Therapeutic approaches in patients with β-thalassemia

Beta-thalassemia (β-thal) is a congenital hemoglobinopathy explained by a decreased level (β+) or absence (βο) of β-globin gene expression. Microcytic hypochromic anemia and various clinical symptoms comprising severe anemia to clinically nonsymptomatic features. Treatment with an ordered blood transfusion and iron chelator agents can decrease transfusion iron overload that causes normal maturation. These patients also are at high risk for secondary iron overload because of erythropheron (GF15–TWSG1) release from erythroblasts resulting in erythroid hyperplasia. Based on the previous studies, chemicals such as hydroxyurea and 5-azacytidine are useful in treating β-hemoglobinopathy, including β-thal and sickle cell disease (SCD). Regarding both side effects and lifelong treatment of these chemical components, researchers have recently regarded gene-based treatments. These techniques, such as micro RNA gene silencing, viral-mediated gene editing, and clustered regulatory interspaced short palindromic repeats (CRISPR)-CAS9 systems, are the most commonly used gene therapy methods. Nowadays, ɣ-globin (fetal globin) gene reactivation is one of the most popular treatments for β-thal. Researches showed that these gene modification methods for γ-globin gene reactivation are also useful in increasing hemoglobin F (HbF) and helping patients with β-thal. In this review study, new therapeutic approaches to manage this disorder are regarded.

Cause of Death, Mortality and Occult Blood in Colorectal Cancer Screening

Fecal hemoglobin (f-Hb) detected by the guaiac fecal occult blood test (gFOBT) may be associated with mortality and cause of death in colorectal cancer (CRC) screening participants. We investigated this association in a randomly selected population of 20,694 participants followed for 33 years. We followed participants from the start of the Hemoccult-II CRC trial in 1985–1986 until December 2018. Data on mortality, cause of death and covariates were retrieved using Danish national registers. We conducted multivariable Cox regressions with time-varying exposure, reporting results as crude and adjusted hazard ratios (aHRs). We identified 1766 patients with at least one positive gFOBT, 946 of whom died in the study period. Most gFOBT-positive participants (93.23%) died of diseases unrelated to CRC and showed higher non-CRC mortality than gFOBT-negative participants (aHR: 1.20, 95% CI 1.10–1.30). Positive gFOBT participants displayed a modest increase in all-cause (aHR: 1.28, 95% CI: 1.18–1.38), CRC (aHR: 4.07, 95% CI: 3.00–5.56), cardiovascular (aHR: 1.22, 95% CI: 1.07–1.39) and endocrine and hematological mortality (aHR: 1.58, 95% CI: 1.19–2.10). In conclusion, we observed an association between positive gFOBT, cause of death and mortality. The presence of f-Hb in the gFOBT might indicate the presence of systemic diseases.

Thalassemia and COVID-19: Susceptibility and Severity

Context: COVID-19 results in an imbalance between procoagulant and anticoagulant homeostatic mechanisms that could be complicated with thrombotic events. In β-thalassemia patients, the presence of comorbidities, iron overload, adrenal hypofunction, splenectomy, and chronic hypercoagulable state might increase the susceptibility to COVID-19 and its severity. Evidence Acquisition: The search was conducted in PubMed, Web of Science, and Scopus databases for the key terms of β-thalassemia/thalassemia and COVID-19 until July 2021. Results: The survey of published observational studies (mostly multicenter and case reports) indicated a lower prevalence of COVID-19 in β-thalassemia patients compared with the general population, as well as mild to moderate COVID-19 in these patients, especially in those without comorbidity. β-Thalassemia children were susceptible to COVID-19 but with less severity compared to adults. There is no report of pulmonary embolism and thrombotic events in β-thalassemia patients with COVID-19; however, coagulation abnormality and pulmonary microembolism have been found in these patients. Conclusions: Findings could be interpreted by the presence of high hemoglobin F (HbF) levels, the advantage of hydroxyurea (HU) therapy, splenectomy, and iron chelation therapy in these patients. However, due to the low sample size and studying mainly young patients, the results should be interpreted with caution, and it still needs more studies with a larger sample size to confirm these findings.

β-Thalassemia: evolving treatment options beyond transfusion and iron chelation

After years of reliance on transfusion alone to address anemia and suppress ineffective erythropoiesis in β-thalassemia, many new therapies are now in development. Luspatercept, a transforming growth factor–β inhibitor, has demonstrated efficacy in reducing ineffective erythropoiesis, improving anemia, and possibly reducing iron loading. However, many patients do not respond to luspatercept, so additional therapeutics are needed. Several medications in development aim to induce hemoglobin F (HbF): sirolimus, benserazide, and IMR-687 (a phosphodiesterase 9 inhibitor). Another group of agents seeks to ameliorate ineffective erythropoiesis and improve anemia by targeting abnormal iron metabolism in thalassemia: apotransferrin, VIT-2763 (a ferroportin inhibitor), PTG-300 (a hepcidin mimetic), and an erythroferrone antibody in early development. Mitapivat, a pyruvate kinase activator, represents a unique mechanism to mitigate ineffective erythropoiesis. Genetically modified autologous hematopoietic stem cell transplantation offers the potential for lifelong transfusion independence. Through a gene addition approach, lentiviral vectors have been used to introduce a β-globin gene into autologous hematopoietic stem cells. One such product, betibeglogene autotemcel (beti-cel), has reached phase 3 trials with promising results. In addition, 2 gene editing techniques (CRISPR-Cas9 and zinc-finger nucleases) are under investigation as a means to silence BCL11A to induce HbF with agents designated CTX001 and ST-400, respectively. Results from the many clinical trials for these agents will yield results in the next few years, which may end the era of relying on transfusion alone as the mainstay of thalassemia therapy.

A very preterm infant born to mother of mirror syndrome secondary to fetomaternal hemorrhage: a case report

Background Mirror syndrome (MS) is defined as maternal edema with fetal hydrops and placental edema with different etiologies, such as rhesus isoimmunization and twin-twin transfusion syndrome. Herein, we showcased a unique MS case secondary to fetomaternal hemorrhage (FMH). Case presentation A 32-year-old gravida 2 para 0 woman diagnosed with fetal hydrops was admitted to our hospital. Maternal laboratory tests revealed anemia, slightly increased creatinine and uric acid levels, hypoproteinemia, and significantly increased alpha-fetoprotein and hemoglobin-F levels. Therefore, FMH was diagnosed initially. Two days after admission, the woman had unexpectedly progressive anasarca and started to feel chest distress, palpitations, lethargy, and oliguria, and MS was suspected. An emergency cesarean section was performed to terminate the pregnancy. The maternal clinical symptoms and laboratory tests rapidly improved after delivery. A very preterm infant with a 2080-g birthweight at 31 weeks gestation survived after emergency cesarean section, active resuscitation, emergency blood transfusion, abdominocentesis, and advanced life support. Conclusions FMH could develop into MS, providing new insights into the etiology of MS. Once MS is diagnosed, emergency cesarean section might be an alternative treatment. The very preterm infant survived with a favorable long-term outcome, and a well-trained perinatal work team is needed for such cases.

Nf1 and Sh2b3 mutations cooperate in vivo in a mouse model of juvenile myelomonocytic leukemia

Juvenile myelomonocytic leukemia (JMML) is initiated in early childhood by somatic mutations that activate Ras signaling. While some patients have only a single identifiable oncogenic mutation, others have one or more additional alterations. Such secondary mutations, as a group, are associated with an increased risk of relapse after hematopoietic stem cell transplantation, or transformation to acute myeloid leukemia. These clinical observations suggest a cooperative effect between initiating and secondary mutations. However, the roles of specific genes in the prognosis or clinical presentation of JMML have not been described. In this study, we investigate the impact of secondary SH2B3 mutations in JMML. We find that patients with SH2B3 mutations have adverse outcomes, as well as higher white blood cell counts and hemoglobin F levels in the peripheral blood. We further demonstrate this interaction in genetically engineered mice. Deletion of Sh2b3 cooperates with conditional Nf1 deletion in a dose-dependent fashion. These studies illustrate that haploinsufficiency for Sh2b3 contributes to the severity of myeloproliferative disease and provide an experimental system for testing treatments for a high-risk cohort of JMML patients.

The Role of Certain Congenital Infections in Aplastic Anemia and Prognostic Value of Fetal Hemoglobin as a Follow-Up Marker

Background: TORCH infection has a role in aplastic anemia (AA). Fetal hemoglobin may be high in certain acquired hematological conditions such as aplastic anemia. We conducted this study to evaluate the correlation between certain congenital infections and severity of aplastic anemia and to study fetal Hb as a follow up marker during treatment of aplastic anemia. The aim of study was to correlation between certain congenital infection and severity of aplastic anemia and to study of hemoglobin F (HbF) as a follow up marker during treatment of aplastic anemia. Methods: Our prospective study was conducted on 20 children aged up to 18 years diagnosed with aplastic anemia following either bone marrow aspiration or biopsy that proves bone marrow hypocellularity with absence infiltrative BM disease or inherited BM disease recruited from Pediatric Hematology-Oncology Unit of Tanta University Hospital. Patients were classified according to level of HbF in to high HbF group and normal HbF group. Results: TORCH infections were detected in certain numbers of patients . HbF decreased in high HbF group after treatment. There was significant increase in CBC parameters in high HbF group than normal HbF group after treatment. There was insignificant decrease in mortality in high HbF group than normal HbF group. Mild to moderate cases were significantly higher with TORCH IgM +ve cases Conclusions: Acquired AA is associated with TORCH infection. In treated cases of AA, improvement of hematological parameters is associated with high HbF and from these results, it can be used as a prognostic marker to monitor the successful response of these cases to the used line of treatment.

Multispectral Imaging for MicroChip Electrophoresis Enables Point-of-Care Newborn Hemoglobin Variant Screening

Hemoglobin (Hb) disorders affect nearly 7% of the world's population. Globally, around 400,000 babies are born annually with sickle cell disease (SCD), primarily in sub-Saharan Africa where morbidity and mortality rates are high. Although treatments are available for Hb disorders, screening, early diagnosis, and monitoring are not widely accessible due to technical challenges and cost, especially in low-and-middle-income countries. We hypothesized that multispectral imaging will allow sensitive hemoglobin variant identification in existing affordable paper-based Hb electrophoresis, which is a clinical standard test for Hb variant screening. To test this hypothesis, we developed the first integrated point-of-care multispectral Hb variant test: Gazelle-Multispectral. Here, we evaluated the accuracy of Gazelle-Multispectral for Hb variant newborn screening in 321 completed tests in subjects younger than 6 months with known hemoglobin variants including hemoglobin A (Hb A), hemoglobin F (Hb F), hemoglobin S (Hb S) and hemoglobin C (Hb C). Gazelle-multispectral detected levels of Hb A, Hb F, Hb S, and Hb C, demonstrated high correlations with the results reported by laboratory gold standard high performance liquid chromatography (HPLC) at Pearson Correlation Coefficient = 0.97, 0.97, 0.89, and 0.94. Gazelle-multispectral demonstrated 100% sensitivity and 100% specificity in both disease vs normal and disease vs trait, 98.1% sensitivity and 97.0% specificity in trait vs normal in comparison to HPLC in newborns. The ability to obtain rapid and accurate results on newborn samples suggest that Gazelle-Multispectral is suitable for large-scale newborn screening and potentially for accurate diagnosis of SCD in low resource settings.

A double blind, placebo controlled randomized evaluation of the efficacy of a Polyherbal Preparation (FaradinR) in treating sickle cell anaemia in Nigerian children

Introduction: The goal of management of sickle cell anaemia (SCA), for many years, has been to manage acute intermittent crises and slow down chronic end organ damage. In the past few decades, with increasing understanding of its pathophysiology, compounds primarily preventive in action are being investigated and used. Faradin® (a poly-herbal traditional supplement mixture) has been used aspreventive measure against painful episodes by SCA patients as an over the counter medication and anecdotal evidence suggests that it reduced the frequency and severity of painful crises as well as transfusion requirements. Alternative medications that are both affordable and available should be considered viable alternatives provided safety and efficacy are assured because of the high disease burden in Nigeria.Methods: This was a double controlled randomized study was carried out on twenty children. Each enrolled patient was randomized into either the herbal mixture or placebo after permission to participate in the study was obtain from the parents/guardian for children below 15 years or from both parents/guardian and the patients where the latter are older than 15 years. The main exclusion criterion was prior use or exposure to Faradin. Primary end points were pain alteration, death during study and blood transfusion frequency. Secondary endpoints were hemoglobin levels, neutrophil count, platelet count, hemoglobin F and A2 levels, serum bilirubin, nitric oxide concentration, drug toxicity and severe complications of sickle cell anemia reported during the study.Results: There was no severe adverse event, deaths or transfusion recorded in the two groups throughout the duration of the study. Mean hematocrit was increased in the Faradin group and reticulocyte count was increased by 12 %. Faradin reduced the total white cell count to half its baseline level and increased hemoglobin F levels by 10%. Weight and appetite were reported to increased and engenders a generalfeeling of wellbeing.Conclusion: Faradin appears to be an efficacious, nontoxic, available and affordable remedy for treating SCA patients in our setting.

Fetal Hemoglobin Levels as Indicator of Frequency and Duration of Blood Donation

Hemoglobin F is normal hemoglobin seen in minute amount in adults. Increase in its level in adults is an indication of erythropoietic stress, which in most cases is linked to hemoglobinopathy. This study was undertaken to assess if physiological erythropoietic stress as seen in commercial blood donation, can increase it and thus be used as an indicator of frequency and duration of blood donation. The study involved 152 subjects including 88 commercial blood donors and 64 controls. Hemoglobin F was expressed as percentage concentration of the total hemoglobin. Results showed that hemoglobin F significantly increased in commercial blood donors when compared with the controls. There was also strong positive correlation between hemoglobin F level and age of the donors which was not the case with the controls. The results indicate that hemoglobin F level can be used as an indicator of the frequency and duration of blood donation. Though blood donation has some health benefits, the disadvantages of frequent donation outweigh these benefits and should be discouraged.