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PHM142 Fall 2016 Instructor: Dr. Jeffrey Henderson Thalassemia Jaime Dang, Winnie Li, Wuqi Lin (Qiqi), Carol Wong September 20, 2016 Background on Thalassemia • Inherited hemoglobin disorder, displaying autosomal recessive inheritance pattern [1] • “Mediterranean Anemia”: relatively high rate in populations residing near the Mediterranean Sea. [2] • Symptoms: ↓ hemoglobin; anemia; bone and spleen enlargement [3] Pathophysiology • Reduced or absent synthesis of hemoglobin protein chains – formation of abnormal hemoglobin [1] • Ineffective erythropoiesis Peripheral hemolysis Subsequent anemia [1] • 2 main forms: o Alpha-thalassemia o Beta-thalassemia Types of Thalassemia [1] • Alpha thalassemias: deficient synthesis of alpha-globin chains • Beta thalassemias: range from slight reduction of beta-globin chain synthesis to complete absence of beta-globin • Range from asymptomatic to intermediate and major in terms of severity Source: Musallam, Khaled M., et al. (2013) Cause (DNA Mutations) [2] • Deletion of HBA/HBB genes (genes responsible for making alpha and betaglobin proteins) • Change sequence in regions outside gene but needed for regulation • Directly change sequence within HBA/HBB gene • Ex. Mutations in the TATA box Source: Hartwell, Hood et al. (2004) Alpha Thalassemia - Genetics • Two HBA genes: HBA1, HBA2 [2] • Two copies of each gene = 4 total • Mutations are on chromosome 16 [1] • Severity of disorder is dependent on the number of abnormal genes [2] o Normal o Silent carrier (no symptoms) o Mild or severe anemia o Death Source: Hartwell, Hood et al. (2004) Beta Thalassemia • Only one HBB (beta-globin) gene • 1 normal wild-type allele, but 400+ mutant alleles [2] • Type of disorder is dependent on the number of abnormal genes [2] o Beta-plus (β+): reduced synthesis of beta-globin protein o Beta-zero (β0): no beta-globin chain synthesis at all • Microcytes (M): abnormally small RBC [3] • Poikilocytes (P): abnormally shaped RBC • Source: Advani, Pooja. (2015) Treatments [4] Allogeneic hematopoietic stem cell transplantation (HSCT) • Hematopoiesis: pluripotent stem cells in the bone marrow can differentiate into committed progenitor cells and then red blood cells, white blood cells, and megakaryocytes. • Stem cells can also come from blood sources, e.g. umbilical cord Treatments [5] Allogeneic Hematopoietic stem cell transplantation (HSCT) Only complete cure for thalassemia; usually for homozygous patients • Eliminate bone marrow in thalassemia patient • Transplantation of multipotent hematopoietic stem cells from a healthy HLA-matched donor to the patient • Immunosuppressants are used to facilitate the allogeneic engraftment • Graft-versus-host disease may occur → life threatening Treatments [1, 6] • Blood transfusions are the most common type of treatment, but not all thalassemia are transfusion-dependent In general, thalassemia majors (more severe thalassemia) are more dependent on blood transfusions than thalassemia intermedia. Source: Musallam, Khaled M., et al. (2013) However, it should be noted that frequent blood transfusions may lead to iron overload because the body cannot effectively excrete excess iron Iron Overload • Ineffective erythropoiesis → ↑GDF15 → ↓ Hepcidin levels → ↑ ferroportin → ↑ absorption of iron → IRON OVERLOAD [1,7,10,12,13] • When transferrin (bind iron in plasma) becomes 100% saturated, non-transferrinbound-iron (NTBI) load in organs and cause damage – most importantly, heart disease [1,7,8,9,13] Source: Silverthorn, D. (2007) & Pak, M., et al. (2005) 3 Iron Chelators [11,13] 1. Deferoxamine (DFO) o o 1 iron: 1 chelator Subc. IV administration – painful poor adherence 2. Deferiprone (DFP) o o 1 iron: 3 chelators PO, second line therapy, >6yrs age, genetic polymorphism, not approved for use in Canada 3. Deferasirox (DFX) o o 1 iron: 2 chelators PO Source: Symeonidis, AS. (2009) Additive Effect of DFO+DFP • Continuous infusion of DFO augmented with oral DFP [8] • Rapidly reduces liver iron, serum ferritin, myocardial siderosis, improves left ventricular ejection fraction, improves survival [13] Source: Evans, P., et al. (2010) Pharmacological Mechanism of DFP+DFO • DFP enhances DFO’s ability to chelate iron by rapidly accessing and shuttling NTBI that are otherwise only slowly available to DFO (i.e. intracellular iron pools in cardiac myocytes) [8,13] Source: Hoffbrand, A., et al. (2012) Summary 1. Thalassemia(inherited hemoglobin disorder) can be broadly divided into: (a) Alpha thalassemia - deficient synthesis of alpha-globin chains (b) Beta thalassemia - range from reduction (β+) to complete absence (β0) of beta-globin chains 2. Severity of disorder depends on number of abnormal/deleted alpha and beta globin genes (HBA1, HBA2, HBB), ranging from asymptomatic to intermediate and major 3. HSCT can be used to cure thalassemia but challenges include finding a matched donor and dealing with potential complications 4. Blood transfusions can help with thalassemia majors but risk of iron overload 5. The body responds to ineffective erythropoiesis by decreasing hepcidin levels, which increases ferroportin, and allows for more iron transport out of cell into plasma. A major consequence of iron overload (NTBI) is heart disease. 6. Iron chelation therapy is used to prevent thalassemia-related iron overload. When combined, deferiprone shuttles NTBI to deferoxamine, having an additive effect, and superior efficacy compared to DPO monotherapy. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. Musallam, Khaled M., et al. “Non-transfusion-dependent thalassemias.” 2013. Haematol. 98(6): 833-44. Hartwell, L., et al. Genetics: From Genes to Genomes. 4th ed. Boston, MA: McGraw-Hill Higher Education, 2004. Print. Advani, P. "Beta Thalassemia." Medscape. Ed. Emmanuel Besa. N.p., 24 Dec. 2015. Web. Silverthorn, D. Human Physiology: An Integrated Approach. San Francisco: Pearson/Benjamin Cummings, 2007. Print. Lucarelli, G., et al. "Hematopoietic Stem Cell Transplantation in Thalassemia and Sickle Cell Anemia." 2012. Cold Spring Harb Perspect Med. 2(5): a011825. Rafaella, O.,et al. "Liver Iron Concentrations And Urinary Hepcidin In Β-Thalassemia." 2007. haematologica. 92(5): 583-588. Rivella., S. “Ineffective erythropoiesis and thalassemias.” 2009. Current Opinion in Hematology. 16:187-194. Evans, P., et al. “Mechanisms for the shuttling of plasma non-transferrin-bound iron (NTBI) onto deferoxamine by deferiprone.” 2010. Transl Res. 156(2): 55-67. Vlachaki, E., et al. “Five Years of Deferasirox Therapy for Cardiac Iron in B-Thalassemia Major.” 2015. Hemoglobin. 39(5): 299-304. Pak, M., et al. “Suppression of hepcidin during anemia requires erythropoietic activity.” 2006. Blood. 108(12):3730-3735. Symeonidis, AS. “The role of iron and iron chelators in zygomycosis.” 2009. Clin Microbiol Infect. 5:26-32. Hoffbrand, A., et al. “How I treat transfusional iron overload.” 2012. Blood. 120: 3657-3669. Borgna-Pignatti, C., Marsella, M. “Iron Chelation in Thalassemia Major.” 2015. Clinical therapeutics. 37(12): 2866-2877.