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Frederic Galacteros - One of the best experts on this subject based on the ideXlab platform.
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allosteric control of Hemoglobin s fiber formation by oxygen and its relation to the pathophysiology of sickle cell disease
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Eric R Henry, James Hofrichter, Troy Cellmer, Emily B Dunkelberger, Belhu B Metaferia, David Ostrowski, Rodolfo Ghirlando, John M Louis, Stephane Moutereau, Frederic GalacterosAbstract:The pathology of sickle cell disease is caused by polymerization of the Abnormal Hemoglobin S upon deoxygenation in the tissues to form fibers in red cells, causing them to deform and occlude the circulation. Drugs that allosterically shift the quaternary equilibrium from the polymerizing T quaternary structure to the nonpolymerizing R quaternary structure are now being developed. Here we update our understanding on the allosteric control of fiber formation at equilibrium by showing how the simplest extension of the classic quaternary two-state allosteric model of Monod, Wyman, and Changeux to include tertiary conformational changes provides a better quantitative description. We also show that if fiber formation is at equilibrium in vivo, the vast majority of cells in most tissues would contain fibers, indicating that it is unlikely that the disease would be survivable once the nonpolymerizing fetal Hemoglobin has been replaced by adult Hemoglobin S at about 1 y after birth. Calculations of sickling times, based on a recently discovered universal relation between the delay time prior to fiber formation and supersaturation, show that in vivo fiber formation is very far from equilibrium. Our analysis indicates that patients survive because the delay period allows the majority of cells to escape the small vessels of the tissues before fibers form. The enormous sensitivity of the duration of the delay period to intracellular Hemoglobin composition also explains why sickle trait, the heterozygous condition, and the compound heterozygous condition of Hemoglobin S with pancellular hereditary persistence of fetal Hemoglobin are both relatively benign conditions.
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Abnormal Hemoglobins with high oxygen affinity and erythrocytosis
Hematology and Cell Therapy, 1996Co-Authors: Henri Wajcman, Frederic GalacterosAbstract:More than 200 Hemoglobin variants with high oxygen affinity have been reported since 1966. In about one third of these, the increase in oxygen affinity is responsible for a compensatory erythrocytosis. The degree of erythrocytosis depends primarly upon the molecular defect of the Hemoglobin molecule. Measurement of the oxygen binding properties of the blood (or of the stripped lysate) is a convenient test both for the diagnosis of these variants and for evaluation of their severity. In the severe cases the affinity of the Abnormal Hemoglobin is identical to that of isolated subunits and the heme heme interaction is abolished; erythrocythemia is usually observed. Conversely, when the increase in oxygen affinity is moderate no clinical Abnormal features are noticed. A high oxygen affinity variant has to be suspected when the Hemoglobin level is at the upper limits of the normal in females or individuals with a mild iron deficiency. Several high oxygen affinity Hemoglobins are also unstable and a hemolytic process may mask the increase of the Hb level. These patients, despite Hb levels close to the normal, are anemic from a functional view point. Examples have been reported in the literature in which the high oxygen affinity Hemoglobin was found in coincidence with another red cell Abnormality: such a situation leads usually to a more severe syndrome than the simple heterozygous state.
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unstable alpha chain Hemoglobin variants with factitious beta thalassemia biosynthetic ratio hb questembert α131 h14 ser pro and hb caen α132 h15 val gly
American Journal of Hematology, 1993Co-Authors: Henri Wajcman, Corinne Vasseur, Y Blouquit, J Rosa, Dominique Labie, A Najman, O Reman, M Leporrier, Frederic GalacterosAbstract:: Hb Questembert [alpha 131(H14)Ser-->Pro] was found in several members of a French family suffering from congenital Heinz body anemia. The unstable Hemoglobin was expressed in the peripheral red blood cells at a very low level. Globin biosynthetic studies revealed a high specific activity of the Abnormal chain and an alpha-/beta-labeling ratio similar to that of beta-thalassemia trait. Hb Caen [alpha 132(H15) Val-->Gly] is another unstable variant with the same globin biosynthesis Abnormality. In both cases the structural modification is localized at the end of the H helix, a region encoded by the third exon. The mechanism for the unbalanced globin synthesis is not yet clear. It may be related 1) to a defect in chain assembly, 2) to an increased rate of degradation of the variant chain followed by the release of unlabeled beta-chains from the Abnormal Hemoglobin, thus leading to an apparent suppression of beta-chain synthesis, or 3) to a modified stability of the Abnormal alpha-globin mRNA.
Henri Wajcman - One of the best experts on this subject based on the ideXlab platform.
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the first case of hb groene hart α119 h2 pro ser cct tct α1 homozygosity confirms that a thalassemia phenotype is associated with this Abnormal Hemoglobin variant
Hemoglobin, 2007Co-Authors: Piero C Giordano, Henri Wajcman, Florens G A Versteegh, Peter Van Delft, Sonja Zweegman, Nicole Akkermans, Sandra G J Arkesteijn, Cornelis L HarteveldAbstract:Hb Groene Hart [α119(H2)Pro→Ser, CCT→TCT (α1)] has been reported in heterozygotes of Moroccan origin and also in association with the common −α3.7 deletion. In all cases, the mutated protein was not detectable but was apparently associated with a mild α-thalassemia (thal) phenotype, presumably due to a modification of the α-globin chain domain that is recognized by the a Hemoglobin stabilizing protein (AHSP). The present case of Hb Groene Hart homozygosity, confirms that the α-thal phenotype is associated with this α-globin chain. Hb Groene Hart must be quite frequent not only in Morocco but probably also among the northern African coastal population.
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Abnormal Hemoglobins with high oxygen affinity and erythrocytosis
Hematology and Cell Therapy, 1996Co-Authors: Henri Wajcman, Frederic GalacterosAbstract:More than 200 Hemoglobin variants with high oxygen affinity have been reported since 1966. In about one third of these, the increase in oxygen affinity is responsible for a compensatory erythrocytosis. The degree of erythrocytosis depends primarly upon the molecular defect of the Hemoglobin molecule. Measurement of the oxygen binding properties of the blood (or of the stripped lysate) is a convenient test both for the diagnosis of these variants and for evaluation of their severity. In the severe cases the affinity of the Abnormal Hemoglobin is identical to that of isolated subunits and the heme heme interaction is abolished; erythrocythemia is usually observed. Conversely, when the increase in oxygen affinity is moderate no clinical Abnormal features are noticed. A high oxygen affinity variant has to be suspected when the Hemoglobin level is at the upper limits of the normal in females or individuals with a mild iron deficiency. Several high oxygen affinity Hemoglobins are also unstable and a hemolytic process may mask the increase of the Hb level. These patients, despite Hb levels close to the normal, are anemic from a functional view point. Examples have been reported in the literature in which the high oxygen affinity Hemoglobin was found in coincidence with another red cell Abnormality: such a situation leads usually to a more severe syndrome than the simple heterozygous state.
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Abnormal Hemoglobins with high oxygen affinity and erythrocytosis
Hematology and Cell Therapy, 1996Co-Authors: Henri Wajcman, F GalacterosAbstract:More than 200 Hemoglobin variants with high oxygen affinity have been reported since 1966. In about one third of these, the increase in oxygen affinity is responsible for a compensatory erythrocytosis. The degree of erythrocytosis depends primarly upon the molecular defect of the Hemoglobin molecule. Measurement of the oxygen binding properties of the blood (or of the stripped lysate) is a convenient test both for the diagnosis of these variants and for evaluation of their severity. In the severe cases the affinity of the Abnormal Hemoglobin is identical to that of isolated subunits and the heme heme interaction is abolished; erythrocythemia is usually observed. Conversely, when the increase in oxygen affinity is moderate no clinical Abnormal features are noticed. A high oxygen affinity variant has to be suspected when the Hemoglobin level is at the upper limits of the normal in females or individuals with a mild iron deficiency. Several high oxygen affinity Hemoglobins are also unstable and a hemolytic process may mask the increase of the Hb level. These patients, despite Hb levels close to the normal, are anemic from a functional view point. Examples have been reported in the literature in which the high oxygen affinity Hemoglobin was found in coincidence with another red cell Abnormality: such a situation leads usually to a more severe syndrome than the simple heterozygous state.
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unstable alpha chain Hemoglobin variants with factitious beta thalassemia biosynthetic ratio hb questembert α131 h14 ser pro and hb caen α132 h15 val gly
American Journal of Hematology, 1993Co-Authors: Henri Wajcman, Corinne Vasseur, Y Blouquit, J Rosa, Dominique Labie, A Najman, O Reman, M Leporrier, Frederic GalacterosAbstract:: Hb Questembert [alpha 131(H14)Ser-->Pro] was found in several members of a French family suffering from congenital Heinz body anemia. The unstable Hemoglobin was expressed in the peripheral red blood cells at a very low level. Globin biosynthetic studies revealed a high specific activity of the Abnormal chain and an alpha-/beta-labeling ratio similar to that of beta-thalassemia trait. Hb Caen [alpha 132(H15) Val-->Gly] is another unstable variant with the same globin biosynthesis Abnormality. In both cases the structural modification is localized at the end of the H helix, a region encoded by the third exon. The mechanism for the unbalanced globin synthesis is not yet clear. It may be related 1) to a defect in chain assembly, 2) to an increased rate of degradation of the variant chain followed by the release of unlabeled beta-chains from the Abnormal Hemoglobin, thus leading to an apparent suppression of beta-chain synthesis, or 3) to a modified stability of the Abnormal alpha-globin mRNA.
F Galacteros - One of the best experts on this subject based on the ideXlab platform.
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Abnormal Hemoglobins with high oxygen affinity and erythrocytosis
Hematology and Cell Therapy, 1996Co-Authors: Henri Wajcman, F GalacterosAbstract:More than 200 Hemoglobin variants with high oxygen affinity have been reported since 1966. In about one third of these, the increase in oxygen affinity is responsible for a compensatory erythrocytosis. The degree of erythrocytosis depends primarly upon the molecular defect of the Hemoglobin molecule. Measurement of the oxygen binding properties of the blood (or of the stripped lysate) is a convenient test both for the diagnosis of these variants and for evaluation of their severity. In the severe cases the affinity of the Abnormal Hemoglobin is identical to that of isolated subunits and the heme heme interaction is abolished; erythrocythemia is usually observed. Conversely, when the increase in oxygen affinity is moderate no clinical Abnormal features are noticed. A high oxygen affinity variant has to be suspected when the Hemoglobin level is at the upper limits of the normal in females or individuals with a mild iron deficiency. Several high oxygen affinity Hemoglobins are also unstable and a hemolytic process may mask the increase of the Hb level. These patients, despite Hb levels close to the normal, are anemic from a functional view point. Examples have been reported in the literature in which the high oxygen affinity Hemoglobin was found in coincidence with another red cell Abnormality: such a situation leads usually to a more severe syndrome than the simple heterozygous state.
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increased in vivo production of thromboxane in patients with sickle cell disease is accompanied by an impairment of platelet functions to the thromboxane a2 agonist u46619
Arteriosclerosis Thrombosis and Vascular Biology, 1993Co-Authors: I Foulon, D Bachir, F Galacteros, Jacques MacloufAbstract:Thrombosis represents an important cause of mortality in patients with sickle cell disease, in addition to the complications caused by the primary defect of inherited Abnormal Hemoglobin. To study the involvement of platelets in these complications, we assessed the biosynthesis of thromboxane A2 in samples from 49 patients with sickle cell disease and in 33 control subjects. The urinary excretion of the major arachidonic acid metabolite of platelet origin (11-dehydro-thromboxane B2) and of the vascular endothelial cell (2,3-dinor-6-ketoprostaglandin F1 alpha) were very significantly increased (p < 0.0002) in the patients. In a small group of patients (n = 14), we further investigated the ex vivo response of their platelets to U46619, a stable analogue of thromboxane A2. We observed decreased aggregation and [14C]serotonin release compared with control (p < 0.05); similarly, we found impaired p47 protein phosphorylation (p < 0.05). In contrast, platelets from these patients responded normally to thrombin (0.1 unit/mL). In vivo desensitization of platelets from these patients to thromboxane may constitute a form of regulation that may prevent the propagation of aggregation by this potent inducer, as has been hypothesized in in vitro studies. Our results may also provide a rationale for using antiplatelet drugs in the prophylaxis of thrombotic complications in sickle cell patients.
Pranee Winichagoon - One of the best experts on this subject based on the ideXlab platform.
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Thalassemia and Abnormal Hemoglobin.
International Journal of Hematology, 2002Co-Authors: Suthat Fucharoen, Pranee WinichagoonAbstract:Thalassemia and Abnormal Hemoglobins are common genetic disorders in Asia. Thalassemia is not only an important public health problem but also a socio-economic problem of many countries in the region. The approach to deal with the thalassemic problem is to prevent and control birth of new cases. This requires an accurate identification of the couple at high risk for thalassemia. However, the diagnosis of thalassemia carrier states need several tests which are not practical for screening the population at large. Recently we have used two simple laboratory tests to screen for potential thalassemia carriers and Hemoglobin E individuals. There is also a new development in using the automatic HPLC to diagnose thalassemic diseases and the carriers. This system gives both qualitative and quantitative analysis of Hemoglobin components in the same run with good precision and reproducibility. The system has been applied to study thalassemia and Abnormal Hb in adult and cord blood. This system has enabled us to do both prenatal and postnatal diagnosis of thalassemia within the few minutes. However, none of these screening tests can accurately give specific diagnosis of the thalassemia genotype. Specific thalassemia mutation can be carried out by DNA analysis. Many DNA techniques have been used for point mutation detection and small deletion. For the last few years there is a development of DNA chip technology that has been applied for thalassemia mutation as well. Clinically, thalassemia is very heterogeneous in the manifestation. In spite of seemingly identical genotypes, severity of.beta thalassemic patients can vary greatly. Heterogeneity in the clinical manifestation of beta thalassemic diseases may occur from the nature of beta globin gene mutation, alpha thalassemia gene interaction and difference in the amount of Hb F production which is partly associated with a specific beta globin haplotype. However, there is still some beta thalassemia cases that have a mild clinical symptom without those known genetic fators interaction suggesting that there are other additional factors responsible for the mildness of the disease.
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standardization on laboratory diagnosis of thalassemia and Abnormal Hemoglobin
Southeast Asian Journal of Tropical Medicine and Public Health, 1999Co-Authors: Supan Fucharoen, Pranee Winichagoon, A PiankijagumAbstract:Abstract Thalassemia is one of the most common single gene disorders. The geographic distribution of thalassemia and Abnormal Hemoglobin has been known for many years. A worldwide significant spread of these Abnormal genes, especially from Southeast Asia, occurred in the last two decades. This has resulted in a dramatic increase of Hb E disorders and various Southeast Asian thalassemia genotypes, which means that requests for Hemoglobinopathy investigations are likely to increase in many laboratories worldwide. Hemoglobinopathy screening and diagnosis may need to be undertaken antenatally, neonatally and in certain hematological situations. The introduction of automation for Hemoglobinopathy screening, including the automated cell counting and HPLC system, is an important advance in technology for hematology laboratories. The instruments need to be calibrated and standardized to get an accurate data for interpretation. Internal and external control samples are also needed. Combination of test results is usually required to achieve a proper diagnosis, which in turn, provide a self-check for each laboratory test.
Shigeru Okadaa - One of the best experts on this subject based on the ideXlab platform.
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high incidence of α thalassemia Hemoglobin e and glucose 6 phosphate dehydrogenase deficiency in populations of malaria endemic southern shan state myanmar
International Journal of Hematology, 2005Co-Authors: Aung Myint Than, Teruo Harano, K Harano, Aye Aye Myint, Tetsuya Ogino, Shigeru OkadaaAbstract:Samples from 916 members of various ethnic groups from malaria-endemic southern Shan State, Myanmar, were analyzed for α-thalassemia (α-thal), β -thalassemia (β -thal), Abnormal Hemoglobin variants, and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Of these subjects, 530 (57.9%) were found to have at least one of these red cell genetic disorders.The overall frequencies for the various red cell genetic disorders were as follows: α-thal, 37.5% (343/916); Hemoglobin E (Hb-E), 20.3% (186/916); G6PD-Mahidol, 17.5% (160/916); and β-thal, 0.3% (3/916). The frequencies of combined disorders were 6.9% (63/ 916) for α-thal/Hb-E, 5.7% (52/916) for α-thal/G6PD-Mahidol, 2.8% (26/916) for Hb-E/G6PD-Mahidol, 1.1% (10/916) for α-thal/Hb-E/G6PD-Mahidol, and 0.1% (1/916) for α-thal/β-thal/G6PD-Mahidol. Of the various ethnic and non-ethnic groups, the Bamar population showed the highest frequencies of α-thal (56.9%, 177/311), Hb-E (28.3%, 88/311), and G6PD-Mahidol (21.2%, 66/311) (all duplicated and triplicated cases were included). In addition, 2 new mutations, an a gene triplication (/αααanti3.7; 0.2%, 2/916) and Hb-Neapolis (0.1%, 1/916), were detected. Our results showed that race was the dominant factor affecting the frequencies of red cell genetic disorders in malaria-endemic areas of Myanmar.
