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“Thalassemia: Pathophisiology and treatment update” Dr. Ricardo Helman Hospital Israelita Albert Einstein São Paulo – Brazil
Hemoglobin Molecule 4 polypeptide chains and 4 heme groups
Normal hemoglobin
• 2 cadeias a e 2 cadeias b ® HbA
• 2 cadeias a e 2 cadeias d ® HbA2
• 2 cadeias a e 2 cadeias g ® HbF
• vida fetal predomina HbF
• padrão adulto em torno de 1 ano
Definition
1. Heterogeneous group of hereditary diseases
2. Decrease or absence of synthesis of 1 or more
Globin chains of the hemoglobin molecule
1925 - Thomas Cooley e Peter Lee Severe anemia, splenomegaly and bone abnormalities Characteristics in children of Mediterranean origin Talassemia - thalassa = mar
1940 - Genetic disease, Mendelian, widely distributed
50 - Heterogeneous disease, at least 2 types: a and b
60 e 70 - Methods for studying globin synthesis in vitro
Subsequent years - molecular biology techniques Definition of the molecular pathology of the various forms of Thalassemia
Historic
Incidence in Brazil
Prevalence and Geographical Distribution
3% of the world 's population = carrier of 1 b - tal gene
Ferrara: 20% Sardinia: 11 to 34% Sicily: 10% Greece: 5 to 15%
Lowest frequency: Africa, Turkey, Iran Sporadic: Northern Europe
USA and Brazil: descendants of Italians, Greeks and Blacks
Pathophysiology Normal
Synthesis of 1 alpha chain: 1 non-alpha chain
Thalassemia
Deficiency of synthesis of 1 or + globin chains
Decreased hemoglobin synthesis hypochromia
Unbalance between the production of a and non-a chains disastrous consequences
Representation of the genomic structure of the α- and β-globin loci.
Stefano Rivella Haematologica 2015;100:418-430 ©2015 by Ferrata Storti Foundation
Rund D & Rachmilewitz E – N Engl J Med 2005; 353:1135-46
The excess of alpha globin causes the formation of Inclusion bodies (Heinz bodies) with lysis
Of intramedullary erythrocyte cells (Ineffective erythropoiesis)
Pathophysiology
Representation of some of the pathways regulating steady state and stress erythropoiesis and their relationship to ineffective
erythropoiesis in β-thalassemia.
Stefano Rivella Haematologica 2015;100:418-430 ©2015 by Ferrata Storti Foundation
Olivieri NF - New Engl Med 1999; 341: 99-109
Illustration of the relationship between anemia, hypoxia, Epo, erythropoiesis and iron metabolism in β-tha-lassemia.
Stefano Rivella Haematologica 2015;100:418-430
Cunningham MJ et al. Blood 2004;104:34–39
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0–15 years 16–24 years >25 years
Cardiac
Cirrhosis Endocrine
Num
ber o
f tha
lass
emia
com
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Complications
Talassemia Intermédia Hematopoese Extramedular
Talassemia Major
Cunningham MJ et al. Blood 2004;104:34–39
0
10
20
30
40
50
60
70
80
0–15 years 16–24 years >25 years
Cardiac
Cirrhosis Endocrine
Num
ber o
f tha
lass
emia
com
plic
atio
ns
Complicações
Treatment
} Hematopoietic stem cell transplantation } Blood Transfusion } Iron Chelation } Splenectomy } hidroxiuréia } Eritropoetina
} Gene Terapy
1. Lawson SE et al. Br J Haematol 2003;120:289–295; 2. Li CK et al. Pediatr Hematol Oncol 2004;21:411–419; 3. Cohen A et al. Am J Hematol 1989;30:254–256; 4. Arruda VR et al. N Engl J Med 1997;336:964–965; 5. Chaidos A et al. Acta Haematol 2004;111:189–195; 6. Puthenveetil G & Malik P. Curr Hematol Rep 2004;3:298–305
Potential use of JAK2 inhbitors in β-thalassemia.
Stefano Rivella Haematologica 2015;100:418-430
Iron Overload • Increased intestinal absorption
• Repeated transfusion of red blood cells
1 Red cell concentrate unit 200 mg iron
Iron concentration transfusion dependet patient = 0,4 a 0,5 mg Fe/Kg/dia
Iron overload Free Iron
NTBI
Stress oxidativo
Lipid peroxidation
Injury of organelles Lysosomes, mitochondria
TGF b
Collagen Synthesis Lysosomal Fragility Enzyme leakage
cell death Fibrosys
Liver: Coloração de Perls
Necrópsia Paciente MF
RNM hepática
The top four images were collected from a patient having a liver iron of 6 mg/g. The bottom four images were collected from a normal volunteer. All images darken as the echo time (TE) lengthens, but the iron-heavy tissue darkens faster. The half life of this process is called T2* and the rate is called R2* (R2*=1000/T2*)
R2* x Conc iron of liver biopsy
Wood JC et al. Blood 2005; 106:1460-1465
R=0,97
T2* Normal Deposição de Fe em b-tal
RNM cardíaca T2*
Wood JC. Curr Opin Hematol 2007; 14: 183-190
Pesaro’s Criteria
1. Hepatomegaly 2. Hepatic fibrosis 3. Iron chelation
OS
´I – 87% ´II- 85% ´III-80%
Bone Marrow Transplantation
Gaziev J e col, Bone Marrow Transplant. 2008; 42: S41
BMT
1. Iron chelation does not seem to be so fundamental 2. Adults can be transplanted! 3. Do not predict risk in adults! 4. There is no acute and chronic GVHD difference 5. There is a difference in mortality
Obrigado! [email protected]
