All forms of beta-globin chain disease results in an underproduction of Hg A.

Unpaired alpha globin chains in red blood cells cause dyserythropoeisis and hemolysis.

Deficient production of beta globin chains leads to the accumulation of excess, unstable alpha-globin tetramers in erythroid cells.

In beta thalassemia, an excess of unpaired alpha globulin impedes red cell development and survival, leading to ineffective erythropoiesis, hemolysis, chronic anemia, and compromised quality of life.

Peripheral hemolysis causes red blood cells to express prothrombotic markers on their surface, promoting a hypercoagulable state which can manifest is venous or arterial thrombosis, pulmonary hypertension, cerebr0vascular events, including infarcts which increase with aging.

The above complications are more common in patients with non-transfusion dependent beta thalassemia than in patients with transfusion dependent beta thalassemia as those receiving transfusions have an amelioration of anemia and ineffective erythropoiesis.

For patients who undergo splenectomy there is increased vascular morbidity, as reversing the scavenger role of the spleen in ridding  the body of pathologic red blood cells.

Free Alpha-globin protein is unstable and generates cytotoxic reactive oxygen species and cellular precipitates that impaired the maturation in viability of red blood cell precursors, resulting in ineffective erythropoiesis  and premature hemolysis of circulating red cells.

Patients with identical beta-globin genotypes may have very different clinical phenotypes ranging from transfusion dependent beta-thalassemia major to mild forms of thalassemia intermedia.

Patients with severe beta-Thalassemia mutations in the homozygous or compound heterozygous state have more severe clinical manifestations, whereas patients who coinherit Alpha Thalassemia tend to have milder disease.

Variation in increased gamma globin synthesis or decrease in gamma globin synthesis act as modifiers of beta-thalassemia.

The degree of imbalance between alpha-globin and beta-globin can be reduced by the more effective synthesis of gamma-globin chainsand hemoglobin F after birth.

The three most common are coinheritance of a mild β-thalassemia allele, hemoglobin H, and hemoglobin E/β, due to coinheritance of a β thalassemia allele and allele for βE-globin.

The three main leader thalassemia phenotypes are assigned on the basis of clinical presentation,: beta thalassemia trait, or beta thalassemia minor which results from heterogeneous inheritance of beta-thalassemia mutation and is characterized by borderline asymptomatic anemia with microcytosis and hypochromia, and beta thalassemia major.

Patients with beta-thalassemia minor have a higher hospitalization rate and morbidity among these patients than controls without explanation.

Patients with beta thalassemia have ineffective erythropoiesis and peripheral hemolysis leading to a state of chronic anemia that can cause growth and developmental delay, fatigue, leg ulcers, and can promote organ failure in adolescents and young adults.

Clinical symptoms in all thalassemias arise less from impaired hemoglobin production, and more from accumulation of unpaired globin chains produced in normal amounts.

Accumulation of the globin chains results because of the deficit in synthesis of the affected chain and are therefore highly unstable.

Ineffective erythropoiesis leads to bone marrow expansion and osseous changes associated with pain and deformity, accounting for characteristic features of beta thalassemia such as cranial facial protrusions.

Extra medullary foci of hematopoiesis in the spleen and liver and other tissues of the body can occur in the development of pseudo tumors: they can emerge in the paraspinal canal or chest and cause compression syndromes that may require emergency management.

Beta thalassemia carriers account for approximately 1.5% of the world population, and around 40,000 infants are born each year with beta thalassemia with half classified as transfusion dependent.

More than 90% of patients with beta thalassemia live in areas extending from Africa to southern Europe and the Middle East, toward Southeast Asia.

In some countries including Cyprus, Greece and Italy screening and prevention programs reduced the number of affected individuals.

Accumulation of unpaired globin chains causes precipitation of inclusion bodies that damage mitochondria, nuclear and plasma membranes of developing erythroblasts, and cause apoptosis resulting in premature death of developing erythroid precursors.

Extramedullary hematopoiesis results when ineffective erythropoiesis is severe or prolonged.

Pulmonary hypertension is a common complication in severe forms of thalassemia

Supportive measures include: folic acid replacement and monitoring for the development of pulmonary hypertension, osteoporosis, and bone fractures, poor dentition, heart failure, and aplastic crisis with parvovirus B-19 infection.

Long-term transfusion therapy can support an maintain the patient’s hemoglobin level at 9-10 g/dL, thus improving well being while simultaneously suppressing enhanced erythropoiesis, extramedullary hematopoiesis and skeletal changes.

Iron overload is a major clinical consideration in beta thalassemia and is measured through analysis of serum ferritin and MRI imaging of the heart and liver (T2 imaging).

In patients with transfusion dependent  beta thalassemia, transfusional iron intake saturates the capacity of serum transferrin and leads to the emergence of non-transferrin bound iron species that accumulate in body tissues, commonly liver, followed by the heart and endocrine organs, causing damage to vital organs.

Serum ferritin levels above 2500 ng/mL are associated with an increased risk of heart disease and death, whereas levels below 1000 ng/mL are associated with prolonged survival.

Liver iron levels above 7 mg per gram are associated with increase risks of liver disease, ink levels above 15 mg per gram or associated with increased risk of heart disease.

Patients receiving long-term transfusion therapy also require iron chelation management.

Patients with non-transfusion dependent beta thalassemia may have elevated ferritin levels and have hepatic fibrosis, proteinuria, renal failure, and endocrine and bone disease and cancers, endothelial damage and hypercoagulability due to ineffective erythropoiesis.

Advancing age is an important risk factor for complications associated with beta thalassemia-vascular and hepatic diseases.

Blood banking typing of erythrocytes for Rh and ABO antigens prior to the first transfusion helps future cross-matching processes and minimizes the chances of alloimmunization.

Washed, leukocyte-poor red blood cells is recommended.

Allogeneic hematopoietic transplantation may be curative in some patients with thalassemia major.

Studies have shown up to 90% long-term survival rate in patients with favorable characteristics such as, young age, HLA match, and no organ dysfunction.

Gene therapy by harvesting autologous hematopoietic stem cells And then genetically modifying them with a lentiviral vector expressing a normal globin gene is presently being investigated.

Betibeglogene autotemecel Gene therapy can result in sustained hemoglobin A levels and a total hemoglobin level high enough to enable transfusion independence in most patients with beta thalassemia, including those younger than 12 years of age.

After appropriate conditioning therapy to destroy existing stem cells, the modified hematopoietic stem cells are reinfused into the patient.

Allogeneic hematopoietic stem cell transplantation is a potentially curative therapy, with the best outcomes in patients younger than 14 years of age who have an HLA identical donor.

CRISPR-Cas9 CD34 cell targeting of the BC11A transcription factor increases fetal hemoglobin.

Xagamglogene autotemcel cell (exa-cel)is a non-viral cell therapy designed to reactivate fetal hemoglobin synthesis by means of ex vivo clustered, regularlyinterspersed, short palindrome repeats (CRISPR)-CAS9 gene editing of autologous CD34 positive in hematopoietic stem and progenitor cells at the erythroid specific enhancer region of BCL11A.

Treatment with exa-cell, preceded by myeloablation resulted in transfusion independence in 91% of patients with transfusion dependent beta-thalassemia.

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