Studies of a mosaic patient with DBA and chimeric mice reveal erythroid cell-extrinsic contributions to erythropoiesis.

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.

Caplacizumab as rescue therapy in refractory TTP involving neurologic features.

BACKGROUND: The role of caplacizumab in the routine treatment of immune thrombotic thrombocytopenic purpura (iTTP) remains to be established. CASE SUMMARY: A 56-year-old woman was transferred to our center with iTTP and neurologic features. At the outside hospital, she was initially diagnosed and managed as Immune Thrombocytopenia (ITP). Upon transfer to our center, daily plasma exchange, steroids, and rituximab were initiated. After an initial improvement, refractoriness became evident with a decline in platelet count and continued neurologic abnormalities. Initiation of caplacizumab resulted in rapid hematologic and clinical responses. CONCLUSION: Caplacizumab is a valuable treatment modality in iTTP, particularly in cases associated with refractoriness or neurologic features.

Hemoglobin and End-Organ Damage in Individuals with Sickle Cell Disease.

Background: Sickle cell disease (SCD) is an inherited, chronic, multifaceted blood disorder. Patients with SCD develop anemia, which has been associated with end-organ damage (EOD). Objectives: This retrospective, observational, repeated-measures study systematically characterizes the relationship between hemoglobin (Hb) level and EOD in adolescent and adult patients with SCD. Methods: The study population comprised patients with SCD aged ≥12 years with available Hb data from a US provider-centric health care database. For each patient, each Hb value over time was included as a separate observation. Study outcomes-the onset of any new EOD, including chronic kidney disease, pulmonary hypertension, stroke, and leg ulcer-were ascertained during the 1-year period after each Hb assessment. The association between Hb levels and risk of new EOD was estimated using multivariable generalized estimating equations. Results: A total of 16,043 unique patients with SCD contributed 44,913 observations. Adjusted odds of any EOD during the 1-year follow-up were significantly lower with higher Hb level. Risk reductions with higher Hb levels for chronic kidney disease, pulmonary hypertension, and leg ulcer were comparable. The risk of new EOD was significantly lower among adolescent and adult patients with higher Hb levels. Conclusions: In patients with SCD, higher Hb levels are associated with a reduced risk of developing EOD. Therapeutic strategies that result in higher Hb levels may offer clinical and economic value for patients with SCD. (Curr Ther Res Clin Exp. 2023; 84:XXX-XXX).

Staphylococcal enterotoxin B increased severity of experimental model of multiple sclerosis.

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.

Immunoassay for human serum erythroferrone.

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 nontransfused ß-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 ß-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.

Health-Related Quality-of-Life Impacts Associated with Transfusion-Dependent ß-Thalassemia in the USA and UK: A Qualitative Assessment.

BACKGROUND: Individuals living with transfusion-dependent ß-thalassemia (TDT) experience reduced health-related quality of life due to fatigue and chronic pain, which cause disruptions to daily life. Currently, limited qualitative data exist that describe these impacts. OBJECTIVE: This study aimed to examine the ways in which symptoms and current treatments of TDT impact health-related quality of life, to holistically describe the humanistic burden of TDT, and to identify the unmet needs of individuals living with TDT. METHODS: Adults (aged ≥ 18 years) with TDT and caregivers of adolescents (aged 12‒17 years) with TDT participated in semi-structured one-on-one virtual interviews and focus group discussions. Interviews were conducted in the USA and UK and lasted approximately 60 minutes. After transcription, the interviews were analyzed thematically using a framework approach. RESULTS: A total of ten interviews/focus group discussions (six interviews and four focus group discussions) were conducted with 14 adults with TDT and two caregivers of adolescents with TDT. A framework analysis revealed five themes describing health-related quality of life (negative impacts on daily activities, social life, family life, work and education, and psychological well-being) and three themes describing the lived experience of TDT (impact of red blood cell transfusions and iron chelation therapy, treatment, and stigma). Physical, psychological, and treatment-related factors contributed to negative impacts on daily activities, social and family life, and work and education. Concerns about reduced lifespan, relationships and family planning, and financial independence were detrimental to participants' mental well-being. Participants reported having high resilience to the many physical and psychological challenges of living with TDT. A lack of TDT-specific knowledge among healthcare professionals, particularly regarding chronic pain associated with the disease, left some participants feeling ignored or undermined. Additionally, many participants experienced stigma and were reluctant to disclose their disease to others. CONCLUSIONS: Individuals living with TDT experience substantial negative impacts on health-related quality of life that disrupt their daily lives, disruptions that are intensified by inadequate healthcare interactions, demanding treatment schedules, and stigma. Our study highlights the unmet needs of individuals living with TDT, especially for alternative treatments that reduce or eliminate the need for red blood cell transfusions and iron chelation therapy.

Cryoglobulinemia Leading to the Diagnosis of Low Grade Serous Ovarian Carcinoma.

We present the case of a 64-year-old female who was referred by her oncologist to benign hematology clinic for persistent asymptomatic cryoglobulinemia. Workup led to diagnosis of a rare low grade ovarian serous carcinoma. We briefly review the pathophysiology and clinical significance of cryoglobulinemia and the diagnosis and management of low grade serous ovarian carcinoma.

A Journey From Appendicitis to a Rare Appendiceal Mucinous Neoplasm.

We present here a 66-year-old Caucasian male whose persistent abdominal pain thought to be due to appendicitis and associated acute splanchnic thrombosis. He was initially managed with antibiotics and anticoagulation. But further work up revealed a low-grade appendiceal mucinous neoplasm causing the splanchnic vein thrombosis. Additionally, diagnosis and management of this rare tumor and appropriate work up for splanchnic thrombosis will be briefly reviewed here.

Beliefs about chelation among thalassemia patients.

BACKGROUND: Understanding patients' views about medication is crucial to maximize adherence. Thalassemia is a congenital blood disorder requiring chronic blood transfusions and daily iron chelation therapy. METHODS: The Beliefs in Medicine Questionnaire (BMQ) was used to assess beliefs in chelation in thalassemia patients from North America and London in the Thalassemia Longitudinal Cohort (TLC) of the Thalassemia Clinical Research Network (TCRN). Chelation adherence was based on patient report of doses administered out of those prescribed in the last four weeks. RESULTS: Of 371 patients (ages 5-58y, mean 24y), 93% were transfused and 92% receiving chelation (26% deferoxamine (DFO; a slow subcutaneous infusion via portable pump), 63% oral, 11% combination). Patients expressed high "necessity" for transfusion (96%), DFO chelation (92%) and oral chelation (89%), with lower "concern" about treatment (48%, 39%, 19% respectively). Concern about oral chelation was significantly lower than that of DFO (p<0.001). Self-reported adherence to chelation was not associated with views about necessity or concerns, but negatively correlated with perceived sensitivity to DFO (Sensitive Soma scale; r=-0.23, p=0.01) and side effects of oral chelation (r=-0.14, p=0.04). High ferritin iron levels, potentially indicating lower adherence, were found in 41% of patients reporting low necessity of oral chelation compared to 24% reporting high necessity (p=0.048). Concerns about treatment were associated with lower quality of life and more symptoms of anxiety and depression. CONCLUSIONS: Despite their requirement for multimodal therapy, thalassemia patients have positive views about medicine, more so than in other disease populations. Patients may benefit from education about the tolerability of chelation and strategies to effectively cope with side effects, both of which might be beneficial in lowering body iron burden. CLINICALTRIALS.GOV IDENTIFIER: NCT00661804.

Stroke in sickle cell disease and the promise of recent disease modifying agents.

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.

Iron chelation adherence to deferoxamine and deferasirox in thalassemia.

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.

Hb E/beta-thalassaemia: a common & clinically diverse disorder.

Haemoglobin E-beta thalassaemia (Hb E/ß-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/ß-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.

A case of Sß+ sickle cell disease diagnosed in adulthood following acute stroke: it's 2021, are we there yet?

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 (Sß+ 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 Sß+ type, as well as the pathophysiology and current management of stroke in SCD.

Education and employment status of children and adults with thalassemia in North America.

BACKGROUND: 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. PROCEDURES: 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. RESULTS: 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. CONCLUSIONS: 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.

Intravascular large B-cell lymphoma in Hispanics: a case series and literature review.

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.

Pernicious anemia: a myelodysplastic syndrome look-alike.

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.

SCCmec Genotypes of Methicillin-Resistant Staphylococcus aureus in Nasal Carriage of Multiple Sclerosis Patients in Iran.

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.

Atypical manifestations of sarcoidosis in a Hispanic male.

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.

Transfusional iron burden and liver toxicity after bone marrow transplantation for acute myelogenous leukemia and hemoglobinopathies.

BACKGROUND: While it is appropriate to treat transfusional iron overload to limit end-organ injury after bone marrow transplantation (BMT) for beta-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.

Patient-reported outcomes of deferasirox (Exjade, ICL670) versus deferoxamine in sickle cell disease patients with transfusional hemosiderosis. Substudy of a randomized open-label phase II trial.

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.