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ABSTRACT Background: Hemophilia A is an X-linked chronic bleeding disorder due to deficiency of the coagulation factor VIII. According to the residual level of FVIII activity, patients can present with severe (FVIII levels <1 %), moderate (1-5 %) or mild (6-40 %) phenotypes. While long-term prophylaxis is the current standard of care and has been shown to be effective in minimizing bleeding episodes, episodes of hemarthrosis, that could lead to arthropathy and disability, are still reported. This systematic review aimed to evaluate available data concerning current treatment outcomes in severe hemophilia A patients without inhibitors in Brazil, focusing on the frequency of bleeding episodes and adherence to therapy of patients under prophylactic treatment. Method: A literature search strategy was used in the MEDLINE (via PubMed), Embase, LILACS and SciElo databases from 2014 onwards, since it was the moment that prophylaxis effectively became available in the Brazilian National Health Service, even though prophylactic treatment had been officially incorporated in 2011 focused on concerning bleeding episodes and adherence rate of this population. Results: Searches yielded 536 articles. After removal of duplicates, 417 articles were screened for eligibility. Eventually, 104 articles were selected for full-text assessment. Finally, only five publications met eligibility criteria and were selected for the descriptive review. Conclusion: Available information on efficacy of severe hemophilia A management in Brazil currently relies on scarce and possibly biased information. It should be strongly emphasized that Brazil is in great need of a structured and coordinated effort to improve collection, analysis, and reporting of data on hemophilia A patients

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ABSTRACT Venetoclax is a promising alternative for patients with acute myeloid leukemia who are considered unfit for conventional chemotherapy; however, its employment still faces challenges mostly related to drug resistance. Here, we provide further biological mechanisms underlying the previously described and potentially novel intrinsic sources of poor response to venetoclax departing from ex vivo response data. Acute myeloid leukemia data including FLT3 mutation status, gene expression data, and ex uiuo response data were extracted from the publicly available BeatAML 1.0 study database and aided sample categorization that supported differential gene expression analysis that, in turn, supported gene set enrichment analysis. CIBERSORTx-based bulk RNA sequencing deconvolution of BeatAML 1.0 data allowed us to categorize samples according to their cell type content. We observed that inflammation-related gene sets, such as cytokines and inflammatory response, NLRP3 inflammasome activation, and activation of adaptive immune response, were concordantly positively enriched across all the conditions reported to be associated with poor ex uiuo venetoclax response, whereas samples from good ex uiuo responders’ mostly enriched gene sets related to mitochondrial activity, and early myeloid progenitor cell molecular programs. Besides the alternative reliance on BCL2A1, we highlight inflammation as a common element present across multiple sources of venetoclax ex uiuo response modulation in acute myeloid leukemia samples. Hence, a potential key modulator for venetoclax response.

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ABSTRACT Background: Patients with sickle cell disease were presumed to be at high risk for severe COVID-19 outcomes due to their compromised immunity and chronic comorbidities. This study aimed to evaluate vaccination patterns, healthcare utilization, and clinical outcomes in a cohort of sickle cell disease patients during the COVID-19 pandemic in Rio de Janeiro. Methods: A total of 289 over 18-year-old patients from the Epidemiology and Donor Evaluation Study (REDS-III) Brazil sickle cell disease cohort were followed between January 2021 and August 2023. Sociodemographic data, emergency department visits, hospitalizations, mortality rates, and COVID-19 vaccination status were collected. SARS-CoV-2 infection was confirmed by reverse transcription polymerase chain reaction testing for symptomatic or hospitalized patients. Results: Of the participants, 89.2% completed the primary vaccination schedule, 62.2% received the first booster, 30% the second booster, and 4.1% completed all five doses. Emergency visits increased slightly during the pandemic but were primarily due to vaso-occlusive crises. Of the 119 patients tested for SARS-CoV-2, six were positive, presenting mild symptoms with no COVID-19-related deaths. Vaccination rates in the cohort were similar to those in the general population, with Oxford/AstraZeneca and Pfizer being the most used vaccines. Discussion: The findings suggest that COVID-19 infection was not a significant trigger for vaso-occlusive crises or severe disease outcomes. High vaccination adherence likely played a key role in preventing severe COVID-19, alongside other factors such as social isolation and herd immunity. However, the overlap between symptoms of vaso-occlusive crises and COVID-19 may have caused diagnostic challenges. Importantly, the low morbidity and mortality observed emphasize the protective effect of vaccines, despite the presence of thromboplastic activity and pro-inflammatory states inherent to sickle cell disease. Addressing vaccine hesitancy remains crucial, particularly as booster doses show declining adherence. Conclusion: COVID-19 had a limited clinical impact on this cohort, with no significant role in triggering vaso-occlusive crises or severe outcomes. High vaccination rates and potential environmental or biological factors may have contributed to this protective effect.

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Abstract Objective This study aimed to determine the frequency of genetic alterations as deletions and duplications in cytochrome P450 (CYP450) and glutathione S-transferases (GST) genes, as well as to investigate whether there is a relationship between these alterations and neutrophilic hematologic recovery in adult patients diagnosed with acute myeloid leukemia. Method DNA samples from 70 patients diagnosed with acute myeloid leukemia were evaluated using the Multiplex Ligation-dependent Probe Amplification technique. The presence or absence of polymorphisms was compared regarding the time to neutrophilic recovery (neutrophil count ≥1.0 × 109/L) using Kaplan-Meier curves, with the comparison between the curves being performed using the non-parametric log-rank test. Results The median age of the participants was 57 years, with a higher proportion of females (57.2%) and white individuals (61.4%)’. A total of 76 polymorphisms (CYP450 + GST) were identified, comprising 38 deletions and 38 duplications. Kaplan-Meier curves revealed that the neutrophilic recovery time was longer for the group with polymorphisms (p-value = 0.0056). Conclusion The study demonstrated that CYP450 and GST genes are polymorphic, and these polymorphisms may lead to longer neutrophilic recovery after induction treatment of acute myeloid leukemia remission.

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Abstract Aim To determine the prevalence of ocular graft-versus-host disease after allogeneic hematopoietic stem cell transplantation and to characterize the risk factors associated with its development in a pediatric population. Methods This retrospective chart review included 105 patients during a five-year period (2013-2017) from the Pediatric Oncology Institute (GRAACC-UNIFESP). The diagnosis of graft-versus-host disease was performed by the treating hematologist in conjunction with an ophthalmologist in accordance to National Institutes of Health (NIH) consensus criteria. Results Systemic graft-versus-host disease occurred in 44 of 105 (41.9%) patients, predominantly in males (54.5%) whereas ocular disease was diagnosed in seven (6.7%) of the patients. All the analyzed risk factors including diagnosis, type of conditioning regimen, use of radiotherapy in conditioning, donor sex, type and source of graft, human leukocyte antigen mismatch, and sex mismatch were not statistically significantly associated with the development of ocular disease, except for age. Ocular graft-versus-host disease patients presented a higher mean age compared to patients without ocular disease (p-value = 0.015). Conclusion Although less prevalent than in adults, ocular morbidity remains a concern in pediatric patients following allogeneic transplantation. Early diagnosis and regular ophthalmic follow-ups are recommended after the transplantation regardless of systemic graft-versus-host disease status.

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Abstract Background Hematopoietic stem cell expansion relies on direct cell-cell interactions mediated by adhesion molecules, integrins, and cytokines. Unrestricted somatic stem cells have emerged as novel stromal cells supporting hematopoietic stem cell expansion in co-culture conditions via secretion of hematopoiesis-related cytokines and the expression of adhesion molecules. Previous research showed fibrin increased hematopoiesis-related gene expression in these cells. This study focused on the adhesive characteristics of unrestricted somatic stem cells on 3D fibrin scaffolds. Methods Unrestricted somatic stem cells were isolated from umbilical cord blood and characterized using flow cytometry and multilineage differentiation assays. Scanning electron microscopy and DAPI staining were employed to analyze cell attachment to fibrin. Viability on fibrin was assessed through MTT assays. Quantitative polymerase chain reaction was conducted to evaluate the expression of intercellular adhesion molecule 1 (ICAM-1), integrin subunit αv (ITGAV), and integrin subunit β3 (ITGB3) in cells cultured on 3D fibrin scaffolds. Results Cells were positive for CD73, CD105, and CD166 but negative for CD45. Alizarin red and Oil red O stains confirmed calcium deposition and lipid vacuoles. MTT assays revealed that fibrin positively impacts viability. ITGAV expression was significantly increased in cells cultured on fibrin compared to those cultured on plastic tissue culture plates (Control Group). Furthermore, ITGB3 expression showed no significant change in both groups, while ICAM-1 expression was downregulated in cells cultured on fibrin. Conclusions Our study revealed that fibrin has a positive impact on the expression of ITGAV, which plays a crucial role in direct cell-cell interactions affecting hematopoietic stem cell expansion.

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Abstract Introduction Inherited platelet disorders are rare conditions characterized by altered platelet function and/or reduced platelet counts. Diagnosing these disorders is challenging and may result in delays, misdiagnosis, and inappropriate treatment. In low- and middle-income countries, data are scarce. Here, we describe a cohort of patients at a reference center in Brazil. Methods A descriptive analysis was conducted on patients followed at the Thrombosis and Hemostasis outpatient clinic of the Hospital das Clinicas, University of São Paulo, Brazil.Medical records of 857 patients with thrombocytopenia or bleeding disorders of unknown cause, evaluated between 1998 and 2023, were reviewed. Of these, 60 patients had a confirmed or suspected diagnosis of an inherited platelet disorder and were included in the study. Results Among the 60 patients, the majority were female (75 %), with a median age of 48 years. The suspicion of a platelet disorder was based on clinical presentation, family history, and laboratory findings. Overall, 65 % of the patients had abnormal platelet function, while 35 % presented with thrombocytopenia. A positive family history was reported in 62 % of those with low platelet counts and in 51 % of patients with platelet function abnormalities. Previous misdiagnoses included immune thrombocytopenia and von Willebrand disease. Overall, the bleeding phenotype was mild, with a median ISTH-BAT (International Society on Thrombosis and Haemostasis Bleeding Assessment Tool) score of 6. Patients with reduced platelet counts tended to have lower ISTH-BAT score. Conclusions Identifying inherited platelet disorders is essential for proper treatment and follow-up. This study emphasizes the need for careful assessment of family history, bleeding risk, platelet count, morphology, and function for diagnosis, particularly in low-resource settings without access to advanced genetic testing.

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ABSTRACT Background: Anemia affects around 1.6 billion people worldwide and presents a significant challenge for healthcare providers. Despite the hemoglobin concentration being commonly used for diagnosis, identifying underlying causes remains challenging, particularly in vulnerable groups like children under five and pregnant women. Genetic factors, notably variations in the TMPRSS6 gene, are implicated in iron deficiency anemia, yet the precise relationship with anemia remains unclear. Methods: A thorough literature search was conducted across databases, including Embase, Google Scholar, and PubMed, focusing on studies investigating TMPRSS6 gene polymorphisms and anemia. Thirteen eligible studies, comprising 2082 cases and 2684 controls, underwent meta-analysis using Review Manager 5.4 software. Various genetic models were assessed, including allelic, homozygous, heterozygous, dominant, and recessive, with no significant relationship found between the TMPRSS6 rs855791 polymorphism and anemia. Conclusion: This meta-analysis provides robust evidence suggesting no significant association between the TMPRSS6 rs855791gene polymorphism and anemia. These findings underscore the complexity of genetic factors contributing to anemia and emphasize the importance of the further investigation to unravel the mechanisms underlying this relationship for improved diagnostic and therapeutic approaches.

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Abstract Platelet refractoriness caused by alloimmunization to anti-HLA antibodies remains present in daily hemotherapy: the frequent need for platelet transfusions may influence the long-term survival of treated patients. This study aimed to perform a systematic review with meta-analysis to investigate the chances of anti-HLA antibody formation triggering immune-induced platelet refractoriness in platelet transfused individuals. By adopting Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria, a search was conducted of publications in online databases between 1976 and July 2022. The risk of bias in the studies was assessed according to the data quality assessment proposed by the ‘A MeaSurement Tool to Assess systematic Reviews’ (AMSTAR-2) tool. Meta-analysis was performed by evaluating the Forest and Funnel Plots. From 832 published articles, 50 were read in full with 14 studies being included in this systematic review. The forest plot showed a likely low heterogeneity (I²: 12.3%; p-value = 0.32), and high odds ratio (174.57; confidence interval: 73.23-416.16) showing platelet refractoriness is triggered by anti-HLA alloantibodies. In this study, anti-HLA antibody formation contributed to an approximate 175-fold higher chance of triggering immune-induced platelet refractoriness. Some explanations about why some statistical differences were observed are offered by studies. This study demonstrates the need for developing policies to identify and monitor anti-HLA antibodies in patients, as well as for HLA matching, and makes some suggestions for future research to promote the prevention of patient sensitization due to platelet transfusions including the development of platelet refractoriness.

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Abstract Despite sickle cell disease (SCD) being a well-recognized and highly prevalent condition identified early through neonatal screening programs, it represents a substantial public health challenge due to high morbidity and premature mortality rates. Hydroxyurea (HU) is the only available disease-modifying therapy for SCD approved in Brazil. Indeed, its underutilization highlights the need for improved therapeutic strategies to enhance adherence and management of SCD. Innovative formulations of HU might favor treatment adherence and precise dosing. Thus, we aimed to describe HU's pharmacological characteristics, clinical efficacy, and tolerability, including dose escalation. Recent interventional and observational studies revealed the efficacy and safety of an innovative formulation: dispersible scored tablets of 100 mg and 1000 mg, allowing easier dose adjustments and, consequently, more precise dosing. The 100 mg tablets scored can be cut into two parts of 50 mg, and the 1000 mg tablets can be cut into four parts of 250 mg. The fractionating dose is possible due to the formulation technology that allows the tablet to be cut with a uniform amount of drug in each part. This new formulation of HU, suitable for children, may influence the prognosis of SDC, regardless of associated symptoms.

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Abstract There is no physiological mechanism for the excretion of iron in humans, and excess iron may lead to severe tissue damage if not adequately treated. Iron overload can be caused by genetic factors (hemochromatosis) or acquired conditions (e.g., ineffective erythropoiesis, transfusions, iatrogenic iron treatment, viral hepatitis, alcohol intake, severe liver disease, metabolic dysfunction), and, in many cases, by a conjunction of these factors. Historically, guidelines for the genetic investigation of patients with iron overload have been based on data obtained from Caucasian individuals in Europe and North America. However, due to the genetic heterogeneity of iron overload gene mutations worldwide, these recommendations might not be applicable to other ethnic groups. This study analyzed previously published genetic data obtained from Brazilian patients with iron overload and found a relevant but small prevalence of HFE C282Y/C282Y patients when compared to European populations, while mutations of the TFR2, SCL40A1, HJV, HAMP, BMP6 and SLC11A1 genes seem to be important. This study proposes an adapted algorithm for the investigation and management of iron overload in Brazil.

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Abstract Chronic lymphocytic leukemia, characterized by an accumulation of monoclonal B lymphocytes, is the most common adult leukemia. The disease predominantly affects older adults, with a significant proportion being asymptomatic at diagnosis. This manuscript provides a comprehensive review of chronic lymphocytic leukemia, including its epidemiology, clinical presentation, diagnostic criteria, and treatment strategies. Prognostic factors, particularly IGHV mutation status and chromosomal abnormalities, are discussed as critical determinants of disease behavior and treatment response. Recent advances in targeted therapies, such as Bruton's tyrosine kinase inhibitors (BTKi) and B-cell lymphoma 2 inhibitors (BCL-2i), have changed the treatment landscape by demonstrating superior efficacy to chemoimmunotherapy. However, disparities in access to care, particularly in low- and middle-income countries such as Brazil, highlight the need for equitable treatment approaches. The discussion of measurable residual disease (MRD) assessment for prognostication and treatment planning is also highlighted. This review highlights the need for continued research and integration of novel therapies to optimize patient outcomes in chronic lymphocytic leukemia.