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We follow a patient with Diamond-Blackfan anemia (DBA) mosaic for a pathogenic RPS19 haploinsufficiency mutation with persistent transfusion-dependent anemia. Her anemia remitted on eltrombopag (EPAG), but surprisingly, mosaicism was unchanged, suggesting that both mutant and normal cells responded. When EPAG was withheld, her anemia returned. In addition to expanding hematopoietic stem/progenitor cells, EPAG aggressively chelates iron. Because DBA anemia, at least in part, results from excessive intracellular heme leading to ferroptotic cell death, we hypothesized that the excess heme accumulating in ribosomal protein-deficient erythroid precursors inhibited the growth of adjacent genetically normal precursors, and that the efficacy of EPAG reflected its ability to chelate iron, limit heme synthesis, and thus limit toxicity in both mutant and normal cells. To test this, we studied Rpl11 haploinsufficient (DBA) mice and mice chimeric for the cytoplasmic heme export protein, FLVCR. Flvcr1-deleted mice have severe anemia, resembling DBA. Mice transplanted with ratios of DBA to wild-type marrow cells of 50:50 are anemic, like our DBA patient. In contrast, mice transplanted with Flvcr1-deleted (unable to export heme) and wild-type marrow cells at ratios of 50:50 or 80:20 have normal numbers of red cells. Additional studies suggest that heme exported from DBA erythroid cells might impede the nurse cell function of central macrophages of erythroblastic islands to impair the maturation of genetically normal coadherent erythroid cells. These findings have implications for the gene therapy of DBA and may provide insights into why del(5q) myelodysplastic syndrome patients are anemic despite being mosaic for chromosome 5q deletion and loss of RPS14.

In this report, we present a 29-year-old African American female who was brought to a local emergency department after being found unresponsive by her mother. The etiology of her stroke and severe hemolysis remained unknown, despite her mother reporting the patient’s history of co-inheritance of sickle cell trait and beta-thalassemia trait, and extensive workup during her prolonged hospitalization. She was diagnosed with sickle cell disease (Sβ+ type) two years after discharge when she was referred to a sickle cell specialist for persistent anemia. Here, we also briefly review the challenges to diagnose rarer subtypes of sickle cell disease (SCD), in this case Sβ+ type, as well as the pathophysiology and current management of stroke in SCD.

Objective Biomagnetic liver susceptometry (BLS) is a noninvasive method to quantify liver iron concentration (LIC). Here we report our findings from a prospective study which validates in vivo LIC from a SQUID biosusceptometer by in vitro LIC in fresh tissue and paraffin-embedded biopsies from patients at risk for iron overload.Materials and Methods LIC was measured by BLS and biopsy. LIC by biopsy were measured in 40 dry weight fresh tissue and paraffin-embedded liver biopsy samples. LIC from biopsies and total iron scores from histology were compared to biosusceptometry. In addition, the wet-to-dry weight ratio was determined.Results Liver iron concentrations measured by BLS and in 40 fresh tissue biopsies were related by a factor of 6.0 ± 0.2 (r2 = 0.88). Similar results were obtained from comparisons with deparaffinized biopsies (6.6±0.3, r2=0.87) and histology (6.7±1.3, r2=0.47). In contrast, a mean wet-to-dry weight ratio of 4.1 ± 0.7 was achieved from biopsies immediately weighed after the biopsy procedure.ConclusionLIC derived from two independent measures, the historical biopsy gold standard and biosusceptometry, were highly correlated. When comparing biosusceptometry with wet weight biopsies, the liver tissue sample size is critical.

Sickle cell disease (SCD) is an inherited hemoglobinopathy affecting approximately 100,000 individuals in the United States. Cerebrovascular disease is among the most common and debilitating complications of SCA, with 53% experiencing silent cerebral infarct by age 30 and 3.8% experiencing overt stroke by age 40 years. This review highlights the burden of cerebrovascular disease in SCD, including both stroke and silent cerebral infarct (SCI). We then discuss the pathophysiology of stroke and cerebral fat embolism in the absence of a patent foramen ovale. This review also reveals that options for primary and secondary stroke prevention in SCD are still limited to hydroxyurea and blood transfusion, and that the role of aspirin and anticoagulation in SCD stroke has not been adequately studied. Limited data suggest that the novel disease-modifying agents for SCD management may improve renal dysfunction, leg ulcers, and lower the abnormally high TCD flow velocity. Further research is urgently needed to investigate their role in stroke prevention in SCD, as these novel agents target the main stroke contributors in SCD - hemolysis and vaso-occlusion. This literature review also explores the role of healthcare disparities in slowing progress in SCD management and research in the United States, highlighting the need for more investment in patient and clinician education, SCD management, and research.

Severe cytopenias (anemia, thrombocytopenia, neutropenia or any combination of these) are common causes of ER visits and hospital admissions. In adults, the etiology of cytopenias has a broad differential diagnosis including vitamin and mineral deficiencies, autoimmune conditions, infections, bone marrow failure disorders, or malignancies. We present a case of severe anemia and thrombocytopenia who was initially diagnosed with myelodysplastic syndrome (MDS) based on the results of a bone marrow biopsy. However, subsequent workup revealed that she had B12 deficiency secondary to pernicious anemia. This case highlights how performing a bone marrow biopsy without investigating secondary causes of cytopenia and bone marrow dysplasia can lead to a false diagnosis of MDS. Confirmation of the appropriate diagnosis spared the patient emotional trauma and unnecessary treatment with hypomethylating agents.

Sarcoidosis is a multisystem granulomatous disease of unknown etiology that can present with nonspecific features, often resulting in delayed diagnosis. The diagnosis requires the demonstration of non-caseating granulomas on biopsy. While the prevalence of sarcoidosis in the USA is rare, the disease is rarer yet in Hispanics. It is for this reason that we report herein the case of a Hispanic gentleman with a unique clinical manifestations of sarcoidosis. With what began as a two-month history of joint pain and skin rash, this 55-year-old man was hospitalized with multiple joint pain, weight loss, fatigue and a pruritic rash with leonine facies in the setting of anemia, leukopenia, hypercalcemia, elevated serum creatinine, and urine Bence-Jones proteinuria. CT imaging of the chest was nonspecific, but skin biopsy revealed non-caseating granulomatous disease. After completing an infectious and malignancy evaluation, the patient was diagnosed with sarcoidosis, which was treated successfully with low-dose steroid therapy.

Intravascular large B-cell Lymphoma (IVLBCL) is a rare subtype of extra nodal non-Hodgkin’s lymphoma, which is challenging to diagnose and has a poor prognosis. Here we describe three non-White Hispanic patients newly diagnosed with IVLBCL within 14-month period. All of them presented with persistent fever of unknown origin and symptomatic severe anemia as the initial manifestations. Two out of three cases were successfully diagnosed in a timely manner by fat pad biopsy and have remained disease free up to 34 months after chemotherapy. The third case was diagnosed by bone marrow biopsy and deceased one week later after choosing home hospice care. To date, this is the largest published case series of IVLBCL in non-White Hispanics.

Background Microbial superantigens might initiate or exacerbate autoimmune responses against particular tissues, organs or systems. This study aimed to examine the prevalence of sea, seb, sec, sed, and tsst-1 genes of Staphylococcus aureus in nasal carriage and their association with multiple sclerosis (MS). Methods Nasal swabs were collected from 150 MS patients and 150 healthy individuals (control group) to isolate S. aureus and investigate their superantigen genes (sea, seb, sec, sed and tsst-1) using PCR. Results A total of 300 participants were enrolled in the study, matched for age and gender (150 patients in the MS group and 150 in the control group). The prevalence of S. aureus colonization in MS patients and control groups was 42% and 23.3%, respectively. There was a statistically significant association between S. aureus colonization and MS disease (p

Background: Sickle cell disease (SCD) is an inherited, chronic, and multifaceted condition. Anemia affects most patients with SCD, and low hemoglobin (Hb) levels have been demonstrated to be correlated with end-organ damage (EOD) such as stroke, chronic kidney disease (CKD), end-stage renal disease (ESRD), and pulmonary hypertension (PH). This study sought to estimate the relationship between Hb and risk of EOD based on large-scale, longitudinal analyses of recent data. Methods: Patients with SCD aged 12 years and older and at least 1 Hb level reported from January 2013 to March 2019 in the large, US-representative, provider-centric Symphony Health claims database were included. For each qualifying patient, Hb values were identified and included as separate observations. Onset of new EOD, including stroke, CKD (including ESRD), and PH were ascertained during the 1-year period after the date of each Hb assessment (index date). History of EOD and other comorbid conditions were identified using claims from the database start date (January 1, 2012) or first activity date, whichever was later, up to the index date, to differentiate from newly diagnosed EOD. Patient demographics and clinical characteristics were summarized descriptively. Bivariate analyses of Hb levels and EOD were assessed using generalized estimating equations (GEE) regression with a logistic link function to account for clustering of observations at the patient level. Multivariable GEE regression was employed to evaluate the independent association between Hb and EOD, adjusting for patient demographics and other SCD complications. Results: A total of 16,754 patients with SCD aged 12 years and older were identified (mean age: 34.7 years, 37.7% male), contributing 41,692 observations of Hb levels (mean [SD], 9.8 [2.0] g/dL). In univariate analyses, higher Hb levels were significantly associated with lower odds of new EOD of any type (Figure). In multivariable analyses, after controlling for age, gender, and history of other SCD complications, patients with Hb b %12 g/dL had significantly lower odds of new EOD versus patients with Hb Conclusions: In this large-scale, longitudinal analysis, a significant reduction in the risk of new EOD was observed among SCD patients with higher Hb levels. History of any EOD significantly correlated with presence of new EOD. New SCD treatments that can increase Hb levels can potentially offer clinical and economic value. Disclosures Ershler: Pharmacosmos Therapeutics Inc: Consultancy, 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, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. De Castro:GlycoMimetics: Membership on an entity's Board of Directors or advisory committees; FORMA Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: 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. Pakbaz:Amgen: Membership on an entity's Board of Directors or advisory committees; Dova: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Terumo BCT: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Global Blood Therapeutics: Speakers Bureau. Moynahan:Global Blood Therapeutics: Research Funding; Novartis: Research Funding; Policy Analysis Inc.: Current Employment. Weycker:Policy Analysis Inc.: Current Employment, Current equity holder in publicly-traded company; Global Blood Therapeutics: Research Funding; Novartis: Research Funding. Pham:Policy Analysis Inc.: Current Employment; Global Blood Therapeutics: Research Funding; Novartis: Research Funding. Delea:Policy Analysis Inc.: Current Employment, Current equity holder in private company; Global Blood Therapeutics: Research Funding; Novartis: Research Funding. Agodoa:Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Cong:Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company.

Diamond-Blackfan Anemia (DBA) is a rare, inherited bone marrow (BM) failure syndrome characterized by pure red cell aplasia generally presenting within the first year of life. The majority of cases are due to heterozygous mutations in ribosomal genes, either autosomal dominant inherited or sporadicde novoevents. Despite the recognition of the importance of ribosomal biology, the underlying mechanisms are still poorly understood. The only curative treatment is hematopoietic stem cell transplantation, otherwise steroids or transfusions will cause significant long-term morbidity. There is an unmet need for new therapies. We describe the unique clinical course and molecular analyses of a 32-year-old Hispanic woman, provide insights into disease pathophysiology as well as hope for an effective new treatment. She was diagnosed with DBA at the age of one month with isolated severe normochromic anemia. She failed various therapies, including corticosteroids, danazol, growth factors, and additional immunosuppression and developed significant iron overload despite desferal chelation. She was enrolled in a phase II clinical trial investigating the safety and efficiency of the thrombopoietin receptor agonist eltrombopag (EPAG) in patients with moderate aplastic anemia or unilineage cytopenias (NCT01328587). EPAG was administered in an escalating manner reaching 300mg daily. She achieved transfusion-independence by 16 weeks. This dose was continued for an additional 6 months and discontinued for protocol-defined robust response, ie Hb >10g/dL. After discontinuation, her hemoglobin steadily declined over a period of 8 months. EPAG was reinitiated, her Hb again rapidly improved and the EPAG dose was slowly tapered. Seven years since enrollment, the patient has remained on drug, currently at a dose of 25mg daily with normal blood cell counts and no EPAG related toxicity. BM cytogenetics and morphology have remained normal throughout follow up, as has a myeloid somatic mutation panel. Next generation sequencing has revealed a novel, pathogenic mutation in intron 4(c.356+3>C) of theRPS19gene affecting a splice donor site previously implicated in DBA. Testing of both parents was negative, documenting this to be ade novomutation. With digital droplet PCR (ddPCR), we have monitored the variant allele frequency (VAF) in fibroblasts (germline) and different hematopoietic populations (Figure 1). Fibroblasts showed a VAF 50% (heterozygous), while her whole BM and whole blood show a lower VAF between 25% and 37%, both before and on EPAG treatment. Across lineages were analyzed when she was on EPAG, lymphocytes showed the highest VAF (42% to 45%), followed by HSPCs and granulocytes at 24% to 32%. Of note, the erythrocytes progenitors (CD45-CD71+) had the lowest VAF of 8% to 14%. Sequencing of myeloid and erythroid colony forming units (CFU) with both pre and on EPAG BM samples confirmed only heterozygous mutations or wild-type (WT) CFUs in percentages comparable to their respective VAF detected by bulk ddPCR. These results suggest the emergence of WT clones within the BM either through mosaicism or a reversion event. The discrepancy in VAF between peripheral and BM samples is consistent with a proliferative advantage for WT clones, especially in the erythroid and myeloid lineages. Yet despite the presence of WT HSPCs, profound transfusion-dependent anemia persisted in this patient long-term. An imbalance between globin chain and heme production has been documented to result from ribosomal dysfunction in DBA, leading to increased iron-mediated cellular stress and death of erythroid progenitors. We hypothesize the residual mutant cells suppress the growth of WT cells, given the close proximity of large numbers of erythroid cells aggregated by macrophages in erythroid islands, potentially via passage of free iron. These observations have implications for the development of gene addition or gene correction therapies for DBA, suggesting that correcting a fraction of HSPCs will not revert the phenotype. Given the potent intracellular chelation activity of EPAG, and the lack of the EPAG target MPL receptor on erythroid progenitors, we hypothesize that iron chelation is a potential mechanism for improvement of red blood cell production by EPAG in DBA. The results in our patient have encouraged the opening of a prospective clinical trial (NCT04269889) to further explore the potential of EPAG for DBA patients. Figure Disclosures Young: Pharos I&BT Co., Ltd.:Research Funding.Pakbaz:Amgen:Membership on an entity's Board of Directors or advisory committees;Dova:Membership on an entity's Board of Directors or advisory committees;Novartis:Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Terumo BCT:Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Global Blood Therapeutics:Speakers Bureau.Dunbar:Novartis:Research Funding.

Background: Asymptomatic nasal colonization of Methicillin-Resistant Staphylococcus aureus is common in Multiple Sclerosis patients. SCCmec types I to III are mainly attributed to HA-MRSA strains whereas SCCmec types IV and V have commonly been reported in CA-MRSA infections. Here, we assessed the frequency of nasal carriage of MRSA in MS patients. This study aimed to evaluate MRSA SCCmec typing in MS nasal carriage. Methods: A cross-sectional descriptive study was conducted from Feb and Jun 2017 in MS Research Center, Tehran University of Medical Sciences (TUMS), Iran. Overall, 620 nasal swabs were collected (325 from MS patients and 295 from control group). Antimicrobial susceptibility test was performed using the disk diffusion and E-test method. Presence of mecA gene was confirmed by PCR assay and multiplex PCR was performed for SCCmec typing of MRSA isolates. Results: The frequency of MRSA among the MS patients and control group was almost equal (9.2% and 10.1%, respectively). SCCmec typing detected only types III, IV and V in both groups and type IV was the most predominant type in MS patients and control group. SCCmec type III was more prevalent in control group than MS patients (40% vs. 20%). Moreover, the frequency of SCCmec type V in MS patients was significantly higher than control group (36.7% vs. 3.3%). Conclusion: Although most MRSA isolates were collected from inpatients, interestingly there is a high frequency of SCCmec types IV and V in MS group. Moreover, MRSA isolates were not resistant to more antibiotics in SCCmec type III than types IV-V.

Background Superantigens can be absorbed trans-mucosal and trans-cutaneous in individuals colonized with superantigen producing Staphylococcus aureus. Ability of superantigens to activate a large numbers of T cells suggests that they may play a role in the course of autoimmune diseases including human multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). In this study we investigated the role of staphylococcal enterotoxin B in immunologic and pathologic changes in experimental animal model of multiple sclerosis. Methods C57BL/6 female mice were treatment with SEB protein prior or post immunization with MOG33-35 peptide. Mice were monitored daily and scored for clinical symptoms following EAE induction. Spleen and spinal cord of mice were removed and used for ELISA and histological studies, respectively. Results Treatment with SEB prior induction of EAE, increased clinical score, the concentration of IL-17A, IFN-γ and histological changes compared to control group. Treatment with SEB after induction of EAE caused these changes, but less severe. Discussion Since SEB causes demyelination of spinal cord and increases the level of pro-inflammatory cytokine response, infiltration of T-lymphocytes and macrophages to CNS, it may exacerbate the clinical signs of EAE in mice and multiple sclerosis in human.

International audience; Erythroferrone (ERFE) is a glycoprotein hormone secreted by erythroblasts in response to stimulation by erythropoietin (EPO). We previously demonstrated that ERFE messenger RNA expression and serum protein concentration increase in mice subjected to hemorrhage or EPO therapy, that ERFE acts on hepatocytes to suppress hepcidin, and that the resulting decrease in hepcidin augments iron delivery for intensified erythropoiesis. We also showed that ERFE contributes to pathological hepcidin suppression and iron overload in mice with non transfused beta-thalassemia. We now report the development and technical validation of a rabbit monoclonal antibody-based sandwich immunoassay for human ERFE. We use this assay to show that blood loss or EPO administration increases serum ERFE concentrations in humans, and that patients with both nontransfused and transfused b-thalassemia have very high serum ERFE levels, which decrease after blood transfusion. The assay should be useful for human studies of normal and disordered erythropoiesis and its effect on iron homeostasis.

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BACKGROUND: Life expectancy for individuals with sickle cell disease (SCD) is shorter in California than in other states with multiple contributing factors. These include a shortage of adult hematologists expert in SCD management, lack of resources for the provision of comprehensive care, and limited options for disease modifying therapies. Adults with SCD are vulnerable to negative social determinants of health including low income, challenges with attaining adequate education and employment, and racial disparities. Adults with SCD may not be well educated about health maintenance and treatment options. We piloted an adult sickle cell clinic under the direction of an adult hematologist with expertise in SCD management in California's Inland Empire. The program was instituted in January of 2017 at an academic medical center. Here we report on an interim analysis of the impact of the clinic on patients' decision-making regarding treatment options, including opioids and healthcare utilization (annual inpatient and emergency department (ED)visits). METHODS: Data was collected from electronic medical records (EMR) for 65 consecutive adults with SCD who were seen by the adult sickle cell hematologist at least once either in the clinic or as an inpatient consult between January 2017- July 2019. For patients seen as outpatient, expectations were outlined as monthly clinic visits for 30 minutes each, including 10 - 15 minutes of education about SCD and available treatments. Individualized care plans aimed at decreasing the frequency of pain episodes were implemented and discussed at each visit. Care plans generally involved recommendations for disease modifying therapies not previously available to them. Cayenne Wellness Center, a community based organization partner, provided additional education and psychosocial economic assessment to offer resources including transportation to patients in need. Patients were grouped as adherent, non-adherent or inpatient consult and followed over time. They were assigned to the non-adherent group if they met 2 out of the 3 following criteria: clinic no-shows of >50%, appointment interval >3 months, and patients' choice to not comply with the agreed upon disease modifying therapy or to only stay on opioids. We reviewed annual admissions, ED visits, and opioid use from the EMR. For adults who joined the clinic in 2019 or relocated, only opioid use was included in this report. RESULTS: Thirty-three percent (N= 22) of adults with SCD in the current sample chose not to follow up with the hematology clinic after their first inpatient consultation. For the remaining 43 patients, the median age was 34 years (range 19 to 59); 60% were female and 20% were diagnosed with Hgb SC. Forty nine percent (N=21) were classified as adherent. Twenty three percent (N=10) of patients had joined the clinic in 2019 or relocated. In the adherent group, 43% of patients had a 79% decrease in their annual admission rates and 37% had a 100% decrease in the average number of ED visits. At their first clinic visit, 72% (N=31) of patients were noted to be using opioids at home. Over time, 53% of the adherent group had a decrease in opioid use, while 36% of the non-adherent group had an increase in opioid use. CONCLUSION: This pilot clinic showed that regular adult hematology sickle cell clinic follow up to individualize and optimize therapies and provide education can improve patient outcomes. Individuals who were adherent to disease modifying treatment regimens and had regular hematology outpatient follow up showed a decrease in ED visits, admissions, and opioid use. Disclosures Vichinsky: GBT: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; bluebird bio: Consultancy, Research Funding. Pakbaz:Novartis: Honoraria, Speakers Bureau.

Introduction: Despite convincing evidence toward causal role of Lipoprotein(a) in occlusive arterial disease, the data is conflicting when it comes to venous thromboembolism (VTE) and pulmonary embolism (PE). Also it is not known if intervention to normalize Lipoprotein(a) will decrease risk of recurrent VTE and PE eliminating the need for life long anticoagulation. To our knowledge this isfirst data set report focusing on evaluating association between Lipoprotein(a) and VTE in patients younger than 50 years old. Methods: Inthis retrospective study, chart review was completed for twenty-six consecutive patients referred to hematology clinic with diagnosis of deep vein thrombosis (DVT) or PE in year 2017-2018 . Four patients older than 50 years old at the time of acute events were excluded. Lipoprotein(a) had only been measured in patients who had negative hypercoagulable work up with normal lipid panel but had obesity . Protein C, S and anti-thrombin were not measured if patients were already on anticoagulation. Serum level of Lipoprotein(a) greater than 75 nmol/L was considered to be elevated. Results: Total of 22 patients (18 females) were included in the data analysis. Nine patients had DVT, 5 patients had PE, and 8 patients had both DVT and PE. Median age was 34 (12-47). Lipoprotein(a) level was not checked on eight patients who had SLE (n=1), surgery (n=1), Factor V Leiden mutation (n=1), protein S deficiency (n=1), anti-phospholipid syndrome (n=2), prothrombin gene mutation (n=1), and one patient who had lost follow up. The median Lipoprotein(a) level was 107 (8-276). Serum Lipoprotein(a) was elevated in 8 out of the 14 screened patients (57%) with the median of 135 (107-276). Out of 8 patients with elevated Lipoprotein(a), only 1 patient had additional clinical risk factors for thrombosis (history of smoking, alcohol abuse, hypertriglyceridemia and elevated LDL). In an attempt to normalize Lipoprotein(a) level, 3 patients were started on niacin but only one tolerated maximum 1000 mg niacin daily which resulted in decrease in level but did not achieve normalization. Conclusion: This data suggests that elevated serum Lipoprotein(a) in females younger than 50 years old is associated with DVT/PE events. Further investigation is required to confirm this finding. At this time it is not known if attempt to normalize Lipoprotein(a) will prevent recurrent PE/DVT and eliminate need for long life anticoagulation in patients with unprovoked VTE who have elevated lipoprotein(a). Disclosures Pakbaz: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Advances in the management of thalassemia have resulted in increased life expectancy and new challenges. We conducted the first survey of education and employment status of people with thalassemia in North America.A total of 633 patients (349 adults and 284 school age children) enrolled in the Thalassemia Clinical Research Network (TCRN) registry in Canada and the U.S. were included in the data analysis. Predictors considered for analysis were age, gender, race/ethnicity, site of treatment (Canada vs. United States), transfusion and chelation status, serum ferritin, and clinical complications.Seventy percent of adults were employed of which 67% reported working full-time. Sixty percent had a college degree and 14% had achieved some post-college education. Eighty-two percent of school age children were at expected grade level. In a multivariate analysis for adults, Whites (OR = 2.76, 95% CI: 1.50-5.06) were more likely to be employed compared to Asians. Higher education in adults was associated with older age (OR = 1.67, 95% CI: 1.29-2.15), female gender (OR = 2.08, 95% CI: 1.32-3.23) and absence of lung disease (OR = 14.3, 95% CI: 2.04-100). Younger children (OR = 5.7 for 10-year increments, 95% CI: 2.0-16.7) and Canadian patients (OR = 5.6, 95% CI: 1.5-20) were more likely to be at the expected education level. Neither transfusion nor chelation was associated with lower employment or educational achievement.Individuals with thalassemia in North America can achieve higher education; however, full-time employment remains a problem. Transfusion and chelation do not affect employment or education status of this patient population.

Background/Aims: There is increasing evidence demonstrating the value of transfusions in sickle cell disease (SCD). However, resultant iron overload can be life threatening if untreated. Chelation therapy with deferoxamine requires parenteral infusions that can negatively impact quality of life and adherence to treatment. Methods: As part of a phase II trial, SCD patient-reported outcomes were evaluated. One hundred and ninety-five patients were randomized (2:1) to receive oral deferasirox (5–30 mg/kg/day) or deferoxamine (20–50 mg/kg, 5 days per week); 121 had previously received deferoxamine. Results: At each time point, significantly more patients who had previously received deferoxamine were ‘satisfied/very satisfied’ with deferasirox, or found treatment to be ‘convenient/very convenient’ compared with deferoxamine (p < 0.001). In these patients, fewer hours were lost from daily activities with deferasirox than deferoxamine treatment. Most patients (77%) preferred deferasirox, and more were willing to continue taking deferasirox than deferoxamine at end-of-study (84 vs. 11%, respectively). Conclusions: Patients with SCD are therefore more satisfied with deferasirox, which has a lower impact on daily activities than deferoxamine. Given the high levels of satisfaction, it is likely that quality of life will be improved. These results also suggest that treatment adherence with deferasirox may be better than with deferoxamine, which should lead to improved long-term outcomes.

Accurate measurement of liver storage iron is important for the management of iron overload from regular red blood cell transfusion therapy. In clinical trials testing iron chelator efficacy in iron overloaded patients, with different centers involved, it is mandatory to standardize the procedures of liver iron concentration (LIC) measurements. The agreement (precision and bias) of the SQUID biosusceptometer in Oakland/USA (CHO) and Torino/Italy (TOR) was evaluated in comparison to the validated System in Hamburg/Germany (UKE). In a blinded round-robin test, liver iron concentrations were quantified within 1 month by the 3 SQUID biosusceptometer systems, in 20 patients with thalassemia, sickle cell disease or CDA type-1 and in 10 normal subjects. Mean LIC values were determined from 5 vertical scans at each of two, different positions. Prediction of LIC at CHO and TOR in comparison with UKE was excellent, with coefficients of determination between sites of R 2 = 0.97, resulting in inter-site standard deviations of 276 and 315 μg/g liver, respectively. A significant proportional underestimation of 27% was noted for the TOR system. A systematically lower skin–liver distance of 1.0 mm at the TOR site could only account for 10% of the underestimated LIC. Intra-site precision was within an acceptable range for repeated measurements in the majority of iron overloaded subjects.

Serum ferritin (SF) and liver iron concentration (LIC), as measured by SQUID biosusceptometry, were assessed in a convenience sample of transfusion independent thalassemia patients (nTx-Thal, n=26), regularly transfused thalassemia (Tx-Thal, n=89), or sickle cell patients (SCD, n=45) to investigate the severity of iron overload and the relationship between SF and LIC in nTx-Thal compared to SCD and Tx-Thal. SF correlated with LIC (RS=0.53, P

Purpose We evaluated bone mineral density (BMD) and risk factors for poor bone mineralization in children with sickle cell anemia (SCA). Patients and Methods Twenty-five children with severe manifestations of SCA (frequent hospitalizations, growth delay, or need for chronic red cell transfusions) were enrolled. Bone density was assessed at lumbar spine and proximal femur with dual-energy X-ray absorptiometry (DXA), and Z-scores were calculated by comparison with age, sex, and ethnicity-specific reference data. Results The median age of the study population was 12.8 years (10.2–19.8 years). Calcium intake was inadequate in 60%, and serum 25-hydroxy vitamin D (25-OHD) level

Adherence to deferoxamine (DFO) is vital for the long-term survival of patients with thalassemia; however, currently no measure exists to quantify adherence directly. In this study, 90 patients with thalassemia major underwent liver iron concentration (LIC) assessment by SQUID biosusceptometer, were asked to rate their adherence to DFO using a Numerical Likert Scale (NLS), and were educated about complications of iron overload. Of 38% (n= 28) of patients who rated themselves as very compliant, 19 had elevated LIC related to inadequate dosing of DFO and nine reported nonadherence in the past. Adherence improved after counseling and LIC decreased by 25% (7-60%) in eight previously noncompliant patients who returned for subsequent LIC over 15 months. In conclusion, the NLS seems to be a simple but reliable tool to assess patients' adherence to DFO. Education and frequent noninvasive LIC assessments can improve adherence and iron burden. Elevated LIC does not necessarily reflect concurrent noncompliance; however, it can be an indication of nonadherence in the past.

The impact of thalassemia major and thalassemia intermedia and their associated complications on quality of life (QOL) is largely unknown. Determining the degree of health impairment as perceived by the patient is essential information needed to recommend suitable therapy. The objective of this study was to evaluate QOL in transfusion-independent patients with thalassemia (non-Tx) compared with that in transfused patients (Tx) and to identify the factors that affect QOL in thalassemia. A convenient sample of 48 thalassemia patients (29 Tx and 19 non-Tx) with mean age of 14.6 years (SD = 7.5 years) were selected during a comprehensive visit to complete a Dartmouth Primary Care Cooperative Information Chart System (COOP) questionnaire. Patients rated QOL from excellent (1) to poor (5) on five dimensions of health status. Scores of 4 or 5 represent major limitations. These results were augmented by a brief medical history and chart review. Forty-one percent of Tx patients and 47% of non-Tx patients reported severe impairments in 1-6 and 1-2 domains, respectively. The most commonly reported affected domains were feelings such as anxiety, depression, and concern of overall health status or indications of recent deterioration in health. In contrast with previous beliefs, transfusion-independent thalassemia patients also suffer serious impairment in QOL. Presented data suggest that all patients with thalassemia undergo QOL assessment so that interventions focused on affected domains can be implemented.

Treatment of hepatitis C virus (HCV) in the general population has improved over the last decade. Patients treated with peginterferon alfa (PegIFN) and ribavirin (RBV) combination therapy demonstrate overall 50-55% sustained viral response (SVR) with rates as high as 80% in patients with genotypes 2 and 3. Because RBV induces hemolysis and subsequently increases blood transfusion requirements, combination therapy has been considered contraindicated for hemoglobinopathies. This report reviews the response to interferon alfa and RBV (IFN/RBV) and PegIFN/RBV combination therapies in patients treated in the Northern California Comprehensive Thalassemia Center. A total of six thalassemia major patients were treated with IFN/RBV (n = 5; age: 4-38 years) or with PegIFN/RBV (n = 1; age: 26 years). Quantitative HCV RNA polymerase chain reaction and liver iron level assessment were completed. Transfusion volumes were obtained from patients' medical records. On IFN/RBV combination, four of five patients demonstrated SVR. The one patient on PegIFN/RBV showed end-treatment viral response after 6 months of therapy (genotype 3), but subsequently relapsed. Liver iron pretreatment level ranged from 0.2 to 22 mg/g dry weight, with a mean +/- SD of 7.9 +/- 7.7. Transfusion requirement increased by a median of 43.5% (range: 32-137%). Five of the six patients had liver iron measurements within 1 year following completion of treatment, with quantitative liver iron increasing in two patients by 2.5 mg/g dry weight, decreasing in two patients by 3 and 14 mg/g dry weight, and remaining unchanged in one patient. All patients were able to complete combination therapy, although dose reductions were required. Patients with thalassemia and high iron overload can obtain SVR after combination therapy with rates similar to those in the general population and without significant complications. Although transfusion requirements increased in most patients, iron burden was not necessarily increased.

Although the pathogenesis of sickle cell disease lies in disordered hemoglobin structure and function, downstream effects of sickle hemoglobin include changes in hemostatic system that overall result in a pro-thrombotic phenotype. These changes include thrombin activation, decreased levels of anticoagulants, impaired fibrinolysis and platelet activation. Limited studies to date suggest that biomarkers of activation can be affected by currently available anti-thrombotic drugs, and provocative data from pilot studies indicate there may be improvement in clinically important outcomes. Therefore, clinical trials with antithrombotic therapies, are justified with both SCD related complications (VOC, pain) and thrombotic complications as outcome events of interest.

Background: The importance of sialic acid binding adhesin (sabA) as a new outer membrane protein in gastroduodenal diseases has been recognized. The prevalence rate of sabA gene varies in different geographic areas. Objectives: The aim of this study was to determine the frequency of sabA gene in Helicobacter pylori (H. pylori) strains isolated from different clinical outcomes in Tehran, Iran. Patients and Methods: The study included 120 patients with dyspeptic symptoms admitted to the endoscopy suite of gastroenterology section of Firouzgar University Hospital, Tehran, Iran from March to August 2011. Gastric biopsy specimens were evaluated for the presence of H. pylori using standard microbiological method and polymerase chain reaction (PCR) assay. The sabA genopositive was determined by PCR in H. pylori strains. Results: H. pylori isolates were recovered from 82 patients with duodenal ulcer (DU; n = 17), gastric ulcer (GU; n = 15), gastric cancer (GC; n = 13), and gastritis (G; n = 37). The frequency of sabA gene in H. pylori strains was 100% in gastric cancer, 86.7% in gastric ulcer, and 83.3% in both gastritis and duodenal ulcer. Conclusions: This is a report on the prevalence of sabA gene in H. pylori isolated from different gastric patients in Iran. The results showed a high prevalence of sabA in our clinical H. pylori isolates.

Haemoglobin E-beta thalassaemia (Hb E/β-thalassaemia) is the genotype responsible for approximately one-half of all severe beta-thalassaemia worldwide. The disorder is characterized by marked clinical variability, ranging from a mild and asymptomatic anaemia to a life-threatening disorder requiring transfusions from infancy. The phenotypic variability of Hb E/β-thalassaemia and the paucity of long-term clinical data, present challenges in providing definitive recommendations for the optimal management of patients. Genetic factors influencing the severity of this disorder include the type of beta-thalassaemia mutation, the co-inheritance of alpha-thalassaemia, and polymorphisms associated with increased production of foetal haemoglobin. Other factors, including a variable increase in serum erythropoietin in response to anaemia, previous or ongoing infection with malaria, previous splenectomy and other environmental influences, may be involved. The remarkable variation, and the instability, of the clinical phenotype of Hb E beta-thalassaemia suggests that careful tailoring of treatment is required for each patient, and that therapeutic approaches should be re-assessed over-time.

The Thalassemia Clinical Research Network collected adherence information from 79 patients on deferoxamine and 186 on deferasirox from 2007 to 2009. Chelation adherence was defined as percent of doses administered in the last 4 weeks (patient report) out of those prescribed (chart review). Chelation history since 2002 was available for 97 patients currently on deferoxamine and 217 on deferasirox, with crude estimates of adherence from chart review. Self-reported adherence to both deferoxamine and deferasirox were quite high, with slightly higher adherence to the oral chelator (97 vs. 92%). Ninety percent of patients on deferasirox reported at least 90% adherence, compared with 75% of patients on deferoxamine. Adherence to both chelators was highest in children, followed by adolescents and older adults. Predictors of lower deferoxamine adherence were smoking in the past year, problems sticking themselves (adults only), problems wearing their pump, and fewer transfusions in the past year. Predictors of lower deferasirox adherence were bodily pain and depression. Switching chelators resulted in increased adherence, regardless of the direction of the switch, although switching from deferoxamine to deferasirox was far more common. As adherence to deferoxamine is higher than previously reported, it appears beneficial for patients to have a choice in chelators.

Hemoglobin E thalassemia accounts for about one-half of all cases of severe beta thalassemia. There is marked variability in its clinical severity ranging from an asymptomatic to a transfusion-dependent phenotype. The phenotypic variability and inadequate longitudinal data present challenges in determining the optimal management of patients. This article summarizes findings on the natural history of Hemoglobin E thalassemia and some factors responsible for its clinical heterogeneity. Major genetic factors include the type of beta thalassemia mutation, the co-inheritance of alpha thalassemia, and polymorphisms associated with increased synthesis of fetal hemoglobin. Other factors, including response to anemia, and the influence of infection with malaria and other environmental influences, may be important. The remarkable variation and instability of clinical phenotypes in Hemoglobin E thalassemia require individual management plans for each patient, which should be reassessed over time.

Thalassemia is a congenital blood disorder often requiring chronic blood transfusions and iron chelation therapy [1,2]. While advances in treatment have resulted in increased life expectancy [3], extended life spans have exposed previously unidentified issues, including bodily pain. The aim of this study was to examine the prevalence, severity, predictors, and effects of pain in 265 adults/adolescents and 103 children with thalassemia. Overall, 69% of adults/adolescents reported bodily pain on the SF-36v2 health survey, with 28% reporting at least moderate pain. Parents reported pain in 56% of children using the PF-28 child health questionnaire, with only 11% reporting pain fairly often. There were no significant differences in pain in children with thalassemia compared with the general population. In adults/adolescents, pain increased significantly with age (P = 0.005), more so than in the general population. This study highlights the fact that children and young adults with thalassemia experience pain comparable to the general population, whereas older adults (aged 35+) experience greater pain. Our findings show that increased pain is associated with decreased quality of life and increased anxiety and depression.

There is increasing evidence demonstrating the value of transfusions in sickle cell disease (SCD). However, resultant iron overload can be life threatening if untreated. Chelation therapy with deferoxamine requires parenteral infusions that can negatively impact quality of life and adherence to treatment.As part of a phase II trial, SCD patient-reported outcomes were evaluated. One hundred and ninety-five patients were randomized (2:1) to receive oral deferasirox (5-30 mg/kg/day) or deferoxamine (20-50 mg/kg, 5 days per week); 121 had previously received deferoxamine.At each time point, significantly more patients who had previously received deferoxamine were 'satisfied/very satisfied' with deferasirox, or found treatment to be 'convenient/very convenient' compared with deferoxamine (p0.001). In these patients, fewer hours were lost from daily activities with deferasirox than deferoxamine treatment. Most patients (77%) preferred deferasirox, and more were willing to continue taking deferasirox than deferoxamine at end-of-study (84 vs. 11%, respectively).Patients with SCD are therefore more satisfied with deferasirox, which has a lower impact on daily activities than deferoxamine. Given the high levels of satisfaction, it is likely that quality of life will be improved. These results also suggest that treatment adherence with deferasirox may be better than with deferoxamine, which should lead to improved long-term outcomes.

Background While it is appropriate to treat transfusional iron overload to limit end-organ injury after bone marrow transplantation (BMT) for β-thalassemia major (TM), this approach after BMT for sickle cell disease (SCD) and hematological malignancies has not been studied. Procedure Fifteen children with SCD (n = 4), TM (n = 6), or acute myelogenous leukemia (AML, n = 5) underwent HLA-identical sibling BMT between 2000 and 2003. Prospective evaluations of iron biomarkers were performed and the three groups were compared. Results The pre-BMT duration and volume of RBC transfusions varied among the three groups, but baseline ferritin and liver iron concentration (LIC) were similar. In contrast, liver histology differed. Liver inflammation was present in four TM patients and portal fibrosis was observed in five TM and one SCD patient. Hepatic veno-occlusive disease (VOD) developed in 5 of 15 patients. VOD was not associated with age, ferritin, ALT, or transfusions, but an association with liver inflammation and elevated LIC was suggested. Phlebotomy was performed in five patients after BMT. Changes in LIC were minimal in non-phlebotomized patients (P = 0.02). Conclusion Iron biomarkers demonstrated significant iron overload before BMT in patients with malignant and non-malignant disorders. However, iron overload was associated with liver inflammation and VOD primarily in TM patients. The clinical significance of iron overload in patients after BMT remains uncertain, but this is the first study to suggest that VOD may be associated with transfusional iron burden. Pediatr Blood Cancer 2008;50:319–324. © 2007 Wiley-Liss, Inc.