Beta thalassemia (BT) is a hereditary disease that affects the formation of the beta chains of the hemoglobin molecule. This leads to the defective hemoglobin and red blood cell production resulting in hemolysis. In the majority of cases, BT is an autosomal recessive disease, however, there are reported cases of an autosomal dominant variant of the disease. BT is more common in certain regions, such as the Mediterranean, Africa, and Asia. This disease may be classified into three categories (BT major, intermedia, and minor) depending on whether affected individuals are homozygous or heterozygous. Moreover, it can occur simultaneously with other abnormalities of hemoglobin formation. Consequently, BT varies widely in its presentation.

BT major (Cooley anemia) is usually diagnosed before the age of 2 years. The major features include hemolytic anemia, microcytic and hypochromic red blood cells, splenomegaly, failure to thrive, diarrhea, growth retardation, fever, and vomiting. Additional features of BT major are leg ulcers, the thickening of the cranium (due to hyperactive bone marrow), increased frequency of long bone fractures, and stunting. Regular blood transfusions are required to manage this condition and consequently, manifestations of iron overload are seen. These may be cardiac in nature, exemplified by heart failure, pericarditis, and dilated myocardiopathy. Liver cirrhosis secondary to iron deposition is also common, along with an increased risk of hepatitis and hepatocellular carcinoma [1]. Furthermore, iron overload can lead to delayed sexual maturation, hypogonadism, diabetes mellitus, and hormonal imbalance caused by the dysfunction of the thyroid, parathyroid, and pituitary glands [2]. Most BT deaths occur due to cardiac complications pericarditis and dilated cardiomyopathy) [3]. Infectious complications, such as human immunodeficiency virus infection and hepatitis viruses B and C infection are also possible in patients receiving multiple transfusions, but are less frequent nowadays due to vaccination and blood screening methods. Other complications may include osteoporosis, hypersplenism, venous thrombosis and pulmonary hypertension.

Affected individuals who do not receive proper therapy have pale or brown pigmented skin or are affected by jaundice. They have a particular appearance with mongoloid eyes, bossing of the skull, depressed nose bridge, maxillary hypertrophy, prominent malar eminence and genu valgus.

BT intermedia is often diagnosed later in life than the major form and exhibits less severe symptoms. These may include splenomegaly, iron overload, and cholelithiasis.

People who have the BT trait, otherwise referred to as BT minor, have a heterozygous genotype and typically do not experience any symptoms.

• Splenomegaly

  splenomegaly with non-distinctive hematologic features. [ncbi.nlm.nih.gov]

  Anemia with splenomegaly such as myelofibrosis, chronic lymphocytic leukemia, and mantle cell lymphoma. [visualdx.com]

  Patients with Hb H disease often have symptomatic hemolytic anemia and splenomegaly. [merckmanuals.com]

• Anemia

  This condition causes severe symptoms with life-threatening anemia that requires regular blood transfusions. [kidshealth.org]

  In these cases, one copy of the altered gene in each cell is sufficient to cause the signs and symptoms of beta thalassemia. erythroblastic anemia Mediterranean anemia microcytemia, beta type thalassemia, beta type Akhavan-Niaki H, Derakhshandeh-Peykar [ghr.nlm.nih.gov]

  It is also called thalassemia minor (thalassemia trait) in its mild form and Cooley’s anemia (or thalassemia major) when severe. [momjunction.com]

  The symptoms vary from none to severe anemia. [news-medical.net]

  Beta thalassemia major is also known as Cooley’s anemia. [rarediseases.org]

• Asymptomatic

  The genotypic spectrum includes homozygous and heterozygous defects, which result in a phenotypic spectrum ranging from transfusion dependence to the asymptomatic carrier state. [bestpractice.bmj.com]

  Thalassemia minor is clinically asymptomatic but some subjects may have moderate anemia. [ncbi.nlm.nih.gov]

  The heterozygous form may be asymptomatic or marked by mild anemia. β-thalassemia ( beta-thalassemia ) that caused by diminished synthesis of beta chains of hemoglobin. [medical-dictionary.thefreedictionary.com]

  Prototypical Forms of Alpha Thalassemia Variant Chromosome 16 Signs and symptoms Alpha thalassemia silent carrier One of four gene deletions Asymptomatic Alpha thalassemia trait Two of four gene deletions Asymptomatic Hemoglobin Constant Spring Reduced [aafp.org]

• Fatigue

  Affected individuals also have anemia, which can cause pale skin, weakness, fatigue, and more serious complications. People with beta thalassemia are at an increased risk of developing abnormal blood clots. [ascopost.com]

  “Inadequate transfusion increases the risk of certain complications of thalassemia and results in chronic fatigue.” Beyond fatigue, under-treatment of anemia can hinder growth and even lead to heart failure. [celgene.com]

  With thalassemia, the red blood cells are destroyed at a faster rate, leading to anemia, a condition that can cause fatigue and other complications. [kidshealth.org]

  The reduced levels of red blood cells can lead to a number of health issues including dizziness, weakness, fatigue, bone abnormalities and more serious complications. [ajmc.com]

  You can also take steps on your own to cope with fatigue, such as choosing a healthy diet and exercising regularly. [mayoclinic.org]

• Pain

  Occasionally, pain and stiffness in the arms, legs or back can occur as blood clumps up in the vessels. Others problems can include an increased risk of infection, an enlarged spleen, eye problems and more. [nicklauschildrens.org]

  Painful episodes – The pain of sickling disorders is acute and can be quite severe; even very young children may require prescription medications for pain relief. [idph.state.il.us]

  Five percent of patients discontinued treatment with luspatercept in the trial due to AEs, most commonly due to arthralgia (1%), back pain (1%), bone pain (<1%), and headache (<1%). [targetedonc.com]

  The most common adverse reactions (> 10%) were headache, bone pain, arthralgia, fatigue, cough, abdominal pain, diarrhea, and dizziness. The recommended starting dose is 1 mg/kg once every 3 weeks by subcutaneous injection. [ascopost.com]

  The most common adverse reactions (>10%) in patients with beta thalassemia were headache, bone pain, arthralgia, fatigue, cough, abdominal pain, diarrhea, and dizziness. FDA granted this application fast track and orphan drug designations. [fda.gov]

• Splenectomy

  (Patients with thalassemia minor only rarely require splenectomy.) [emedicine.medscape.com]

  Keywords: Anesthesia, beta thalassemia, splenectomy How to cite this article: Jyothi B, Sushma K S, Syeda S, Raza SO. Anaesthetic management of beta thalassemia major with hypersplenism for splenectomy in pediatric age group: Report of four cases. [aeronline.org]

  The operation performed most often on the spleen for hematological disorders is splenectomy. Only in some indications such as Gaucher's disease has partial splenectomy replaced total splenectomy. [ncbi.nlm.nih.gov]

  Bilirubin stones, if present, should be removed by laparoscopy or at the same time splenectomy is performed. [symptoma.com]

  Results Patients underwent open splenectomy (47%) and laparoscopic splenectomy (53%). The operative complications were bleeding (13%) and injury to the spleen during port insertion (6%). After splenectomy, the patients were followed up for 1 year. [mmj.eg.net]

• Diarrhea

  The most common adverse reactions (> 10%) were headache, bone pain, arthralgia, fatigue, cough, abdominal pain, diarrhea, and dizziness. The recommended starting dose is 1 mg/kg once every 3 weeks by subcutaneous injection. [ascopost.com]

  The most common adverse reactions (>10%) in patients with beta thalassemia were headache, bone pain, arthralgia, fatigue, cough, abdominal pain, diarrhea, and dizziness. FDA granted this application fast track and orphan drug designations. [fda.gov]

  See thalassemia. β-thalassemia Thalassemia major Hematology A hemoglobinopathy caused by a defect in the synthesis of Hb β chain Clinical Pallor, fatigability, FTT, fever due to infections, diarrhea, bone deformities, hepatosplenomegaly Management Transfusions [medical-dictionary.thefreedictionary.com]

  The most common adverse reactions were headache, bone pain, arthralgia, fatigue, cough, abdominal pain, diarrhea, and dizziness. [mdmag.com]

  3.6% of patients experienced serious adverse reactions, the most common of which were headache (26% for Reblozyl vs 24% for placebo), bone pain (20% vs 8%), arthralgia (19% vs 12%), fatigue (14% vs 13%), cough (14% vs 11%), abdominal pain (14% vs 12%), diarrhea [ajmc.com]

• Failure to Thrive

  Children with beta thalassemia major may have a swollen abdomen or symptoms of anemia or failure to thrive. If the doctor suspects beta thalassemia, he or she will take a blood sample for testing. [kidshealth.org]

  Children develop life-threatening anemia, have failure to thrive, and may develop jaundice. People with BT major are prone to complications such as infection, and osteoporosis. [secure.ssa.gov]

  CASE PRESENTATION: An 8-month-old ethnic Gypsy male infant with failure to thrive from birth, mild jaundice and splenomegaly. Clinical signs were compatible with severe microcytic anemia requiring bi-monthly blood transfusions. [ncbi.nlm.nih.gov]

  They do not gain weight and grow at the expected rate (failure to thrive) and may develop yellowing of the skin and whites of the eyes (jaundice). Affected individuals may have an enlarged spleen, liver, and heart, and their bones may be misshapen. [ghr.nlm.nih.gov]

  The major features include hemolytic anemia, microcytic and hypochromic red blood cells, splenomegaly, failure to thrive, diarrhea, growth retardation, fever, and vomiting. [symptoma.com]

• Vomiting

  Side effects include headache, nausea (feeling sick to the stomach), vomiting, diarrhea, joint pain, and tiredness. Folic Acid Supplements Folic acid is a B vitamin that helps build healthy red blood cells. [nhlbi.nih.gov]

  From about the age of 3 months children with this condition become very pale, lethargic, lose their appetite, have repeated episodes of diarrhoea and vomiting and are prone to picking up infections; they then fail to fail to grow and thrive; if untreated [sickle-thal.nwlh.nhs.uk]

  The major features include hemolytic anemia, microcytic and hypochromic red blood cells, splenomegaly, failure to thrive, diarrhea, growth retardation, fever, and vomiting. [symptoma.com]

  Parents must understand the importance of prompt assessment of the infant by a pediatric hematologist when fever, pallor, unexplained irritability, diarrhea, vomiting or other signs of illness are present. [idph.state.il.us]

• Heart Failure

  Some of the complications include: Heart failure Problems caused by iron overload- these include hypothyroidism, hypoparathyroidism, liver fibrosis, etc. [momjunction.com]

  Without treatment, affected individuals may die early due to diseases such as heart failure. [celgene.com]

  The excessive iron levels lead to iron toxicity, reflected as: growth failure sexual immaturity diabetes mellitus hypofunctioning of several endocrine glands heart failure due to cardiac muscle weakening liver cirrhosis following fibrosis. [news-medical.net]

• Tachycardia

  This complication is characterised by dyspnoea, tachycardia, fever and hypotension during or within six hours of transfusion. [ncbi.nlm.nih.gov]

  Thalassemia patients should be monitored for symptoms of anemia (shortness of breath, hypoxia, tachycardia). These symptoms should improve with blood transfusion. C. Laboratory Tests to Monitor Response To, and Adjustments in, Management. [clinicaladvisor.com]

• Hypotension

  This complication is characterised by dyspnoea, tachycardia, fever and hypotension during or within six hours of transfusion. [ncbi.nlm.nih.gov]

  Characterized by evolution in just a few hours, in association with hypotension, alteration of consciousness, or shock, OPSI is a major concern after splenectomy, with a high mortality risk of 40–50% [17]. [mmj.eg.net]

• Jaundice

  Symptoms In alpha thalassemia there can be no symptoms or in severe cases hemolytic anemia and an enlarged spleen, paleness, jaundice, and fatigue. [differencebetween.net]

  Other symptoms include: poor growth pallor jaundice enlargement of the liver and spleen due to the breakdown of red cells containing the abnormal hemoglobin leg ulcers bone changes secondary to marrow expansion the appearance of other masses due to the [news-medical.net]

  Affected individuals who do not receive proper therapy have pale or brown pigmented skin or are affected by jaundice. [symptoma.com]

  Children develop life-threatening anemia, have failure to thrive, and may develop jaundice. People with BT major are prone to complications such as infection, and osteoporosis. [secure.ssa.gov]

  Diagnostic methods Diagnosis is suspected in infants younger than 2 years of age with severe microcytic anemia, mild jaundice and hepatosplenomegaly. [orpha.net]

• Hepatosplenomegaly

  See thalassemia. β-thalassemia Thalassemia major Hematology A hemoglobinopathy caused by a defect in the synthesis of Hb β chain Clinical Pallor, fatigability, FTT, fever due to infections, diarrhea, bone deformities, hepatosplenomegaly Management Transfusions [medical-dictionary.thefreedictionary.com]

  Chapter 5.104 - Beta Thalassemia Symptoms - Class 12th Biology Principles of Inheritance and Variation Symptoms - Haemolytic Anaemia Hepatosplenomegaly Cardiac Enlargement Skeletal Deformities Biology Class 12th Chapter: Principles of Inheritance and [youtube.com]

  Slight hepatosplenomegaly and possibly a recurrent jaundice in a mild form can be present. Also, target cells can be observed in the blood count. [lecturio.com]

  Findings in untreated or poorly transfused individuals with thalassemia major, as seen in some developing countries, are growth retardation, pallor, jaundice, poor musculature, hepatosplenomegaly, leg ulcers, development of masses from extramedullary [ncbi.nlm.nih.gov]

  Patients may also present with growth retardation, skeletal abnormalities, and hepatosplenomegaly. With regular blood transfusions, life expectancy is good. Without transfusions, life expectancy is limited to a few years. [openanesthesia.org]

• Osteoporosis

  The most common disease-related complications were bone disease, facial deformity (62.3%), and osteoporosis (28.3%), and 3 of those with osteoporosis had bone fractures. [hindawi.com]

  Osteoporosis Osteoporosis in BTM patients is one of the most frequent complications, multiple factors contributing to their appearance, being a major cause of morbidity in these patients as well. [intechopen.com]

  Before AFF, the patient had been treated with zoledronic acid for three years and remained another one year without osteoporosis therapy. [ncbi.nlm.nih.gov]

  Other complications are hypersplenism, venous thrombosis and osteoporosis. [orpha.net]

• Skin Rash

  The most frequent adverse events reported during treatment with DFX include transient, mild-to-moderate gastrointestinal disturbances and skin rash. These events rarely require drug discontinuation and most resolve spontaneously. [ojrd.biomedcentral.com]

  The most common treatment-related adverse events are gastrointestinal disorders, skin rash, and a mild, nonprogressive increase in serum creatinine concentration. 51 Cases of renal failure, hepatic failure, cytopenias, and gastrointestinal hemorrhage [nature.com]

  The most common treatment-related adverse events are gastrointestinal disorders, skin rash, and a mild, nonprogressive increase in serum creatinine concentration. 51. Galanello R. Origa R. [gimjournal.org]

• Dizziness

  The reduced levels of red blood cells can lead to a number of health issues including dizziness, weakness, fatigue, bone abnormalities and more serious complications. [ajmc.com]

  The most common adverse reactions (> 10%) were headache, bone pain, arthralgia, fatigue, cough, abdominal pain, diarrhea, and dizziness. The recommended starting dose is 1 mg/kg once every 3 weeks by subcutaneous injection. [ascopost.com]

  The most common adverse reactions (>10%) in patients with beta thalassemia were headache, bone pain, arthralgia, fatigue, cough, abdominal pain, diarrhea, and dizziness. FDA granted this application fast track and orphan drug designations. [fda.gov]

  The most common adverse reactions were headache, bone pain, arthralgia, fatigue, cough, abdominal pain, diarrhea, and dizziness. [mdmag.com]

• Lethargy

  Critical Essential Core Tested Community Questions (7) (M1.HE.48) A 23-year-old Sicilian male presents to his primary care physician complaining of lethargy, joint pain, and urinary frequency. [medbullets.com]

  If untreated, beta thalassemia major can lead to severe lethargy, paleness, and delays in growth and development. The body attempts to compensate by producing more blood, which is made inside the bones in the marrow. [medical-dictionary.thefreedictionary.com]

• Seizure

  Christine Gleason, a well-known neonatologist specializing in fetal physiology and drug/alcohol effects on the brain.Discusses hot topics such as ethical decisions in the neonatal-perinatal period * maternal medical disorders of fetal significance, seizure [books.google.de]

Beta thalassemia is diagnosed via electrophoresis or high-performance liquid chromatography (HPLC), which are techniques that allow the detection of hemoglobin abnormalities. Non-invasive prenatal diagnosis of BT involves analysis of fetal deoxyribonucleic acid material found in the maternal circulation [4] or by amniocentesis at 14-20 weeks’ gestation or chorionic villi sampling at 8-10 weeks’ gestation. Analysis should be extensive, as over 200 mutations that can cause the disease are known today. They consist of deletions, insertions or gene substitutions.

Electrophoresis and column chromatography show increased hemoglobin A2 levels, up to 4-6%. Severe iron deficiency may mask this manifestation. Hemoglobin F may also be increased. In cases where minor disease is suspected, free erythrocyte porphyrin should be tested. High levels will be found in iron deficiency patients and lead poisoning cases, while normal levels are encountered in beta thalassemia trait individuals.

Hemolysis is demonstrated by low haptoglobin and increased indirect bilirubin and lactate dehydrogenase. The anemia that characterizes chronic disorders is ruled out by determining iron, transferrin and ferritin levels. A bone marrow examination is indicated when other causes of microcytic anemia cannot otherwise be excluded. Prussian blue stain diagnoses sideroblastic anemia.

Complete blood count may reveal low hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin to varying degrees, depending on the severity of the disease [5]. Erythroblasts and abnormal red blood cells may be visualized through a peripheral smear. BT minor may be found incidentally in blood tests, typified by mild, asymptomatic, microcytic anemia, in addition to the presence of target cells and Heinz bodies in the peripheral smear [6]. Extramedullary hematopoiesis is also a common feature which is particularly observed in the liver.

Radiological evidence of BT includes thinning of the bone cortex and several other bone changes often seen in the skull, long bones, and vertebrae [7].

The minor form of thalassemia does not require treatment, but patients should be informed about the nature of their condition. When iron deficiency anemia coexists, it should be promptly corrected. Thalassemia major patients, on the other hand, require scrupulous long-term transfusion therapy, combined with iron chelation and splenectomy. A type of treatment that addresses the etiology of the disease consists of allogeneic hematopoietic transplantation, preferable whenever possible because of its curative nature [8]. However, the physician must keep an open mind about graft failure, graft versus host disease and the required chronic immunosuppressive therapy, all associated with this approach. Supportive measures, consisting of folic acid replacement and complication monitoring and treatment are also important. Gene therapy is currently being investigated. It consists of modified autologous hematopoietic stem cells transplant. The stem cells will previously be modified by a lentiviral vector expressing a normal globin gene and then infused to the patient that had undergone hematopoietic stem cells destruction therapy [9].

Transfusions are needed in order to maintain the hemoglobin level at 9-10 g/dL. This way, extramedullary hematopoiesis and skeletal changes are prevented and life quality is improved. Alloimmunization can be prevented by only administering similar erythrocytes in terms of ABO and RH antigens. The usual dose is 8-15 mL RBCs per kilogram of body weight [10]. One study [11] suggests that with this dose, however, males are undertransfused and more often require splenectomy or develop spinal cord compression as a result of paraspinal extramedullary hematopoiesis.

Other new techniques include genome editing techniques that interfere with single-mutation sites and replace them with normal genome [8 ].

Splenectomy is considered to decrease the amount of transfused blood needed and is indicated when the hematocrit value reaches 70% [10 ]. Patients should undergo Haemophilus influenzae, Meningococcus species and Pneumococcus species vaccination first and be at least 6 or 7 years old in order to minimize the risk for postsplenectomy sepsis. They should receive penicillin prophylaxis after the operation and be monitored for postsplenectomy thrombocytosis and ischemic events.

Bilirubin stones, if present, should be removed by laparoscopy or at the same time splenectomy is performed. Several novel therapeutic modalities are currently being investigated: immunomodulation agents, demethylating agents, short-chain fatty acid derivatives, histone deacetylase inhibitors, activin type IIA receptor fusion proteins, erythropoietin [12] and autologous CD34+ hematopoietic progenitor cells that were transduced with a lentiviral vector encoding the normal human beta-globin gene.

Prognosis is good for thalassemia minor, as they have no significant morbidity or mortality. For those with thalassemia major, prognosis depends on their will to undergo regular transfusions and iron chelation therapy. Disease progression is marked by chronic complications, such as high-output cardiac failure, bone changes, gallstones, liver dysfunction and endocrine dysfunction. Neurologic complications, such as peripheral neuropathy, cognitive impairment or cerebrovascular disease, often subclinical, are also possible [13].

Beta thalassemia is caused by beta-globin genes mutations, leading to impaired beta-globin synthesis, reduced hemoglobin levels and anemia. The disease is transmitted in an autosomal recessive manner. Depending on the severity of the disease, the beta-globin synthesis may be close to zero (beta-plus thalassemia) or the protein may not be produced at all (beta-zero thalassemia). On a genetic level, the cause is a missense or nonsense mutation in the beta-globin gene. In the minor form, only one of the beta-globin genes is defective, while in the major form both genes are impaired.

The severity of the disease is influenced not only by the genetic traits of the individuals, but by other factors, as well, like the level of expression of fetal hemoglobin, the existence of concomitant alpha thalassemia and sickle cell trait. While the first two factors decrease the severity of the anemia, sickle cell plus beta thalassemia patients may have severe symptoms and may experience complications of sickle cell disease.

The disease is most frequently encountered in Southeast Asia, Africa and the Mediterranean area. Symptoms become apparent after the age of six months, when the complete switch from fetal to adult hemoglobin synthesis has been made.

The severity of the disease is dependent on the imbalance between the alpha globin and no alpha (beta and gamma) globin chains. A diminished amount of beta globin chains causes the alpha chains that remain unassembled to precipitate and trigger oxidative stress to the membrane of the erythrocyte, leading to apoptosis [14].

As most genetic diseases, this condition cannot be prevented. However, genetic counseling for carriers of the beta thalassemia trait and for symptomatic patients is advisable. Most patient's behavior is improved once they find out the nature of their condition [15], but this knowledge does not modify their marriage decisions [16]. Screening programs in teenagers have been implemented in some countries, with beneficial results [17]. Prenatal diagnosis is available and seems to stimulate couples where at least one parent has the disease to have children and reduces overall disease incidence, despite the fact that positive results do not always stimulate parents to terminate the pregnancy [18].

Beta thalassemia is a congenital disease consisting of impaired synthesis of beta globin chains. The severity of this condition varies according to the magnitude of the defect. Thus, thalassemia minor, also known as thalassemia trait, represents a person carrying the mutation, but who is experiencing no symptoms. Beta thalassemia intermedia is characterized by minor anemia symptoms and variable phenotype, while beta thalassemia major patients experience severe disease requiring chronic transfusion therapy. The term beta-0 thalassemia designates the condition where the production of beta globin chain is completely absent, while beta + thalassemia patients still have the ability to produce diminished amounts of this protein.

Patients exhibit signs of anemia, such as pale skin or jaundice, weakness, fatigability, splenomegaly, growth retardation, delayed puberty, leg ulcers and bone deformities due to extramedullary hematopoiesis. Chronic transfusion therapy brings important amounts of iron to the transfused organism, making chelation therapy imperious. Still, iron overload can happen and lead to cardiac and endocrine dysfunction or liver dysfunction. Diagnosis is made using methods like electrophoresis or high-performance liquid chromatography, showing hemoglobin abnormalities. Prenatal diagnosis is also possible. Treatment consists of long-term transfusion therapy, combined with iron chelation and splenectomy. Allogeneic hematopoietic transplantation may be curative and gene therapy is currently being studied.

Beta thalassemia is a congenital disease affecting the production of hemoglobin, the protein that contains iron and carries oxygen to all the cells in the body. If this protein is not properly formed, the number of red blood cells diminishes and anemia sets in, leading to pale skin, weakness, and so on. The disease may be more or less severe, deppending on how serious the genetic defect is. Thalassemia major, the most serious form, causes symptoms within the first 2 years of life and causes such severe anemia, that it can threaten the child's life. The patient experiences failure to thrive (insufficient growth and development), jaundice, enlarged internal organs (heart and spleen), delayed puberty, hormonal abnormalities and abnormally shaped bones. The treatment consists of blood transfusions. These transfusions, unfortunately, bring large amounts of iron to the organism, that may accumulate inside the body. Thalassemia intermedia and minor are milder forms of the disease.

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