Thalassemia

Thalassemia

Chuck Harris

November 30, 2012

Abstract
Thalassemia, an inherited blood disorder, is explored in depth to assist future practitioners with an understanding of the pathophysiology, identification, and treatment of the condition. Beta-thalassemia, also known as Cooley’s anemia, is the most common thalassemia affecting approximately 1000 patients in the United States. Alpha-thalassemia affects persons of Chinese, Vietnamese, Cambodian, and Laotian decent. Blacks are affected by both alpha- and beta-thalassemias. Incidence, prevalence, morbidity, and mortality of each disorder is explored. Public health providers need to understand the distinction between thalassemia and iron deficiency anemia, as misdiagnosis can lead to fatal events. Iron replacement therapy is contraindicated and more complex treatments are required for those with thalassemia, including chelation therapy and bone marrow transplantation. Proper identification and treatment of this anemia is important as it has a direct effect in the longevity of the patient. In the United States, socioeconomic and cultural barriers exist in identification and treatment since this disorder is common in minority cultures.

Thalassemia
Thalassemia was discovered by pediatric hematologist Thomas Cooley (June 23, 1871 - October 13, 1945) (Clark, 2010). Thalassemia, first known as "Cooley 's Anemia" is an inherited blood disorder characterized by microcytic, hyperchromic blood cells where the body creates an abnormal form of hemoglobin which excessively destroys red blood cells (RBCs) which lead to anemia (Clark, 2010). Thalassemia occurs in people who are of Mediterranean, Greek, Italian, Chinese, Asian, Indian, Laotian, and Vietnamese ancestry. Thalassemia is also common in Blacks. Cooley 's Anemia has also been called Mediterranean Disease, Mediterranean Anemia, Erythroblastic Anemia, beta-thalassemia, and alpha-thalassemia. The latter, alpha- and beta-thalassemia, refers to the area in the genetic makeup that has been effected (Clark, 2010; Durkin, 2013). The origin of the word thalassemia comes from the Greek work “thalassa” which means “sea” and “a + haima” which means “without blood” (Clark, 2010). There are three clinical forms of thalassemia: major, intermedia, and minor. The severity of the disease depends upon if the origin of the thalassemic trait is homozygous or heterozygous (Clark, 2010).
Introduction to Normal Body Function In normal body function, the hemoglobin is an oxygen transporting protein of the erythrocyte. The hemoglobin takes up oxygen from the lungs and exchanges it for carbon dioxide in the tissues. Hemoglobin is responsible for the ruby-red color of the blood. There are about 300 hemoglobin molecules in a single erythrocyte. In normal hemoglobin structure there are two polypeptide chains for each hemoglobin molecule which is comprised of four colorful complexes of iron plus protoporphyrin. Additionally, “each polypeptide chain has about 150 amino acids arranged in a knotted sausage configuration” (Clark, 2010, p. 967).

Pathophysiology
In patients with thalassemia RBC synthesis is impaired at the cellular level. There is a defect in the synthesis of the polypeptide chains which are needed for hemoglobin production. Depending upon which part of the chain, the alpha or beta, determines the type of thalassemia the patient will be diagnosed with and how it will be treated (Clark, 2010). “In α-thalassemia, the biosynthesis of the α-globin subunit of adult hemoglobin, hemoglobin A, is deficient. In β-thalassemia, β-globin synthesis is diminished” (Benz, E.J., 2011, 770).
Unlike iron deficiency anemia, thalassemia patients need to be careful with iron levels and avoid iron supplementation because the defect in the polypeptide chain breaks down RBCs and cannot properly eliminate the iron stores and iron starts to build up in the tissues and organs increasing the risk of toxicity especially in the liver and heart (Durkin, 2013; Clark, 2010). If the “plasma iron content exceeds the binding capacity of available plasma transferrin levels, a nontransferrin-bound iron combines with oxygen to form hydroxl and oxygen radicals” which lead to toxicities and “cause damage to cell membranes, protein, DNA , and organs” (Lambing, Kachalsky & Mueller, 2011, p. 176).
Role of Inflammation Inflammation’s role in the development of thalassemia is found in the chain synthesis. When there is a depression of beta-chain formation there is a reduced amount of hemoglobin in erythrocytes which in turn leads to an accumulation of free alpha-chains (Clark, 2010). These “free alpha-chains are unstable and easily precipitate in the cell” (Clark, 2010, p. 1077). When this precipitation occurs the erythroblasts that contain them “are destroyed by mononuclear phagocytes in the marrow, resulting in ineffective erythropoiesis and anemia” (Clark, 2010, p. 1077).
Role of Immune Response Immune response plays a role in the production of abnormal structures within the RBCs. The abnormalities have been described as:
Immunological abnormalities, including increased immunoglobulin production, deficient activity of the complement system, decrease opzonization, and granulocyte phagocytosis have been documented. There is also evidence that both the cell-mediated immune (CMI) response and lymphocyte subsets in thalassemia are also abnormal. Factors such as frequent blood transfusion and splenectomy may have profound effects on the immune system. (Pattanapanyasat, et. al, 2000, p. 11)
Role of Stress Response The stress response involved in the development of thalassemia is an oxidative type of stress which causes “endothelial dysfunction, a condition which is evident in adults suffering from various cardiovascular disease including thalassemia” (Kukongviriyapan et al., 2008, p. 130). In thalassemia the oxidative stress response is increase almost double. Additionally, when there is an excess number of alpha-globin chains in the beta-thalassemic patient there is “auto-oxidation of membrane protein and ensuing cell lysis” (Kukongviriyapan et al., 2008, p. 131). Oxidative stress is exacerbated by the increased iron released by cell lysis in patients with thalassemia (Kukongviriyapan et al., 2008).
Fluid and Electrolyte Imbalances The fluid and electrolyte imbalances are impairment of anion and cation transport in the disease of thalassemia. Thalassemic RBCs from a splenectomized patient will loose K due to an increase in selective permeability of the membrane to K, which will cause the RBCs to shrink and increase cellular rigidity (Kukongviriyapan et al., 2008). Na, K, and ATPase activity (membrane bound enzyme) is reduced in thalassemia like cells, where as it is increased in severe alpha-and-beta thalassemic cells. The reduced membrane associated ATPase activity is also due to the premature destruction of red blood cells both in the bone marrow and by the reticuloendothelial system (Akran, Mahboob, 2004, p. 20).
Genetics
Thalassemia major and thalassemia intermedia are both homozygous inherited forms of the disease. Thalassemia minor 's gene is heterozygous (Clark, 2010). Genetic counseling is encouraged for those who are at high risk for having a child who could possibly be affected by thalassemia. Beta-thalassemia testing can be performed through hemaglobin analysis. DNA testing for specific beta-thalassemia markers is “well established and extensively applied to genetic counselling [sic] and prenatal diagnosis” (Higgs, Engel, & Stamatoyannopoulos, 2011, p. 378). Currently, new non-invasive fetal DNA testing using maternal circulation methods of detection are being explored (Higgs, Engel, & Stamatoyannopoulos, 2011).
Signs and Symptoms
Thalassemia can easily be overlooked or confused with other anemias. Oftentimes thalassemia is misdiagnosed as another anemia or overlooked as it is not one of the more common anemias encountered on a daily basis. Additionally, since thalassemias are generally not recognized at birth due to a lack of knowledge of the underlying trait in parents and the lack of knowledge of the risk that the trait may be present, neonates born with a lesser form of thalassemia can be overlooked and diagnosed with other illnesses that may mimic other common newborn diseases (such as jaundice). The neonate is oftentimes well at birth, but starts to develop anemia, bone abnormalities, and failure to thrive (Clark, 2010). Initially infants may develop jaundice of skin and eyes around 3 to 6 months of age. If left untreated or misdiagnosed, infants can develop life threatening conditions such as splenomegaly, hepatomegaly, and anorexia (Clark, 2010). These infants may also experience epitaxis and other bleeding anomalies as well as frequent infections ( Clark, 2010; Durkin, 2013).
In more severe cases of thalassemia, children may have a component of mental retardation as well as stature abnormalities such as small bodies with large heads. Infants can have Mongoloid features caused by thickening of bones due to hyperactivity in the bone marrow. These bone and structure anomalies increase these children 's risk of pathologic fractures due to the thinning of long bones and expansion of narrow bone cavities. (Clark, 2010; Durkin, 2013).
Thalassemia major and thalassemia intermedia (anemia, jaundice, splenomegaly, hemosiderosis) oftentimes present with more alarming and clinically significant findings depending upon the degree and extent of the disease. Thalassemia minor, however, can be easily overlooked due to a lack of symptomatology and possible misdiagnosis with iron deficiency, if lab studies are not carefully reviewed (Clark, 2010).
Treatments for thalassemia (mainly thalassemia major) include folic acid supplementation, packed red blood cell (PRBC) transfusions, bone marrow transplantation, and chelation therapy. Generally, thalassemia intermedia and minor do not require treatment (Clark, 2010; Durkin, 2013).
Morbidity and Mortality
Thalassemia is “one of the most common genetic diseases worldwide, with at least 60,000 severely affected individuals born every year” (Engel, Higgs, & Stamatoyannopoulos, 2011, p. 376). There is an estimated 1000 people who are affected by Thalassemia in the United States and an unknown number of individuals who carry the genetic trait yet are unaffected (Durkin, 2013).
Consequences
Due to the pathophysiological structure abnormality, the body lacks the ability to dispose of the nontransferrin-bound iron caused by the disease as well as the packed red blood cell (PRBC) therapy that is oftentimes used to treat this disease. Since the body has an excessive amount of circulating iron from the blood transfusion overload the body 's natural balancing system (Kachalsky, Lambing, & Mueller, 2011). When there is excessive iron circulating there is increased demands upon the liver 's storage capacity and when this limit is met the liver is likely to develop fibrosis or cirrhosis due to the excess iron deposits. When this excess is stored in the heart muscles there is the potential of developing cardiac arrhythmias and other life threatening cardiac diseases. Oftentimes thalassemia patients die from cardiac complications, such as cardiomegaly. “Non-induced cardiac failure and arrhythmias are responsible for as many as 71% of deaths in patients with thalassemia” (Kachalsky, Lambing, & Mueller, 2011, p. 178).
In children with thalassemia there is an increased risk of developing metabolic disorders such as diabetes in addition to the aforementioned hepatic and cardiovascular complications. Just as adults are subject to cardiac and hepatic diseases and complications children are equally, if not more, at risk for development of these conditions over time if subject to chronic PRBC therapy at a young age (Clark, 2010).
Since PRBC therapy is initiated for treatment of thalassemias, children who have undergone numerous PRBC infusions should be monitored frequently, especially if they are having recurrent episodes that require blood transfusion therapy. In some cases patients may need to undergo chelation therapy to remove the excess iron stores from the patient 's body in order to prevent some of the complications that arise from excess iron stores. Close monitoring of ferritin levels should be performed and both acute and chronic care providers need to be aware of the patient 's disease and treatment history (Kachalsky, Lambing, & Mueller, 2011).
In the past, chelation therapy via subcutaneious injection (desferrioxamine) was the only method of iron excess removal available to patients, however, recent oral chelation drugs (deferiprone and deferasirox) have been introduced and when the two therapies are used together there has been significant improvement in iron balances in both the liver and heart (Engel, Higgs, & Stamatoyannopoulos, 2012). In the past few decades research in genetic testing and stem cell transplantation has been studied and initial evidence is promising, but funding and access to stem cell research and therapy is limited at this time for it to be a best-practice.
Conclusion
While thalassemia may not be a mainstream blood disorder that is discussed in the news or given a lot of airtime by media regarding its incidence and prevalence, it is an all-too-real blood disorder that impacts thousands of children and adults per year in all countries. The need for awareness and education is crucial to the successful identification and treatment of this disease. Fortunately, research and medication innovations may help increase the longevity of those who are diagnosed with thalassemia, especially the more life-threatening versions. One of the main purposes of this overview of thalassemia is to educate future healthcare professionals about thalassemia and how to identify and treat the condition, as it is only a small part of the myriad of blood disorders that are reviewed during the educational process. By having some background and understanding of how thalassemia presents and exactly what pathophysiologic process is taking place within the body, future practitioners can include thalassemia into their differential diagnosis when an anemia presents.

References
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References: Akran, H. &amp; Mahboob, T. (2004). Red cell Na-K-ATPase activity and electrolyte homeostasis in thalassemia Benz, E. J., Md. (2011). Newborn screening for [alpha]-thalassemia-- keeping up with globalization Clark, S. (Ed.). (2010). Pathophysiology: The biologic basis for disease in adults and children (6th ed.) Durkin, M. T. (Ed.). (2013). Professional guide to diseases (10th ed.). Philadelphia, PA: Lippincott Williams &amp; Wilkins Engel, J. D., Higgs, D. R., &amp; Stamatoyannopoulos, G. (28 January 2012). Thalassaemia. The Lancet, 378, 373-383 Kachalsky, E., Lambing, A., &amp; Mueller, M.L. (April 2012). The dangers of iron overload: Bring in the iron police Myers, T. (Ed.) (2009). Mosby 's medical dictionary (8th ed.). St. Louis, MS: Mosby Elsevier.