Transcript Thalassemia

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
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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.