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E Rachmilewitz

Publications and source records attributed to E Rachmilewitz.

At least 19 recordsLinked to original sources
PubMed2001

Pathophysiology of alpha- and beta-thalassemia: therapeutic implications.

At the molecular level, the underlying cause of thalassemia is any of a number of genetic lesions that reduce or abolish the production of the globin chains of hemoglobin. The resulting chain imbalance is the key factor initiating the damage to the red blood cell (RBC) and it is the major pathophysiological event in all forms of the thalassemia syndromes. In this review we will outline some of the cellular and systemic processes that have been implicated in the development of the disease. When relevant, we will discuss the ways in which these processes can be altered in a therapeutic manner.

Erythrocyte Membrane↗
PubMed2000

New trends in the treatment of beta-thalassemia.

Thalassemia is the world's most common hereditary disease, and is a paradigm of monogenic genetic diseases. Because of increased population mobility, the disease is found today throughout the world, even in places far from the tropical areas in which it arose. Therapy of thalassemia has in the past been confined to transfusion and chelation. Recently, novel modes of therapy have been developed for thalassemia, based on the pathophysiology and molecular pathology of the disease, both of which have been extensively studied. This review will discuss the therapeutic modalities currently in use for the supportive treatment of thalassemia, both those that are standard therapy and those that are in clinical trials. We will include transfusion, chelation (intravenous and oral), antioxidants and various inducers of fetal hemoglobin (hydroxyurea, erythropoietin, butyrates, hemin). Most of the newer therapies are suitable primarily for thalassemia intermedia patients. In addition, the treatment modalities currently in use for the curative treatment of thalassemia major will be discussed, including bone marrow transplantation in its various forms. Experimental therapeutic methods, such as intrauterine bone marrow transplantation and gene therapy, are included. Physicians caring for thalassemia patients have an increasing variety of treatment options available. Future clinical studies will determine the place of newer agents and modalities in improving the quality of life as well as the life expectancy of thalassemia patients.

Humans↗
PubMed2000

Bone mineral metabolism in adults with beta-thalassaemia major and intermedia.

Bone disease is an important cause of morbidity in older patients with beta-thalassaemia major and intermedia. We studied 27 women and 23 men with beta-thalassaemia major (37) and intermedia (13) whose mean age was 32.3 +/- 9.7 years. Bone mineral density (BMD) of the lumbar spine, femoral neck and distal radius was determined by dual-energy X-ray absorbiometry (DXA). The longitudinal change in BMD over a mean of 5.6 years was determined in 19 patients. Serum 25-hydroxyvitamin D, insulin growth factor-1 (IGF-1), bone formation markers bone-alkaline phosphatase, osteocalcin and the resorption marker urinary N-telopeptide cross-linked type 1 collagen (NTx) were determined. The BsmI vitamin D receptor (VDR) gene polymorphism was analysed. Reduced BMD (Z-score < -2) was present in 89%, 62% and 73% of patients in the spine, hip and radius respectively. Vitamin D deficiency was found in 62%, decreased IGF-1 in 72% and increased urinary NTx in 84% of patients. Serum IGF-1 correlated with spine and hip BMD (r = 0.4, r = 0.39, P < 0.01 respectively), and NTx correlated with the hip BMD Z-score (r = 0.35 P < 0.05). The mean annual percentage change in spine BMD was -1.36%. Patients with the VDR BB genotype had lower spine BMD than patients with the bb genotype. In conclusion, bone loss continues in adult thalassaemia patients and is associated with increased bone resorption and decreased IGF-1. The BsmI VDR gene polymorphism is associated with osteopenia in thalassaemia.

25-Hydroxyvitamin D 2↗
PubMed1999

ABL1 methylation is a distinct molecular event associated with clonal evolution of chronic myeloid leukemia.

Methylation of the proximal promoter of the ABL1 oncogene is a common epigenetic alteration associated with clinical progression of chronic myeloid leukemia (CML). In this study we queried whether both the Ph'-associated and normal ABL1 alleles undergo methylation; what may be the proportion of hematopoietic progenitors bearing methylated ABL1 promoters in chronic versus acute phase disease; whether methylation affects the promoter uniformly or in patches with discrete clinical relevance; and, finally, whether methylation of ABL1 reflects a generalized process or is gene-specific. To address these issues, we adapted the techniques of methylation-specific PCR and bisulfite-sequencing to study the regulatory regions of ABL1 and other genes with a role in DNA repair or genotoxic stress response. In cell lines established from CML blast crisis, which only carry a single ABL1 allele nested within the BCR-ABL fusion gene, ABL1 promoters were universally methylated. By contrast, in clinical samples from patients at advanced stages of disease, both methylated and unmethylated promoter alleles were detectable. To distinguish between allele-specific methylation and a mixed cell population pattern, we studied the methylation status of ABL1 in colonies derived from single hematopoietic progenitors. Our results showed that both methylated and unmethylated promoter alleles coexisted in the same colony. Furthermore, ABL1 methylation was noted in the vast majority of colonies from blast crisis, but not chronic-phase CML. Both cell lines and clinical samples from acute-phase CML showed nearly uniform hypermethylation along the promoter region. Finally, we showed that ABL1 methylation does not reflect a generalized process and may be unique among DNA repair/genotoxic stress response genes. Our data suggest that specific methylation of the Ph'-associated ABL1 allele accompanies clonal evolution in CML.

Alleles↗
PubMed1998

Heme arginate therapy for beta thalassemia: in vitro versus in vivo effects.

Hemin has a profound effect on erythroid cell maturation and promotes fetal hemoglobin synthesis in vitro. In beta-thalassemia, increasing fetal hemoglobin levels can ameliorate the anemia. We administered heme arginate, a novel stable form of hemin, to 4 patients with thalassemia intermedia and studied the in vitro versus in vivo effects. In erythroid cultures, there was a marked rise in total hemoglobin and hemoglobin F. In vivo, 3 of 4 patients had a rise in hemoglobin levels (from 0.4 to 1.1 g%), which was statistically significant in 1 patient. There were no serious adverse effects. Heme arginate may be useful in the treatment of thalassemia intermedia.

Adult↗
PubMed1997

Genetic analysis of beta-thalassemia intermedia in Israel: diversity of mechanisms and unpredictability of phenotype.

Molecular analysis was performed on 95 Israeli patients with thalassemia intermedia, representing 60 families of Arab (Moslem and Christian), Jewish, Druze, and Samaritan origin. There was a wide range of phenotypic severity, with baseline hemoglobin levels ranging from 5.5 to 10.7. Eighteen thalassemia mutations were found (29 genotypes), which were subdivided into groups, according to the severity of mutations. A consistently mild phenotype (10 families) was caused by compound heterozygosity for a silent mutation, such as -101 C-T or by coexistence of triplicated alpha-globin genes with thalassemia trait. In 39 thalassemia intermedia families, the genotype which was found was one which led to severe thalassemia intermedia, or, in other families, was associated with thalassemia major. Elevated hemoglobin F ameliorated the disease in some patients with a severe genotype. We did not find a beneficial effect of concurrent alpha-thalassemia in any of the families studied. In 11 families, only one beta-thalassemia allele was identified. One was a dominant thalassemia intermedia allele. Three additional families with heterozygous beta-thalassemia had excess alpha-globin genes (5 or 6 total). In 7 of these heterozygotes, no explanation was found for the thalassemia intermedia phenotype. Our results suggest a substantial influence of as yet unknown genetic modifiers. These findings have important implications for prenatal diagnosis and for the genetic counseling of families with thalassemia intermedia.

Alleles↗
PubMed1996

Enhanced aggregability of red blood cells of beta-thalassemia major patients.

beta-Thalassemia major (TM), a congenital hemoglobinopathy, is associated with hemodynamic disorders and with structural red blood cell (RBC) anomalies that may indicate impairment of RBC rheological properties. To gain insight into the possible contribution of RBC to the hemodynamic disorders, we studied RBC aggregability, which plays a central role in blood flow, particularly in the microcirculation. RBC aggregate size distribution and morphology of TM RBC were determined using a novel system for image analysis of blood cells in a flow chamber. It was found that the aggregability of RBC of TM patients is markedly enhanced. These cells form large clusters, as opposed to normal rouleaux, and higher shear stress is required to disperse them. The aggregate size of TM RBC is reduced to the normal range after the patients have received a blood transfusion. This study suggests that the hemodynamic disorders observed in TM may be linked to the enhanced RBC aggregability and that improvement of RBC rheological properties may be considered in the treatment of thalassemia.

Adolescent↗
PubMed1995

Thalassemia major 1995: older patients, new therapies.

There have been many advances in supportive treatment used for beta-thalassemia major. Survival has increased substantially, and an increasing number of patients reach adolescence and adulthood. These older patients present new clinical challenges. Complications of transfusion, most commonly hepatitis C, are still a cause of mortality and morbidity. The achievement of optimal growth and development, including fertility, is an important goal of conservative management. Long-term survival has also been achieved with bone marrow transplantation. Assessment of growth, development and iron balance in the years after transplantation reveals residual problems requiring treatment despite cure of thalassemia. New therapies of beta-thalassemia are still being developed, both supportive and curative in nature. Supportive care improvements include oral chelation and methods to increase HbF production. Advances in curative modalities include use of new sources of stem cells, such as cord blood and fetal liver. In the future, gene therapy may allow for cure of the older patient without the mortality and morbidity of allogenic transplantation. Treatment of thalassemia major requires consideration of the available therapeutic options for each patient, and the risk/benefit ratio of a supportive versus curative approach.

Age Factors↗
PubMed1993

A chronic hypercoagulable state and life-long platelet activation in beta thalassemia major.

Increased frequency of thromboembolic events has been recently observed in patients with thalassemia major (TM), causing hypoxemia and cor pulmonale. Autopsy findings demonstrated "old" and recent pulmonary and renal infarcts as well as premature atherosclerosis. Studies to determine hypercoagulability showed: impaired platelet aggregation, increased circulating platelet aggregates, shortened platelet survival, enhanced excretion of urinary metabolites of thromboxane A2 (TXA2) and prostacyclin and decreased plasma levels of Protein C, Protein S or anti-thrombin III. Erythrocytes from TM patients enhanced thrombin formation in a "prothrombinase" assay (using a chromogenic substrate). Chronic anti-thrombotic therapy may be indicated in thalassemic patients to prevent the cardiac and pulmonary complications.

Blood Platelet Disorders↗
PubMed1992

Characterization and comparison of the red blood cell membrane damage in severe human alpha- and beta-thalassemia.

The aim of the present work was to understand the pathophysiology of the severe human thalassemias as represented by beta-thalassemia intermedia and hemoglobin (Hb) H (alpha-thalassemia) disease. We have previously shown that the material properties of the red blood cell (RBC) and its membrane differ in severe alpha- and beta-thalassemia, and we now show that this difference is probably caused by accumulation of alpha-globin chains at the cytoskeleton in beta-thalassemia, whereas beta-globin chains are associated with the cytoskeleton in alpha-thalassemia. In both alpha- and beta-thalassemia, some of these globin chains have become oxidized as evidenced by loss of the free thiols. Furthermore, there is similar evidence of oxidation of protein 4.1 in beta-thalassemia, whereas beta-spectrin appears to be subject to oxidation in alpha-thalassemia. These observations support the idea that the association of partly oxidized globin chains with the cytoskeleton results in oxidation of adjacent skeletal proteins. The abnormality of protein 4.1 in beta-thalassemia is consistent with a prior observation, and is also in accord with the known importance of protein 4.1 in maintenance of membrane stability, a property that is abnormal in beta-thalassemic membranes.

Blotting, Western↗
PubMed1991

Evolution of a genetic disease in an ethnic isolate: beta-thalassemia in the Jews of Kurdistan.

beta-Thalassemia is a hereditary disease caused by any of 90 different point mutations in the beta-globin gene. Specific populations generally carry a small number of mutations, the most common of which are those that are widely distributed regionally. The present study constitutes an extensive molecular characterization of this disease in a small, highly inbred ethnic group with a high incidence of beta-thalassemia--the Jews of Kurdistan. An unusual mutational diversity was observed. In 42 sibships 13 different mutations were identified, of which 3 are newly discovered: a C----A transversion at -88 to the cap site, a frameshift in codon 36/37, and an A----G transition in the polyadenylylation signal. Four of the mutations are unique to Kurdish Jews and have not been discovered in any other population. A fifth was found outside Kurdish Jews only in an Iranian from Khuzistan, a region bordering Kurdistan. Two-thirds of the mutant chromosomes carry the mutations unique to Kurdish Jews. We traced the origin of the mutations to specific geographic regions within Kurdistan. This information, supported by haplotype analysis, suggests that thalassemia in central Kurdistan (northern Iraq) has evolved primarily from multiple mutational events. In Turkish Kurdistan, the primary mechanism is genetic admixture with the local population. In Iranian Kurdistan, a founder effect appears to be partly responsible. We conclude that several evolutionary mechanisms contributed to the evolution of beta-thalassemia in this small ethnic isolate.

Base Sequence↗
PubMed1989

Cellular and membrane properties of alpha and beta thalassemic erythrocytes are different: implication for differences in clinical manifestations.

To define how excess unpaired alpha- and beta-globin chains in severe beta-thalassemia and severe alpha-thalassemia interacting with the membrane might alter cellular and membrane properties, we performed a series of biophysical and biochemical analyses on erythrocytes obtained from affected patients. Detailed analysis of cellular and membrane deformability characteristics showed that both forms of thalassemic erythrocytes have excess surface area in relation to cell volume and increased membrane dynamic rigidity. The deformability characteristics of thalassemic erythrocytes in hypertonic media differed significantly from that of normal erythrocytes of identical cell density. These findings suggest that dynamic rigidity of thalassemic erythrocytes is influenced not only by cytoplasmic viscosity determined by cell hemoglobin concentration but also by the extent and type of globin interacting with the membrane. In contrast to the above-noted similarities, major differences were noted in the mechanical stability of the alpha- and beta-thalassemic membranes and in their state of cell hydration. While the mechanical stability of alpha-thalassemic membranes was normal or marginally elevated, the stability of beta-thalassemic membranes was markedly decreased to half the normal value. Cell-density analysis showed that the alpha-thalassemic erythrocytes were uniformly less dense than normal, while beta-thalassemic erythrocytes had a broad-density distribution, with all populations having both lower and higher than normal density values, implying cellular dehydration in beta-thalassemia and not in alpha-thalassemia. Membrane-protein analysis revealed that excess globin chains were bound to the membrane skeletons of both alpha- and beta-thalassemic erythrocytes, with the highest amounts being found in membrane skeletons derived from erythrocytes of splenectomized individuals with beta-thalassemia intermedia. These data demonstrate that interaction of excess alpha- and beta-globin chains with membranes produces different cellular changes and suggest that the observed differences in the pathophysiology of alpha- and beta-thalassemias may be related to different cellular effects induced by the excess in beta- and alpha-globin chains.

Anion Exchange Protein 1, Erythrocyte↗