Materiały źródłowe

• #1 Thalassemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK545151/

  Thalassemia is a heterogeneous group of blood disorders affecting the hemoglobin genes and resulting in ineffective erythropoiesis. […] Thalassemias are a heterogeneous grouping of genetic disorders that result from a decreased synthesis of alpha or beta chains of hemoglobin (Hb). […] It is caused by either a genetic mutation or a deletion of certain key gene fragments. […] Alpha thalassemia is caused by alpha-globin gene deletion which results in reduced or absent production of alpha-globin chains. […] Beta thalassemia results from point mutations in the beta-globin gene. […] The excess unpaired alpha-globin chains in beta-thalassemia aggregate and form precipitates that damage red cell membranes and result in intravascular hemolysis. […] Coinheritance of alpha thalassemia: Beta-thalassemia patients with coinheritance of alpha thalassemia have a milder clinical course due to a less severe alpha-beta chain imbalance.

• #2 Beta Thalassemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK531481/

  Thalassemias are a common cause of microcytic anemia and are due to impaired synthesis of the globin protein component of hemoglobin. […] Beta-thalassemia refers to an inherited mutation of the beta-globin gene, causing a reduced beta-globin chain of hemoglobin. […] The pathogenesis of beta-thalassemia is two-fold. First, there is decreased hemoglobin synthesis causing anemia and an increase in HbF and HbA2 as there are decreased beta chains for HbA formation. Second, and of most pathologic significance in beta-thalassemia major and intermedia, the relative excess alpha chains form insoluble alpha chain inclusions that cause marked intramedullary hemolysis. This ineffective erythropoiesis leads to severe anemia and erythroid hyperplasia with bone marrow expansion and extramedullary hematopoiesis.

• #3 Thalassemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK545151/

  Thalassemia is autosomal recessive, which means both the parents must be affected with or carriers for the disease to transfer it to the next generation. […] It is caused by mutations or deletions of the Hb genes, resulting in underproduction or absence of alpha or beta chains. […] There are over 200 mutations identified as the culprits for causing thalassemias. […] Alpha thalassemia is caused by deletions of alpha-globin genes, and beta thalassemias are caused by a point mutation in splice site and promoter regions of the beta-globin gene on chromosome 11. […] Thalassemia treatment depends on the type and severity of the disease. […] Gene therapy: It is the latest advancement in severe thalassemia management. […] These techniques target specific mutation sites and replace them with the normal sequence.

• #4 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Thalassemia-Pathophysiology.aspx

  The DNA mutations related to thalassemia are inherited from parents with the condition, which follows an autosomal recessive pattern. If both parents possess one gene mutation, any children will have a 25% chance of inheriting a gene mutation, regardless of whether the parents are symptomatic. If one or both parents possess multiple gene mutations, the risk of gene inheritance increases, and the child is more likely to experience symptoms.

• #5 Genetics of Thalassemia | IntechOpen

  https://www.intechopen.com/chapters/84254

  -Thalassemia is a common genetic disorder caused by mutations in -globin gene that results in reduced -globin production. […] More than 400 different types of deletional and non deletional types of mutations in – or -globin genes have been reported till date with diverse clinical manifestations, ranging from asymptomatic to fatal anemia. […] -Thalassemia (complete absence of hemoglobin subunit beta) alleles result from nonsense, frameshift, or splicing mutations. […] +-Thalassemia alleles are produced by pathogenic variants in the promoter area (either the CACCC or the TATA box), the polyadenylation signal, or the 5 or 3 untranslated region, or by splicing abnormalities. […] The complex -thalassemia (delta-beta- and gamma-delta-beta-thalassemia) results from deletion of variable part of HBB gene cluster.

• #6 Beta thalassemia – Wikipedia

  https://en.wikipedia.org/wiki/Beta_thalassemia

  More than 350 mutations have been identified which can cause beta thalassemia; 20 of these account for 80% of beta-thalassemia cases. […] Two major groups of mutations can be distinguished: Nondeletion forms and Deletion forms. […] Due to globin defects, beta thalassemia patients do not have normal levels of adult hemoglobin (HbA), and instead have elevated levels of HbA2.

• #7 Thalassemia: Types, Traits, Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/14508-thalassemias

  Thalassemia is an inherited blood disorder that affects your bodys ability to produce hemoglobin and healthy red blood cells. […] If you have thalassemia, your body produces fewer healthy hemoglobin proteins, and your bone marrow produces fewer healthy red blood cells. […] Hemoglobin consists of four protein chains, two alpha globin chains and two beta globin chains. Each chain both alpha and beta contains genetic information, or genes, passed down from your parents. […] The thalassemia you have depends on whether your alpha or beta chain contains the genetic defect. The extent of the defect will determine how severe your condition is. […] Thalassemia is classified as trait, minor, intermedia and major to describe how severe the condition is. […] You inherit four genes, two from each parent, that make alpha globin protein chains. When one or more genes are defective, you develop alpha thalassemia.

• #8 Alpha thalassemia: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/alpha-thalassemia/

  Alpha thalassemia typically results from deletions involving the HBA1 and HBA2 genes. […] Such changes are often referred to as nondeletion variants. […] Both the HBA1 and HBA2 genes provide instructions for making a protein called alpha-globin, which is a component (subunit) of hemoglobin. […] Deletions and nondeletion variants in one or more alleles reduce the amount of alpha-globin cells produce. Nondeletion variants tend to reduce alpha-globin more than deletions. […] Hb Bart syndrome, the most severe form of alpha thalassemia, results from the loss or alteration of all four alpha-globin alleles. Such changes prevent the production of any normal alpha-globin. […] HbH disease is usually caused by loss or alteration of three of the four alpha-globin alleles, which sharply reduces the amount of normal alpha-globin produced.

• #9 Thalassemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK545151/

  Thalassemia is a heterogeneous group of blood disorders affecting the hemoglobin genes and resulting in ineffective erythropoiesis. […] Thalassemias are a heterogeneous grouping of genetic disorders that result from a decreased synthesis of alpha or beta chains of hemoglobin (Hb). […] It is caused by either a genetic mutation or a deletion of certain key gene fragments. […] Alpha thalassemia is caused by alpha-globin gene deletion which results in reduced or absent production of alpha-globin chains. […] Beta thalassemia results from point mutations in the beta-globin gene. […] The excess unpaired alpha-globin chains in beta-thalassemia aggregate and form precipitates that damage red cell membranes and result in intravascular hemolysis. […] Coinheritance of alpha thalassemia: Beta-thalassemia patients with coinheritance of alpha thalassemia have a milder clinical course due to a less severe alpha-beta chain imbalance.

• #10 Genetics of Thalassemia | IntechOpen

  https://www.intechopen.com/chapters/84254

  -Thalassemia is a common genetic disorder caused by mutations in -globin gene that results in reduced -globin production. […] More than 400 different types of deletional and non deletional types of mutations in – or -globin genes have been reported till date with diverse clinical manifestations, ranging from asymptomatic to fatal anemia. […] -Thalassemia (complete absence of hemoglobin subunit beta) alleles result from nonsense, frameshift, or splicing mutations. […] +-Thalassemia alleles are produced by pathogenic variants in the promoter area (either the CACCC or the TATA box), the polyadenylation signal, or the 5 or 3 untranslated region, or by splicing abnormalities. […] The complex -thalassemia (delta-beta- and gamma-delta-beta-thalassemia) results from deletion of variable part of HBB gene cluster.

• #11 Genetics of Thalassemia | IntechOpen

  https://www.intechopen.com/chapters/84254

  -Thalassemia also caused by deletion of the LCR regions of HBBgene. […] Alpha and beta thalassemia have been found to arise from mutations that alter known promoter or enhancer sequences for alpha or beta globin genes. […] Many mutations have been described that disrupt normal splicing of the mRNA precursor. […] Some thalassemic splicing mutations directly disrupt the canonical splicing signals used to mark the beginning and end of each intron so that normal splicing can occur. […] Mutations that create a premature translation termination codon (nonsense codon) account for the most common forms of thalassemia, in terms of numbers of patients affected. […] The physiologic consequences of translation termination are very clear; functional globin not synthesized and thalassemia results.

• #12 Genetics of Thalassemia | IntechOpen

  https://www.intechopen.com/chapters/84254

  -Thalassemia also caused by deletion of the LCR regions of HBBgene. […] Alpha and beta thalassemia have been found to arise from mutations that alter known promoter or enhancer sequences for alpha or beta globin genes. […] Many mutations have been described that disrupt normal splicing of the mRNA precursor. […] Some thalassemic splicing mutations directly disrupt the canonical splicing signals used to mark the beginning and end of each intron so that normal splicing can occur. […] Mutations that create a premature translation termination codon (nonsense codon) account for the most common forms of thalassemia, in terms of numbers of patients affected. […] The physiologic consequences of translation termination are very clear; functional globin not synthesized and thalassemia results.

• #13 Alpha thalassemia: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/alpha-thalassemia/

  Alpha thalassemia typically results from deletions involving the HBA1 and HBA2 genes. […] Such changes are often referred to as nondeletion variants. […] Both the HBA1 and HBA2 genes provide instructions for making a protein called alpha-globin, which is a component (subunit) of hemoglobin. […] Deletions and nondeletion variants in one or more alleles reduce the amount of alpha-globin cells produce. Nondeletion variants tend to reduce alpha-globin more than deletions. […] Hb Bart syndrome, the most severe form of alpha thalassemia, results from the loss or alteration of all four alpha-globin alleles. Such changes prevent the production of any normal alpha-globin. […] HbH disease is usually caused by loss or alteration of three of the four alpha-globin alleles, which sharply reduces the amount of normal alpha-globin produced.

• #14 Alpha Thalassemia: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/955496-overview

  Alpha thalassemia is a widespread, inherited anemia that results from impaired production of globin, a molecule essential to the synthesis of hemoglobin A (HbA, or 22) in red blood cells. […] Alpha thalassemia syndromes result from deficient expression of one or more of the four -globin genes on chromosome 16, causing reduced or absent synthesis of -globin chains. […] The severity of alpha thalassemia is primarily dependent on the number of -globin genes that have been deleted or inactivated, but it can be affected by co-existing factors as well. […] In the more widespread + thalassemia (formerly called alpha thalassemia-2), there is decreased production of globin from a given allele, usually resulting from relatively small deletions of 3.7 kb or 4.2 kb that remove a single -globin gene out of the two present on the allele.

• #15 Beta-thalassemia | Genetics in Medicine

  https://www.nature.com/articles/gim201012

  Beta-thalassemia is caused by the reduced (beta+) or absent (beta0) synthesis of the beta globin chains of the hemoglobin tetramer. […] The clinical severity of beta-thalassemia is related to the extent of imbalance between the alpha and nonalpha globin chains. […] The nonalpha globin chains include, in addition to the beta globin chains, also the gamma chains, which are a specific component of fetal Hb (HbF; alpha2gamma2) and are present in a small amount in normal adult individuals and in increased but variable amount in the beta-thalassemia syndromes. […] Within the red blood cell precursors, when the beta globin chains are reduced or absent, the unassembled alpha chains precipitate and lead to oxidative damage of the cell membrane, thereby resulting in apoptosis (ineffective erythropoiesis).

• #16 Beta Thalassemia: Practice Essentials, Etiology, Epidemiology

  https://emedicine.medscape.com/article/206490-overview

  Beta thalassemia is due to mutations in one or both of the beta-globin genes that result in impaired synthesis of the beta-globin protein component of Hb, and subsequently in anemia. […] More than 350 beta-globin gene mutations have been identified in patients with beta thalassemia; this underlies the wide genotypic and phenotypic variability of the disease. […] The severe imbalance of globin chain synthesis (alpha beta) results in ineffective erythropoiesis and severe microcytic hypochromic anemia. […] The excess unpaired alpha-globin chains aggregate to form precipitates that damage red cell membranes, resulting in intravascular hemolysis. […] Premature destruction of erythroid precursors results in intramedullary death and ineffective erythropoiesis. […] Although beta thalassemia is caused by mutations in the beta-globin gene (which is located on chromosome 11), many additional factors influence the clinical manifestations of the disease.

• #17 Beta Thalassemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK531481/

  Thalassemias are a common cause of microcytic anemia and are due to impaired synthesis of the globin protein component of hemoglobin. […] Beta-thalassemia refers to an inherited mutation of the beta-globin gene, causing a reduced beta-globin chain of hemoglobin. […] The pathogenesis of beta-thalassemia is two-fold. First, there is decreased hemoglobin synthesis causing anemia and an increase in HbF and HbA2 as there are decreased beta chains for HbA formation. Second, and of most pathologic significance in beta-thalassemia major and intermedia, the relative excess alpha chains form insoluble alpha chain inclusions that cause marked intramedullary hemolysis. This ineffective erythropoiesis leads to severe anemia and erythroid hyperplasia with bone marrow expansion and extramedullary hematopoiesis.

• #18 Thalassemia – McMaster Pathophysiology Review

  https://www.pathophys.org/thalassemia/

  Thalassemia results when mutations affecting the genes involved in Hb biosynthesis lead to decreased Hb production. […] The clinical phenotype results from both the diminished amount of the particular globin chain as well as from the resultant chain imbalance that occurs because of normal production of the other globin chain. […] Deficient synthesis of the beta chain of hemoglobin causes red cells have low HbA levels, thus explaining their phenotype and impaired ability to transport oxygen. […] Imbalance between alpha and beta globin production leads to a precipitation of the relatively overabundant alpha globin chain within the RBCs their precursors. […] A combination of factors, including ineffective erythropoiesis and tissue hypoxia, lead to increased iron absorption via the GI tract; via hepcidin inhibition.

• #19 Beta thalassemia – Wikipedia

  https://en.wikipedia.org/wiki/Beta_thalassemia

  Beta thalassemia is an inherited blood disorder, and a form of thalassemia resulting in variable outcomes ranging from clinically asymptomatic to severe anemia individuals. It is caused by reduced or absent synthesis of the beta chains of hemoglobin, the molecule that carries oxygen in the blood. […] Beta thalassemia occurs due to a mutation of the HBB gene leading to deficient production of the hemoglobin subunit beta-globin; the severity of the disease depends on the nature of the mutation, and whether or not the mutation is homozygous. […] The body’s inability to construct beta-globin leads to reduced or zero production of adult hemoglobin thus causing anemia. […] The other component of hemoglobin, alpha-globin, accumulates in excess leading to ineffective production of red blood cells, increased hemolysis, and iron overload.

• #20 Beta Thalassemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK531481/

  Thalassemias are a common cause of microcytic anemia and are due to impaired synthesis of the globin protein component of hemoglobin. […] Beta-thalassemia refers to an inherited mutation of the beta-globin gene, causing a reduced beta-globin chain of hemoglobin. […] The pathogenesis of beta-thalassemia is two-fold. First, there is decreased hemoglobin synthesis causing anemia and an increase in HbF and HbA2 as there are decreased beta chains for HbA formation. Second, and of most pathologic significance in beta-thalassemia major and intermedia, the relative excess alpha chains form insoluble alpha chain inclusions that cause marked intramedullary hemolysis. This ineffective erythropoiesis leads to severe anemia and erythroid hyperplasia with bone marrow expansion and extramedullary hematopoiesis.

• #21 Beta Thalassemia: Practice Essentials, Etiology, Epidemiology

  https://emedicine.medscape.com/article/206490-overview

  Beta thalassemia is due to mutations in one or both of the beta-globin genes that result in impaired synthesis of the beta-globin protein component of Hb, and subsequently in anemia. […] More than 350 beta-globin gene mutations have been identified in patients with beta thalassemia; this underlies the wide genotypic and phenotypic variability of the disease. […] The severe imbalance of globin chain synthesis (alpha beta) results in ineffective erythropoiesis and severe microcytic hypochromic anemia. […] The excess unpaired alpha-globin chains aggregate to form precipitates that damage red cell membranes, resulting in intravascular hemolysis. […] Premature destruction of erythroid precursors results in intramedullary death and ineffective erythropoiesis. […] Although beta thalassemia is caused by mutations in the beta-globin gene (which is located on chromosome 11), many additional factors influence the clinical manifestations of the disease.

• #22 thalassemias PATHOGENESIS AND PATHOLOGY PPT | PPT

  https://www.slideshare.net/slideshow/thalassemias-pathogenesis-and-pathology-ppt/269788005

  Excess alpha chains […] In the absence of their partners ( chains), they are unstable and precipitate in the red cell precursors, giving rise to large intracellular inclusions that interfere with red cell maturation. […] The end result is an extremely rigid red cell with a shortened survival (i.e. hemolysis). […] The anemia is due to two main components: Ineffective erythropoiesis (intramedullary). Extravascular hemolysis in RES esp. Spleen. […] The pathophysiology of -thalassaemia. […] A group of inherited single gene disorders resulting in reduced or no production of one or more globin chains. […] This results in an imbalance of globin chain production, with the normal excess chain producing the pathological effects: Damage to RBC precursors ineffective red cell production in BM. Damage to mature red cells hemolytic anemia Resulting in hypochromic, microcytic anemia. […] Thalassemia is a genetic blood disorder caused by decreased production of the alpha or beta globin chains that make up hemoglobin. […] Thalassemia results from a genetic mutation affecting either the alpha or beta globin chains, leading to imbalanced globin chain production and anemia.

• #23 Pathophysiology and treatment of patients with… | F1000Research

  https://f1000research.com/articles/6-2156

  Thalassemia (thal) is an autosomal recessive, hereditary, chronic hemolytic anemia due to a partial or complete deficiency in the synthesis of -globin chains (-thal) or -globin chains (-thal) that compose the major adult hemoglobin. […] The unpaired globin chains are unstable; they precipitate intracellularly, resulting in hemolysis, premature destruction of red blood cell [RBC] precursors in the bone marrow, and a short life-span of mature RBCs in the circulation. […] The breakdown products of Hb, heme and iron, catalyze chemical reactions that generate free radicals, including reactive oxygen species (ROS), which in excess are toxic, causing damage to vital organs such as the heart and liver and the endocrine system. […] The chronic anemia and its associated hypoxia in thal stimulate increased production of RBCs (chronic stress erythropoiesis). This is mediated by overproduction of erythropoietin (EPO), the main erythropoietic stimulating hormone, and other factors, such as members of the transforming growth factor (TGF)- and activin receptor-II (ActR-II) trap ligands.

• #24 Beta Thalassemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK531481/

  Thalassemias are a common cause of microcytic anemia and are due to impaired synthesis of the globin protein component of hemoglobin. […] Beta-thalassemia refers to an inherited mutation of the beta-globin gene, causing a reduced beta-globin chain of hemoglobin. […] The pathogenesis of beta-thalassemia is two-fold. First, there is decreased hemoglobin synthesis causing anemia and an increase in HbF and HbA2 as there are decreased beta chains for HbA formation. Second, and of most pathologic significance in beta-thalassemia major and intermedia, the relative excess alpha chains form insoluble alpha chain inclusions that cause marked intramedullary hemolysis. This ineffective erythropoiesis leads to severe anemia and erythroid hyperplasia with bone marrow expansion and extramedullary hematopoiesis.

• #25 Thalassemia – McMaster Pathophysiology Review

  https://www.pathophys.org/thalassemia/

  Thalassemia results when mutations affecting the genes involved in Hb biosynthesis lead to decreased Hb production. […] The clinical phenotype results from both the diminished amount of the particular globin chain as well as from the resultant chain imbalance that occurs because of normal production of the other globin chain. […] Deficient synthesis of the beta chain of hemoglobin causes red cells have low HbA levels, thus explaining their phenotype and impaired ability to transport oxygen. […] Imbalance between alpha and beta globin production leads to a precipitation of the relatively overabundant alpha globin chain within the RBCs their precursors. […] A combination of factors, including ineffective erythropoiesis and tissue hypoxia, lead to increased iron absorption via the GI tract; via hepcidin inhibition.

• #26 Thalassemia pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Thalassemia_pathophysiology

  The excess beta-chains form unstable tetramers (called Hemoglobin H or HbH of 4 beta chains) which have abnormal oxygen dissociation curves. […] In the presence of excess beta-globin chains, red blood cell membrane instability develops and hemolysis ensues. […] The severity of the thalassemias is correlated with the number of affected globin loci: the greater the number of affected loci, the more severe will be the manifestations of the disease. […] In beta thalassemia, red cell precursors can detoxify and tolerate a moderate amount of free alpha globin, that is stabilized by alpha hemoglobin stabilizing protein and eliminated by ubiquitin proteasome system and autophagy. […] The synthesis of gamma globin gene and HbF can reduce the degree of imbalance between alpha and beta chains.

• #27 Thalassemia pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Thalassemia_pathophysiology

  The excess beta-chains form unstable tetramers (called Hemoglobin H or HbH of 4 beta chains) which have abnormal oxygen dissociation curves. […] In the presence of excess beta-globin chains, red blood cell membrane instability develops and hemolysis ensues. […] The severity of the thalassemias is correlated with the number of affected globin loci: the greater the number of affected loci, the more severe will be the manifestations of the disease. […] In beta thalassemia, red cell precursors can detoxify and tolerate a moderate amount of free alpha globin, that is stabilized by alpha hemoglobin stabilizing protein and eliminated by ubiquitin proteasome system and autophagy. […] The synthesis of gamma globin gene and HbF can reduce the degree of imbalance between alpha and beta chains.

• #28 Thalassemia pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Thalassemia_pathophysiology

  The excess beta-chains form unstable tetramers (called Hemoglobin H or HbH of 4 beta chains) which have abnormal oxygen dissociation curves. […] In the presence of excess beta-globin chains, red blood cell membrane instability develops and hemolysis ensues. […] The severity of the thalassemias is correlated with the number of affected globin loci: the greater the number of affected loci, the more severe will be the manifestations of the disease. […] In beta thalassemia, red cell precursors can detoxify and tolerate a moderate amount of free alpha globin, that is stabilized by alpha hemoglobin stabilizing protein and eliminated by ubiquitin proteasome system and autophagy. […] The synthesis of gamma globin gene and HbF can reduce the degree of imbalance between alpha and beta chains.

• #29 Beta Thalassemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK531481/

  Thalassemias are a common cause of microcytic anemia and are due to impaired synthesis of the globin protein component of hemoglobin. […] Beta-thalassemia refers to an inherited mutation of the beta-globin gene, causing a reduced beta-globin chain of hemoglobin. […] The pathogenesis of beta-thalassemia is two-fold. First, there is decreased hemoglobin synthesis causing anemia and an increase in HbF and HbA2 as there are decreased beta chains for HbA formation. Second, and of most pathologic significance in beta-thalassemia major and intermedia, the relative excess alpha chains form insoluble alpha chain inclusions that cause marked intramedullary hemolysis. This ineffective erythropoiesis leads to severe anemia and erythroid hyperplasia with bone marrow expansion and extramedullary hematopoiesis.

• #30 Beta thalassemia – Wikipedia

  https://en.wikipedia.org/wiki/Beta_thalassemia

  Beta thalassemia is an inherited blood disorder, and a form of thalassemia resulting in variable outcomes ranging from clinically asymptomatic to severe anemia individuals. It is caused by reduced or absent synthesis of the beta chains of hemoglobin, the molecule that carries oxygen in the blood. […] Beta thalassemia occurs due to a mutation of the HBB gene leading to deficient production of the hemoglobin subunit beta-globin; the severity of the disease depends on the nature of the mutation, and whether or not the mutation is homozygous. […] The body’s inability to construct beta-globin leads to reduced or zero production of adult hemoglobin thus causing anemia. […] The other component of hemoglobin, alpha-globin, accumulates in excess leading to ineffective production of red blood cells, increased hemolysis, and iron overload.

• #31 Pathophysiology and treatment of patients with… | F1000Research

  https://f1000research.com/articles/6-2156

  Thalassemia (thal) is an autosomal recessive, hereditary, chronic hemolytic anemia due to a partial or complete deficiency in the synthesis of -globin chains (-thal) or -globin chains (-thal) that compose the major adult hemoglobin. […] The unpaired globin chains are unstable; they precipitate intracellularly, resulting in hemolysis, premature destruction of red blood cell [RBC] precursors in the bone marrow, and a short life-span of mature RBCs in the circulation. […] The breakdown products of Hb, heme and iron, catalyze chemical reactions that generate free radicals, including reactive oxygen species (ROS), which in excess are toxic, causing damage to vital organs such as the heart and liver and the endocrine system. […] The chronic anemia and its associated hypoxia in thal stimulate increased production of RBCs (chronic stress erythropoiesis). This is mediated by overproduction of erythropoietin (EPO), the main erythropoietic stimulating hormone, and other factors, such as members of the transforming growth factor (TGF)- and activin receptor-II (ActR-II) trap ligands.

• #32 Beta Thalassemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK531481/

  Thalassemias are a common cause of microcytic anemia and are due to impaired synthesis of the globin protein component of hemoglobin. […] Beta-thalassemia refers to an inherited mutation of the beta-globin gene, causing a reduced beta-globin chain of hemoglobin. […] The pathogenesis of beta-thalassemia is two-fold. First, there is decreased hemoglobin synthesis causing anemia and an increase in HbF and HbA2 as there are decreased beta chains for HbA formation. Second, and of most pathologic significance in beta-thalassemia major and intermedia, the relative excess alpha chains form insoluble alpha chain inclusions that cause marked intramedullary hemolysis. This ineffective erythropoiesis leads to severe anemia and erythroid hyperplasia with bone marrow expansion and extramedullary hematopoiesis.

• #33 Pathophysiology and treatment of patients with… | F1000Research

  https://f1000research.com/articles/6-2156

  However, this attempt is futile (ineffective erythropoiesis) due to oxidative stress-increased apoptosis and abortive differentiation. […] The key pathophysiological mechanism leading to the ineffective erythropoiesis in -thal is the continuous production and accumulation of free excess -globin in the erythroid precursors. […] In -thal, oxidative stress is mainly the consequence of the unstable Hbs (hemichromes) and IO and it mediates many of its symptoms due to oxidative damage to RBCs (anemia), platelets, (hypercoagulable state) and leukocytes (recurrent infections) as well as cells in various vital organs (heart and liver) and the endocrine glands. […] Although oxidative stress is not the primary etiology of thal, it plays a major role in its pathophysiology. […] The transcription factor forkhead box O3 (Foxo3) is a key player in the development of erythroid precursors. […] In -thal mice, Foxo3 is downregulated in late erythroid precursors owing to hyper-activation of the EPOR-PI3K/AKT/mTOR pathway, which leads to oxidative damage and ineffective erythropoiesis. […] The main therapeutic modality is blood transfusion that improves the anemia but exacerbates IO.

• #34 Beta-Thalassemia: A Pharmacological Drug-Based Treatment

  https://www.mdpi.com/2813-2998/3/1/8

  Ineffective erythropoiesis is often caused by increased activity of tumor growth factor β (TGF-β) superfamily ligands during later-stage erythropoiesis, which inhibits the growth of erythroid precursors. The SMAD2/3 pathway—in particular, SMAD2/3 signaling—is involved in this inhibitory effect. TGF-β superfamily ligands activate specific receptors during maturation, including ActRIIB, which elevates the phosphorylation of SMAD2/3 protein, halting erythroid maturation and reducing the number of red blood cells. Luspatercept is a medication that promotes erythroid maturation by acting as a ligand trap and competing with ActRIIB to bind to TGF-β superfamily ligands. By decreasing abnormally elevated SMAD2/3 signaling, luspatercept helps to regulate erythroid maturation and improve red blood cell production.

• #35 Diagnosis of thalassemia (adults and children) – UpToDate

  https://www.uptodate.com/contents/diagnosis-of-thalassemia-adults-and-children/print

  The thalassemias are a group of hemoglobinopathies in which the normal ratio of alpha globin to beta globin production is disrupted due to a genetic variant in one or more alpha or beta globin genes. This abnormal alpha chain to beta chain ratio causes the unpaired chains to precipitate, leading to destruction of red blood cell (RBC) precursors in the bone marrow (ineffective erythropoiesis) and in the circulation (hemolysis). Individuals with thalassemia have variable degrees of anemia and extramedullary hematopoiesis, which in turn can cause bone changes, impaired growth, and iron overload. […] The pathogenesis and treatment of thalassemia, including the role of hematopoietic stem cell transplantation, monitoring of iron stores, and iron chelation, are discussed in detail separately. […] Pathogenesis – (See „Pathophysiology of thalassemia”.)

• #36

  https://journals.lww.com/md-journal/fulltext/2021/11120/molecular_genetics_of___thalassemia__a_narrative.4.aspx

  Several algorithms have been designed to reduce the pathological imbalance of the / ratio using several nucleic acid-based technologies such as RNAi, lentiviral mediated gene therapy, splice-switching oligonucleotides, and gene-editing technology. […] The primary variation in -thalassemia is seen as different mutations, ranging from silent to dominantly inherited mutations. […] The critical pathophysiological mechanism leading to IE in -thalassemia is the continual production of -globin and accumulation of complementary excess -globin in erythroid precursor cells. […] The discovery of Janus kinase 2 (JAK2) as a vital mediator of IE and splenomegaly in -thalassemia indicated that the application of small organic molecules to inhibit JAK2 could reduce IE and splenomegaly. […] The central regulator of iron homeostasis, hepcidin, is chronically repressed in this disorder, leading to unchecked intestinal iron absorption and consequent iron overload. […] Recent discoveries and understanding of the switch from fetal to adult hemoglobin have opened up new pharmacological and genetic targets for HbF reactivation.

• #37

  https://omim.org/entry/613985

  Ribeil et al. (2007) demonstrated that in human erythroblasts, the chaperone HSP70 is constitutively expressed and, at later stages of maturation, translocates into the nucleus and protects GATA1 from CASP3 cleavage. […] Arlet et al. (2014) showed in vitro that, during the maturation of beta-thalassemia major erythroblasts, HSP70 interacts directly with free alpha-globin chains. Consequently, HSP70 is sequestered in the cytoplasm and GATA1 is no longer protected, resulting in end-stage maturation arrest and apoptosis. Transduction of a nuclear-targeted HSP70 mutant or a CASP3-uncleavable GATA1 mutant restored terminal maturation of beta-thalassemia major erythroblasts, providing a rationale for targeted therapies.

• #38 Beta Thalassemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK531481/

  Thalassemias are a common cause of microcytic anemia and are due to impaired synthesis of the globin protein component of hemoglobin. […] Beta-thalassemia refers to an inherited mutation of the beta-globin gene, causing a reduced beta-globin chain of hemoglobin. […] The pathogenesis of beta-thalassemia is two-fold. First, there is decreased hemoglobin synthesis causing anemia and an increase in HbF and HbA2 as there are decreased beta chains for HbA formation. Second, and of most pathologic significance in beta-thalassemia major and intermedia, the relative excess alpha chains form insoluble alpha chain inclusions that cause marked intramedullary hemolysis. This ineffective erythropoiesis leads to severe anemia and erythroid hyperplasia with bone marrow expansion and extramedullary hematopoiesis.

• #39 Beta-thalassemia | Genetics in Medicine

  https://www.nature.com/articles/gim201012

  Beta-thalassemia is caused by the reduced (beta+) or absent (beta0) synthesis of the beta globin chains of the hemoglobin tetramer. […] The clinical severity of beta-thalassemia is related to the extent of imbalance between the alpha and nonalpha globin chains. […] The nonalpha globin chains include, in addition to the beta globin chains, also the gamma chains, which are a specific component of fetal Hb (HbF; alpha2gamma2) and are present in a small amount in normal adult individuals and in increased but variable amount in the beta-thalassemia syndromes. […] Within the red blood cell precursors, when the beta globin chains are reduced or absent, the unassembled alpha chains precipitate and lead to oxidative damage of the cell membrane, thereby resulting in apoptosis (ineffective erythropoiesis).

• #40 Beta-thalassemia | Genetics in Medicine

  https://www.nature.com/articles/gim201012

  Beta-thalassemia is caused by the reduced (beta+) or absent (beta0) synthesis of the beta globin chains of the hemoglobin tetramer. […] The clinical severity of beta-thalassemia is related to the extent of imbalance between the alpha and nonalpha globin chains. […] The nonalpha globin chains include, in addition to the beta globin chains, also the gamma chains, which are a specific component of fetal Hb (HbF; alpha2gamma2) and are present in a small amount in normal adult individuals and in increased but variable amount in the beta-thalassemia syndromes. […] Within the red blood cell precursors, when the beta globin chains are reduced or absent, the unassembled alpha chains precipitate and lead to oxidative damage of the cell membrane, thereby resulting in apoptosis (ineffective erythropoiesis).

• #41 Thalassemia pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Thalassemia_pathophysiology

  Genetic variations in BCL11A causing persistent HbF production reduce the clinical severity of beta thalassemia. […] The genetic mutations present in beta-thalassemias are very diverse, and a number of different mutations can cause reduced or absent beta-globin synthesis. […] Two major groups of mutations can be distinguished: Nondeletion forms and Deletion forms.

• #42 A comprehensive review of hydroxyurea for β-haemoglobinopathies: the role revisited during COVID-19 pandemic | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-021-01757-w

  Hydroxyurea has shown to enhance the F cell percentage in the circulations through several mechanisms. […] Hydroxyurea improves the clinical severity of haemoglobinopathies by influencing the haemorheology. […] Hydroxyurea is a cytotoxic drug which was initially prescribed for malignancies. […] Hydroxyurea induces stress erythropoiesis by inhibiting the synthesis of DNA, thus giving a selective advantage to the expansion of the F cell population over the rapidly dividing HbA producing erythroid progenitors. […] Hydroxyurea exerts a bi-modal effect on erythropoiesis in a dose-dependent manner by downregulating the expression of GATA1 and upregulating GATA2. […] Hydroxyurea alters the expression of several microRNAs (miR) which act on these molecular targets to induce fetal haemoglobin.

• #43 A comprehensive review of hydroxyurea for β-haemoglobinopathies: the role revisited during COVID-19 pandemic | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-021-01757-w

  Hydroxyurea is one of the earliest drugs that showed promise in the management of haemoglobinopathies that include -thalassaemia and sickle cell disease. […] However, during COVID-19 pandemic, it has become a valuable adjunct to transfusion therapy in patients with -haemoglobinopathies. […] Hydroxyurea is an S-phase-specific drug that reversibly inhibits ribonucleoside diphosphate reductase enzyme which catalyses an essential step in the DNA biosynthesis. […] Through several molecular pathways described in this review, hydroxyurea exerts many favourable effects on the haemoglobin content, red blood cell indices, ineffective erythropoiesis, and blood rheology in patients with -haemoglobinopathies. […] Hydroxyurea is one of the medications that has shown promise in achieving this. […] The primary mechanism of action of hydroxyurea in -haemoglobinopathy is upregulation of -globin gene expression in erythroid cells.

• #44 Beta thalassemia – Wikipedia

  https://en.wikipedia.org/wiki/Beta_thalassemia

  Beta thalassemia is an inherited blood disorder, and a form of thalassemia resulting in variable outcomes ranging from clinically asymptomatic to severe anemia individuals. It is caused by reduced or absent synthesis of the beta chains of hemoglobin, the molecule that carries oxygen in the blood. […] Beta thalassemia occurs due to a mutation of the HBB gene leading to deficient production of the hemoglobin subunit beta-globin; the severity of the disease depends on the nature of the mutation, and whether or not the mutation is homozygous. […] The body’s inability to construct beta-globin leads to reduced or zero production of adult hemoglobin thus causing anemia. […] The other component of hemoglobin, alpha-globin, accumulates in excess leading to ineffective production of red blood cells, increased hemolysis, and iron overload.

• #45 Thalassemia: Types, Traits, Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/14508-thalassemias

  Your anemia symptoms and how severe your condition is depends on how many genes are defective and which part of the beta globin protein chain contains the defect. […] Standard treatments for thalassemia major are blood transfusions and iron chelation. […] A bone marrow transplant from a compatible sibling offers the best chance at a cure for thalassemia. […] Heart disease from iron overload is the leading cause of death in people with thalassemia, so keeping up with your iron chelation therapy is extremely important.

• #46 Beta-thalassemia | Genetics in Medicine

  https://www.nature.com/articles/gim201012

  Recently, the mechanism of iron hyperabsorption in beta-thalassemia has been at least partly elucidated. Iron absorption is essentially controlled by hepcidin, a small peptide secreted by the hepatocytes, which blocks iron uptake in the intestine and iron release from the reticuloendothelial system. […] Hepcidin expression is enhanced by iron overload and inflammation, whereas it is inhibited by anemia and hypoxia. […] Recent studies have shown that serum from untransfused thalassemia patients have high level of growth differentiation factor 15, a member of the transforming growth factor superfamily-like BMPs, whose production is related to the expansion of the erythroid compartment. […] Consequently, the secretion of ferritin is reduced and its serum level relatively decreased. […] In contrast, in thalassemia major, red cell transfusions decrease the erythropoietic drive and increase iron overload, resulting in relatively high hepcidin level, which reduces dietary iron absorption and iron release from macrophages. […] The associated complications of iron overload may present later, but it may be as severe as those seen in individuals with thalassemia major who depend on transfusions.

• #47

  https://journals.lww.com/md-journal/fulltext/2021/11120/molecular_genetics_of___thalassemia__a_narrative.4.aspx

  Several algorithms have been designed to reduce the pathological imbalance of the / ratio using several nucleic acid-based technologies such as RNAi, lentiviral mediated gene therapy, splice-switching oligonucleotides, and gene-editing technology. […] The primary variation in -thalassemia is seen as different mutations, ranging from silent to dominantly inherited mutations. […] The critical pathophysiological mechanism leading to IE in -thalassemia is the continual production of -globin and accumulation of complementary excess -globin in erythroid precursor cells. […] The discovery of Janus kinase 2 (JAK2) as a vital mediator of IE and splenomegaly in -thalassemia indicated that the application of small organic molecules to inhibit JAK2 could reduce IE and splenomegaly. […] The central regulator of iron homeostasis, hepcidin, is chronically repressed in this disorder, leading to unchecked intestinal iron absorption and consequent iron overload. […] Recent discoveries and understanding of the switch from fetal to adult hemoglobin have opened up new pharmacological and genetic targets for HbF reactivation.

• #48 Beta-thalassemia | Genetics in Medicine

  https://www.nature.com/articles/gim201012

  Recently, the mechanism of iron hyperabsorption in beta-thalassemia has been at least partly elucidated. Iron absorption is essentially controlled by hepcidin, a small peptide secreted by the hepatocytes, which blocks iron uptake in the intestine and iron release from the reticuloendothelial system. […] Hepcidin expression is enhanced by iron overload and inflammation, whereas it is inhibited by anemia and hypoxia. […] Recent studies have shown that serum from untransfused thalassemia patients have high level of growth differentiation factor 15, a member of the transforming growth factor superfamily-like BMPs, whose production is related to the expansion of the erythroid compartment. […] Consequently, the secretion of ferritin is reduced and its serum level relatively decreased. […] In contrast, in thalassemia major, red cell transfusions decrease the erythropoietic drive and increase iron overload, resulting in relatively high hepcidin level, which reduces dietary iron absorption and iron release from macrophages. […] The associated complications of iron overload may present later, but it may be as severe as those seen in individuals with thalassemia major who depend on transfusions.

• #49 Beta-thalassemia | Genetics in Medicine

  https://www.nature.com/articles/gim201012

  Recently, the mechanism of iron hyperabsorption in beta-thalassemia has been at least partly elucidated. Iron absorption is essentially controlled by hepcidin, a small peptide secreted by the hepatocytes, which blocks iron uptake in the intestine and iron release from the reticuloendothelial system. […] Hepcidin expression is enhanced by iron overload and inflammation, whereas it is inhibited by anemia and hypoxia. […] Recent studies have shown that serum from untransfused thalassemia patients have high level of growth differentiation factor 15, a member of the transforming growth factor superfamily-like BMPs, whose production is related to the expansion of the erythroid compartment. […] Consequently, the secretion of ferritin is reduced and its serum level relatively decreased. […] In contrast, in thalassemia major, red cell transfusions decrease the erythropoietic drive and increase iron overload, resulting in relatively high hepcidin level, which reduces dietary iron absorption and iron release from macrophages. […] The associated complications of iron overload may present later, but it may be as severe as those seen in individuals with thalassemia major who depend on transfusions.

• #50 Beta-thalassemia | Genetics in Medicine

  https://www.nature.com/articles/gim201012

  Recently, the mechanism of iron hyperabsorption in beta-thalassemia has been at least partly elucidated. Iron absorption is essentially controlled by hepcidin, a small peptide secreted by the hepatocytes, which blocks iron uptake in the intestine and iron release from the reticuloendothelial system. […] Hepcidin expression is enhanced by iron overload and inflammation, whereas it is inhibited by anemia and hypoxia. […] Recent studies have shown that serum from untransfused thalassemia patients have high level of growth differentiation factor 15, a member of the transforming growth factor superfamily-like BMPs, whose production is related to the expansion of the erythroid compartment. […] Consequently, the secretion of ferritin is reduced and its serum level relatively decreased. […] In contrast, in thalassemia major, red cell transfusions decrease the erythropoietic drive and increase iron overload, resulting in relatively high hepcidin level, which reduces dietary iron absorption and iron release from macrophages. […] The associated complications of iron overload may present later, but it may be as severe as those seen in individuals with thalassemia major who depend on transfusions.

• #51 Thalassemia – McMaster Pathophysiology Review

  https://www.pathophys.org/thalassemia/

  Iron deposition occurs in visceral organs (mainly in the endocrine glands, the heart, and the liver) causing failure. […] Alpha globin precipitation leads to cell membrane damage. […] Uncompensated anemia creates a strong stimulus through erythropoietin (EPO) signalling to ramp up erythropoiesis. This causes erythroid hyperplasia within the bone marrow, which expands and destroys adjacent areas of bone such as the cortex, impairing bone growth and creating malformations. […] RBC membrane dysfunction increases the expression of negatively charged phosphatidylserines, which have been shown to induce platelet activation.

• #52 Thalassemia: Types, Traits, Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/14508-thalassemias

  Your anemia symptoms and how severe your condition is depends on how many genes are defective and which part of the beta globin protein chain contains the defect. […] Standard treatments for thalassemia major are blood transfusions and iron chelation. […] A bone marrow transplant from a compatible sibling offers the best chance at a cure for thalassemia. […] Heart disease from iron overload is the leading cause of death in people with thalassemia, so keeping up with your iron chelation therapy is extremely important.

• #53 Beta Thalassemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK531481/

  The spectrum of disease severity is due to the bi-allelic inheritance of two copies of the beta-globin gene, one on each chromosome 11, as well as the heterogeneous pool of disease-causing mutations. […] Beta-thalassemia can also coexist with other hemoglobinopathies (hemoglobin S, C, and E, for example) and cause variably clinically significant anemias in the heterozygous beta-thalassemia carrier. […] The pathophysiology of delta-beta-thalassemia parallels that of beta-thalassemia, except there is not an increased HbA2 since the delta chain is also affected.

• #54 Beta Thalassemia: Practice Essentials, Etiology, Epidemiology

  https://emedicine.medscape.com/article/206490-overview

  The level of expression of fetal Hb (ie, the expression level of the gamma-globin gene) in red blood cells determines, in part, the severity of the disease. […] Patients with coinheritance of alpha thalassemia have a milder clinical course because they have a less severe alpha-beta chain imbalance. […] The coexistence of sickle cell trait and beta thalassemia is a major and symptomatic hemoglobinopathy with most of the symptoms and complications of sickle cell disease.

• #55 Thalassemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK545151/

  Thalassemia is a heterogeneous group of blood disorders affecting the hemoglobin genes and resulting in ineffective erythropoiesis. […] Thalassemias are a heterogeneous grouping of genetic disorders that result from a decreased synthesis of alpha or beta chains of hemoglobin (Hb). […] It is caused by either a genetic mutation or a deletion of certain key gene fragments. […] Alpha thalassemia is caused by alpha-globin gene deletion which results in reduced or absent production of alpha-globin chains. […] Beta thalassemia results from point mutations in the beta-globin gene. […] The excess unpaired alpha-globin chains in beta-thalassemia aggregate and form precipitates that damage red cell membranes and result in intravascular hemolysis. […] Coinheritance of alpha thalassemia: Beta-thalassemia patients with coinheritance of alpha thalassemia have a milder clinical course due to a less severe alpha-beta chain imbalance.

• #56 Beta Thalassemia: Practice Essentials, Etiology, Epidemiology

  https://emedicine.medscape.com/article/206490-overview

  The level of expression of fetal Hb (ie, the expression level of the gamma-globin gene) in red blood cells determines, in part, the severity of the disease. […] Patients with coinheritance of alpha thalassemia have a milder clinical course because they have a less severe alpha-beta chain imbalance. […] The coexistence of sickle cell trait and beta thalassemia is a major and symptomatic hemoglobinopathy with most of the symptoms and complications of sickle cell disease.

• #57 Beta Thalassemia: Practice Essentials, Etiology, Epidemiology

  https://emedicine.medscape.com/article/206490-overview

  The level of expression of fetal Hb (ie, the expression level of the gamma-globin gene) in red blood cells determines, in part, the severity of the disease. […] Patients with coinheritance of alpha thalassemia have a milder clinical course because they have a less severe alpha-beta chain imbalance. […] The coexistence of sickle cell trait and beta thalassemia is a major and symptomatic hemoglobinopathy with most of the symptoms and complications of sickle cell disease.

• #58

  https://journals.lww.com/md-journal/fulltext/2021/11120/molecular_genetics_of___thalassemia__a_narrative.4.aspx

  -thalassemia is a hereditary hematological disease caused by over 350 mutations in the -globin gene (HBB). Identifying the genetic variants affecting fetal hemoglobin (HbF) production combined with the -globin genotype provides some prediction of disease severity for -thalassemia. […] Genetic studies have successfully characterized the causal variants and pathways involved in HbF regulation, providing novel therapeutic targets for HbF reactivation. […] Advances in understanding the underlying pathophysiology of -thalassemia have enabled clinicians and researchers to develop novel therapeutic modalities. […] Differences in the severity of the phenotype are usually related to the extent of imbalance between – and non–globin chain synthesis and the predominance of the free -chain. […] The first primary determinant of -thalassemia severity is the type of allele (0, +, ++), ameliorated by coinheritance of interacting -thalassemia and coinheritance of an innate ability to increase the production of chains.

• #59 Beta Thalassemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK531481/

  The spectrum of disease severity is due to the bi-allelic inheritance of two copies of the beta-globin gene, one on each chromosome 11, as well as the heterogeneous pool of disease-causing mutations. […] Beta-thalassemia can also coexist with other hemoglobinopathies (hemoglobin S, C, and E, for example) and cause variably clinically significant anemias in the heterozygous beta-thalassemia carrier. […] The pathophysiology of delta-beta-thalassemia parallels that of beta-thalassemia, except there is not an increased HbA2 since the delta chain is also affected.

• #60 Beta Thalassemia: Practice Essentials, Etiology, Epidemiology

  https://emedicine.medscape.com/article/206490-overview

  The level of expression of fetal Hb (ie, the expression level of the gamma-globin gene) in red blood cells determines, in part, the severity of the disease. […] Patients with coinheritance of alpha thalassemia have a milder clinical course because they have a less severe alpha-beta chain imbalance. […] The coexistence of sickle cell trait and beta thalassemia is a major and symptomatic hemoglobinopathy with most of the symptoms and complications of sickle cell disease.

• #61 Beta Thalassemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK531481/

  The spectrum of disease severity is due to the bi-allelic inheritance of two copies of the beta-globin gene, one on each chromosome 11, as well as the heterogeneous pool of disease-causing mutations. […] Beta-thalassemia can also coexist with other hemoglobinopathies (hemoglobin S, C, and E, for example) and cause variably clinically significant anemias in the heterozygous beta-thalassemia carrier. […] The pathophysiology of delta-beta-thalassemia parallels that of beta-thalassemia, except there is not an increased HbA2 since the delta chain is also affected.

• #62 Thalassemia: Types, Traits, Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/14508-thalassemias

  Thalassemia is an inherited blood disorder that affects your bodys ability to produce hemoglobin and healthy red blood cells. […] If you have thalassemia, your body produces fewer healthy hemoglobin proteins, and your bone marrow produces fewer healthy red blood cells. […] Hemoglobin consists of four protein chains, two alpha globin chains and two beta globin chains. Each chain both alpha and beta contains genetic information, or genes, passed down from your parents. […] The thalassemia you have depends on whether your alpha or beta chain contains the genetic defect. The extent of the defect will determine how severe your condition is. […] Thalassemia is classified as trait, minor, intermedia and major to describe how severe the condition is. […] You inherit four genes, two from each parent, that make alpha globin protein chains. When one or more genes are defective, you develop alpha thalassemia.

• #63 Thalassaemia — Knowledge Hub

  https://www.genomicseducation.hee.nhs.uk/genotes/knowledge-hub/thalassaemia/

  Beta thalassaemia is also inherited in an autosomal recessive manner. However, due to the variable clinical effect of the genotypes, this inheritance can also be complex. […] Although only one gene (the beta () globin gene, HBB, on chromosome 11) is involved in the pathogenesis of beta thalassaemia, the type of variant greatly dictates the phenotype. Variants resulting in an absence of protein production are more severe (denoted as the o allotype) than variants allowing some -chain formation (+ allotype) or normal levels of globin with reduced function ( allotype). […] For example, if the parents are both of the o/ genotypes, they have a one-in-four chance of having a child with beta thalassaemia major. However, if they are of the +/ genotype, their offspring is extremely unlikely (barring de novo variants) to have beta thalassaemia major.

• #64 Thalassaemia — Knowledge Hub

  https://www.genomicseducation.hee.nhs.uk/genotes/knowledge-hub/thalassaemia/

  Beta thalassaemia is also inherited in an autosomal recessive manner. However, due to the variable clinical effect of the genotypes, this inheritance can also be complex. […] Although only one gene (the beta () globin gene, HBB, on chromosome 11) is involved in the pathogenesis of beta thalassaemia, the type of variant greatly dictates the phenotype. Variants resulting in an absence of protein production are more severe (denoted as the o allotype) than variants allowing some -chain formation (+ allotype) or normal levels of globin with reduced function ( allotype). […] For example, if the parents are both of the o/ genotypes, they have a one-in-four chance of having a child with beta thalassaemia major. However, if they are of the +/ genotype, their offspring is extremely unlikely (barring de novo variants) to have beta thalassaemia major.

• #65

  https://journals.lww.com/md-journal/fulltext/2021/11120/molecular_genetics_of___thalassemia__a_narrative.4.aspx

  -thalassemia is a hereditary hematological disease caused by over 350 mutations in the -globin gene (HBB). Identifying the genetic variants affecting fetal hemoglobin (HbF) production combined with the -globin genotype provides some prediction of disease severity for -thalassemia. […] Genetic studies have successfully characterized the causal variants and pathways involved in HbF regulation, providing novel therapeutic targets for HbF reactivation. […] Advances in understanding the underlying pathophysiology of -thalassemia have enabled clinicians and researchers to develop novel therapeutic modalities. […] Differences in the severity of the phenotype are usually related to the extent of imbalance between – and non–globin chain synthesis and the predominance of the free -chain. […] The first primary determinant of -thalassemia severity is the type of allele (0, +, ++), ameliorated by coinheritance of interacting -thalassemia and coinheritance of an innate ability to increase the production of chains.

• #66 Alpha Thalassemia: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/955496-overview

  Alpha thalassemia is a widespread, inherited anemia that results from impaired production of globin, a molecule essential to the synthesis of hemoglobin A (HbA, or 22) in red blood cells. […] Alpha thalassemia syndromes result from deficient expression of one or more of the four -globin genes on chromosome 16, causing reduced or absent synthesis of -globin chains. […] The severity of alpha thalassemia is primarily dependent on the number of -globin genes that have been deleted or inactivated, but it can be affected by co-existing factors as well. […] In the more widespread + thalassemia (formerly called alpha thalassemia-2), there is decreased production of globin from a given allele, usually resulting from relatively small deletions of 3.7 kb or 4.2 kb that remove a single -globin gene out of the two present on the allele.

• #67 Alpha thalassemia: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/alpha-thalassemia/

  Alpha thalassemia typically results from deletions involving the HBA1 and HBA2 genes. […] Such changes are often referred to as nondeletion variants. […] Both the HBA1 and HBA2 genes provide instructions for making a protein called alpha-globin, which is a component (subunit) of hemoglobin. […] Deletions and nondeletion variants in one or more alleles reduce the amount of alpha-globin cells produce. Nondeletion variants tend to reduce alpha-globin more than deletions. […] Hb Bart syndrome, the most severe form of alpha thalassemia, results from the loss or alteration of all four alpha-globin alleles. Such changes prevent the production of any normal alpha-globin. […] HbH disease is usually caused by loss or alteration of three of the four alpha-globin alleles, which sharply reduces the amount of normal alpha-globin produced.

• #68 Alpha thalassemia: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/alpha-thalassemia/

  Alpha thalassemia typically results from deletions involving the HBA1 and HBA2 genes. […] Such changes are often referred to as nondeletion variants. […] Both the HBA1 and HBA2 genes provide instructions for making a protein called alpha-globin, which is a component (subunit) of hemoglobin. […] Deletions and nondeletion variants in one or more alleles reduce the amount of alpha-globin cells produce. Nondeletion variants tend to reduce alpha-globin more than deletions. […] Hb Bart syndrome, the most severe form of alpha thalassemia, results from the loss or alteration of all four alpha-globin alleles. Such changes prevent the production of any normal alpha-globin. […] HbH disease is usually caused by loss or alteration of three of the four alpha-globin alleles, which sharply reduces the amount of normal alpha-globin produced.

• #69 Alpha thalassemia: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/alpha-thalassemia/

  Alpha thalassemia typically results from deletions involving the HBA1 and HBA2 genes. […] Such changes are often referred to as nondeletion variants. […] Both the HBA1 and HBA2 genes provide instructions for making a protein called alpha-globin, which is a component (subunit) of hemoglobin. […] Deletions and nondeletion variants in one or more alleles reduce the amount of alpha-globin cells produce. Nondeletion variants tend to reduce alpha-globin more than deletions. […] Hb Bart syndrome, the most severe form of alpha thalassemia, results from the loss or alteration of all four alpha-globin alleles. Such changes prevent the production of any normal alpha-globin. […] HbH disease is usually caused by loss or alteration of three of the four alpha-globin alleles, which sharply reduces the amount of normal alpha-globin produced.

• #70 Hypocholesterolaemia in Thalassaemia – Pathogenesis, Implications and Clinical Effects – touchONCOLOGY

  https://touchoncology.com/haematology/journal-articles/hypocholesterolaemia-in-thalassaemia-pathogenesis-implications-and-clinical-effects/

  Hypocholesterolaemia in the absence of a cholesterol metabolism genetic disorder is a constant clinical feature of patients with severe thalassaemia. The pathophysiology of hypocholesterolaemia in severe forms of thalassaemia should be clarified by studies investigating cholesterol metabolism and balance. However, being presumably related to erythropoietic cell division, hypocholesterolaemia is most prevalent in patients with thalassaemia intermedia, where it may be a marker of disease severity but does not correlate with age, sex, liver injury, Hb level and iron overload in thalassaemic patients. Such reduced levels of cholesterol cannot protect thalassaemic patients from the development of atherosclerotic disease because of the well-recognised role of iron accumulation in the pathogenesis of the atherogenic process; in this context, iron chelation could be an useful tool to modify their risk of atherosclerosis. Conversely, such low levels of cholesterol in thalassaemic patients seem to reflect the inability of the organism to balance the increased cholesterol requirement for red cell membrane formation; thus, it is conceivable that the availability of cholesterol, ordinarily used in steroid hormone synthesis to control infection and to control hypercoagulability, could be at least in part reduced. Additional studies are required to establish whether hypocholesterolaemia promotes complications of thalassaemia and whether cholesterol supplementation can be recommended for the management of thalassaemia intermedia.

• #71 Hypocholesterolaemia in Thalassaemia – Pathogenesis, Implications and Clinical Effects – touchONCOLOGY

  https://touchoncology.com/haematology/journal-articles/hypocholesterolaemia-in-thalassaemia-pathogenesis-implications-and-clinical-effects/

  The pathogenetic mechanism for hypocholesterolaemia was investigated in a interesting study conducted using a model of artificial microemulsion termed LDE (a cholesterol-rich microemulsion), whose composition resembled that of LDL. It was demonstrated that LDL clearance, the mechanism that removes LDL from the circulation, was enhanced in heterozygous -thalassaemia patients. However, despite the fact that hypocholesterolaemia in thalassaemia was first described many years ago, there is no definitive explanation for the mechanism underlying this clinical condition in severe forms of thalassaemia. Two main pathogenetic mechanisms have been proposed: the presence of enhanced cholesterol consumption required for cell membrane formation, and the presence of a hyperplastic and overactive reticuloendothelial system, which may be responsible for an increased uptake of LDL. The first mechanism seems to be the more complete and would also explain the difference always reported in cholesterol level among patients with thalassaemia intermedia and major. In fact, in the studies by Ricchi and by Hartman it was clearly demonstrated that patients with thalassaemia intermedia have both lower cholesterol and lower haemoglobin (Hb) levels than patients with thalassaemia major. In both studies, patients were accurately selected by eliminating biases (severe liver disorders, hyperthyroidism, fat malabsorption and other factors that could per se modify cholesterol levels). According to current guidelines, patients with thalassaemia major have pre-transfusional Hb ranging from 9.5 to 10g/dl, with the aim being to reduce erythroid marrow activity. These data may strongly support the hypothesis that the consistently high Hb levels in chronically transfused patients (with thalassaemia major) may mean that this group of patients can sustain a more complete degree of marrow suppression with respect to that present in thalassaemia intermedia patients. Therefore, in patients with thalassaemia intermedia, a particularly accelerated erythropoiesis and enhanced cholesterol consumption for red cell membrane formation could be responsible for the lower levels of cholesterolaemia. In support of this hypothesis, several clinical and biochemical observations indicate a marked erythropoietic marrow expansion in patients with thalassaemia intermedia. In fact, such patients, in the absence of surgery, pregnancy or concomitant illnesses, usually do not receive blood transfusions. Consistent with this situation, levels of circulating soluble transferrin receptor, the best estimate of total erythropoiesis in the absence of iron deficiency, were found to be lower in patients with thalassaemia major than in patients with thalassaemia intermedia. Interestingly, in the study by Ricchi et al., patients with severe forms of thalassaemia intermedia had particularly low levels of cholesterol. Finally, in a study evaluating hypocholesterolaemia among thalassaemia intermedia patients, a significant inverse correlation was found between cholesterol level and soluble transferrin receptor. Further studies are needed to better elucidate the relationship between Hb and cholesterol level and other parameters of erythropoietic activity, such as soluble transferrin receptor, reticulocyte count and extramedullary erythropoiesis in patients affected by thalassaemia.

• #72 Hypocholesterolaemia in Thalassaemia – Pathogenesis, Implications and Clinical Effects – touchONCOLOGY

  https://touchoncology.com/haematology/journal-articles/hypocholesterolaemia-in-thalassaemia-pathogenesis-implications-and-clinical-effects/

  The pathogenetic mechanism for hypocholesterolaemia was investigated in a interesting study conducted using a model of artificial microemulsion termed LDE (a cholesterol-rich microemulsion), whose composition resembled that of LDL. It was demonstrated that LDL clearance, the mechanism that removes LDL from the circulation, was enhanced in heterozygous -thalassaemia patients. However, despite the fact that hypocholesterolaemia in thalassaemia was first described many years ago, there is no definitive explanation for the mechanism underlying this clinical condition in severe forms of thalassaemia. Two main pathogenetic mechanisms have been proposed: the presence of enhanced cholesterol consumption required for cell membrane formation, and the presence of a hyperplastic and overactive reticuloendothelial system, which may be responsible for an increased uptake of LDL. The first mechanism seems to be the more complete and would also explain the difference always reported in cholesterol level among patients with thalassaemia intermedia and major. In fact, in the studies by Ricchi and by Hartman it was clearly demonstrated that patients with thalassaemia intermedia have both lower cholesterol and lower haemoglobin (Hb) levels than patients with thalassaemia major. In both studies, patients were accurately selected by eliminating biases (severe liver disorders, hyperthyroidism, fat malabsorption and other factors that could per se modify cholesterol levels). According to current guidelines, patients with thalassaemia major have pre-transfusional Hb ranging from 9.5 to 10g/dl, with the aim being to reduce erythroid marrow activity. These data may strongly support the hypothesis that the consistently high Hb levels in chronically transfused patients (with thalassaemia major) may mean that this group of patients can sustain a more complete degree of marrow suppression with respect to that present in thalassaemia intermedia patients. Therefore, in patients with thalassaemia intermedia, a particularly accelerated erythropoiesis and enhanced cholesterol consumption for red cell membrane formation could be responsible for the lower levels of cholesterolaemia. In support of this hypothesis, several clinical and biochemical observations indicate a marked erythropoietic marrow expansion in patients with thalassaemia intermedia. In fact, such patients, in the absence of surgery, pregnancy or concomitant illnesses, usually do not receive blood transfusions. Consistent with this situation, levels of circulating soluble transferrin receptor, the best estimate of total erythropoiesis in the absence of iron deficiency, were found to be lower in patients with thalassaemia major than in patients with thalassaemia intermedia. Interestingly, in the study by Ricchi et al., patients with severe forms of thalassaemia intermedia had particularly low levels of cholesterol. Finally, in a study evaluating hypocholesterolaemia among thalassaemia intermedia patients, a significant inverse correlation was found between cholesterol level and soluble transferrin receptor. Further studies are needed to better elucidate the relationship between Hb and cholesterol level and other parameters of erythropoietic activity, such as soluble transferrin receptor, reticulocyte count and extramedullary erythropoiesis in patients affected by thalassaemia.

• #73 Pathophysiology and treatment of patients with… | F1000Research

  https://f1000research.com/articles/6-2156

  However, this attempt is futile (ineffective erythropoiesis) due to oxidative stress-increased apoptosis and abortive differentiation. […] The key pathophysiological mechanism leading to the ineffective erythropoiesis in -thal is the continuous production and accumulation of free excess -globin in the erythroid precursors. […] In -thal, oxidative stress is mainly the consequence of the unstable Hbs (hemichromes) and IO and it mediates many of its symptoms due to oxidative damage to RBCs (anemia), platelets, (hypercoagulable state) and leukocytes (recurrent infections) as well as cells in various vital organs (heart and liver) and the endocrine glands. […] Although oxidative stress is not the primary etiology of thal, it plays a major role in its pathophysiology. […] The transcription factor forkhead box O3 (Foxo3) is a key player in the development of erythroid precursors. […] In -thal mice, Foxo3 is downregulated in late erythroid precursors owing to hyper-activation of the EPOR-PI3K/AKT/mTOR pathway, which leads to oxidative damage and ineffective erythropoiesis. […] The main therapeutic modality is blood transfusion that improves the anemia but exacerbates IO.

• #74 Pathophysiology and treatment of patients with… | F1000Research

  https://f1000research.com/articles/6-2156

  However, this attempt is futile (ineffective erythropoiesis) due to oxidative stress-increased apoptosis and abortive differentiation. […] The key pathophysiological mechanism leading to the ineffective erythropoiesis in -thal is the continuous production and accumulation of free excess -globin in the erythroid precursors. […] In -thal, oxidative stress is mainly the consequence of the unstable Hbs (hemichromes) and IO and it mediates many of its symptoms due to oxidative damage to RBCs (anemia), platelets, (hypercoagulable state) and leukocytes (recurrent infections) as well as cells in various vital organs (heart and liver) and the endocrine glands. […] Although oxidative stress is not the primary etiology of thal, it plays a major role in its pathophysiology. […] The transcription factor forkhead box O3 (Foxo3) is a key player in the development of erythroid precursors. […] In -thal mice, Foxo3 is downregulated in late erythroid precursors owing to hyper-activation of the EPOR-PI3K/AKT/mTOR pathway, which leads to oxidative damage and ineffective erythropoiesis. […] The main therapeutic modality is blood transfusion that improves the anemia but exacerbates IO.

• #75 Pathophysiology and treatment of patients with… | F1000Research

  https://f1000research.com/articles/6-2156

  Thalassemia (thal) is an autosomal recessive, hereditary, chronic hemolytic anemia due to a partial or complete deficiency in the synthesis of -globin chains (-thal) or -globin chains (-thal) that compose the major adult hemoglobin. […] The unpaired globin chains are unstable; they precipitate intracellularly, resulting in hemolysis, premature destruction of red blood cell [RBC] precursors in the bone marrow, and a short life-span of mature RBCs in the circulation. […] The breakdown products of Hb, heme and iron, catalyze chemical reactions that generate free radicals, including reactive oxygen species (ROS), which in excess are toxic, causing damage to vital organs such as the heart and liver and the endocrine system. […] The chronic anemia and its associated hypoxia in thal stimulate increased production of RBCs (chronic stress erythropoiesis). This is mediated by overproduction of erythropoietin (EPO), the main erythropoietic stimulating hormone, and other factors, such as members of the transforming growth factor (TGF)- and activin receptor-II (ActR-II) trap ligands.

• #76 Pathophysiology and treatment of patients with… | F1000Research

  https://f1000research.com/articles/6-2156

  However, this attempt is futile (ineffective erythropoiesis) due to oxidative stress-increased apoptosis and abortive differentiation. […] The key pathophysiological mechanism leading to the ineffective erythropoiesis in -thal is the continuous production and accumulation of free excess -globin in the erythroid precursors. […] In -thal, oxidative stress is mainly the consequence of the unstable Hbs (hemichromes) and IO and it mediates many of its symptoms due to oxidative damage to RBCs (anemia), platelets, (hypercoagulable state) and leukocytes (recurrent infections) as well as cells in various vital organs (heart and liver) and the endocrine glands. […] Although oxidative stress is not the primary etiology of thal, it plays a major role in its pathophysiology. […] The transcription factor forkhead box O3 (Foxo3) is a key player in the development of erythroid precursors. […] In -thal mice, Foxo3 is downregulated in late erythroid precursors owing to hyper-activation of the EPOR-PI3K/AKT/mTOR pathway, which leads to oxidative damage and ineffective erythropoiesis. […] The main therapeutic modality is blood transfusion that improves the anemia but exacerbates IO.

• #77 Pathophysiology and treatment of patients with… | F1000Research

  https://f1000research.com/articles/6-2156

  However, this attempt is futile (ineffective erythropoiesis) due to oxidative stress-increased apoptosis and abortive differentiation. […] The key pathophysiological mechanism leading to the ineffective erythropoiesis in -thal is the continuous production and accumulation of free excess -globin in the erythroid precursors. […] In -thal, oxidative stress is mainly the consequence of the unstable Hbs (hemichromes) and IO and it mediates many of its symptoms due to oxidative damage to RBCs (anemia), platelets, (hypercoagulable state) and leukocytes (recurrent infections) as well as cells in various vital organs (heart and liver) and the endocrine glands. […] Although oxidative stress is not the primary etiology of thal, it plays a major role in its pathophysiology. […] The transcription factor forkhead box O3 (Foxo3) is a key player in the development of erythroid precursors. […] In -thal mice, Foxo3 is downregulated in late erythroid precursors owing to hyper-activation of the EPOR-PI3K/AKT/mTOR pathway, which leads to oxidative damage and ineffective erythropoiesis. […] The main therapeutic modality is blood transfusion that improves the anemia but exacerbates IO.

• #78

  https://journals.lww.com/md-journal/fulltext/2021/11120/molecular_genetics_of___thalassemia__a_narrative.4.aspx

  -thalassemia is a hereditary hematological disease caused by over 350 mutations in the -globin gene (HBB). Identifying the genetic variants affecting fetal hemoglobin (HbF) production combined with the -globin genotype provides some prediction of disease severity for -thalassemia. […] Genetic studies have successfully characterized the causal variants and pathways involved in HbF regulation, providing novel therapeutic targets for HbF reactivation. […] Advances in understanding the underlying pathophysiology of -thalassemia have enabled clinicians and researchers to develop novel therapeutic modalities. […] Differences in the severity of the phenotype are usually related to the extent of imbalance between – and non–globin chain synthesis and the predominance of the free -chain. […] The first primary determinant of -thalassemia severity is the type of allele (0, +, ++), ameliorated by coinheritance of interacting -thalassemia and coinheritance of an innate ability to increase the production of chains.

• #79 Thalassemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK545151/

  Thalassemia is autosomal recessive, which means both the parents must be affected with or carriers for the disease to transfer it to the next generation. […] It is caused by mutations or deletions of the Hb genes, resulting in underproduction or absence of alpha or beta chains. […] There are over 200 mutations identified as the culprits for causing thalassemias. […] Alpha thalassemia is caused by deletions of alpha-globin genes, and beta thalassemias are caused by a point mutation in splice site and promoter regions of the beta-globin gene on chromosome 11. […] Thalassemia treatment depends on the type and severity of the disease. […] Gene therapy: It is the latest advancement in severe thalassemia management. […] These techniques target specific mutation sites and replace them with the normal sequence.

• #80 Beta-Thalassemia: A Pharmacological Drug-Based Treatment

  https://www.mdpi.com/2813-2998/3/1/8

  Ineffective erythropoiesis is often caused by increased activity of tumor growth factor β (TGF-β) superfamily ligands during later-stage erythropoiesis, which inhibits the growth of erythroid precursors. The SMAD2/3 pathway—in particular, SMAD2/3 signaling—is involved in this inhibitory effect. TGF-β superfamily ligands activate specific receptors during maturation, including ActRIIB, which elevates the phosphorylation of SMAD2/3 protein, halting erythroid maturation and reducing the number of red blood cells. Luspatercept is a medication that promotes erythroid maturation by acting as a ligand trap and competing with ActRIIB to bind to TGF-β superfamily ligands. By decreasing abnormally elevated SMAD2/3 signaling, luspatercept helps to regulate erythroid maturation and improve red blood cell production.

• #81 Beta-Thalassemia: A Pharmacological Drug-Based Treatment

  https://www.mdpi.com/2813-2998/3/1/8

  Sotatercept is a ligand trap that prohibits TGF-β superfamily members, including ActRB and GDF-11. In β-thalassemia, overexpressed GDF-11 causes maturation arrest of late erythroid precursors and defective erythropoiesis. In preclinical studies, it was found that taking an ActRIIA ligand trap reduced GDF-11 amount, decreased the levels of reactive oxidative stress, and advanced terminal maturation in infant erythroblasts. […] Mitapivat of the PKR tetramer binds to an allosteric site that is different from that of FBP, allowing for the activation of the enzyme in both its wild-type and mutant forms. The latter allows activation even in many mutant PKR enzymes that are not induced by FBP. Through this mechanism, it may prove beneficial in the treatment of hemolytic anemias characterized by elevated erythrocyte energy demands and pyruvate-kinase-deficient states (PKD specifically).

• #82

  https://journals.lww.com/md-journal/fulltext/2021/11120/molecular_genetics_of___thalassemia__a_narrative.4.aspx

  Several algorithms have been designed to reduce the pathological imbalance of the / ratio using several nucleic acid-based technologies such as RNAi, lentiviral mediated gene therapy, splice-switching oligonucleotides, and gene-editing technology. […] The primary variation in -thalassemia is seen as different mutations, ranging from silent to dominantly inherited mutations. […] The critical pathophysiological mechanism leading to IE in -thalassemia is the continual production of -globin and accumulation of complementary excess -globin in erythroid precursor cells. […] The discovery of Janus kinase 2 (JAK2) as a vital mediator of IE and splenomegaly in -thalassemia indicated that the application of small organic molecules to inhibit JAK2 could reduce IE and splenomegaly. […] The central regulator of iron homeostasis, hepcidin, is chronically repressed in this disorder, leading to unchecked intestinal iron absorption and consequent iron overload. […] Recent discoveries and understanding of the switch from fetal to adult hemoglobin have opened up new pharmacological and genetic targets for HbF reactivation.

• #83 A comprehensive review of hydroxyurea for β-haemoglobinopathies: the role revisited during COVID-19 pandemic | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-021-01757-w

  Hydroxyurea is one of the earliest drugs that showed promise in the management of haemoglobinopathies that include -thalassaemia and sickle cell disease. […] However, during COVID-19 pandemic, it has become a valuable adjunct to transfusion therapy in patients with -haemoglobinopathies. […] Hydroxyurea is an S-phase-specific drug that reversibly inhibits ribonucleoside diphosphate reductase enzyme which catalyses an essential step in the DNA biosynthesis. […] Through several molecular pathways described in this review, hydroxyurea exerts many favourable effects on the haemoglobin content, red blood cell indices, ineffective erythropoiesis, and blood rheology in patients with -haemoglobinopathies. […] Hydroxyurea is one of the medications that has shown promise in achieving this. […] The primary mechanism of action of hydroxyurea in -haemoglobinopathy is upregulation of -globin gene expression in erythroid cells.

• #84 A comprehensive review of hydroxyurea for β-haemoglobinopathies: the role revisited during COVID-19 pandemic | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-021-01757-w

  Hydroxyurea has shown to enhance the F cell percentage in the circulations through several mechanisms. […] Hydroxyurea improves the clinical severity of haemoglobinopathies by influencing the haemorheology. […] Hydroxyurea is a cytotoxic drug which was initially prescribed for malignancies. […] Hydroxyurea induces stress erythropoiesis by inhibiting the synthesis of DNA, thus giving a selective advantage to the expansion of the F cell population over the rapidly dividing HbA producing erythroid progenitors. […] Hydroxyurea exerts a bi-modal effect on erythropoiesis in a dose-dependent manner by downregulating the expression of GATA1 and upregulating GATA2. […] Hydroxyurea alters the expression of several microRNAs (miR) which act on these molecular targets to induce fetal haemoglobin.

• #85 Beta-Thalassemia: A Pharmacological Drug-Based Treatment

  https://www.mdpi.com/2813-2998/3/1/8

  Hydroxyurea (HU) increases the production of HbF, which is the main carrier of oxygen. To explain HbF induction, two mechanisms have been proposed. […] By phosphorylating ULK1 (encoded by ULK1 gene), mTORC1 inhibits autophagy. Inhibition of mTORC1 can improve thalassemia by enhancing autophagic removal of free globin. […] By depleting DNA methyltransferase-1 (DNMT1), decitabine can inhibit DNA methylation and other changes. Thus, it activates β-globin gene (HBG) expression. HB expression maintains a β/non-β chain balance, which results in effective erythropoiesis. Thus, matured RBC forms.

• #86

  https://journals.lww.com/md-journal/fulltext/2021/11120/molecular_genetics_of___thalassemia__a_narrative.4.aspx

  Several algorithms have been designed to reduce the pathological imbalance of the / ratio using several nucleic acid-based technologies such as RNAi, lentiviral mediated gene therapy, splice-switching oligonucleotides, and gene-editing technology. […] The primary variation in -thalassemia is seen as different mutations, ranging from silent to dominantly inherited mutations. […] The critical pathophysiological mechanism leading to IE in -thalassemia is the continual production of -globin and accumulation of complementary excess -globin in erythroid precursor cells. […] The discovery of Janus kinase 2 (JAK2) as a vital mediator of IE and splenomegaly in -thalassemia indicated that the application of small organic molecules to inhibit JAK2 could reduce IE and splenomegaly. […] The central regulator of iron homeostasis, hepcidin, is chronically repressed in this disorder, leading to unchecked intestinal iron absorption and consequent iron overload. […] Recent discoveries and understanding of the switch from fetal to adult hemoglobin have opened up new pharmacological and genetic targets for HbF reactivation.

• #87 SciELO Brazil – Thalassemia, a human blood disorder Thalassemia, a human blood disorder

  https://www.scielo.br/j/bjb/a/73sD7WKNCqMVfBgh6zsTkSQ/

  The imbalanced alpha and beta chain synthesis (that is usual) induces aggregation of beta chains inside the RBCs. […] The severe irregularity of globin chain synthesis (alpha beta) brings about extreme microcytic hypochromic anemia. […] The condition results in death before age twenty. […] Regular blood transfusions and extensive continuous therapeutic care are required throughout life in this type of anemia. […] Without treatment, this overabundant iron will be stored in the liver, heart, spleen, and other organs and could prompt a sudden death due to major systemic failure. […] A novel CRISPR technology to edit faulty genes is a new game changer that showed promising results in disease models that made it a new hope to the diseased. […] The CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) along with the CRISPR-associated system, Cas (known as Crispr-Cas) is a powerful gene editing tool which has revolutionized the field of molecular biology in terms of gene therapies to treat hereditary genetic disorders.

• #88 Thalassemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK545151/

  Thalassemia is autosomal recessive, which means both the parents must be affected with or carriers for the disease to transfer it to the next generation. […] It is caused by mutations or deletions of the Hb genes, resulting in underproduction or absence of alpha or beta chains. […] There are over 200 mutations identified as the culprits for causing thalassemias. […] Alpha thalassemia is caused by deletions of alpha-globin genes, and beta thalassemias are caused by a point mutation in splice site and promoter regions of the beta-globin gene on chromosome 11. […] Thalassemia treatment depends on the type and severity of the disease. […] Gene therapy: It is the latest advancement in severe thalassemia management. […] These techniques target specific mutation sites and replace them with the normal sequence.

• #89 SciELO Brazil – Thalassemia, a human blood disorder Thalassemia, a human blood disorder

  https://www.scielo.br/j/bjb/a/73sD7WKNCqMVfBgh6zsTkSQ/

  The imbalanced alpha and beta chain synthesis (that is usual) induces aggregation of beta chains inside the RBCs. […] The severe irregularity of globin chain synthesis (alpha beta) brings about extreme microcytic hypochromic anemia. […] The condition results in death before age twenty. […] Regular blood transfusions and extensive continuous therapeutic care are required throughout life in this type of anemia. […] Without treatment, this overabundant iron will be stored in the liver, heart, spleen, and other organs and could prompt a sudden death due to major systemic failure. […] A novel CRISPR technology to edit faulty genes is a new game changer that showed promising results in disease models that made it a new hope to the diseased. […] The CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) along with the CRISPR-associated system, Cas (known as Crispr-Cas) is a powerful gene editing tool which has revolutionized the field of molecular biology in terms of gene therapies to treat hereditary genetic disorders.

• #90 Thalassemia: Types, Traits, Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/14508-thalassemias

  Your anemia symptoms and how severe your condition is depends on how many genes are defective and which part of the beta globin protein chain contains the defect. […] Standard treatments for thalassemia major are blood transfusions and iron chelation. […] A bone marrow transplant from a compatible sibling offers the best chance at a cure for thalassemia. […] Heart disease from iron overload is the leading cause of death in people with thalassemia, so keeping up with your iron chelation therapy is extremely important.

• #91

  https://link.springer.com/article/10.1007/BF01958947

  The observed clinical variability of -thalassaemia can be explained by the heterogeneity of pathological changes of the -globin gene cluster. […] It can be seen that the clinical expression of this monogenic trait depends on the nature of the -globin gene lesion itself as well as on influences exerted by genetic changes affecting the – and the -globin genes. […] Practically, the advances in the molecular understanding of this disease facilitated selective screening and prenatal diagnosis programmes resulting in a much decreased burden of medical services particularly in endemic countries such as Cyprus or Sardinia. […] Much effort is presently directed towards the improvement of patient management by developing somatic gene therapy strategies. […] However, it will probably take quite some time before this option will be available to the peadiatrician in clinical practice.

• #92 Diagnosis of thalassemia (adults and children) – UpToDate

  https://www.uptodate.com/contents/diagnosis-of-thalassemia-adults-and-children/print

  The thalassemias are a group of hemoglobinopathies in which the normal ratio of alpha globin to beta globin production is disrupted due to a genetic variant in one or more alpha or beta globin genes. This abnormal alpha chain to beta chain ratio causes the unpaired chains to precipitate, leading to destruction of red blood cell (RBC) precursors in the bone marrow (ineffective erythropoiesis) and in the circulation (hemolysis). Individuals with thalassemia have variable degrees of anemia and extramedullary hematopoiesis, which in turn can cause bone changes, impaired growth, and iron overload. […] The pathogenesis and treatment of thalassemia, including the role of hematopoietic stem cell transplantation, monitoring of iron stores, and iron chelation, are discussed in detail separately. […] Pathogenesis – (See „Pathophysiology of thalassemia”.)

• #93 Thalassemia – Hemolytic Anemias – Anemia and Other Nonmalignant Blood Disorders – Hematology – Diseases – McMaster Textbook of Internal Medicine

  https://empendium.com/mcmtextbook/chapter/B31.II.15.53.

  Thalassemia is a chronic inherited anemia, most commonly caused by reduced (+) or absent (0) synthesis of alpha-globin and/or beta-globin chains, the key protein components of the adult hemoglobin (Hb) tetramer, HbA (alpha2beta2) (Table 1). […] The imbalanced production of globin chains leads to excess of the unaffected globin chain (eg, excess alpha-globin chains in beta thalassemia), which is unstable, resulting in ineffective intramedullary erythropoiesis (decreased Hb production) and extramedullary hemolysis (reduced red blood cell [RBC] survival).

• #94 Thalassemia pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Thalassemia_pathophysiology

  The pathophysiology of alpha- and beta-thalassemia involves abnormal production of globin chains. […] The pathogenesis of thalassemias can involve a various of mutational events, such as deletions, insertions, or point mutations (substitutions). […] The altered genetic sequence results in a gene product (protein) that is nonfunctional or dysfunctional, such that the new globin chain cannot effective deliver oxygen to peripheral tissues. […] The number of alleles that are lost on each globin-cluster determines the severity of the disease. […] Regardless of the type of mutation, the thalassemias are inherited in a Mendelian autosomal recessive fashion. […] Alpha-thalassemias result in decreased alpha-globin production, therefore fewer alpha-globin chains are produced, resulting in an excess of beta-chains in adults and excess gamma-globin chains in newborns.

• #95 Thalassemia: Types, Traits, Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/14508-thalassemias

  Thalassemia is an inherited blood disorder that affects your bodys ability to produce hemoglobin and healthy red blood cells. […] If you have thalassemia, your body produces fewer healthy hemoglobin proteins, and your bone marrow produces fewer healthy red blood cells. […] Hemoglobin consists of four protein chains, two alpha globin chains and two beta globin chains. Each chain both alpha and beta contains genetic information, or genes, passed down from your parents. […] The thalassemia you have depends on whether your alpha or beta chain contains the genetic defect. The extent of the defect will determine how severe your condition is. […] Thalassemia is classified as trait, minor, intermedia and major to describe how severe the condition is. […] You inherit four genes, two from each parent, that make alpha globin protein chains. When one or more genes are defective, you develop alpha thalassemia.

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