Continuing Education Activity

Thalassemia is a heterogeneous group of blood disorders affecting the hemoglobin genes and resulting in ineffective erythropoiesis. Decreased hemoglobin production results in anemia in early childhood, and frequent blood transfusions are required to maintain hemoglobin levels. This activity outlines the evaluation and treatment of thalassemia and highlights the role of an interprofessional team in managing patients with this condition.

Objectives:

• Summarize the etiology of thalassemias.
• Review of different laboratory and bedside evaluation techniques in the management of thalassemia patients.
• Outline the treatment and management options available for thalassemia.
• Identify interprofessional team strategies for improving care coordination and communication to improve outcomes in thalassemia.

Introduction

Thalassemias are a heterogeneous group of genetic disorders characterized by reduced synthesis of alpha or beta chains of hemoglobin (Hb). Hemoglobin serves as the oxygen-carrying component of red blood cells. It consists of two proteins: alpha and beta. If the body does not produce sufficient amounts of either of these two proteins, red blood cells do not form correctly and cannot carry sufficient oxygen, resulting in anemia that begins in early childhood and persists throughout life. Thalassemia is an inherited disease, meaning that at least one parent must be a carrier. 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. The alpha globin gene has 4 alleles, and disease severity ranges from mild to severe depending on the number of deletions of the alleles. Four-allele deletion is the most severe form, in which no alpha globins are produced, and the excess gamma chains (present during the fetal period) form tetramers. It is incompatible with life and results in hydrops fetalis. One allele deletion is the mildest form and is mostly clinically silent.

Beta thalassemia results from point mutations in the beta-globin gene. It is divided into three categories based on the zygosity of the beta-gene mutation. A heterozygous mutation (beta-plus thalassemia) results in beta-thalassemia minor, in which beta chains are underproduced. It is mild and usually asymptomatic. Beta thalassemia major is caused by a homozygous mutation (beta-zero thalassemia) of the beta-globin gene, resulting in the total absence of beta chains. It manifests clinically as jaundice, growth retardation, hepatosplenomegaly, endocrine abnormalities, and severe anemia requiring life-long blood transfusions. The condition between these two types is called beta-thalassemia intermedia, characterized by mild to moderate clinical symptoms. 

• One mutated gene: Mild signs and symptoms. The condition is called thalassemia minor.
• Two mutated genes: Signs and symptoms will be moderate to severe. This condition is called thalassemia major, or Cooley anemia. Babies born with two mutated beta hemoglobin genes are usually healthy at birth, but the disease starts to manifest after 6 months of life when fetal hemoglobin (Hb-gamma) disappears and is replaced by adult Hb.

The excess unpaired alpha-globin chains in beta-thalassemia aggregate and form precipitates that damage red cell membranes and result in intravascular hemolysis. This premature death of erythroid precursor cells leads to ineffective erythropoiesis and, subsequently, to extramedullary hematopoiesis. 

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.

Coexistence of sickle cell trait: The presence of sickle cell trait with beta-thalassemia is a common hemoglobinopathy and can lead to manifestations of sickle cell disease. Unlike sickle cell trait, in which major Hb is HbA, in the co-existence state, the major Hb is HbS, which constitutes more than 60% of Hb, depending on the nature of the disease (beta-zero or beta-plus0)

Hemoglobin (HbE) is also a common Hb variant found in the Southeast Asian population. It is associated with a beta-thalassemia phenotype, as individuals with thalassemia in this region are commonly found to have HbE.  

Two new terms used more frequently in clinical settings are transfusion-requiring and non-transfusion-requiring thalassemias; all basic classifications fall into these two types, depending on the need for frequent blood transfusions.[1][2][3]

Etiology

Alpha thalassemia is an autosomal recessive disorder, which means both parents must be affected or carriers for the disease to be transmitted to the next generation. It is caused by mutations or deletions in the Hb genes, resulting in reduced or absent alpha-chain production. More than 200 mutations have been identified as causing thalassemias. Alpha thalassemia is caused by deletions of alpha-globin genes, and beta thalassemias are caused by a point mutation in the splice site and promoter regions of the beta-globin gene on chromosome 11.[4]

Epidemiology

Alpha-thalassemia is prevalent in Asian and African populations, whereas beta-thalassemia is more prevalent in Mediterranean populations, although it is relatively common in Southeast Asia and Africa as well. Prevalence in these regions may be as high as 10%. The true number of patients with thalassemia in the United States is unknown, as there is no effective screening method in place.[4] 

History and Physical

The presentation of thalassemia varies widely depending on the type and severity. A complete history and physical examination can provide several clues that are sometimes not obvious to the patient. The following findings can be noted:

Skin

Skin can show pallor due to anemia and jaundice due to hyperbilirubinemia resulting from intravascular hemolysis. Patients usually report fatigue due to anemia as the first presenting symptom. Extremities examination can show ulcerations. Chronic iron deposition due to multiple transfusions can result in bronze skin.

Musculoskeletal

Extramedullary expansion of hematopoiesis results in deformed facial and other skeletal bones and an appearance known as chipmunk face. 

Cardiac

Iron deposition in cardiac myocytes due to chronic transfusions can disrupt the cardiac rhythm, and the result is various arrhythmias. Due to chronic anemia, overt heart failure can also result.

Abdominal

Chronic hyperbilirubinemia can lead to precipitation of bilirubin gallstones and manifest as typical colicky pain of cholelithiasis. Hepatosplenomegaly can result from chronic iron deposition and also from extramedullary hematopoiesis in these organs. Splenic infarcts or autophagy result from chronic hemolysis due to poorly regulated hematopoiesis.

Hepatic

Hepatic involvement is a common finding in thalassemias, particularly due to chronic transfusion requirements. Chronic liver failure or cirrhosis can result from chronic iron deposition or transfusion-related viral hepatitis.

Slow Growth Rates

Anemia can inhibit a child's growth rate, and thalassemia can delay puberty. Particular attention should be paid to the child's growth and development in relation to age.

Endocrinopathies

Iron overload can lead to its deposition in various organ systems and to decreased function of those systems. The deposition of iron in the pancreas can lead to diabetes mellitus; in the thyroid or parathyroid glands, it can lead to hypothyroidism and hypoparathyroidism, respectively. The deposition in joints leads to chronic arthropathies. In the brain, iron prefers to accumulate in the substantia nigra and manifests as early-onset Parkinson's disease and various other psychiatric problems. These symptoms fall within the spectrum of hemochromatosis.[5]  

Evaluation

Several laboratory tests have been developed to screen and diagnose thalassemia: 

Complete blood count (CBC): CBC is often the first investigation in a suspected case of thalassemia. A CBC showing low hemoglobin and low MCV is the first indication of thalassemia, after ruling out iron deficiency as the cause of anemia. The calculation of the Mentzer index (mean corpuscular volume divided by red cell count) is useful. A Mentzer index below 13 suggests thalassemia, whereas an index above 13 suggests anemia due to iron deficiency.[6]

Peripheral blood smear: A blood smear (also called peripheral smear and manual differential) is used to assess additional red cell properties. Thalassemia can present with the following findings on the peripheral blood smear:

• Microcytic cells (low MCV)
• Hypochromic cells
• Variation in size and shape (anisocytosis and poikilocytosis)
• Increased percentage of reticulocytes
• Target cells
• Heinz bodies

Iron studies (serum iron, ferritin, unsaturated iron-binding capacity (UIBC), total iron-binding capacity (TIBC), and percent saturation of transferrin) are also done to rule out iron deficiency anemia as the underlying cause.

Erythrocyte porphyrin levels may be checked to distinguish an unclear beta-thalassemia minor diagnosis from iron deficiency or lead poisoning. Individuals with beta-thalassemia will have normal porphyrin levels, but those with the latter conditions will have elevated porphyrin levels.

Hemoglobin electrophoresis: Hemoglobinopathy (Hb) evaluation assesses the type and relative amounts of hemoglobin present in red blood cells. Hemoglobin A (HbA), composed of both alpha and beta-globin chains, is the type of hemoglobin that typically makes up 95% to 98% of hemoglobin in adults. Hemoglobin A2 (HbA2) is normally 2% to 3% of hemoglobin, while hemoglobin F usually makes up less than 2% of hemoglobin in adults.

Beta thalassemia disturbs the balance of beta and alpha hemoglobin chain formation. Patients with beta-thalassemia major typically have higher percentages of HbF and HbA2, with absent or very low HbA. Those with beta-thalassemia minor usually have a mild elevation of HbA2 and a mild decrease of HbA. HbH is a less common form of hemoglobin that may be seen in some cases of alpha thalassemia. HbS is the hemoglobin prevalent in people with sickle cell disease.

Hemoglobinopathy (Hb) assessment is used for prenatal screening when parents are at high risk for hemoglobin abnormalities and state-mandated newborn hemoglobin screening. 

DNA analysis: These tests help confirm mutations in the alpha- and beta-globin genes. DNA testing is not a routine procedure but can be used to diagnose thalassemia and to determine carrier status, if needed.

Because relatives with thalassemia mutations increase an individual's risk of carrying the same mutation, family studies may be necessary to assess carrier status and the types of mutations present in other family members.

Genetic testing of amniotic fluid is useful in those rare instances where a fetus has an increased risk for thalassemia. This is particularly important if both parents likely carry a mutation, as this increases the risk that their child may inherit a combination of abnormal genes, resulting in a more severe form of thalassemia. Prenatal diagnosis with chorionic villi sampling at 8 to 10 weeks or by amniocentesis at 14 to 20 weeks’ gestation can be carried out in high-risk families.[7][6]

Multisystem evaluation: All relevant systems should be evaluated regularly, given their frequent involvement in disease progression. Biliary tract and gallbladder imaging, abdominal ultrasonography, cardiac MRI, and serum hormone measurements are examples that can be performed or repeated, depending on clinical suspicion and the case description. 

Treatment / Management

Thalassemia treatment depends on the type and severity of the disease.

Mild thalassemia (Hb: 6 to 10g/dl):

Signs and symptoms are generally mild with thalassemia minor, and little, if any, treatment is needed. Occasionally, patients may need a blood transfusion, particularly after surgery, following childbirth, or to help manage thalassemia complications.

Moderate to severe thalassemia (Hb less than 5 to 6g/dl):

• Frequent blood transfusions: More severe forms of thalassemia often require regular blood transfusions, possibly every few weeks. The goal is to maintain hemoglobin (Hb) at approximately 9-10 mg/dL to promote patient well-being and to monitor erythropoiesis and suppress extramedullary hematopoiesis. To limit transfusion-related complications, washed, packed red blood cells (RBCs) at approximately 8 to 15 mL cells per kilogram (kg) of body weight over 1 to 2 hours are recommended.

• Chelation therapy: Due to chronic transfusions, iron begins to accumulate in various organs of the body. Iron chelators (deferasirox, deferoxamine, deferiprone) are given concomitantly to remove extra iron from the body.
• Stem cell transplant: Stem cell transplant, (bone marrow transplant), is a potential option in selected cases, such as children born with severe thalassemia. It can eliminate the need for lifelong blood transfusions.[8] However, this procedure has complications, and the clinician must weigh them against the benefits. Risks include graft-versus-host disease, chronic immunosuppressive therapy, graft failure, and transplantation-related mortality.[9] 
• Gene therapy is a recent advance in the management of severe thalassemia. It involves harvesting the patient's autologous hematopoietic stem cells (HSCs) and genetically modifying them with vectors that express the normal genes. These are then reinfused into patients after they have undergone the required conditioning to eliminate existing HSCs. The genetically modified HSCs produce normal hemoglobin chains, and normal erythropoiesis ensues.

• Genome editing techniques: Another recent approach is the editing of genomic libraries using zinc-finger nucleases, transcription activator-like effectors, and clustered regularly interspaced short palindromic repeats (CRISPR) with the Cas9 nuclease system. These techniques target specific mutation sites and replace them with the normal sequence. The limitation of this technique is its inability to produce a sufficient number of corrected genes to cure the disease.[10]

• Splenectomy: Patients with thalassemia major often undergo splenectomy to limit the number of required transfusions. Splenectomy is the usual recommendation when the annual transfusion requirement exceeds 200-220 mL RBCs/kg/year, with a hematocrit of 70%. Splenectomy not only limits the number of required transfusions but also controls the spread of extramedullary hematopoiesis. Postsplenectomy immunizations are necessary to prevent bacterial infections, including Pneumococcus, Meningococcus, and Haemophilus influenzae. Postsplenectomy sepsis is possible in children, so this procedure is deferred until 6 to 7 years of age, and then penicillin is given for prophylaxis until they reach a certain age. 

• Cholecystectomy: Patients may develop cholelithiasis due to increased hemoglobin (Hb) breakdown and bilirubin deposition in the gallbladder. If it becomes symptomatic, patients should undergo cholecystectomy at the same time as they undergo splenectomy.   

Diet and exercise:

Reports indicate that drinking tea reduces iron absorption from the gastrointestinal tract. In patients with thalassemia, tea may be a healthy beverage to consume routinely. Vitamin C helps in iron excretion from the gut, especially when used with deferoxamine. But using vitamin C in large quantities and without concomitant deferoxamine use, there is a higher risk for fatal arrhythmias. Therefore, the recommendation is to use low doses of vitamin C in combination with iron chelators (e.g., deferoxamine).[10]

Differential Diagnosis

The differential diagnosis of Thalassemia includes:

• Iron deficiency anemia: This is ruled out by iron studies and the Mentzer index.
• Anemia of chronic disease and renal failure: Elevated markers of inflammation (CRP, ESR) point in this direction.
• Sideroblastic anemias: These are ruled out by iron studies and peripheral blood smear.
• Lead poisoning: This is ruled out by measuring serum protoporphyrin level.

Prognosis

Thalassemia minor is usually asymptomatic and has a good prognosis. It normally does not increase morbidity or mortality. Thalassemia major is a severe disease, and the long-term prognosis depends on adherence to transfusion and iron chelation therapies.[11] 

Complications

Thalassemia major can produce the following complications:

• Jaundice and gallstones due to hyperbilirubinemia
• Cortical thinning and distortion of bones due to extramedullary hematopoiesis
• High output cardiac failure due to severe anemia, cardiomyopathies, and arrhythmias - cardiac involvement is the major cause of mortality in thalassemia patients
• Hepatosplenomegaly due to extramedullary hematopoiesis and excess iron deposition due to repeated blood transfusions
• Excess iron can lead to findings characteristic of primary hemochromatosis, such as endocrine abnormalities, joint problems, and skin discoloration.
• Neurological complications such as peripheral neuropathies
• Slow growth rate and delayed puberty
• Increased risk of parvovirus B19 infection [12][13]

Deterrence and Patient Education

Patients should be educated to monitor their condition by adhering to an appropriate treatment plan and adopting healthy lifestyle habits.

• Avoid excess iron. Unless a physician recommends otherwise, patients should avoid multivitamins or other supplements containing iron.
• Eat a healthy diet. Eating a balanced diet that contains plenty of nutritious foods can help the patient feel better and boost energy. Doctors sometimes also recommend taking a folic acid supplement to help make new red blood cells. 
• Avoid infections. Patients should strive to minimize their risk of infection, particularly after splenectomy. Annual influenza, meningococcal, pneumococcal, and hepatitis B vaccines are recommended to prevent infections.

Patients should also receive education about the hereditary nature of the disease. If both parents have thalassemia minor, there is a 1/4th chance that they will have a child with thalassemia major. If one parent has beta-thalassemia minor and the other parent has a beta-globin gene defect (e.g., sickle cell disease), they should also be counseled about the possibility of disease transmission to their children. Patients with thalassemias should understand that their disease is not due to iron deficiency and that iron supplements will not cure the anemia; in fact, they may cause further iron accumulation if they are already receiving blood transfusions.[14]

Enhancing Healthcare Team Outcomes

Thalassemia has negative repercussions for many organs, and without a cure, it has high morbidity. The disorder is best managed by an interprofessional team that includes a thalassemia care team, a cardiologist, a hepatologist, an endocrinologist, and a psychologist. Additionally, family care, nursing support, and social support are integral to management. A lead consultant should oversee patient care, and a nurse specialist, along with other specialists in the relevant fields, should be involved to address all aspects of the disease. Patient education is crucial, and social worker involvement, including a geneticist, is essential. In some parts of the world, preventive strategies include prenatal screening and restrictions on issuing marriage licenses to two people with the same disease. Screening children and pregnant women who visit clinicians is an effective strategy to reduce disease morbidity. The social worker should ensure that the caregiver/patient has adequate support and financial resources to continue treatment. Nurses should educate patients about the importance of treatment adherence to prevent serious complications and monitor treatment progress. Pharmacists may soon play a greater role as there are new drug products to assist in gene therapy on the horizon that can eliminate the need for ongoing transfusions. Active collaboration and discussion among interprofessional team members facilitate a better understanding of disease progression and control.

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References

1.

He LN, Chen W, Yang Y, Xie YJ, Xiong ZY, Chen DY, Lu D, Liu NQ, Yang YH, Sun XF. Elevated Prevalence of Abnormal Glucose Metabolism and Other Endocrine Disorders in Patients with β-Thalassemia Major: A Meta-Analysis. Biomed Res Int. 2019;2019:6573497. [PMC free article: PMC6500678] [PubMed: 31119181]

2.

Vichinsky E, Cohen A, Thompson AA, Giardina PJ, Lal A, Paley C, Cheng WY, McCormick N, Sasane M, Qiu Y, Kwiatkowski JL. Epidemiologic and clinical characteristics of nontransfusion-dependent thalassemia in the United States. Pediatr Blood Cancer. 2018 Jul;65(7):e27067. [PubMed: 29637688]

3.

Ahmadpanah M, Asadi Y, Haghighi M, Ghasemibasir H, Khanlarzadeh E, Brand S. In Patients with Minor Beta-Thalassemia, Cognitive Performance Is Related to Length of Education, But Not to Minor Beta-Thalassemia or Hemoglobin Levels. Iran J Psychiatry. 2019 Jan;14(1):47-53. [PMC free article: PMC6505049] [PubMed: 31114617]

4.

Jalil T, Yousafzai YM, Rashid I, Ahmed S, Ali A, Fatima S, Ahmed J. Mutational Analysis Of Beta Thalassaemia By Multiplex Arms-Pcr In Khyber Pakhtunkhwa, Pakistan. J Ayub Med Coll Abbottabad. 2019 Jan-Mar;31(1):98-103. [PubMed: 30868793]

5.

Puar N, Newell B, Shao L. Blueberry Muffin Skin Lesions in an Infant With Epsilon Gamma Delta Beta Thalassemia. Pediatr Dev Pathol. 2019 Nov-Dec;22(6):599-600. [PubMed: 31088202]

6.

Singha K, Taweenan W, Fucharoen G, Fucharoen S. Erythrocyte indices in a large cohort of β-thalassemia carrier: Implication for population screening in an area with high prevalence and heterogeneity of thalassemia. Int J Lab Hematol. 2019 Aug;41(4):513-518. [PubMed: 31099487]

7.

Ansari S, Rashid N, Hanifa A, Siddiqui S, Kaleem B, Naz A, Perveen K, Hussain Z, Ansari I, Jabbar Q, Khan T, Nadeem M, Shamsi T. Laboratory diagnosis for thalassemia intermedia: Are we there yet? J Clin Lab Anal. 2019 Jan;33(1):e22647. [PMC free article: PMC6430353] [PubMed: 30221402]

8.

Jariwala K, Mishra K, Ghosh K. Comparative study of alloimmunization against red cell antigens in sickle cell disease & thalassaemia major patients on regular red cell transfusion. Indian J Med Res. 2019 Jan;149(1):34-40. [PMC free article: PMC6507543] [PubMed: 31115372]

9.

Sarkar SK, Shah MS, Begum M, Yunus AM, Aziz MA, Kabir AL, Khan MR, Rahman F, Rahman A. Red Cell Alloantibodies in Thalassaemia Patients Who Received Ten or More Units of Transfusion. Mymensingh Med J. 2019 Apr;28(2):364-369. [PubMed: 31086152]

10.

Darvishi Khezri H, Emami Zeydi A, Sharifi H, Jalali H. Is Vitamin C Supplementation in Patients with β-Thalassemia Major Beneficial or Detrimental? Hemoglobin. 2016 Aug;40(4):293-4. [PubMed: 27492769]

11.

Zhang H, Zhabyeyev P, Wang S, Oudit GY. Role of iron metabolism in heart failure: From iron deficiency to iron overload. Biochim Biophys Acta Mol Basis Dis. 2019 Jul 01;1865(7):1925-1937. [PubMed: 31109456]

12.

Benites BD, Cisneiros IS, Bastos SO, Lino APBL, Costa FF, Gilli SCO, Saad STO. Echocardiografic abnormalities in patients with sickle cell/β-thalassemia do not depend on the β-thalassemia phenotype. Hematol Transfus Cell Ther. 2019 Apr-Jun;41(2):158-163. [PMC free article: PMC6517685] [PubMed: 31084765]

13.

Paul A, Thomson VS, Refat M, Al-Rawahi B, Taher A, Nadar SK. Cardiac involvement in beta-thalassaemia: current treatment strategies. Postgrad Med. 2019 May;131(4):261-267. [PubMed: 31002266]

14.

Manzoor I, Zakar R. Sociodemographic determinants associated with parental knowledge of screening services for thalassemia major in Lahore. Pak J Med Sci. 2019 Mar-Apr;35(2):483-488. [PMC free article: PMC6500821] [PubMed: 31086537]

Disclosure: Hamza Bajwa declares no relevant financial relationships with ineligible companies.

Disclosure: Hajira Basit declares no relevant financial relationships with ineligible companies.