Overview of Thalassemias PDF

OVERVIEW OF THALASSEMIAS For internal training and educational purposes only. Not for distribution or discussion outside of Agios. Overview of Thalassemias Table of Contents Introduction.....................................................................................................................

OVERVIEW OF THALASSEMIAS For internal training and educational purposes only. Not for distribution or discussion outside of Agios. Overview of Thalassemias Table of Contents Introduction.............................................................................................................................................................................................................i 1: Hemoglobin and Hemoglobin Disorders............................................................................................................................................ 1 2: β-Thalassemia................................................................................................................................................................................................... 9 3: α-Thalassemia................................................................................................................................................................................................24 Glossary..................................................................................................................................................................................................................34 Bibliography.........................................................................................................................................................................................................36 For internal training and educational purposes only. Not for distribution or discussion outside of Agios. Overview of Thalassemias Introduction The information contained in this module is for internal training purposes only. It should not be distributed nor should the information be discussed or used in proactive or reactive conversations with healthcare providers (HCPs). Any discussion with customers can only occur with approved materials. This module provides an overview of hemoglobin and the hemoglobin disorders alpha (α)- and beta (β)-thalassemia. First, this module reviews the structure and function of hemoglobin and its role in disease. Next, the epidemiology, genetics, pathophysiology, and clinical presentations of β-thalassemia are discussed. This module ends with a discussion of the epidemiology, genetics, pathophysiology, and clinical presentation of α-thalassemia. For internal training and educational purposes only. Not for distribution or discussion outside of Agios. i Overview of Thalassemias 1: Hemoglobin and Hemoglobin Disorders Introduction This section will introduce the structure and function of hemoglobin and discuss the most common hemoglobin disorders. Learning Objectives By the end of this section, you should be able to: Describe the structure and function of hemoglobin Discuss the most common hemoglobin disorders 1.1: Hemoglobin Hemoglobin is a protein-iron compound in the blood that carries oxygen from the lungs to tissues and carries carbon dioxide away from tissues to the lungs.1 Hemoglobin is found within mature red blood cells, which are primarily packets of hemoglobin that allow gas diffusion as they circulate throughout the body.2 The iron in hemoglobin is contained in a pigment called heme, which is bound to a protein chain, or globin.2 Heme is what gives red blood cells their red color.2 Did You Know? Iron Recycling The iron in hemoglobin is largely recycled by specialized cells in the spleen and liver that engulf old and damaged red blood cells.3,4 These cells break down red blood cells and release their iron into the blood.3 From there, the iron is delivered to immature red blood cells in the bone marrow to be incorporated into newly-synthesized hemoglobin.4 Hemoglobin Structure Hemoglobin comprises 4 subunits, each of which contain a heme molecule with an iron molecule at its center, surrounded by a globin protein.2 Each hemoglobin molecule contains 2 pairs of different globin proteins: 2 α-globin proteins and 2 non-α-globin proteins (typically β-, gamma [γ-], or delta [δ-] globin).2,5,6 The following interactivity shows a 3-dimensional figure of hemoglobin. For internal training and educational purposes only. Not for distribution or discussion outside of Agios. 1 Overview of Thalassemias 1.1: The Structure of Hemoglobin This icon represents an interactivity to reinforce knowledge regarding content learned. Please open the iRead® online to view the interactivity. Hemoglobin Function Hemoglobin not only transports oxygen from the lungs and releases it to cells in the tissues— it delivers approximately 20% of the carbon dioxide waste produced by cells back to the lungs.2 The unique properties of hemoglobin make the reversible binding of oxygen a very efficient process.2,7,8 Hemoglobin exhibits cooperative binding, where the binding of a molecule to a receptor increases the chances of another molecule binding.8 After the first oxygen molecule binds to heme in the lung, the hemoglobin molecule changes shape so that sequential binding of each additional oxygen molecule becomes progressively easier (up to a total of 4 oxygen molecules per hemoglobin molecule).2,7 The reverse is also true at the tissue level—after the first oxygen molecule is offloaded at the tissue level, each subsequent oxygen molecule is offloaded more easily.7 In other words, the oxygen affinity of hemoglobin changes with how fully hemoglobin is saturated with oxygen.7 The rate at which hemoglobin binds and releases oxygen is regulated by several factors, each of which ensures that oxygen is delivered to the tissues as needed7: the amount—ie, the partial pressure—of oxygen (PO2) in the microenvironment the partial pressure of carbon dioxide (PCO2) the pH in the microenvironment temperature The following animation describes how these factors impact hemoglobin’s oxygen affinity (ie, the rate at which it takes up and offloads oxygen). 1.1: Factors That Impact Hemoglobin’s Oxygen Affinity7 This icon represents a narrated animation. Please open the iRead® online to view the animation. For internal training and educational purposes only. Not for distribution or discussion outside of Agios. 2 Overview of Thalassemias All of the factors that impact hemoglobin saturation do so by modifying its 3-dimensional structure, which alters its affinity for oxygen.7 Therefore, variants that affect the structure of an individual globin subunit can impact the overall function of the hemoglobin molecule.2 Abnormal hemoglobin may result in an intrinsically altered oxygen affinity; an alteration in the way hemoglobin affinity for oxygen changes with PO2, body temperature, PCO2, or pH; or a combination of these factors.9 Types of Hemoglobin There are several types of hemoglobin, each made up of distinct globin proteins and each predominant during a particular stage of human development, as described in the table below.6,9,10 Types of Hemoglobin5,6,9,10 Type of Hemoglobin Description Embryonic hemoglobin Comprises 2 α-like (zeta [z])-globin proteins and 2 epsilon (Ɛ)-globin proteins Only present early in embryonic development Comprises 2 α-globin and 2 γ-globin proteins Accounts for approximately 75% of hemoglobin at birth but a small amount of hemoglobin in adults HbA, which makes up approximately 97% of adult hemoglobin, comprises 2 α-globin and 2 ß-globin proteins HbA2, which makes up approximately 3% of adult hemoglobin, comprises 2 α-globin proteins and 2 δ-globin proteins Fetal hemoglobin (HbF) Adult hemoglobin (HbA and HbA2) The α-globin proteins contained in hemoglobin are all the same and are encoded by the HBA genes.9 Each of the non-α-globin proteins, also called β-like proteins, are encoded by a different gene6,9-11: ß-globin proteins are encoded by the HBB gene12 δ-globin proteins are encoded by the HBD gene6 Ɛ-globin proteins are encoded by the HBE gene10 γ-globin proteins are encoded by the HBG genes (HBG-G and HBG-A)11,13 For internal training and educational purposes only. Not for distribution or discussion outside of Agios. 3 Overview of Thalassemias The following figure shows the timeline of expression of the different types of hemoglobin and the genes that control production of their β-like globin proteins.5 Figure 1.1: Stages of Development of Embryonic Hemoglobin, HbF, and HbA13 1.2: Hemoglobin Disorders Hemoglobin disorders arise as a result of either1,14: qualitative defects that affect hemoglobin structure (also called hemoglobinopathies), such as sickle cell disease quantitative alterations that reduce hemoglobin production, such as thalassemias Almost 1400 pathogenic variants leading to abnormal globin subunits of hemoglobin have been described.15 Up to 1.5% of the global population may carry a pathogenic variant that affects hemoglobin production, and nearly 1 in 100 couples across the world are at risk of having a child with a hemoglobin disorder.14 Among the most common hemoglobin disorders are sickle cell disease and the α- and βthalassemias, which are briefly described in the following interactivity.15 For internal training and educational purposes only. Not for distribution or discussion outside of Agios. 4 Overview of Thalassemias 1.2: Sickle Cell Disease and Thalassemias2,16-18 This icon represents an interactivity to reinforce knowledge regarding content learned. Please open the iRead® online to view the interactivity. Most hemoglobin variants arise from single nucleotide mutations leading to an amino acid change in 1 of the globin proteins.14 Other variants arise from small deletions, insertions, and fusions; diseases arise when the variant disrupts the production or function of hemoglobin—ie, its ability to carry oxygen.15 Which hemoglobin disorder arises depends on the hemoglobin variant that is inherited and the globin protein that is affected. Some variants result in abnormal globin genes that alter the structure of hemoglobin (eg, in sickle cell disease), while other variants result in reduced or absent globin proteins (eg, in β-thalassemia).2 1.3: Thalassemias Thalassemia syndromes are a diverse group of inherited anemia disorders characterized by reduced production of globin chains.14 The consequence of thalassemia is inadequate hemoglobin production, which can lead to a range of outcomes, from mild to severe.2 Historical Insights Thalassemia The name thalassemia comes from condensing the original name "thalassic anemia", from Thalassa or "the sea" in Greek, because all of the patients described originally were from around the Mediterranean Sea.18 Thalassemias present with altered production of globin proteins, and the individual thalassemia syndrome is named according to the globin whose synthesis is affected.14,17 For example, if production of the α-globin protein is reduced or absent, a patient may be diagnosed with αthalassemia.14,17 If production of the β-globin protein is reduced or absent, a patient may be diagnosed with β-thalassemia.17 If 2 different globin proteins are affected, such as δ and β, a patient may be diagnosed with δβ-thalassemia, and so on.14,17 If production of the α-globin protein is reduced or absent, a patient may be diagnosed with α-thalassemia.14,17 If production of the β-globin protein is reduced or absent, a patient may be diagnosed with β-thalassemia.17 If 2 different globin proteins are affected, such as δ and β, a patient may be diagnosed with δβ-thalassemia, and so on.14,17 For internal training and educational purposes only. Not for distribution or discussion outside of Agios. 5 Overview of Thalassemias Thalassemia syndromes as a whole have been introduced in virtually every ethnic group and geographic location.17 They are most common in the Mediterranean basin and tropical and subtropical regions of Asia and Africa.17 They are particularly prominent along the shores of the Mediterranean, through the Arabian peninsula, Turkey, Iran, India, and southeastern Asia, especially Thailand, Cambodia, and southern China.17 Deeper Dive β-Thalassemia and Malaria β-Thalassemia is most common in areas that are historically affected by malaria, a parasitic infection most commonly transmitted between humans through mosquitos.1,14,17 Individuals who are carriers of β-thalassemia are believed to have a survival advantage, in which infection with the malarial parasite results in milder malarial disease and less impact on reproduction.14,18 Therefore, the gene frequency for β-thalassemia has become fixed at a high level over time in these populations.14,17 The Thalassemia International Federation (TIF) has put forth guidelines for the diagnosis and management of thalassemias, focusing on the 2 broad categories of transfusion-dependent (TDT) and non-transfusion-dependent (NTDT) thalassemias, described in the table below.19,20 Categories of Thalassemias21,22 Category Description TDT People with TDT are incapable of naturally producing sufficient levels of hemoglobin, and they require life-long blood transfusions to survive NTDT NTDT refers to a less severe clinical phenotype of disease in which patients have variable symptoms, and chronic transfusion therapy is not absolutely required Symptoms of NTDT typically present later in life compared with symptoms of TDT, with more severe disease presenting between the ages of 2 and 6 years due to the presence of anemia It is important to recognize that TDT and NTDT are fluid clinical designations based on a patient’s current clinical status, and a patient may move between TDT and NTDT as a result of variations in disease or advances in clinical management.21 You will learn more about the different types of α- and β-thalassemias in the next sections. For internal training and educational purposes only. Not for distribution or discussion outside of Agios. 6 Overview of Thalassemias Knowledge Check Questions 1.1 Select the correct response from the dropdowns. The most prominent type of hemoglobin, HbA, comprises 2 |α, γ, δ|-globin chains and 2 |β, γ, δ|-globin chains.6 1.2 Match the following genes with the globin proteins they encode.6,9,10,12 (Select an item on the left and then select the corresponding item on the right.) 1.3 1.4 1.5 A HBA 1 δ-globin B HBB 2 γ-globin C HBD 3 β-globin D HBE 4 ε-globin E HBG-G and HBG-A 5 α-globin Thalassemia syndromes are a diverse group of inherited ________ disorders characterized by defects in the production of 1 or more of the hemoglobin subunits, resulting in imbalanced accumulation of globin protein and inadequate hemoglobin production.17 A hypoxemia B anemia C uremia D hypokalemia In which of the following areas are thalassemias most prevalent?17 A The United States B The United Kingdom C The Mediterranean D South America True or False? Patients with TDT are incapable of naturally producing sufficient levels of hemoglobin, and they require life-long blood transfusions to survive.21 A True B False For internal training and educational purposes only. Not for distribution or discussion outside of Agios. 7 Overview of Thalassemias Answers 1.1 α; β (Section 1.1: Hemoglobin) 1.2 A, 5; B, 3; C, 1; D, 4; E, 2 (Section 1.1: Hemoglobin) 1.3 B (Section 1.2: Hemoglobin Disorders) 1.4 C (Section 1.3: Thalassemias) 1.5 A (Section 1.3: Thalassemias) For internal training and educational purposes only. Not for distribution or discussion outside of Agios. 8 Overview of Thalassemias 2: β-Thalassemia Introduction This section will provide details about β-thalassemia, including its genetic background and epidemiological data as well as the pathophysiology behind the disease and how the disease presents. Learning Objectives By the end of this section, you should be able to: Describe the classifications of the β-thalassemia syndromes Explain the epidemiology of the β-thalassemia syndromes Discuss the genetics of the β-thalassemia syndromes Describe the pathophysiology and progression of the β-thalassemia syndromes Describe the clinical presentation of the β-thalassemia syndromes 2.1: Overview and Classifications β-thalassemia syndromes represent a group of hereditary blood disorders characterized by reduced or absent β-globin synthesis.22 Remember that HbA, which makes up approximately 97% of adult hemoglobin, comprises 2 α-globin and 2 β-globin proteins.6 The ratio of α-globin to β-globin is typically close to 1.17 Reduced or absent production of β-globin proteins results in an α-globin to β-globin chain imbalance and decreased production of functional hemoglobin.17,22 The extent to which the α-globin/β-globin ratio is affected typically correlates with clinical severity in patients with β-thalassemia.17 The extent to which the α-globin/β-globin ratio is affected typically correlates with clinical severity in patients with β-thalassemia.17 In β-thalassemia syndromes, if the production of β-globin chains is completely absent, the disease may be referred to as β-zero (β0)-thalassemia.17 If β-globin synthesis is only partially reduced, it may be referred to as β+-thalassemia.17 Patients with β-thalassemia have been traditionally categorized as having β-thalassemia major, β-thalassemia intermedia, or β-thalassemia minor (also called β-thalassemia trait or βthalassemia carrier), based on the extent of their α-globin to β-globin chain imbalance and clinical presentation.21 These different categories are summarized in the table below, and you will learn more about the characteristics of each category throughout this section. For internal training and educational purposes only. Not for distribution or discussion outside of Agios. 9 Overview of Thalassemias Categories of β-Thalassemia18 β-Thalassemia Major β-Thalassemia Intermedia β-Thalassemia Minor Severe anemia Mild to moderate anemia May be asymptomatic Dependent on blood transfusions for survival Require blood transfusions occasionally or not at all Mild anemia Experience extramedullary erythropoiesis Possible extramedullary erythropoiesis Iron overload Possible iron overload More recently, patients with β-thalassemias are simply classified as either TDT or NTDT, based on their need for red blood cell transfusions.17 TDT Patients with β-thalassemia major typically fall under the classification of TDT.21 TDT is also known as Cooley’s anemia and is a more severe form of the disease.21,22 TDT typically presents between 6 and 24 months of age, as HbF (2 α-globin and 2 γ-globin proteins) levels begin to decline and the signs and symptoms of defective β-globin synthesis begin to become more pronounced.9,13,17,22 NTDT Patients with β-thalassemia intermedia are typically classified as NTDT.21 Individuals with βthalassemia intermedia typically do not require blood transfusions for survival, although they may receive blood transfusions occasionally for the treatment of disease complications.21 People with β-thalassemia minor may be asymptomatic or have very mild symptoms.17,21 People with β-thalassemia minor are sometimes considered clinically silent carriers of thalassemia.22 For internal training and educational purposes only. Not for distribution or discussion outside of Agios. 10 Overview of Thalassemias The figure below summarizes the different classifications of β-thalassemia. Figure 2.1: Classification of β-Thalassemia17,21 2.2: Epidemiology In the United States, β-thalassemia is considered an orphan disease, or a rare disease that affects less than 200,000 people nationwide.23,24 The figure below summarizes current epidemiology data regarding β-thalassemia in the United States. Figure 2.2: Epidemiology of β-Thalassemia in the United States25,26 For internal training and educational purposes only. Not for distribution or discussion outside of Agios. 11 Overview of Thalassemias Did You Know? Prevalence of β-Thalassemia in the United States More than 50% of California's population is from African, Asian, or Hispanic heritage; groups that are associated with an increased risk of thalassemia.26 As the population of the United States continues to diversify, the prevalence of β-thalassemia is expected to continue rising.26 The life expectancy for people with β-thalassemia can vary, depending on the specific type of β-thalassemia a patient has and their access to medical care.17,27,28 Patients with NTDT typically have a normal life expectancy, although data on mortality and causes of death in NTDT remain limited.27,29 Advancements in medical treatment have also lead to near normal lifespan in patients with TDT; however, this survival is dependent upon regular blood transfusions and adherence to treatment.17,28 Lack of adequate blood transfusions, particularly in developing regions of the world, disease complications, and nonadherence to treatment can lead to decreased life expectancy.25,28 2.3: Genetics of β-Thalassemia β-thalassemia is caused by variants in 1 gene, HBB, which makes it a monogenic disease.12,21 Making the Connection β-Thalassemia Nomenclature Recall from earlier that if the production of β-globin chains is completely absent, the disease may be referred to as β0-thalassemia.17 If β-globin synthesis is only partially reduced, it may be referred to as β+-thalassemia.17 β-thalassemia is typically inherited in an autosomal recessive manner.22 β-thalassemia is typically inherited in an autosomal recessive manner.22 For internal training and educational purposes only. Not for distribution or discussion outside of Agios. 12 Overview of Thalassemias The table below reviews the different genetic backgrounds that a person with β-thalassemia may have. Potential Genetic Backgrounds of a Person With β-Thalassemia1,17-19,22,30 Homozygous recessive Individuals are considered to be homozygous recessive when they carry 2 copies of a variant that causes β-thalassemia1,18 Synthesis of β-globin is reduced (β+) or completely absent (β0), which results in reduced production or total loss of HbA, respectively18 Individuals who are homozygous recessive for β-thalassemia generally present with TDT (β0 or β+) but, in some cases, may have NTDT (mild β+)19,22 Compound heterozygous Individuals who carry 2 different variants (non or partially functional) for β-thalassemia are called compound heterozygotes22,30 These individuals may have thalassemia major or thalassemia intermedia, and thus, may present with either TDT or NTDT19,22 Heterozygous Individuals who carry 1 variant for β-thalassemia and 1 normal HBB gene are called heterozygotes22,30 These individuals are considered carriers of β-thalassemia,17,22 Individuals who are heterozygous may have β-thalassemia minor or be silent carriers19.22 For internal training and educational purposes only. Not for distribution or discussion outside of Agios. 13 Overview of Thalassemias Now that you are familiar with the potential genetic backgrounds that a person with βthalassemia may have, use the following interactivity to review the inheritance of βthalassemia. 2.1: Autosomal Recessive Inheritance of β-Thalassemia30 This icon represents an interactivity to reinforce knowledge regarding content learned. Please open the iRead® online to view the interactivity. Deeper Dive Dominant β-Thalassemia While most individuals with β-thalassemia present with reduced β-globin synthesis, occasionally, some individuals may instead harbor variants that cause them to develop extremely unstable β-globin chains and hyper-unstable hemoglobin.22 These unstable β-globin chains aggregate and precipitate in erythroid progenitor cells, inhibiting the formation of mature red blood cells.22 This rare variant is called dominant β-thalassemia.22 The reduced or absent production of β-globin in individuals with β-thalassemia results in an excess of unpaired α-globin chains, which accumulate in red blood cell (erythroid) progenitor cells inside and outside of the bone marrow.22 This α-globin to β-globin chain imbalance drives the pathology of β-thalassemia.22 The pathologic outcomes of α-globin to β-globin chain imbalance produce the major consequences of β-thalassemia, including chronic hemolytic anemia, ineffective erythropoiesis, and iron overload.17,22 You will learn more about these outcomes later in this section. Modifiers of the β-Thalassemia Phenotype A patient with β-thalassemia may sometimes present with genetic modifiers that affect their βthalassemia phenotype.22,30 An example of a modifier is the inheritance of a variant that causes β-thalassemia from 1 parent and a variant that produces a structurally abnormal hemoglobin from the other parent.22,30 One of the most common structurally abnormal hemoglobins is hemoglobin E (HbE), which produces an unstable hemoglobin molecule.22,30 The interaction of HbE and β-thalassemia results in phenotypes ranging from a condition indistinguishable from β-thalassemia major to a mild form of β-thalassemia intermedia.22 For internal training and educational purposes only. Not for distribution or discussion outside of Agios. 14 Overview of Thalassemias Key Facts HbE/β-Thalassemia Prevalence HbE/β-thalassemia is most prevalent in southeast Asia, where the carrier frequency of HbE is approximately 50% to 60% at the junction of Thailand, Laos, and Cambodia.22,31 Variants that produce HbE are inherited in a similar manner to variants that produce βthalassemia, and offspring have the potential of inheriting HbE/β-thalassemia, which has a spectrum of severity, even if only 1 parent is a carrier for β-thalassemia.30 The figure below illustrates a potential inheritance pattern of HbE/β-thalassemia. Figure 2.3: Inheritance Pattern of HbE/β-Thalassemia30 For internal training and educational purposes only. Not for distribution or discussion outside of Agios. 15 Overview of Thalassemias Spectrum of Disease Individuals with mild-to-moderate forms of HbE/β-thalassemia are typically categorized as NTDT, while individuals with severe forms of HbE/β-thalassemia are typically classified as TDT.21,32 Several factors may influence the severity of HbE/β-thalassemia, including the type of β-thalassemia variant, coinheritance of α-thalassemia, and an innate propensity to produce γglobin.32 The figure below summarizes this spectrum of disease. Figure 2.4: Spectrum of Severity of β-Thalassemia Syndromes32 Deeper Dive Other Compound Heterozygous Patterns In addition to HbE, other structural hemoglobin variants, such as hemoglobin C (HbC) and hemoglobin S (HbS), can be coinherited along with variants that result in β-thalassemia, producing different patterns of β-thalassemia.22 Individuals with HbC/β-thalassemia exhibit a diverse range of phenotypes and severity.22 The presence of HbS in patients with HbS/β-thalassemia results in sickle cell disease.22,30 For internal training and educational purposes only. Not for distribution or discussion outside of Agios. 16 Overview of Thalassemias Approximately 350 β-thalassemia–causing variants have been identified in the HBB gene, each conferring a different level of severity.17 These variants are often point mutations, or a change to a single nucleotide in a functionally important region of the HBB gene that results in reduced or absent production of the β-globin chain.22 Certain HBB mutations are inherited more frequently in certain regions of the world, and the genetic context in which variants in HBB arise plays a complex role in the severity of a patient’s disease.22 2.4: Pathophysiology Recall from earlier in this module that the predominant form of adult hemoglobin, HbA, comprises 2 α-globin chains and 2 β-globin chains.6 The reduced or absent production of βglobin in individuals with β-thalassemia results in an excess of unpaired α-globin chains, which accumulate in red blood cell (erythroid) progenitor cells inside and outside of the bone marrow.21,22 Follow along with this animation to review the pathologic outcomes of α-globin to β-globin chain imbalance. 2.1: Outcomes of α-Globin to β-Globin Chain Imbalance6,17,18,22 This icon represents a narrated animation. Please open the iRead® online to view the animation. The pathologic outcomes of α-globin to β-globin chain imbalance that you learned above produce the major consequences of β-thalassemia18,21: chronic hemolytic anemia ineffective erythropoiesis iron overload Chronic Hemolytic Anemia Chronic hemolytic anemia leads to chronic inadequate oxygenation of tissue caused by premature red blood cell destruction that occurs at a rate faster than the production of new red blood cells can match.1,21 This red blood cell destruction leads to reduced oxygen carrying capacity of the blood and the resulting anemia.18 For internal training and educational purposes only. Not for distribution or discussion outside of Agios. 17 Overview of Thalassemias Chronic hemolytic anemia can lead to acute complications, such as the production of gallstones, as well as long-term consequences, such as effects on growth and organ and vascular function, including enlargement of the heart and heart failure.17,21,22 To compensate for deficient oxygen-carrying capacity of the blood, the body stimulates the production of erythropoietin, a hormone produced by the kidneys that stimulates the bone marrow to produce red blood cells.1,18 Ineffective Erythropoiesis In individuals with β-thalassemia, the bone marrow responds to the production of erythropoietin by increasing the production of erythroid progenitor cells; however, because of ineffective erythropoiesis, very few mature red blood cells make it into the peripheral circulation, and the bone marrow becomes crowded with immature erythroid precursors.17,18 Increased proliferation of erythroid progenitors in the bone marrow can lead to bone deformities and decreased bone mass as the bone marrow expands, widening the bone marrow space and reducing the thickness of cortical bone.17,21 To compensate for the lack of mature red blood cells being formed in the bone marrow, extramedullary erythropoiesis, or the production of red blood cells outside of the bone marrow, primarily in the spleen and/or liver, can also occur.17,21 Iron Overload Iron overload is the increase of iron in tissues that results in damage to involved cells and organs.33,34 Iron overload can be caused by33,34: excessive iron absorption33 ineffective erythropoiesis accompanying chronic hemolysis33,34 blood transfusion33 TDT patients receive regular blood transfusions, which leads to iron overload because the human body lacks a mechanism to excrete excess iron, which may lead to mortality through iron-associated cardiac and hepatic toxicity.22,35 Iron overload may contribute to heart failure, cirrhosis, liver cancer, growth retardation, and endocrine abnormalities.35 In patients with NTDT, ineffective erythropoiesis and hypoxia lead to abnormally low levels of the master iron regulatory hormone hepicidin, increased absorption of iron in the intestines, and primary iron overload.17,19 Blood transfusions can add to the iron burden for patients with NTDT and may lead to secondary iron overload in patients who receive regular transfusions over the long-term.19 For internal training and educational purposes only. Not for distribution or discussion outside of Agios. 18 Overview of Thalassemias 2.5: Clinical Presentation You learned earlier in this module that patients with β-thalassemias are often classified as either TDT or NTDT, based on their need for red blood cell transfusions.17 Patients with βthalassemia minor do not fall into either the NTDT or TDT categories because they are often asymptomatic.17,19,21 Making the Connection TDT and NTDT Patients with β-thalassemia major typically fall under the classification of TDT.21 TDT is a more severe form of the disease.21,22 Patients with β-thalassemia intermedia and β-thalassemia minor are typically classified as NTDT.21 Individuals with β-thalassemia intermedia typically do not require blood transfusions for survival, although they may receive blood transfusions occasionally for the treatment of disease complications.21 People with β-thalassemia minor may be asymptomatic or have very mild symptoms.17,21 TDT typically presents between 6 and 24 months of age, while more severe forms of NTDT typically present between the ages of 2 and 6 years.22 Patients with less severe forms of NTDT may be asymptomatic or present with mild symptoms.22 Ultimately, the main determinant in the clinical presentation and severity of β-thalassemia (NTDT vs TDT) is the extent of α-globin to β-globin chain imbalance within the individual.21 Let’s take a closer look at the clinical presentations of β-thalassemia minor, NTDT, and TDT. Clinical Presentation of β-Thalassemia Minor Individuals who are heterozygous for the β-thalassemia trait are usually asymptomatic, and their diagnosis may be made as a result of family history or as an incidental finding during work-up for a different condition.17 Carrying an abnormal β-globin gene generally does not result in direct clinical symptoms or pathologic consequences for the patient.17 Clinical Presentation of NTDT Individuals with less severe genotypes (eg, β+) present with symptoms that express along a wide spectrum of severity, from mild symptoms to complex presentations that move toward transfusion dependence.17 For internal training and educational purposes only. Not for distribution or discussion outside of Agios. 19 Overview of Thalassemias Clinical features of NTDT may include36: paleness mild to moderate jaundice gallstones liver and spleen enlargement moderate to severe bone modifications leg ulcers a tendency to develop osteopenia and osteoporosis heart complications Clinical Presentation of TDT Individuals with TDT (often those with β0) are typically born without significant anemia due to the production of HbF; however, as HbF (comprising 2 α-globin and 2 γ-globin subunits) levels begin to decline and HbA (comprising 2 α-globin and 2 β-globin subunits) levels increase, the signs and symptoms of defective β-globin synthesis begin to become more pronounced.11-13,17 The initial clinical findings in a young child (typically presenting between the ages of 6 months to 24 months) with TDT may include17,36: failure to thrive progressive paleness feeding problems diarrhea irritability recurrent fever abdominal swelling (caused by enlargement of the liver and spleen) jaundice For internal training and educational purposes only. Not for distribution or discussion outside of Agios. 20 Overview of Thalassemias Individuals with TDT present with anemia that is severe for their age (Hb