Pathophysiology of Beta Thalassemia

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Pathophysiology of beta thalassemia

Author: Stanley L Schrier, MD
Section Editors: William C Mentzer, MD, Donald H Mahoney, Jr, MD
Deputy Editor: Jennifer S Tirnauer, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: May 2019. | This topic last updated: Jun 13, 2018.
INTRODUCTION
Beta thalassemia is an inherited hemoglobinopathy in which the production of one or both beta
globin chains is impaired. The clinical manifestations include hemolytic anemia and impaired iron
handling, the severity of which depends on the degree of impairment in beta globin production.
This topic reviews the pathophysiology of anemia in beta thalassemia, which includes ineffective
erythropoiesis and hemolysis. Related issues are discussed in separate topic reviews:
● Pathophysiology of alpha thalassemia – (See "Pathophysiology of alpha thalassemia".)

● Thalassemia genetics – (See "Molecular genetics of the thalassemia syndromes".)
● Thalassemia laboratory testing – (See "Methods for hemoglobin analysis and
hemoglobinopathy testing".)
● Thalassemia clinical manifestations and diagnosis – (See "Clinical manifestations and
diagnosis of the thalassemias".)
● Thalassemia management – (See "Management and prognosis of the thalassemias" and "Iron
chelators: Choice of agent, dosing, and adverse effects".)
● Hematopoietic cell transplantation for thalassemia – (See "Hematopoietic cell transplantation
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for transfusion-dependent thalassemia" and "Thalassemia: Management after hematopoietic

cell transplantation".)
DISEASE CLASSIFICATION
Thalassemia refers to a spectrum of diseases characterized by reduced or absent production of

one or more globin chains.
Beta thalassemia is caused by beta globin gene mutations that lead to impaired production of beta
globin chains. Beta thalassemia is further classified according to the degree of reduction in beta
globin:
● Beta0 thalassemia refers to mutations that completely abolish beta globin production. Patients
who are homozygous or compound heterozygous for beta0 thalassemia mutations have beta
thalassemia major; they cannot make any beta globin chains and hence cannot make the
normal adult hemoglobin (hemoglobin A [HbA]; alpha2/beta2). These are the patients
originally described by Cooley. They have profound, transfusion-dependent anemia and other
manifestations of severe thalassemia. (See "Clinical manifestations and diagnosis of the
thalassemias", section on 'Clinical manifestations'.)
● Beta+ thalassemia refers to mutations that cause decreased (but not absent) beta globin
production. Patients who are homozygous for beta+ thalassemia mutations can make some
hemoglobin A and are generally less severely affected than those with beta0 thalassemia
mutations. Some authors prefer to simplify differences between beta thalassemia major and
intermedia by referring to them as TD (transfusion-dependent) and NTD (non-transfusion-
dependent) thalassemia.
• Patients with a beta+ thalassemia mutation combined with a beta0 thalassemia mutation
have beta thalassemia major (TD).
• Patients with two beta+ thalassemia mutations have beta thalassemia intermedia (NTD).
(See "Clinical manifestations and diagnosis of the thalassemias", section on 'Overview
and typical presentations'.)
• Individuals with a beta+ thalassemia mutation combined with a normal beta globin gene
have beta thalassemia minor (also called beta thalassemia trait). These individuals have
mild anemia and are often identified incidentally (eg, by family testing or on a complete
blood count done for other reasons). (See "Clinical manifestations and diagnosis of the
thalassemias", section on 'Beta thalassemia minor'.)
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The beta thalassemia mutations are discussed in detail separately. (See "Molecular genetics of the
thalassemia syndromes".)
Alpha thalassemia is an inherited thalassemia syndrome characterized by impaired production of

alpha globin chains, which leads to a relative excess of beta globin chains. The pathophysiology
and diagnosis of alpha thalassemia is discussed separately. (See "Pathophysiology of alpha
thalassemia" and "Clinical manifestations and diagnosis of the thalassemias", section on
'Diagnostic evaluation'.)
IMBALANCED RATIO OF ALPHA TO BETA GLOBIN
Beta globin mutations — Beta thalassemia is caused by one or more mutations in the beta globin
gene that result in an imbalanced ratio of alpha to beta globin. The specific gene mutations
involved and their mechanism of affecting beta globin production are discussed separately. (See
"Molecular genetics of the thalassemia syndromes".)
This imbalance in turn leads to impaired red blood cell (RBC) maturation and destruction of
developing RBC precursors in the bone marrow, called ineffective erythropoiesis or intramedullary
hemolysis; as well as hemolysis, with reduced RBC survival in the peripheral blood. The severe
anemia can result in extramedullary hematopoiesis and increased iron absorption, which can lead
to excess iron stores even in the absence of transfusions.
The variability in the severity of anemia is explained mostly by the severity of the globin imbalance,
which depends on the specific mutation and whether one or both beta globin alleles are affected.
Other modifying factors such as the co-inheritance of alpha thalassemia or hemoglobin E may also
contribute. (See 'Modifiers of disease severity' below.)
Modifiers of disease severity — As noted above, a principal determinant of disease severity in

beta thalassemia is the ratio of alpha to non-alpha globin chains. The major determinant of disease
severity is the specific beta globin mutation (ie, whether it results in partial or total loss of beta
globin production) and the zygosity of the individual (ie, whether the individual inherits one or two
beta thalassemic mutations). (See 'Unbalanced globin chain synthesis' below.)
The other major variables that can affect disease severity also alter the alpha to beta globin ratio
and/or the nature of the beta globin produced:
● Concomitant alpha thalassemia – Alpha thalassemia is due to impaired production of alpha

globin chains; there are four alpha globin chain genes (as opposed to two for beta globin). As
expected from a disorder that reduces alpha globin production, co-inheritance of alpha
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thalassemia trait ameliorates the severity of beta thalassemia by partially normalizing the
alpha to beta globin ratio without greatly affecting the amount of total hemoglobin. (See
"Clinical manifestations and diagnosis of the thalassemias", section on 'Causes of variability in
disease manifestations'.)
● Increased fetal hemoglobin – Certain beta globin gene mutations are associated with higher
levels of gamma globin production that lead to increases in fetal hemoglobin (hemoglobin F),
which can serve as a beta globin-like partner with alpha globin, leading to a less severe
imbalance in the alpha to beta globin ratio (figure 1). These mutations are sometimes referred
to as hereditary persistence of fetal hemoglobin (HPFH). (See "Fetal hemoglobin (hemoglobin
F) in health and disease", section on 'HbF in the thalassemias and hereditary persistence of
fetal hemoglobin'.)
● Sickle-beta thalassemia – Co-inheritance of the sickle hemoglobin mutation on one beta

globin allele and a thalassemic mutation at the other beta globin allele leads to a form of sickle
cell disease, the severity of which depends on the nature of the beta thalassemic mutation (ie,
whether it results in reduced versus absent beta globin production). (See "Overview of variant
sickle cell syndromes", section on 'Sickle-beta thalassemia'.)
● Co-inheritance of hemoglobin E – Hemoglobin E results from a beta globin mutation that

reduces beta globin production. The clinical phenotype is similar to beta thalassemia but less
severe. Hemoglobin E is commonly seen in India and Southeast Asia. (See "Introduction to
hemoglobin mutations", section on 'Hemoglobin E'.)
Co-inheritance of heterozygosity for a beta thalassemia mutation and a hemoglobin E

mutation is responsible for a large proportion of severe beta thalassemia throughout the world
[1]. It occurs at a frequency of 3 to 9 percent in Thailand [2,3]. This combination of mutations
produces remarkable clinical heterogeneity, with hemoglobin concentrations ranging from
approximately 3 to approximately 14 g/dL. The phenotype appears to be especially severe in
Sri Lanka [4]. The pathophysiology of this heterogeneity and its severity remain a puzzle [5].
Co-inheritance of alpha thalassemia appears to have a significant impact [1].
ANEMIA
Overview of anemia mechanisms — The reduced beta globin production in beta thalassemia
leads to an imbalance in the ratio of alpha to beta chains. Excess free alpha chains cannot be
incorporated into hemoglobin; they may remain soluble or aggregate and precipitate. The resulting
abnormalities in the developing and mature red blood cells (RBCs) lead to two major phenomena,
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both of which contribute to anemia:
● Ineffective erythropoiesis – Ineffective erythropoiesis refers to reduced production of RBCs

in the bone marrow due to a combination of apoptotic cell death and hemolysis of developing
RBC precursors. In beta thalassemia this is associated with extramedullary hematopoiesis
(production of RBCs in other tissues besides the bone marrow, such as the liver and spleen).
● Hemolysis – Hemolysis of mature RBCs in beta thalassemia is primarily extravascular,

involving phagocytosis of abnormal RBCs in the reticuloendothelial system.
Some RBCs in beta thalassemia are hypochromic and microcytic due to decreased overall
hemoglobin production. In addition, other grossly abnormal RBC shapes can be seen on the
peripheral blood smear, including target cells, teardrop cells (dacrocytes), fragmented forms
(schistocytes), and burr cells (echinocytes) (picture 1). These shape abnormalities are due to
effects on the RBC membrane and extramedullary hematopoiesis. Nucleated RBCs are also
common, especially following splenectomy. (See "Clinical manifestations and diagnosis of the
thalassemias", section on 'CBC and routine laboratory studies'.)
The reticulocyte count may be variably increased but is often inappropriately low given the degree
of anemia, reflecting the combined effects of increased RBC destruction and decreased effective
RBC production.
Many (but not all) of the findings that contribute to ineffective erythropoiesis and increased
hemolysis have been recapitulated in a mouse model of beta thalassemia (the Hbbth-1 mouse,
beta globin gene deletion), including increased free alpha chains, oxidant injury, membrane rigidity,
and RBC dehydration [6-8].
Unbalanced globin chain synthesis — Hemoglobin is a tetramer consisting of two heterodimers;

each heterodimer has one alpha globin-like chain and one beta globin-like chain (as well as
heme). The beta-like chain (also called "non-alpha" chain) used as an alpha globin partner
undergoes a shift during development, from epsilon in the embryo to gamma in the fetus to beta in
the adult. The shift is accomplished by alternative gene expression and splicing from the beta
globin locus (figure 1). Throughout the process, the ratio of alpha to beta chain synthesis is tightly
controlled, such that it does not deviate much from 1.00 ± 0.05. (See "Structure and function of
normal hemoglobins".)
Beta thalassemia is caused by mutations that impair beta globin chain production leading to an
excess of alpha chains relative to beta chains [9,10]. The free alpha chains cannot form tetramers;
they are unstable and can aggregate and precipitate adjacent to the RBC membrane [11].
Precipitated alpha chains can form "large, single inclusions" in RBC precursors and circulating
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RBCs [9].
An increase in production of the beta-like gamma chain (responsible for forming fetal hemoglobin)
and the delta chain (responsible for forming HbA2) usually occurs but is insufficient to restore the
balance between alpha and beta-like chains or to prevent alpha chain accumulation [12]. The
mechanisms of increased fetal hemoglobin production are discussed separately. (See "Fetal
hemoglobin (hemoglobin F) in health and disease", section on 'Beta thalassemia'.)
The importance of balanced alpha and beta chain production is illustrated by several clinical
observations in individuals with beta thalassemia intermedia, including reduced clinical severity in
individuals who co-inherit an alpha thalassemia mutation (and thus have reduced alpha chain
production), and increased clinical severity in individuals who co-inherit six rather than four alpha
chain genes, and thus have an even greater imbalance [13]. (See "Clinical manifestations and
diagnosis of the thalassemias", section on 'Causes of variability in disease manifestations'.)
Cytoskeletal/membrane damage and cell dehydration — Normal RBC precursors undergo

orderly cytoskeletal and membrane assembly that includes spectrin, band 4.1, and band 3 (the
anion exchanger) (see "Red blood cell membrane: Structure, organization, and dynamics"). In
contrast, in beta thalassemia, incorporation of these proteins frequently is disorderly and
discontinuous, especially in areas of alpha chain aggregates and at earlier stages of erythroid
development [14].
These cytoskeletal abnormalities are thought to be due in large part to oxidant injury, either of
globin chains that bind to them or of the cytoskeletal or integral membrane proteins directly, as
evidenced by loss of free thiols within globin chains and other membrane proteins [15-18].
Oxidation is a normal phenomenon in RBCs (hemoglobin is oxidized to methemoglobin at a rate of
about 0.5 to 3 percent per day); however, in normal RBCs the oxidized methemoglobin
subsequently is reduced (restored to native hemoglobin) via cytochrome b5 reductase (formerly
called methemoglobin reductase) [19]. In thalassemic RBCs, isolated alpha and beta chains are
susceptible to oxidation to form hemichromes, some of which are irreversibly modified [20-22].
These iron containing hemichromes can generate reactive oxygen species (ROS), which in turn
can oxidize adjacent RBC membrane proteins and lipids [23-26].
Oxidant injury is in turn worsened by free iron, levels of which are in turn increased by the effects
of oxidant injury [27] (see 'Iron overload' below). Increased amounts of membrane iron have been
found in association with denatured hemoglobin in beta thalassemic cells [28]. Proteolysis of some
cytoskeletal and membrane proteins may also occur, although this has not been studied directly.
Beta thalassemic erythroid precursors containing apparent alpha globin chain precipitates also
have reduced protein synthetic capacity [29].
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These abnormalities in erythroid precursors lead to increased apoptosis in the bone marrow, while
the abnormalities in the mature RBC lead to rigidity, increased membrane expression of
phosphatidylserine (PS), and neoantigens, all in turn leading to increased hemolysis, especially in
the reticuloendothelial system. (See 'Ineffective erythropoiesis' below and 'Hemolysis' below.)
Abnormal membrane proteins in beta thalassemia include the following:
● Band 3 – Band 3 (also known as anion exchanger 1 [AE1]) is the major integral
transmembrane protein. It is the principle anion exchanger in the RBC membrane; it also has
a major structural role in membrane integrity. Isolated triton-extracted membrane
cytoskeletons from individuals with beta thalassemia contain about twice as much band 3
protein as controls [30].
● Band 4.1 – Band 4.1 is a cytoskeletal protein that stabilizes spectrin-actin interactions. The
function of band 4.1 is decreased by half in individuals with beta thalassemia intermedia [31].
● Spectrin – Spectrin is a major structural protein of the cytoskeleton with binding sites for
numerous membrane proteins. There is conflicting information about the assembly of spectrin
in thalassemic RBCs, although it appears that overall levels of spectrin and its binding
partners (eg, ankyrin, actin) may be reduced [31-34].
The normal organization and assembly of these proteins are illustrated in the figure (figure 2).
Additional information about their functions is presented separately. (See "Red blood cell
membrane: Structure, organization, and dynamics".)
Beta thalassemic RBCs have reduced hemoglobin content as well as reduced cell water (ie, they
are dehydrated). The finding of cellular dehydration is somewhat counterintuitive, but it explains
the appearance of dense cells on the peripheral blood smear (figure 3) and the high mean cell
hemoglobin concentration (MCHC) observed on the complete blood count [35-37]. Dehydration of
thalassemic RBCs is thought to be due to excessive and inappropriate activation of the potassium-
chloride (K-Cl) cotransport system (figure 4), both in bone marrow erythroid precursors and
circulating reticulocytes [35,38]. Excess transport of ions out of the RBC causes a corresponding
loss of water by osmotic mechanisms. This process is excessive in thalassemic RBCs compared
with normal controls [38]. (See "Control of red blood cell hydration".)
Ineffective erythropoiesis — Ineffective erythropoiesis in beta thalassemia is due to expansion of

the developing pool of erythroid precursors and premature destruction of these precursors within
the bone marrow. The magnitude of ineffective erythropoiesis was initially underappreciated, until
studies using radiolabeled iron were performed that demonstrated that in beta thalassemia major,
intramedullary cell death affected as much as 60 to 75 percent of developing RBC precursors [39].
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Subsequently the extent of apoptosis and erythroid expansion (numbers of developing

erythroblasts) were shown to be increased in parallel [40].
Characteristic stages of ineffective erythropoiesis in beta thalassemia include expansion of

erythroid progenitor cells and accelerated differentiation followed by maturation arrest and
apoptosis at the polychromatophilic erythroblast state (two steps before the reticulocyte) [41].
Erythroid expansion is driven by increased erythropoietin levels, although this may be blunted
somewhat by inflammatory cytokines. GDF11, a cytokine in the transforming growth factor beta
family, promotes the expansion of erythroid progenitor cells. Blockade of GDF11 in an animal
model of thalassemia has been shown to correct several features of ineffective erythropoiesis
including anemia, hemolysis, and iron overload. Potential therapies that could reduce GDF11 are
under development for individuals with thalassemia. (See "Regulation of erythropoiesis", section
on 'Activin receptor ligand traps'.)
A major cause of premature death of erythroid precursors is accelerated apoptosis [40,42-44]. One
mechanism of apoptosis was shown to involve sequestration of heat shock proteins such as
HSP70 by free alpha globin chains in the cytoplasm of the RBC precursors, causing maturation
arrest and ultimately cell death [45]. These toxic free alpha chains have been demonstrated as
early in erythropoiesis as the proerythroblast stage [46-48] (see "Regulation of erythropoiesis").
Free alpha chains were also shown to form dense cytoplasmic aggregates in basophilic,
polychromatophilic, and orthochromatophilic normoblasts (the final stages of RBC precursor
development) [14,42,46,47,49,50]. Other proteins that regulate apoptosis such as caspases and
cytochromes have been shown to be abnormally phosphorylated in bone marrow erythroblasts of
some patients [51]. Increased susceptibility of beta thalassemia erythroid precursors to
phagocytosis by bone marrow macrophages has also been demonstrated [52]. Despite this
increase in apoptosis, paradoxically, it has been suggested that reduced apoptosis may contribute
to erythroid expansion [41].
Expanded erythropoiesis may cause expansion of the marrow cavities that leads to bony distortion
of the long bones, head, and face. (See "Clinical manifestations and diagnosis of the
thalassemias", section on 'Skeletal changes'.)
In individuals with severely impaired erythropoiesis, RBC production may occur in extramedullary
sites such as the spine, liver, and spleen. Erythroid expansion in the spine can cause significant
pain and neurologic deficits. (See "Clinical manifestations and diagnosis of the thalassemias",
section on 'Hepatosplenomegaly'.)
Hemolysis — Hemolysis in beta thalassemia is primarily intracorpuscular (due to inherent

abnormalities in the RBC). The mechanism is thought to be related to the excess alpha chains,
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which aggregate and precipitate, in turn damaging the RBC membrane. The RBCs can become
dehydrated and/or rigid, making them less deformable as they move through the vasculature and
the reticuloendothelial system.
Reduced deformability — Deformability (flexibility) is an essential property of the RBC that

enables the cells to traverse the capillary circulation and the sinusoids of the spleen (and liver),
which are tortuous and narrower than the diameter of the RBC. Deformability depends on the RBC
having a specific surface area to volume ratio, relatively low cytoplasmic viscosity, and viscoelastic
membrane properties. Poorly deformable RBCs are trapped and destroyed by reticuloendothelial
macrophages in the spleen and liver. (See "Red blood cell membrane: Structure, organization, and
dynamics".)
These properties of beta thalassemia RBCs are abnormal:
● Some populations of beta thalassemic RBCs are dense and dehydrated, especially in
individuals who have undergone splenectomy [35]
● Beta thalassemic RBCs have increased membrane rigidity, even when the surface area to
volume ratio is normal [35,53]
Reduced deformability makes the cells more susceptible to clearance by the reticuloendothelial
system (extravascular hemolysis). (See 'Reduced survival' below.)
Reduced survival — The survival of thalassemic RBCs is shortened relative to non-

thalassemic RBCs [54]. This is thought to be due to macrophage attack and phagocytosis in the
reticuloendothelial (monocyte-macrophage) system in the spleen and liver. Signals for
macrophages to identify, retard, and engulf thalassemic RBCs have been studied extensively. The
following may contribute:
● Signals for macrophage interactions may be exposed by reduced sialic acid in the membrane
[55].
● Membrane phospholipids such as phosphatidylserine (PS) are recognized by macrophages as

a signal for phagocytosis [56]. In normal RBCs, PS is confined to the inner leaflet of the
membrane and thus is sequestered away from macrophages; in some beta thalassemic
RBCs, the membrane bilayer is scrambled presumably by oxidative damage and PS is
exposed on the outer membrane [57,58]. In some patients, the proportion of these abnormal
cells can be as high as 20 percent.
● Anti-RBC autoantibodies may form as the abnormal membrane proteins are exposed [59].
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Autoreactive IgG have been observed on the surface of thalassemic RBCs.
● Oxidized alpha globin chains may bind to the membrane and alter its structure or deformability
[13,15-17,30,33,54,60].
● Oxidative damage from membrane-associated heme, hemichromes, and/or iron may cause
membrane proteins to aggregate abnormally and create neoantigens [61,62].
● Increased cytokine production, especially tumor necrosis factor, may activate monocytes and
macrophages and make them more phagocytic [63].
The importance of reticuloendothelial clearance of these abnormal cells is illustrated by the

observation that individuals with beta thalassemia who have undergone splenectomy (and thus
lack this clearance mechanism) have a greater proportion of RBCs with unstable and abnormal
membranes [35].
IRON OVERLOAD
Iron overload and iron toxicity contribute to the pathophysiology and complications of beta
thalassemia. Excess iron stores are greatly increased by transfusional iron overload; however, iron
accumulates even without transfusions. The mechanism is complex, and is thought to involve
reduced levels of hepcidin.
Both anemia and increased erythropoiesis lead to suppression of hepcidin and, therefore,
increased iron absorption. An important proximal regulator is erythroferrone, a member of the C1q-
tumor necrosis factor (TNF) family of proteins that is produced by maturing erythroblasts in
response to erythropoietin [64,65]. In states of ineffective erythropoiesis such as thalassemia,
erythroferrone can be markedly elevated; initial studies in an animal model suggest that increased
erythroferrone may be the principal contributor to excessive iron absorption in thalassemia [66].
Reduced levels of hepcidin lead to increased iron uptake from the intestine and bone marrow
macrophages. (See "Regulation of iron balance", section on 'Hepcidin'.)
While hepcidin is suppressed by anemia and erythropoiesis, it is also induced by transfusion, iron
overload, and inflammatory cytokines (as in anemia of chronic disease/inflammation) (see "Anemia
of chronic disease/inflammation", section on 'Pathogenesis'). Available tools to assess this balance
between signals that lead to paradoxically increased versus decreased hepcidin in patients with
thalassemia are lacking.
Increased iron absorption leads to increases in the levels of storage iron as well as free iron, also
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called non-transferrin-bound iron (NTBI). Increased storage iron is apparent as the serum
transferrin saturation and serum ferritin rise. Macrophage iron can be seen in the bone marrow
[48]. (See "Regulation of iron balance", section on 'Transferrin' and "Regulation of iron balance",
section on 'Ferritin'.)
Iron can cause toxic effects on organs and on the bone marrow:
● Excessive iron, especially NTBI, contributes to organ toxicity via the generation of reactive
oxygen species (see "Approach to the patient with suspected iron overload", section on
'Consequences of excess iron stores'). This may affect the heart, kidneys, liver, thyroid,
gonads, and pancreas, leading to decreased function. In a series of 174 patients with
thalassemia major or intermedia who were receiving regular transfusions and chelation
therapy, NTBI was detected in 83 percent; all patients with heart disease had increased NTBI
and all patients without NTBI were free of heart disease [67]. (See 'Organ damage' below.)
● Iron overload may also increase reactive oxygen species in the bone marrow that interfere
with erythropoiesis. (See 'Ineffective erythropoiesis' above.)
The evaluation and management of excess iron stores in patients with thalassemia are discussed
separately. (See "Iron chelators: Choice of agent, dosing, and adverse effects" and "Clinical
manifestations and diagnosis of the thalassemias", section on 'Iron studies'.)
HYPERCOAGULABLE STATE
Several reports have described an increased risk of thromboembolic complications in thalassemia

[68-70]. In a retrospective series of 584 individuals with beta thalassemia intermedia, thrombosis
was observed in 82 (14 percent) [71]. (See "Clinical manifestations and diagnosis of the
thalassemias".)
The mechanisms are incompletely understood. It has been suggested that increased
phosphatidylserine (PS) on the outer leaflet of the RBC membrane may promote thrombosis,
similar to the role of PS in promoting coagulation on the surface of activated platelets [72]. (See
"Overview of hemostasis", section on 'Multicomponent complexes'.)
Other hemostatic changes may include alterations in the levels of procoagulant or anticoagulant
factors, and/or chronic activation of platelets, endothelial cells, or white blood cells [68].
Splenectomy may also increase the risk of thrombosis [73,74]. Similarity to the increased risk of
thromboembolism in sickle cell disease has also been suggested. However, as high quality
evidence for the increased risk of thrombophilia is lacking, we manage patients with thalassemia
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similar to the general population. Further study of this issue is warranted.
ORGAN DAMAGE
Organ damage in beta thalassemia is due to the combined effects of anemia, chronic hypoxia, iron
overload, and possibly other disease features such as a chronic inflammatory state.
● Renal disease – Renal disease may result from extramedullary hematopoiesis involving the
kidney and hyperuricemia and other metabolic effects of increased hematopoietic cell turnover
[75]. Iron overload may also be toxic to the kidney. Some iron chelating agents such as
deferasirox may also be nephrotoxic. (See "Clinical manifestations and diagnosis of the
thalassemias", section on 'Clinical manifestations'.)
● Cardiomyopathy – Cardiac disease including cardiomyopathy and pulmonary hypertension

are multifactorial. Iron toxicity plays a major role in cardiac dysfunction. Other factors may
include hemolysis, chronic anemia, endocrinopathy, vascular changes, and pulmonary
disease. (See "Clinical manifestations and diagnosis of the thalassemias", section on 'Heart
failure and arrhythmias'.)
● Diabetes – Diabetes and other endocrine and metabolic abnormalities may result from iron
deposition and oxidative damage to pancreatic cells. (See "Clinical manifestations and
diagnosis of the thalassemias", section on 'Endocrine and metabolic abnormalities'.)
INFECTION
Protection against severe malaria — Thalassemic red blood cells (RBCs) offer innate protection
against severe malaria due to Plasmodium falciparum [76,77]. This effect is more pronounced in
alpha thalassemia than beta thalassemia, but beta thalassemia does offer some protection. It
appears that the resistance occurs at the stage of parasite multiplication within the RBCs, rather
than parasite invasion [78]. The mechanisms are incompletely understood. Contributing factors
may include oxidant injury, persistence of fetal hemoglobin, and enhanced macrophage clearance
[77,79,80]. (See "Protection against malaria in the hemoglobinopathies".)
Yersinia infection — Infection with Yersinia enterocolitica is a significant cause of morbidity in

patients with thalassemia (as well as other iron overload syndromes such as chronic liver disease
and hereditary hemochromatosis) [81,82]. (See "Epidemiology of yersiniosis".)
Yersinia enterocolitica is a siderophilic (iron-loving) organism; it contains several pathways to
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facilitate iron-uptake, which is essential for its growth [83]. (See "Microbiology and pathogenesis of
Yersinia infections".)
Iron chelation with desferrioxamine may make host iron more bioavailable to Yersinia; transfused
red cells may also be a particularly rich source of iron for these organisms. In a series of 14
individuals with thalassemia who developed a Yersinia infection, 57 percent of the infections
occurred within 10 days of blood transfusion [82]. Recognition of these associations and unusual
manifestations in these patients, such as an appendicitis-like syndrome, may direct clinicians to
earlier anti-yersinial therapy, along with temporary cessation of chelation [81,84]. (See "Clinical
manifestations and diagnosis of Yersinia infections".)
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions around
the world are provided separately. (See "Society guideline links: Hemoglobinopathies".)
SUMMARY
● Beta thalassemia, originally called Cooley’s anemia, is caused by beta globin gene mutations
that lead to impaired production of beta globin chains. Beta thalassemia is further classified as
beta thalassemia major, beta thalassemia intermedia, or beta thalassemia minor (also called
beta thalassemia trait) according to the degree of reduction in beta globin. (See 'Disease
classification' above.)
● Beta thalassemia is caused by one or more mutations in the beta globin gene (figure 1) that
result in an imbalanced ratio of alpha to beta globin. This imbalance in turn leads to impaired
red blood cell (RBC) maturation and destruction of developing RBC precursors in the bone
marrow, called ineffective erythropoiesis or intramedullary hemolysis; as well as hemolysis,
with reduced RBC survival in the peripheral blood. The severity of beta thalassemia may also
be affected by other mutations that affect the ratio of alpha globin to beta globin, including
concomitant alpha thalassemia, hereditary persistence of fetal hemoglobin, concomitant sickle
hemoglobin mutation, or concomitant hemoglobin E. (See 'Imbalanced ratio of alpha to beta
globin' above.)
● Excess free alpha chains that are not incorporated into hemoglobin may remain soluble but
mostly aggregate and precipitate. The resulting abnormalities cause ineffective erythropoiesis
in the bone marrow and hemolysis in the peripheral blood. (See 'Anemia' above.)
13 of 27 6/6/2019, 12:36 AM
● Iron overload and iron toxicity contributes to the pathophysiology and complications of beta
thalassemia. Both anemia and increased erythropoiesis suppress production of the iron
regulatory protein hepcidin, resulting in increased iron absorption. Excess iron stores are
greatly increased by transfusional iron overload; however, iron accumulates even without
transfusions. (See 'Iron overload' above.)
● An increased risk of thromboembolic complications has been reported in individuals with beta
thalassemia, but high quality data regarding this association are lacking. (See
'Hypercoagulable state' above.)
● Organ damage in beta thalassemia (renal disease, cardiomyopathy, diabetes) is due to the
combined effects of anemia, chronic hypoxia, iron overload, and possibly other disease
features such as a chronic inflammatory state. (See 'Organ damage' above.)
● Beta thalassemia may have evolved due to its protective effect against severe falciparum
malaria. However, the risk of infection with the siderophilic (iron-loving) organism Yersinia
enterocolitica is increased due to excess iron and possibly chelation therapy; this is a
significant cause of morbidity in patients with beta thalassemia. (See 'Infection' above.)
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thalassemic red cells. Eur J Haematol 1987; 38:246.
35. Schrier SL, Rachmilewitz E, Mohandas N. Cellular and membrane properties of alpha and
beta thalassemic erythrocytes are different: implication for differences in clinical
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skeletal protein complex and increased red cell membrane rigidity. Blood 1988; 71:1427.
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new therapeutic strategies. Curr Opin Hematol 2016; 23:181.
42. Yuan J, Angelucci E, Lucarelli G, et al. Accelerated programmed cell death (apoptosis) in
erythroid precursors of patients with severe beta-thalassemia (Cooley's anemia). Blood 1993;
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43. Angelucci E, Lucarelli G, Yuan J, et al. rogrammed cell death (PCD) and ineffective
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erythropoiesis in Cooley's anemia. Blood 1996; 88:S2817.
44. Angelucci E, Ma L, Lucarelli G, et al. The role of iron overload in the extent of programmed
cell death (PCD) in patients with Cooley's anemia. Blood 1997; 90:S2839.
45. Arlet JB, Ribeil JA, Guillem F, et al. HSP70 sequestration by free α-globin promotes
ineffective erythropoiesis in β-thalassaemia. Nature 2014; 514:242.
46. Polliack A, Rachmilewitz EA. Ultrastructural studies in -thalassaemia major. Br J Haematol

1973; 24:319.
47. Wickramasinghe SN, Bush V. Observations on the ultrastructure of erythropoietic cells and
reticulum cells in the bone marrow of patients with homozygous beta-thalassaemia. Br J
Haematol 1975; 30:395.
48. Wickramasinghe SN, Hughes M. Ultrastructural studies of erythropoiesis in beta-

thalassaemia trait. Br J Haematol 1980; 46:401.
49. Fessas P, Loukopoulos D, Kaltsoya A. Peptide analysis of the inclusions of erythroid cells in
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50. Wickramasinghe SN, Lee MJ, Furukawa T, et al. Composition of the intra-erythroblastic
precipitates in thalassaemia and congenital dyserythropoietic anaemia (CDA): identification
of a new type of CDA with intra-erythroblastic precipitates not reacting with monoclonal
antibodies to alpha- and beta-globin chains. Br J Haematol 1996; 93:576.
51. Ponnikorn S, Panichakul T, Sresanga K, et al. Phosphoproteomic analysis of apoptotic

hematopoietic stem cells from hemoglobin E/β-thalassemia. J Transl Med 2011; 9:96.
52. Angelucci E, Bai H, Centis F, et al. Enhanced macrophagic attack on beta-thalassemia major
erythroid precursors. Haematologica 2002; 87:578.
53. Dondorp AM, Chotivanich KT, Fucharoen S, et al. Red cell deformability, splenic function and
anaemia in thalassaemia. Br J Haematol 1999; 105:505.
54. Vigi V, Volpato S, Gaburro D, et al. The correlation between red-cell survival and excess of
alpha-globin synthesis in beta-thalassemia. Br J Haematol 1969; 16:25.
55. Knyszynski A, Danon D, Kahane I, Rachmilewitz EA. Phagocytosis of nucleated and mature
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43:251.
56. Allen TM, Williamson P, Schlegel RA. Phosphatidylserine as a determinant of

reticuloendothelial recognition of liposome models of the erythrocyte surface. Proc Natl Acad
Sci U S A 1988; 85:8067.
57. Borenstain-Ben Yashar V, Barenholz Y, Hy-Am E, et al. Phosphatidylserine in the outer leaflet
of red blood cells from beta-thalassemia patients may explain the chronic hypercoagulable
state and thrombotic episodes. Am J Hematol 1993; 44:63.
58. Kuypers FA, Yuan J, Lewis RA, et al. Membrane phospholipid asymmetry in human
thalassemia. Blood 1998; 91:3044.
59. Galili U, Korkesh A, Kahane I, Rachmilewitz EA. Demonstration of a natural antigalactosyl

IgG antibody on thalassemic red blood cells. Blood 1983; 61:1258.
60. Rachmilewitz EA, Shinar E, Shalev O, et al. Erythrocyte membrane alterations in beta-
thalassaemia. Clin Haematol 1985; 14:163.
61. Yuan J, Kannan R, Shinar E, et al. Isolation, characterization, and immunoprecipitation

studies of immune complexes from membranes of beta-thalassemic erythrocytes. Blood
1992; 79:3007.
62. Wanachiwanawin W, Siripanyaphinyo U, Fucharoen S, et al. Activation of monocytes for the

immune clearance of red cells in beta zero-thalassaemia/HbE. Br J Haematol 1993; 85:773.
63. Meliconi R, Uguccioni M, Lalli E, et al. Increased serum concentrations of tumour necrosis
factor in beta thalassaemia: effect of bone marrow transplantation. J Clin Pathol 1992; 45:61.
64. Moura IC, Hermine O. Erythroferrone: the missing link in β-thalassemia? Blood 2015;
126:1974.
65. Kautz L, Jung G, Valore EV, et al. Identification of erythroferrone as an erythroid regulator of
iron metabolism. Nat Genet 2014; 46:678.
66. Kautz L, Jung G, Du X, et al. Erythroferrone contributes to hepcidin suppression and iron
overload in a mouse model of β-thalassemia. Blood 2015; 126:2031.
67. Piga A, Longo F, Duca L, et al. High nontransferrin bound iron levels and heart disease in
thalassemia major. Am J Hematol 2009; 84:29.
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68. Eldor A, Rachmilewitz EA. The hypercoagulable state in thalassemia. Blood 2002; 99:36.
69. Ataga KI, Cappellini MD, Rachmilewitz EA. Beta-thalassaemia and sickle cell anaemia as
paradigms of hypercoagulability. Br J Haematol 2007; 139:3.
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thalassemias. Haematologica 2013; 98:833.
71. Taher AT, Musallam KM, Karimi M, et al. Overview on practices in thalassemia intermedia
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72. Atichartakarn V, Angchaisuksiri P, Aryurachai K, et al. Relationship between hypercoagulable

state and erythrocyte phosphatidylserine exposure in splenectomized haemoglobin E/beta-
thalassaemic patients. Br J Haematol 2002; 118:893.
73. Hirsh J, Dacie JV. Persistent post-splenectomy thrombocytosis and thrombo-embolism: a

consequence of continuing anaemia. Br J Haematol 1966; 12:44.
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falciparum growth in thalassemic red blood cells: further evidence by using biotin labeling
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81. Cherchi GB, Pacifico L, Cossellu S, et al. Prospective study of Yersinia enterocolitica
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infection in thalassemic patients. Pediatr Infect Dis J 1995; 14:579.
82. Adamkiewicz TV, Berkovitch M, Krishnan C, et al. Infection due to Yersinia enterocolitica in a
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iron overload and its treatment. Pediatr Hematol Oncol 1992; 9:247.
Topic 7090 Version 25.0
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GRAPHICS
Alpha and beta globin gene clusters
Schematic representation of the human beta globin gene cluster on chromosome

11 (upper panel) and alpha globin gene cluster on chromosome 16 (lower panel). These
illustrate the position of the globin genes, the locus control region (LCR) for the beta
globin gene cluster, and hypersensitive sites for the beta globin gene cluster (HS 1 to 5)
and the alpha gene cluster (HS-40). After birth, the active genes in the beta globin gene
cluster are those for G-gamma, A-gamma, delta, and beta globin; the genes active after
birth in the alpha globin gene cluster are alpha-2 and alpha-1. Shown between the two
panels is hemoglobin A (HbA), a tetramer of two beta globin chains and two alpha
globin chains.
Figure originally drawn by Dr. Ross Hardison and reproduced with permission from the Globin
Gene Server, which can be found at: http://globin.cse.psu.edu/html/images.html.
Graphic 65642 Version 6.0
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Peripheral blood smear in beta thalassemia intermedia
Peripheral smear from a patient with beta thalassemia intermedia

postsplenectomy. This field shows target cells, hypochromic cells, microcytic
cells, red cell fragments, red cells with bizarre shapes, and a single nucleated
red cell (arrow).
Courtesy of Stanley Schrier, MD.
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Multiprotein complexes in the red blood cell membrane
Schematic representation of two types of multiprotein complexes in the red blood cell membrane.
(Left) Band 3-based macromolecular complex (referred to as Ankyrin complex in the image). This protein
complex attaches to spectrin near the center of the tetramer (dimer-dimer interaction site). Tetrameric band 3 is
bound to ankyrin, which is bound to spectrin. The membrane skeletal protein 4.2 has binding sites for band 3 and
for ankyrin. Transmembrane glycoproteins GPA, Rh, and RhAG bind to band 3, and CD47 and LW associate with
Rh/RhAG. The two cytoplasmic domains of band 3 contain binding sites for soluble proteins, the short C-terminal
domain for CA II, the large N-terminal domain for deoxyhemoglobin, glycolytic enzymes, aldolase, PFK, and
GAPDH.
(Right) Protein 4.1R-based macromolecular complex. This protein complex forms at membrane skeletal junctions.
The junctions contain the ternary complex of spectrin, F-actin, and protein 4.1R, as well as the actin-binding
proteins tropomyosin, tropomodulin, adducin, and dematin. Protein 4.1R enters into an additional ternary
interaction with the transmembrane proteins GPC and p55 and can also bind to band 3, in the form of a dimer,
which also carries GPA. The blood group proteins Rh, Kell, and XK also have binding sites on protein 4.1R. Note,
however, that the abundances of all transmembrane proteins except GPA and GPC are low and therefore not all
proteins will be present on all complexes.
4.1R: protein 4.1R; GLUT1: glucose transporter 1; GPA: glycophorin A; CA II: carbonic anhydrase II; GPC: glycophorin
C; PFK: phosphofructokinase; Hb: hemoglobin; GAPDH: glyceraldehyde 3-phosphate dehydrogenase.
Modified with permission from: Salomao, M, Zhang, X, Yang, Y, et al. Protein 4.1R-dependent multiprotein complex; new
insights into the structural organization of the red blood cell membrane. Proc Natl Acad Sci USA 2008; 105:8026.
Copyright © 2008 National Academy of Sciences, USA.
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Dense red cells in beta thalassemia
Analysis of the density distribution of normal erythrocytes (A), erythrocytes

from a nonsplenectomized individual with beta-thalassemia intermedia (B),
erythrocytes from a splenectomized individual with beta thalassemia intermedia
(C), and HbH erythrocytes (D) on discontinuous Stractan density gradients. The
more dense cells are at the bottom of the gradient; dense populations are
present only in the nonsplenectomized and splenectomized subjects with beta
thalassemia.
Reproduced with permission from Schrier, SL, Rachmilevitz, E, Mohandas, N. Cellular

and membrane properties of alpha and beta thalassemic erythrocytes are different:
Implication for differences in clinical manifestations. Blood 1989; 6:2194. Copyright
© 1989 American Society of Hematology.
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Red blood cell ion transport mechanisms
Schematic representation of the transport mechanisms regulating red cell hydration. The
extracellular concentrations of sodium and calcium are higher than those within the cell, creating
favorable gradients for entry, while the intracellular concentration of potassium is higher than that in
the extracellular fluid, creating a favorable gradient for potassium exit by the K-Cl cotransporter or
the calcium-activated (Gardos) potassium channel. The red transporters are active, the blue
transporters are passive. Band 3 protein primarily functions as a Cl-HCO3 exchanger. Its primary
physiological function is to facilitate CO2 transport from tissues to alveoli; it also plays an important
role in defining red cell shape and membrane stability. Water movement passively follows that of
cations and anions, or changes in tonicity of the red cell's environment. Transport of water can occur
at a much faster rate via water channels (aquaporin-1, Aqp-1).
26 of 27 6/6/2019, 12:36 AM
Contributor Disclosures
Stanley L Schrier, MD Nothing to disclose William C Mentzer, MD Equity Ownership/Stock Options:
Johnson & Johnson [Anemia (Erythropoietin)]. Donald H Mahoney, Jr, MD Nothing to disclose Jennifer S
Tirnauer, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform
to UpToDate standards of evidence.
Conflict of interest policy
27 of 27 6/6/2019, 12:36 AM

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● Pathophysiology of alpha thalassemia – (See "Pathophysiology of alpha thalassemia".)

for transfusion-dependent thalassemia" and "Thalassemia: Management after hematopoietic

Thalassemia refers to a spectrum of diseases characterized by reduced or absent production of

Alpha thalassemia is an inherited thalassemia syndrome characterized by impaired production of

IMBALANCED RATIO OF ALPHA TO BETA GLOBIN

Modifiers of disease severity — As noted above, a principal determinant of disease severity in

● Concomitant alpha thalassemia – Alpha thalassemia is due to impaired production of alpha

● Sickle-beta thalassemia – Co-inheritance of the sickle hemoglobin mutation on one beta

● Co-inheritance of hemoglobin E – Hemoglobin E results from a beta globin mutation that

Co-inheritance of heterozygosity for a beta thalassemia mutation and a hemoglobin E

both of which contribute to anemia:

● Ineffective erythropoiesis – Ineffective erythropoiesis refers to reduced production of RBCs

● Hemolysis – Hemolysis of mature RBCs in beta thalassemia is primarily extravascular,

Unbalanced globin chain synthesis — Hemoglobin is a tetramer consisting of two heterodimers;

Cytoskeletal/membrane damage and cell dehydration — Normal RBC precursors undergo

Abnormal membrane proteins in beta thalassemia include the following:

Ineffective erythropoiesis — Ineffective erythropoiesis in beta thalassemia is due to expansion of

Subsequently the extent of apoptosis and erythroid expansion (numbers of developing

Characteristic stages of ineffective erythropoiesis in beta thalassemia include expansion of

Hemolysis — Hemolysis in beta thalassemia is primarily intracorpuscular (due to inherent

Reduced deformability — Deformability (flexibility) is an essential property of the RBC that

These properties of beta thalassemia RBCs are abnormal:

Reduced survival — The survival of thalassemic RBCs is shortened relative to non-

● Membrane phospholipids such as phosphatidylserine (PS) are recognized by macrophages as

Autoreactive IgG have been observed on the surface of thalassemic RBCs.

The importance of reticuloendothelial clearance of these abnormal cells is illustrated by the

Several reports have described an increased risk of thromboembolic complications in thalassemia

similar to the general population. Further study of this issue is warranted.

● Cardiomyopathy – Cardiac disease including cardiomyopathy and pulmonary hypertension

Yersinia infection — Infection with Yersinia enterocolitica is a significant cause of morbidity in

Yersinia enterocolitica is a siderophilic (iron-loving) organism; it contains several pathways to

SOCIETY GUIDELINE LINKS

1. Olivieri NF, Pakbaz Z, Vichinsky E. Hb E/beta-thalassaemia: a common & clinically diverse

2. Kalpravidh RW, Komolvanich S, Wilairat P, Fucharoen S. Globin chain turnover in

3. Sripichai O, Makarasara W, Munkongdee T, et al. A scoring system for the classification of

4. Jones E, Pasricha SR, Allen A, et al. Hepcidin is suppressed by erythropoiesis in hemoglobin

6. Sorensen S, Rubin E, Polster H, et al. The role of membrane skeletal-associated alpha-

7. Yuan J, Rubin E, Aljurf M, et al. Defective assembly of membrane proteins in erythroid

9. FESSAS P. Inclusions of hemoglobin erythroblasts and erythrocytes of thalassemia. Blood

10. FESSAS P, LOUKOPOULOS D. ALPHA-CHAIN OF HUMAN HEMOGLOBIN:

14. Aljurf M, Ma L, Angelucci E, et al. Abnormal assembly of membrane proteins in erythroid

gens: Proceedings of the Vth International Congress on Medical Chemistry, Farnoux CC (E

25. Hebbel RP. Auto-oxidation and a membrane-associated 'Fenton reagent': a possible

in alpha and beta thalassemia. J Clin Invest 1989; 83:404.

34. Lamchiagdhase P, Wilairat P, Sahaphong S, et al. Defective spectrin dimer self-association in

erythropoiesis in Cooley's anemia. Blood 1996; 88:S2817.

46. Polliack A, Rachmilewitz EA. Ultrastructural studies in -thalassaemia major. Br J Haematol

48. Wickramasinghe SN, Hughes M. Ultrastructural studies of erythropoiesis in beta-

51. Ponnikorn S, Panichakul T, Sresanga K, et al. Phosphoproteomic analysis of apoptotic

56. Allen TM, Williamson P, Schlegel RA. Phosphatidylserine as a determinant of

59. Galili U, Korkesh A, Kahane I, Rachmilewitz EA. Demonstration of a natural antigalactosyl

61. Yuan J, Kannan R, Shinar E, et al. Isolation, characterization, and immunoprecipitation

62. Wanachiwanawin W, Siripanyaphinyo U, Fucharoen S, et al. Activation of monocytes for the

70. Musallam KM, Rivella S, Vichinsky E, Rachmilewitz EA. Non-transfusion-dependent

72. Atichartakarn V, Angchaisuksiri P, Aryurachai K, et al. Relationship between hypercoagulable

73. Hirsh J, Dacie JV. Persistent post-splenectomy thrombocytosis and thrombo-embolism: a

78. Pattanapanyasat K, Yongvanitchit K, Tongtawe P, et al. Impairment of Plasmodium

infection in thalassemic patients. Pediatr Infect Dis J 1995; 14:579.

Topic 7090 Version 25.0

Alpha and beta globin gene clusters