Beta Thalassemia Major (Cooley Anemia)

Etiology

Beta-thalassemia is a hereditary disorder that is caused by more than 200 beta-globin gene point mutations resulting in decreased or absent globin chains (beta+ and beta0) via transcriptional, translational, and splicing of either the hemoglobin subunit beta (HBB) itself or its product. It can also be caused by HBB gene deletion from chromosome 11. The majority of the mutations result in frameshift due to deletion, single nucleotide substitution, and insertion patterns. Furthermore, the disease severity depends on the inheritance of two copies of both alleles present on each chromosome 11. The beta-globin chain production is genotypically allocated by beta+ and beta 0 for decreased production and absent production, respectively. While phenotypic variability is represented by minor or trait, intermedia, and major, it depends on the beta-globin gene production (i.e., beta+ and beta 0) and homozygous or heterozygous status.[2][5]

Epidemiology

Due to changing demographics, beta-thalassemia is present globally. However, it is most prevalent in the Mediterranean, Middle East, Southeast & South Asia, and southern China. The incidence of children born with beta-thalassemia major is about 68,000 worldwide. The prevalence rate is 1.5% (80-90 million carriers) across the globe. The exact prevalence rate in the United States (US) is not known, however, it is speculated that the number is increasing dramatically due to immigration. In 1960, the prevalence rate was 5.6%, and it reached 13% in 2010, which was highest in California due to 26% of immigrant residents. The highest prevalence (10%) is present in the southern and northern parts of Iran in close proximity to the Persian Gulf and the Caspian Sea, respectively. The total estimation for homozygotes is 20,000, and the carriers are approximately 3,750,000 there. In India, about 10,000-20,000 children are born with beta-thalassemia every year. The incidence of beta-thalassemia major (beta-TM) positive newborns was significantly reduced from 272/year in 2002 to 25/year in 2010 due to the introduction of a premarital screening test. In Bangladesh, the prevalence of thalassemia with different severity levels ranges from 60,000 to 70,000 with an estimated 2500 TM cases added per year. One of the proposed reasons for the high prevalence rate among the above-mentioned territories is that they are malaria-endemic regions that have a survival advantage due to a protective phenomenon. The other contributing factor is genetic drift.[2][3][6][7][8][9][10]

Pathophysiology

Hemoglobin is a tetramer formed from two dimers of alpha and non-alpha chains. Adult hemoglobin (HbA or HbA1) comprised of two alpha and two beta globin chains account for 98% of total hemoglobin. The other type is HbA2, which is made up of two alpha and two delta chains. Another type is fetal hemoglobin (HbF), which is present during pregnancy and up to 6 months postpartum and is made of two alpha and two gamma chains.

The primary underlying pathophysiology in thalassemia is ineffective erythropoiesis. It is characterized by decreased HbA production secondary to decreased beta-globin chain production and maturation arrest due to apoptosis of the erythroid precursors caused by an excess of alpha chain precipitates. Another mechanism that plays an important role is oxidative stress. Normally the balance is maintained between antioxidants like reduced glutathione and reactive oxygen species (ROS), a byproduct of cellular respiration, for maintenance of the physiologic environment. In beta-thalassemia, oxidative stress ensues due to the failure of that balance, which results in damage to the red blood cell (RBC) membrane causing anemia, white blood cells (WBC) causing infections, platelets causing hypercoagulability, and affecting other organs as well.[11][12]

History and Physical

Patients with thalassemia minor/trait are usually asymptomatic or present with mild anemia. The presentation of thalassemia intermedia varies clinically and is manifested by pallor, failure to thrive (FTT), lethargy, and fatigue, but they are not transfusion dependent.

Usually, patients with beta TM (Cooley anemia) start having symptoms after 6 months of age due to the transition of HbF to HbA. Unlike thalassemia minor, clinical features of beta TM are of a severe type and include pallor, shortness of breath, irritability, FTT, and hepatosplenomegaly (HSM) due to extramedullary hematopoiesis. Other features include recurrent fever, feeding problems, and abdominal distention. Patients who are either untreated or received poor transfusion (especially in developing countries where there is no availability of well-developed transfusion programs) develop a wide range of symptoms such as retarded growth, brown discoloration of the skin, jaundice, leg ulcers, knock knee (genu valgum), and skeletal deformities such as long bone abnormalities, craniofacial deformities like frontal bossing, prominent cheekbones, depressed nasal bridge, and maxillary hypertrophy resulting from bone marrow expansion giving the chipmunk appearance. In addition to that, gallstone formation usually occurs due to chronic hemolysis.[2][13][14]

Evaluation

In infants and children under 2 years of age, the diagnosis of Cooley anemia (beta TM) is suspected based on clinical features of jaundice, severe hypochromic microcytic anemia, and HSM.

Lab findings: CBC will show microcytic anemia with decreased Hb level of <7g/dL, mean corpuscular volume (MCV) ranges from 50 to 70 fl, and mean corpuscular Hb (MCH) level ranges from 12 to 20pg.

Morphological changes of RBCs like microcytosis, hypochromia, poikilocytosis, anisocytosis, and nucleated RBCs can be seen on the peripheral blood smear. Additionally, target cells, teardrop cells, and basophilic stippling (course type) can also be visualized on the peripheral blood smear. The number of erythroblasts depends on the degree of anemia and after splenectomy. Moreover, either Hb electrophoresis or high-performance liquid chromatography (HPLC) is warranted for definitive diagnosis. It analyzes Hb both quantitatively and qualitatively. Beta-thalassemia major demonstrates a complete absence of beta-globin chain (beta0/beta0), therefore the HbF is 92% to 95%, HbA2 is 5% to 8%, and HbA 0%.

Elevated HbA2 is also caused by hyperthyroidism, vitamin B12 and folic acid deficiency, and anti-retroviral therapy (ATT). Apart from that, prenatal screening and genetic counseling are additional valuable tools in the detection and prevention of beta-thalassemia and other autosomal recessive diseases.  

Radiographic features:  Due to active bone marrow hyperplasia, wide medullary spaces, and trabeculae mimic, a classic “chicken wire” pattern is seen on maxillofacial radiographs. On x-rays of long bones, osteopenia, and cortical thinning secondary to expanded bone marrow spaces can be seen, which often presents with pathological fractures. Similarly, the classic “hair on end” appearance can be seen on a cranial vault radiograph. Additionally, vertebral bodies have a ground-glass appearance. Magnetic resonance imaging (MRI) of the brain, heart, and liver are also done to determine iron deposition in various tissues in cases of suspected iron overload.[2][13][14][15]

Treatment / Management

Medical Treatment: Blood transfusion has been the mainstay treatment of beta-thalassemia major (Cooley anemia). Usually, the patient dies before reaching puberty if he/she does not receive periodic blood transfusions. It provides normal RBCs that compensate for anemia, halts ineffective erythropoiesis, which results in decreased oxidative stress, thus reducing bone deformities, improved symptoms, and increased survival. There is general consensus between the Thalassemia International Federation (TIF) and other national guidelines (the United Kingdom and the United States) about thalassemia management despite few differences in terms of iron overload (IO) and iron chelation therapy (ICT) strategies.

The degree of anemia and/or clinical findings should be considered when the frequency of blood transfusions is decided, and leukoreduced RBCs are preferred. To accelerate growth and minimize symptoms, the pretransfusion goal Hb level is 9-10g/dL or if clinical complications are present irrespective of Hb level, and the post-transfusion is between 14-15g/dL. A higher pretransfusion level of 10-12g/dL is set in cases of a worsening of extramedullary hematopoiesis or cardiac abnormalities. However, care should be taken during regular blood transfusion because of the high risk of iron overload (IO), infections, transfusion reactions, and allogeneic antibody formation.

Clinical features and serum ferritin are reliable tools in close monitoring for IO in routinely transfused TM patients. Iron chelation therapy (ICT) is the treatment of choice for iron overload. Deferoxamine was the first to be used via subcutaneous (SC) or intravenously (IV) route over 8 to 24 hrs, 5 to 7 nights/week. Compliance was the main issue with deferoxamine. Currently, oral ICT such as deferasirox or deferiprone is widely used either alone or in combination and is well tolerated. Due to rapid cell turnover, other nutritional deficiencies such as folate/vitamin B12, and calcium need to be addressed as well.

No added benefit of hydroxyurea has been established in patients receiving adequate blood to achieve the pretransfusion goal. Unlike sickle cell disease (in which it reduces sickling by increasing HbF level), the role of hydroxyurea is unclear in Hb <9 g/dL.

The only definitive treatment at present is allogeneic hematopoietic stem cell transplant (allo-HSCT) in transfusion dependant patients with >90% success rate if it takes place before the IO-related damage occurs. 

Luspatercept: Luspatercept is an erythroid maturation agent that has been approved for anemia in adult beta TM patients who require regular blood transfusions. Recently an open-label phase 3 study (BELIEVE) of adult thalassemia patients, luspatercept has yielded promising results in terms of transfusion independence. 

Gene therapy: This is also in the pipeline to be considered as a potential cure for beta-thalassemia and sickle cell disease (SCD). Several clinical trials are currently underway to establish its efficacy and safety. However, preliminary results of one of the recent ongoing trials have been promising. A total of 3 beta-thalassemia patients (n=3) have been transduced with autologous CD34 HSCs using GLOBE or TNS9.3.55 as lentivirus and have demonstrated minimal and reversible adverse effects. However, to further validate its efficacy and safety, more data is warranted.

Surgical treatment: TM patients can develop hypersplenism and massive splenomegaly, therefore, they require splenectomy as well as vaccination against encapsulated bacteria due to the high risk of infections following splenectomy.

Prevention: Currently implementation of prevention strategies is required to prevent new cases particularly in developing countries where there is limited access to standard medical treatment in addition to high consanguinity practice in the communities. Molecular diagnostics, genetic counseling, carrier detection, and prenatal screening are important tools of comprehensive preventive programs.[2][16][17][18]

Differential Diagnosis

Some of the close differentials are sideroblastic anemia, iron-deficiency anemia (IDA), and anemia of chronic disease (ACD). Others include hemoglobinopathies. Sideroblastic anemia is easily differentiated by ring sideroblasts due to iron deposition and increased erythrocyte protoporphyrin level. Iron-deficiency anemia is ruled out by conducting iron studies (e.g., serum iron, total iron-binding capacity (TIBC)), serum ferritin, and transferrin saturation. Serum ferritin and transferrin saturation are low in iron deficiency. Additionally, RBCs are more likely hypochromic and less microcytic in IDA as compared to thalassemia. HPLC or Hb electrophoresis is used to differentiate other hemoglobinopathies from beta-thalassemia.[2][19]

Prognosis

Prior to 2000, beta-thalassemia major had a poor prognosis. The median survival was approximately 17 years in the US between 1965 to 1975. The median age was 12 years for the cohort born in Italy in the 1960s. But now, life expectancy has dramatically improved due to an interprofessional team approach among health care providers. Furthermore, the introduction of iron chelation therapy ICT (oral & injectable), awareness among patients and health care providers, management of complications, and utilization of standard techniques in the screening of blood products has contributed to improved outcomes. The life span of the affected patients in Palestine has increased from 7 to 8 years in 1996 to 19 to 20 years in 2015. Similarly, in the UK, the mortality rate significantly dropped to 4.7/1000 in the years 2000 to 2003 from 12.7/1000 in the years 1990 to 1999.[2][3][16]

Complications

Patients should be closely monitoring for potential complications owing to ineffective erythropoiesis, bone marrow (BM) overstimulation, and blood transfusion. The complications of the transfusion are of two types.

1. Acute (e.g., severe allergic reactions, septic shock, hemolysis), and
2. Chronic (e.g., diseases associated with iron overload (i.e., cardiomyopathy, endocrinopathy, and hepatotoxicity), alloimmunization, and transfusion-related infections.

Transfusion-related Complications

Iron overload: It is the primary chronic complication associated with long-term RBC transfusion in patients with beta-thalassemia. Transfused RBCs contain the iron load. Iron accumulates over time, and when the body's excess iron eliminating function is overwhelmed, iron starts depositing in various organs, commonly the heart, pancreas, liver, and brain. Cardiac failure secondary to cardiac IO is the leading cause of death in patients with TDT. Usually, the patient dies at a young age (<20) if not promptly addressed.

Iron overload (IO) in the liver results in liver fibrosis, cirrhosis, and eventually hepatocellular carcinoma. Furthermore, the deposition of iron leads to diabetes, hypogonadism, hypothyroidism, and hypoparathyroidism secondary to pituitary gland disruption. Also, it can manifest as bronze skin, growth, and developmental delay. Therefore, ICT is essential in preventing these complications.

Alloimmunizations: It is the production of antibodies against specific RBC antigens or alloantigen (e.g., ABO, Rh, C, c, E, e, D, and Kell antigens) resulting from chronic transfusion. As per the international consensus recommendation, donated blood should be screened and crossmatched, and patients with thalassemia should receive antigen-compatible blood to avoid alloimmunization.

Transfusion-related infections: Viral, bacterial, and parasitic infections are common transfusion-related infections. Donated blood should be screened for HBV, HCV, and HIV as per World Health Organization (WHO) and Thalassemia International Federation (TIF) guidelines. Screening for endemic infections is also recommended in some countries.

Thrombosis/hypercoagulable state: Hypercoagulability is seen in patients with beta-thalassemia major (BTM) and beta-thalassemia intermedia (BTI) who are either poorly transfused, non-transfused, and splenectomized individuals.

Others include: Transfusion-related acute lung injury (TRALI), febrile non-hemolytic transfusion reaction, and delayed hemolytic transfusion reactions.[2][3][15][16]