newborn screening, use of prophylactic penicillin, and introduction of hydroxyurea. The impact of SCD on the bone marrow and peripheral blood counts as individuals with SCD age is not well described in the hydroxyurea era. As a result of increased red blood cell (RBC) turnover due to hemolysis in SCD, potential ineffective erythropoiesis, and well-described systemic inflammatory processes, the increased stress in the bone marrow may manifest as decreased peripheral blood cell counts over time in a during an aging process unique to those with SCD. Objective The objective was to model routine clinical blood measurements (n=5,328) with a longitudinal cohort of 447 patients, resulting in models of circulating blood counts as a potential marker of bone marrow function across the lifespan in adults with SCD. Our working hypothesis was that increasing age would be associated with decreases in certain blood counts, with trends modified by SCD genotype severity. Methods In this large, single institution retrospective cohort study, we analyzed blood count measurements from adults with SCD. We used an accelerated longitudinal cohort design to examine changes in white blood cell count (WBC), hemoglobin (HGB), absolute reticulocyte count (ARC), and platelet count over time. Genotypes were grouped as severe (HbSS or HbSβ 0-thalassemia; n=301), non-severe (HbSC or HbSβ +-thalassemia; n=136), or other (n=10). For HGB and ARC, we adjusted for estimated glomerular filtration rate (eGFR) and serum creatinine. Results Patients ranged in age at enrollment from 18 to 84 (M = 31.9, SD=12.9), with median follow-up time of 3.6 years and a median of 6 measurements per patient. Overall, HGB and ARC decreased across the lifespan; however, trends were moderated by genotype. Compared to individuals with non-severe genotypes, those with the severe genotypes had consistently lower HGB levels that did not differ by age. For ARC, the severe genotypes had higher levels in young adulthood, which slowly decreased with age. WBC also decreased with age for this group. In contrast, individuals with the non-severe genotype showed an increase in WBC by age. Platelet counts decreased with increasing age for those with the severe genotype while those with non-severe genotypes showed an increase with age. Conclusion Severe SCD genotypes are associated with decreases in HGB, ARC, WBC, and platelet count by age. For HGB and ARC, these declines are significantly attenuated by renal function, suggesting that such declines are largely related to worsening renal function with age. However, an intrinsic bone marrow contribution to this aging process should also be explored in future studies. Decreases in WBC and platelet count with time, observed in the severe genotypes, support the presence of pathological processes of bone marrow dysfunction that may worsen with age. A possible etiology of the increasing bone marrow dysfunction in SCD may be a result of bone marrow exhaustion or cellular senescence. Prospective studies to explore contributors to reduced blood counts during the aging process in individuals with SCD are needed. We are actively exploring potential biomarkers associated with this process. Figure 1 Figure 1. Disclosures Carden: Forma Therapeutics: Current Employment. Derebail: Novartis: Consultancy; UpToDate: Patents & Royalties; Travere Therapeutics: Consultancy; Bayer: Consultancy. Ataga: Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy; Forma Therapeutics: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Monomorphic plasmacytoma-type posttransplant lymphoproliferative disorder (PTLD) has not been reported after pediatric hematopoietic stem cell transplantation. We present a child with hepatitis-associated severe aplastic anemia who underwent an unrelated allogeneic hematopoietic stem cell transplantation and subsequently developed graft failure and an Epstein-Barr virus-positive monomorphic plasmacytoma-type PTLD of recipient origin. Despite broad-spectrum antimicrobials, weaning immunosuppression, rituximab administration, and a stem cell boost she died from complications of PTLD and a fungal pulmonary infection on day +78.

Sickle cell disease afflicts millions of people worldwide and approximately 100,000 Americans. Complications are myriad and arise as a result of complex pathological pathways ‘downstream’ to a point mutation in DNA, and include red blood cell membrane damage, inflammation, chronic hemolytic anemia with episodic vaso-occlusion, ischemia and pain, and ultimately risk of cumulative organ damage with reduced lifespan of affected individuals. The National Heart, Lung, and Blood Institute’s 2014 evidence-based guideline for sickle cell disease management states that additional research is needed before investigational curative therapies will be widely available to most patients with sickle cell disease. To date, sickle cell disease has been cured by hematopoietic stem cell transplantation in approximately 1,000 people, most of whom were children, and significantly ameliorated by gene therapy in a handful of subjects who have only limited follow-up thus far. During a timespan in which over 20 agents were approved for the treatment of cystic fibrosis by the Food and Drug Administration, similar approval was granted for only two drugs for sickle cell disease (hydroxyurea and L-glutamine) despite the higher prevalence of sickle cell disease. This trajectory appears to be changing, as the lack of multimodal agent therapy in sickle cell disease has spurred engagement among many in academia and industry who, in the last decade, have developed new drugs poised to prevent complications and alleviate suffering. Identified therapeutic strategies include fetal hemoglobin induction, inhibition of intracellular HbS polymerization, inhibition of oxidant stress and inflammation, and perturbation of the activation of the endothelium and other blood components (e.g. platelets, white blood cells, coagulation proteins) involved in the pathophysiology of sickle cell disease. In this article, we present a crash-course review of disease-modifying approaches (minus hematopoietic stem cell transplant and gene therapy) for patients with sickle cell disease currently, or recently, tested in clinical trials in the era following approval of hydroxyurea.

Sickle cell anemia (SCA) is associated with morbidity and early death. While the switch from fetal to sickle hemoglobin during the first months of life results in hemolytic anemia with reticulocytosis, the role of the reticulocyte in the pathophysiology and prognosis of SCA is not well-defined. Reticulocytes have unique cytoskeletal and membrane components that allow them to be distinguished from mature sickle erythrocytes in the circulation. Reticulocytes in patients with SCA are less dense than more mature and 'sickled' erythrocytes, and have increased adhesive properties. The circulating reticulocyte number in peripheral blood may assist in predicting disease severity in SCA; characterization of patient-specific reticulocyte properties during infancy and childhood may assist in predicting therapeutic response to therapies. Here, we review the biological and clinical data regarding reticulocytes and their potential impact on SCA pathophysiology and disease severity.

Background: Sickle cell disease (SCD) is the most common hereditary red blood cell disorder in the United States (USA) and primarily affects African-Americans. Of the four most common sickle cell genotypes, SS and Sβ0 are associated with greater severity, including more ischemia due to sickling and more profound microvascular changes from chronic sickling, as compared to those with the Sβ+ and SC genotypes. African-Americans suffer from high rates of Type 2 Diabetes mellitus (T2DM), a disease associated with deleterious microvascular changes when blood glucose is poorly controlled. Recent epidemiologic studies suggest the prevalence of T2DM among African-Americans with and without SCD in the USA are similar around 15-20% and that patients with SCD and T2DM are more likely to be overweight than those without T2DM (Zhou etal., Br J Haematol, 2019). However, the prevalence of diabetes among the different genotypes of SCD remains unknown (Skinner etal., Br J Haematol, 2019). Furthermore, the HbA1C, which is often used to screen, diagnose and monitor long-term control of T2DM in patients is not reliable in patients with SCD and data suggests that fructosamine may be a more reliable marker in this patient population (Smaldone, 2008). If SCD patients with T2DM are undiagnosed or undertreated, they may develop preventable complications related to their vasculopathy. In this study, we assessed both the prevalence of T2DM among adults with various SCD genotypes at our institution and the methods of monitoring long-term control among these patients. Methods: The University of North Carolina (UNC) Sickle Cell Database was used to conduct a single- institution, retrospective cross-sectional study of sickle cell patients and matched controls. A query of electronic medical records identified adult patients > 18 years old with both SCD (SC, Sβ+, SS, or Sβ0) and T2DM seen in the UNC Hospital system in the past 5 years Age, race, gender, BMI, and the frequency of fructosamine and HbA1C values were evaluated. Patients were divided into 2 groups - less severe (SC/Sβ+) vs. more severe (SS/Sβ0). Controls without T2DM were randomly selected from the database and matched 2:1 to cases based on SCD genotype, age, race, and gender for body mass index (BMI) comparisons. Unadjusted statistical tests were used to examine how the group with the more severe SCD genotype (SS/Sβ0) differed from the less severe genotype group (SC/Sβ+) based on T2DM diagnosis and BMI. Results: We identified 444 adult patients with SS, Sβ0, SC, or Sβ+ - 283 patients with more severe SCD (SS/Sβ0) and 161 patients with less severe SCD (SC/Sβ+). Twenty-six patients had a co-diagnosis of T2DM; all identified as African-American (see Table 1). A significantly higher proportion of the less severe SCD group were diagnosed with T2DM as compared to the more severe group (χ2 =10.13, p = 0.001). A higher proportion of patients diagnosed with T2DM and SCD had a BMI of 25kg/m2 (i.e. overweight) or greater (76.9%) compared to matched controls (59.6%, χ2 = 2.29, p = 0.13) (see Table 2). Of the patients diagnosed with SCD and T2DM within our database, 81% had an HbA1C resulted in the EMR within the past 5 years and 62% had a fructosamine resulted during the same time period; in the past 6 months 31% had an HbA1C resulted and 19% of patients had a fructosamine resulted. Conclusion: Patients in the less severe SCD group were more likely to be diagnosed with T2DM in our cohort as compared to the more severe genotype group. Notably, the T2DM prevalence for both the severe group (10.6%) and less severe group (3.2%) was lower than that reported by Zhou et al., 2019, suggesting under diagnosis of T2DM among adults with SCD. Our findings also suggest patients with SCD who are overweight or obese may be at risk for T2DM. Variability in the monitoring of T2DM among SCD patients was evident by the ordering patterns of fructosamine and HbA1C. Hematologists treating patients with SCD should be aware of the inaccuracy of HbA1C in this patient population and ensure patients with SCD and T2DM are monitored appropriately. Further investigation is needed to determine if our findings are applicable to larger cohorts. Disclosures Little: Hemex Health, Inc.: Patents & Royalties; GBT: Research Funding. Carden:GBT: Honoraria; NIH: Research Funding.

Background: Sickle cell disease (SCD) affects 100,000 adults and children in the United States (USA). Painful, uncomplicated vaso-occlusive episodes (VOE) are the most common complication of SCD and the #1 reason adults with SCD seek medical attention in the ED. The NHLBI guidelines suggest encouraging oral hydration, along with analgesics, during VOE but to give intravenous (IV) fluids only if the patient cannot drink. However, there exists a clinical equipoise regarding the choice of IV fluids to use during the treatment of VOE in the ED, along with the rate or volume given. Despite lack of guidelines or evidence, the use of large IV volumes of crystalloids given over short periods of time (i.e. bolus) in the ED is common practice and we recently showed normal saline (NS) boluses in particular may be associated with inferior pain control and higher admission rates in pediatric patients with VOE (Carden etal., Am J Hem, 2019). Importantly, investigations into the use and impact these different IV fluids, including IV boluses, and how they may impact clinical outcomes among adult patients with SCD and VOE who present to the ED are lacking. Methods: We conducted a cross-sectional survey of emergency providers at the 2011 annual American College of Emergency Physicians Scientific Assembly, where ED providers from across the United States attend, regarding IV fluid practices during VOE. We specifically used a validated instrument to assess self-reported practices toward patients with SCD regarding IV fluid use, including volumes and rates, during uncomplicated VOE. Basic demographic information was obtained and providers were specifically asked: "Please indicate which type of fluids and rate of administration you give to patients with acute sickle cell pain who are not hypotensive and not severely hypovolemic". Providers responded never, rarely, frequently or always to each fluid type and rate. Results: Of 795 respondents to the survey, 722 indicated they took care of patients with SCD, 669 completely responded to the survey, and of those, 244 respondents only took care of adult patients with SCD. Demographic and experience with SCD patients, as well as preferred fluid type and rate of administration is reported in Table 1. IV fluid use during uncomplicated VOE varied among adult providers, but 83% of providers surveyed used IV fluid crystalloid boluses during VOE. Only 45% of providers recommended oral hydration during VOE among adults. Conclusions: Among adults ED providers who care for patients with SCD in the USA, wide variations in practice utilizing IV fluids are common. Despite no guidelines, IV fluid boluses are commonly given, as was seen in pediatric ED studies, and oral hydration is less commonly recommended among adult ED providers. Further investigation is needed to determine if these practices have an impact on clinical outcomes among euvolemic adult patients with SCD and VOE who present to the ED. Disclosures Carden: GBT: Honoraria; NIH: Research Funding. Tanabe:NIH: Research Funding; AHRQ: Research Funding. Glassberg:ACEP: Research Funding; NHLBI: Research Funding; Pfizer: Research Funding.

Background: Renal medullary carcinoma (RMC) is a rare, aggressive form of renal cell carcinoma almost exclusively (>90%) diagnosed in individuals with sickle cell trait (SCT), and 2/3 of those affected are male. Based on population-surveillance data, only 246 patients were diagnosed with RMC between 2005-2014 (Carden etal. J Sickle Cell Disease and Hemoglobinopathies, 2018) and many patients have metastatic disease at diagnosis (Msaeoul et al., Clin Genitourin Cancer, 2019). Median overall survival (OS) in patients with metastatic RMC (mRMC) at diagnosis is less than 12 months and predictors of survival are largely unknown, although case reports suggest novel chemotherapeutic strategies are important (Carden et al., Ped Blood Cancer, 2017&2018). The role SCT plays in RMC pathobiology, however, is largely unknown, as many patients do not have a complete hemoglobin subtype profile completed at diagnosis. Studies evaluating sickle hemoglobin concentrations (%HbS) in relation to survival for patients with RMC are needed, as SCT is associated with renal dysfunction and researchers have hypothesized that HbS polymerization within red cells traversing the kidney disrupts blood perfusion, which leads to kidney injury and an increased possibility for cancer formation (Msaeoul et al, Clin Cancer Res, 2018). Patients with %HbS≤36%, such as patients with SCT and concomitant alpha-globin gene deletion(s) might be protected against HbS polymerization and renal concentrating defects (Gupta etal., J Clin Invest, 1991). We hypothesize that lower %HbS is associated with higher survival. In this preliminary multi-institutional study, we retrospectively reviewed available charts from patients diagnosed with mRMC and SCT to evaluate for an association between %HbS and OS. Methods: We found nine patients (3 adults, 6 children) who were diagnosed with mRMC and SCT at our various institutions between 2002-2017 who had survival data. Eight patients had %HbS levels by hemoglobin quantification at diagnosis. In a post-hoc analysis, patients were separated into two groups (%HbS>36% and %HbS≤36%), levels similar to that found in patients with alpha-globin gene deletions described by Gupta et al. Fit-curves were determined for OS vs. %HbS. Three-year OS was determined using Kaplan-Meier analysis and the log-rank method. P Results: Clinical characteristics of patients are shown in Table 1. Average age (standard deviation) at diagnosis was 15.2 years (4.9) and most patients were male (87.5%). Six patients had %HbS >36% and 2 patients had %HbS ≤36%. Median OS was 17.8 months. Using fit-function testing, analysis of survival vs. %HbS yielded an exponential relationship (R2=0.69), suggesting higher survival when %HbS≤36% (p=0.05). OS of the two patients with %HbS≤36% was greater than those with %HbS>36%, though results were not statistically significant (p = 0.09). Conclusion: While there are limitations to this small, retrospective analysis, these data suggest that lower intracellular red cell %HbS concentrations could be protective in patients with mRMC and SCT. Chemotherapy and other treatment regimens may also play a role in survival and need to be studied. Further investigation is needed to determine the role SCT plays in RMC pathobiology and to determine if %HbS concentrations, as well as alpha-thalassemia deletion(s), may be protective in patients with RMC. Disclosures Carden: GBT: Honoraria; NIH: Research Funding.

Background: Sickle cell disease (SCD) is the most common inherited blood disorder in the United States (US), affecting approximately 100,000 individuals in the country who are primarily of African descent. One of the most prevalent complications of SCD is pain as a result of episodic vaso-occlusive crises. Over time, many individuals with SCD develop chronic pain and opioid dependence for pain management. L-glutamine (EndariTM) was approved by the US Food and Drug Administration in 2017 for patients 5 years-old and older to reduce complications from SCD after reviewing a phase-III placebo-controlled trial. In this study, L-glutamine led to a reduction in median number of pain crises and increased time to first pain crisis when compared to placebo (Niihara et al, NEJM, 2018). However, the impact of L-glutamine on opioid use over time remains unknown. In this study, we evaluated the effect on opioid use in individuals who were started on L-glutamine for worsening SCD related pain. Methods: After institutional review board approval, we retrospectively reviewed the electronic medical record (EMR) of individuals with SCD followed at the University of North Carolina Pediatric and Adult Sickle Cell clinics prescribed L-glutamine in 2018-2019 for worsening acute and chronic SCD-related pain. The North Carolina state controlled substance reporting system, an online clinical tool which collects information on dispensed controlled substance prescriptions to patients that is freely available to prescribers, was also reviewed for filled opioid prescriptions (and milligram morphine equivalents - MME) for each patient. Data, including health care utilization (e.g. hospitalizations and emergence room (ER) visits) and hemoglobin levels for each patient were also evaluated in the EMR for the four months preceding and the four months after L-glutamine was started to determine if changes were sustained. Results: We identified four female patients (ages ranging from 9 to 24 years-old) with SS genotype and chronic pain with acute exacerbations who had significant opioid prescription reduction after starting L-glutamine. Three individuals were taking the maximum tolerated dosing of hydroxyurea and experiencing escalating pain crises prior to initiation of L-glutamine. One patient was intolerant of hydroxyurea and was on a chronic transfusion program for chronic pain management when she was started on L-glutamine for worsening chronic pain. All patients, or caregivers, reported a reduction in acute on chronic pain after initiating L-glutamine. Each patient had a reduction in 4-month total opioid prescription use (in MME) after starting L-glutamine, ranging from a 21% reduction to 100% reduction (Figure 1). Heath care utilization significantly decreased in 1 patient after starting L-glutamine, with 3 ER visits and 2 hospitalizations in the pre-treatment period and no ER visits or hospitalizations in the post-treatment period. There was no difference in the average hemoglobin levels pre-and-post L-glutamine initiation among the patients (9.8g/dL vs. 9.7g/dL). Discussion: L-glutamine appears to have some benefit in reducing pain and opioid use, as well as healthcare utilization, in a subset of patients with SCD and chronic pain. Although we evaluated a small number of patients, all individuals (or caregivers) reported decreased pain very soon after starting L-glutamine. One patient stopped opioid use altogether in the time period evaluated. Future studies should investigate if effectiveness of L-glutamine may be based on unique red cell metabolic profiles, SCD genotype, or timing of drug initiation in these and similar patients. Future investigations will also determine long-term tolerability of L-glutamine and if the reduction in opioid use is sustained for longer periods among these patients and other responders. Disclosures Carden: GBT: Honoraria; NIH: Research Funding.

Abnormal sickle red blood cell (sRBC) biomechanics, including pathological deformability and adhesion, correlate with clinical severity in sickle cell disease (SCD). Clinical intravenous fluids (IVFs) of various tonicities are often used during treatment of vaso-occlusive pain episodes (VOE), the major cause of morbidity in SCD. However, evidence-based guidelines are lacking, and there is no consensus regarding which IVFs to use during VOE. Further, it is unknown how altering extracellular fluid tonicity with IVFs affects sRBC biomechanics in the microcirculation, where vaso-occlusion takes place. Here, we report how altering extracellular fluid tonicity with admixtures of clinical IVFs affects sRBC biomechanical properties by leveraging novel in vitro microfluidic models of the microcirculation, including 1 capable of deoxygenating the sRBC environment to monitor changes in microchannel occlusion risk and an “endothelialized” microvascular model that measures alterations in sRBC/endothelium adhesion under postcapillary venular conditions. Admixtures with higher tonicities (sodium = 141 mEq/L) affected sRBC biomechanics by decreasing sRBC deformability, increasing sRBC occlusion under normoxic and hypoxic conditions, and increasing sRBC adhesion in our microfluidic human microvasculature models. Admixtures with excessive hypotonicity (sodium = 103 mEq/L), in contrast, decreased sRBC adhesion, but overswelling prolonged sRBC transit times in capillary-sized microchannels. Admixtures with intermediate tonicities (sodium = 111-122 mEq/L) resulted in optimal changes in sRBC biomechanics, thereby reducing the risk for vaso-occlusion in our models. These results have significant translational implications for patients with SCD and warrant a large-scale prospective clinical study addressing optimal IVF management during VOE in SCD.

Vaso-occlusive crisis (VOC) is a complex process that occurs in patients with sickle cell disease (SCD) and is often associated with pain and urgent hospitalization. A major instigator of VOC is microvascular obstruction by pathologically stiffened sickle red blood cells (RBCs), and thus therapy relies heavily on optimizing intravenous fluid (IVF) hydration to increase RBC deformability. However, no evidence-based guidelines regarding the choice of IVF currently exist. We therefore analyzed alterations in biomechanical properties of sickle RBCs isolated from patients with homozygous SCD (hemoglobin SS) after exposure to different osmolarities of clinical IVF formulations. Atomic force microscopy (AFM) was used to assess stiffness of RBCs after exposure to different IVFs. A microfluidic model of the human capillary system was used to assess transit time and propensity to occlusion after exposure to the different IVF formulations. Sickle RBCs exposed to normal saline (NS) had increased stiffness, transit times, and propensity to microchannel occlusion compared to other osmolarities. Normal saline, an IVF formulation often used to treat patients with SCD during VOC, may induce localized microvascular obstruction due to alterations of sickle RBC biomechanical properties. This article is protected by copyright. All rights reserved.

This study was conducted to measure the health literacy (HL) and disease-specific knowledge (DSK) of caregivers for children with sickle cell disease (SCD) and relate them to their child's health care utilization. The authors conducted a cross-sectional study of caregiver-child dyads attending an urban pediatric sickle cell clinic. Caregivers were administered the Shortened Test of Functional Health Literacy (S-TOFHLA) and a locally developed DSK questionnaire. Retrospective review of the child's electronic medical record (EMR) was performed to determine annual emergency department (ED) visits and hospitalizations. A total of 142 caregiver-child dyads were recruited for the study. Less than 5% of caregivers had limited HL, with less education (P =.03) and primary language other than English (P =.04) being the only risk factors. Although caregiver HL was not associated with ED visits or hospitalizations, surprisingly DSK was. Caregivers with higher DSK scores had children with higher annual rates of ED utilization (P =.002) and hospitalizations (P =.001), and these children were also more likely to be classified as high ED utilizers (≥4 visits per year; P =.01). Further, caregiver adherence to medication and clinic visits was associated with their child's age (P =.01). Although HL and DSK are both constructs that measure basic health understanding, they differently affect caregivers' ability to navigate and understand the health care system of children with chronic illnesses. This study suggests that the DSK/health care utilization relationship may be a more important measure than HL for programs following children with sickle cell disease and could also have applications in other pediatric chronic diseases.

A two-year-old girl with congenital dyserythropoietic anemia (CDA) acutely developed fever, tachypnea, and increased oxygen requirement. Chest X-ray revealed bilateral interstitial infiltrates and mild cardiomegaly. Blood cultures grew no infectious agents, while pulmonary specimens grew cytomegalovirus (CMV). Treatment with intravenous ganciclovir was initiated but without response. Final cytologic preparations of bronchoalveolar lavage (BAL) fluid revealed eosinophilic amorphous material consistent with pulmonary alveolar proteinosis (PAP). CDA and PAP are extremely rare disorders in pediatrics. PAP should be considered in patients with hematological disorders who present with acute interstitial pneumonia, after infectious causes are ruled out.

Renal medullary carcinoma (RMC) was first described over two decades ago as the seventh sickle nephropathy. Survival after diagnosis with metastatic disease still rarely extends beyond 1 year, with recent reports of median overall survival in patients treated with platinum therapy being just 10 months. We describe our experience using platinum-based chemotherapy plus the proteasome inhibitor bortezomib to treat metastatic RMC in two pediatric patients who had complete responses. One patient passed away 7 years after diagnosis, while another remains disease free nearly 2 years from diagnosis.

Abstract 4240 Background: Recent data suggests 20–30% of parents of young children in the United States have low health literacy. Caregiver health literacy has implications for recognizing illness and can affect child health outcome. We used the Short Test of Functional Health Literacy in Adults (S-TOFHLA), a 36-item validated measure of functional health literacy (FHL) that can be administered in a short period of time, to identify caregivers of children with sickle cell disease that had inadequate or marginal FHL. We further sought to identify caregivers' disease-specific knowledge (DSK) deficits by administering our own unique questionnaire. We then determined if FHL and DSK were related to emergency department (ED) visits and hospitalizations. Methods: We conducted a cross-sectional study of caregiver-child dyads from a sample of children aged 12 months to 18 years that presented to routine visits in a comprehensive sickle cell clinic at an urban teaching hospital. Caregivers were administered the S-TOFHLA and also given a 22-item questionnaire assessing both demographic data and also qualitative and quantitative measures of DSK. A 12-month retrospective review of the child's electronic medical record was then performed to determine number of annual emergency room visits and hospital admissions at our institution. Results: A total of n=85 caregiver-child dyads were enrolled in the study during one year of recruitment. On the S-TOFHLA, only 3/85 caregivers (3.5%) had inadequate or marginal FHL. Of all 85 caregivers, 82% identified themselves as mothers to the patient, while 6% were fathers. Nearly 97% graduated from high school. We selected 12 unique items assessing DSK on our questionnaire and gave each item a value of 1 point. Caregivers were divided based on correct answers to these 12 items using a median split, with 49/85 caregivers (n1) scoring between 9–12 and 36/85 caregivers (n2) scoring 8 or less. Although there was no difference in FHL outcome between the two groups, those in n1 scored slightly higher on the 36-item S-TOFHLA than those in n2 (average 33/36 vs. 34/36, p=0.01). Group n1 was more likely to have attended college (p=0.03) and children of caregivers in this group were younger (average age 9 years vs. 12 years, p=0.008). Children of caregivers in n1 were nearly twice as likely to visit the ED than those in n2 (p Conclusion: Only 3.5% of caregivers of children with sickle cell disease had inadequate or marginal FHL. Our data suggests caregivers with more DSK were more educated and more likely to identify illness in their children. Knowledge-based questionnaires for chronic childhood illnesses such as sickle cell disease may be more useful than standard measurements of FHL to assess caregivers' ability to identify and react to illness. Disclosures: No relevant conflicts of interest to declare.