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Adeno-Associated Virus-Based Delivery Systems
Published in Kenneth L. Brigham, Gene Therapy for Diseases of the Lung, 2020
Successful gene transfer with integration and regulated gene expression in hematopoietic lines has been reported. Samulski and co-workers (149) used a recombinant AAV vector containing a marked human γ globin gene and DNAse I hypersensitivity sites from the locus control region (LCR) of the β-globin gene cluster to transduce K562 erythroleukemia cells. High-level, hemin-inducible expression of the marked γ-globin gene was detectable in clonal populations. This same gene was regulatable in BFU-E grown from CD34+ human cells (150). About 20% to 40% of BFU-E carried levels at 4% to 71% of endogenous γ-globin mRNA. When pooled BFU-E from the peripheral blood of a patient with sickle cell anemia was used, the hemoglobin F as measured with HPLC increased from 26% to 40%. AAV has been used to transfer the NeoR gene to T and B lymphocyte clones (151). Transduction with antisense for the HIV LTR in an HIV-infected cell line inhibited HIV production and replication (152). Suppression of human α globin gene mRNA by 91% in K562 which express high levels in culture was achieved using the α globin promoter driving the antisense sequence (153).
Hematopoiesis and Storage Iron in Infants
Published in Bo Lönnerdal, Iron Metabolism in Infants, 2020
Several developmental changes occur in the erythropoiesis of the fetus. The site of red blood cell production is primarily in liver tissues by 3 months of gestation age. The bone marrow takes over gradually, starting around 5 months of gestation age (Figure 1). Usually by term of pregnancy, the bone marrow is almost exclusively responsible for erythropoiesis. In preterm newborns, the liver plays a role in red blood cell production even at birth. There are also other developmental changes that occur simultaneously. The size of the red cell gradually becomes smaller during fetal life so that the red cell mean corpuscular volume (MCV) tends to be larger in premature than in full-term newborns. The concentration of hemoglobin seems to rise in the fetus during pregnancy although the details of this development are not well known. Finally, the specific fetal hemoglobin-F is partially replaced by adult hemoglobin-A by term of pregnancy. Thus, premature infants have proportionally more hemoglobin-F than full-term newborns.
Diamond-Blackfan Anemia
Published in Stephen A. Feig, Melvin H. Freedman, Clinical Disorders and Experimental Models of Erythropoietic Failure, 2019
Jeffrey M. Lipton, Blanche P. Alter
Fetal hemoglobin is usually increased and is distributed heterogenously (Figure 3), which indicates that the patients do not have a single clone of completely fetal cells. The hemoglobin F has a fetal composition, with the ratio of Gγ to Aγ exceeding 60:40. The titer of red blood cell (RBC) membrane i antigen is also increased, as in fetuses, whereas the adult counterpart, I antigen, remains at adult levels. These “fetal-like” erythrocyte features and fetal glycolytic and hexose monophosphate (HMP) shunt enzyme activities are seen in newly diagnosed patients and after treatment and persist even in spontaneous remissions. They are not unique to DBA but are characteristic of the “stress erythropoiesis” seen in bone marrow failure.88,89
Prevalence and Risk Factors for Pulmonary Embolism in Pediatric Sickle Cell Disease: A National Administrative Database Study
Published in Pediatric Hematology and Oncology, 2023
Natasha Bala, Joseph Stanek, Vilmarie Rodriguez, Anthony Villella
The incidence of PE in the general pediatric population shows a typical bimodal distribution with peak incidence in infancy and adolescents.15,16 In our study, PE was more common in older children with a median age of 17.4 years (interquartile range of 6.6 to 20.9 years) (Table 1 and Figure 1). This is in alignment with the proportionate increase in SCD-related morbidity and end organ damage due to cumulative effect of chronic vasculopathy as age advances in patients with SCD. Moreover, neonates in the general pediatric population, who developed thromboembolism have underlying risk factors such as congenital heart disease, surgery, infection, dehydration, immobility or presence of a central venous line. In contrast, neonates and infants with sickle cell disease are less likely to have these thrombosis risk factors as well as risk factors commonly associated with sickle cell disease (eg, central venous lines, apheresis, recurrent ACS) due to the protective effects of high hemoglobin F in infancy. This can explain the lack of the bimodal distribution and the higher PE prevalence observed in the adolescent and young adults in our study. The presence of a CVL was significantly associated with PE risk in our study, similarly as is in the general pediatric population,16 and in previous reports of VTE in patients with SCD.3,4,17
Acute myeloid leukemia in a child with familial platelet disorder and a cryptic runx1 intragenic deletion
Published in Pediatric Hematology and Oncology, 2022
Lois M. Dodson, Kristen J. Kurtz, Andrea N. Marcogliese, Brian D. Friend, Alexandra M. Stevens, Kevin E. Fisher
A six-year-old female first presented to hematology clinic for thrombocytopenia and leukocytosis with platelets of 53 000 and white blood cell count (WBC) of 38 000. She had a history of progressive bruising with a platelet count of 100 000 noted one year prior. Family history was notable for multiple first- and second-degree relatives with acute leukemias (Figure 1A). She then developed SARS-CoV-2 pneumonia, an acute drop in platelet count (9000), and was hospitalized. She was noted to have leukocytosis (78 760/µl) with significant monocytosis [31 500/µl (40%)], basophilia [1340/µl (1.7%)] and rare circulating blasts with left shift. She had a mild normocytic anemia with hemoglobin 9.2 g/dL and inappropriately normal reticulocyte count (57 000/µl). Uric acid and lactate dehydrogenase were normal. Hemoglobin F (HbF) was elevated to 38.2%. No hepatosplenomegaly was noted on physical exam. Once the pneumonia improved, hematological abnormalities persisted (Figure 1B).
Outcomes of a preoperative risk-based transfusion assignment protocol in sickle cell disease patients: a single-center retrospective study from Saudi Arabia
Published in Pediatric Hematology and Oncology, 2020
Naif Albolowi, Omima Mustafa, Mohammed Almohammadi, Mohammed Yasir Al-Hindi, Wasil Jastaniah
Finally, the high baseline hemoglobin F level in our patient population may in part explain the lower complication rate. In fact, both our study and an earlier study from Saudi Arabia showed low postoperative complication rates compared to those reported by other groups.12 Overall postoperative complications reported in the TAPS study occurred in 18 (26.9%) of 67 patients.11 The median hemoglobin F level was 7.5% in their study while among our population it was 18.4%.11 The TAPS study results were in favor of preoperative transfusion in case of low and medium risk surgeries.11 These findings suggest that preoperative transfusion practice in patients with high baseline hemoglobin F phenotype need to be studied further in larger population of patients as perioperative complication rate may be different in this phenotype. Another observation in comparing the two study populations is the high baseline hemoglobin level in the no-transfusion group in our study 8.9 g/dl compared to 7.7 g/dl in the TAPS study.11 It is not clear if this finding contributed to the outcome differences. The potential protective effect of hemoglobin F may be attributed to its retarding effect on the polymerization of the deoxy sickle hemoglobin that drives the pathophysiology of SCD.29,30 Hemoglobin F, therefore, reduces cell damage evoked by hemoglobin S polymer.30