Yen Wu

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Public Health 256
THALASSEMIA
Yen Wu Sahar Naderi Daniel Golden
October 25, 2000
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Prevalence in Italy
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Rudolf vonJaksch-Wartenhorst
(1855-1947)
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Thomas B. Cooley
(1871-1945)
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Later Developments
Thalassemia
Cooleys Anemia
From the Greek, ??????? the sea meaning "blood
from the sea", in reference to the Mediterranean
Sea where the disorder was first thought to
originate.
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Regional Distribution
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Hemoglobin
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Graph of GlobinProduction
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Genetic and Hereditary Components
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• Hemoglobin
• Globular protein with four polypeptide units, two
  alpha and two beta chains
• Both alpha and beta chains consist of a alpha
  helical secondary structure
• Each subunit has a nonpolypeptide component
  (heme) with an iron atom that binds to oxygen

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• Hemoglobin is carried by the blood cells to the
  lungs where it picks up oxygen and delivers it to
  the peripheral tissues of the body
• Both beta and alpha proteins must be present for
  hemoglobin to function

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• Genetic Structure of Hemoglobin
• 4 genes (two on each chromosome) form the alpha
  subunits and 2 genes (one on each chromosome)
  form the beta subunits

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• Thalassemia is a recessively inherited disease
• Heterozygous individuals are clinically well

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• Beta thalassemia
• Result of little or no beta-globin being produced
  causing most of the hemoglobin in the body to
  consist of only alpha-globin
• B(0) patients have no beta-globin synthesis and
  B() individuals have a decreased production of
  beta-globin by three to ten times
• Most patients are hetero-hetero for beta
  thalassemia because so many different mutations
  code for it
• Usually only inbred individuals are homozygous
• Thalassemia trait (patients are clinically well)
  is thought to prevent malaria
• Found near the sickle cell gene

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• Mutations
• Most of the beta thalassemia syndromes are caused
  by mutations effecting gene regulation or
  expression rather than gene deletion
• Results in diminished production of mRNA and
  decreased synthesis of structurally normal globin

1 gtacggctgt catcacttag acctcaccct
gtggagccac accctagggt tggccaatct 61
actcccagga gcagggaggg caggagccag ggctgggcat
aaaagtcagg gcagagccat 121 ctattgctta
catttgcttc tgacacaact gtgttcacta gcaacctcaa
acagacacca 181 tggtgcacct gactcctgag
gagaagtctg ccgttactgc cctgtggggc aaggtgaacg
241 tggatgaagt tggtggtgag gccctgggca ggttggtatc
aaggttacaa gacaggttta 301 aggagaccaa
tagaaactgg gcatgtggag acagagaaga ctcttgggtt
tctgataggc 361 actgactctc tctgcctatt
ggtctatttt cccaccctta ggctgctggt ggtctaccct
421 tggacagagg ttctttgagt cctttgggga tctgtccact
cctgatgctg ttatgggcaa 481 ccctaaggtg
aaggctcatg gcaagaaagt gctcggtgcc tttagtgatg
gcctggctca 541 cctggacaac ctcaagggca
cctttgccac actgagtgag ctgcactgtg acaagctgca
601 cgtggatcct gagaacttca gggtgagtct atgggaccct
tgatgttttc tttccccttc 661 ttttctatgg
ttaagttcat gtcataggaa ggg
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Mutation
Phenotype Ethnic Origin Promoter Region
Mutants -101 (C to T)
B() Turkish -88 (C to
A) B()
Mediterranean -87 (C to G)
B() Black American Chain
Terminator Mutants Codon 1 (-1 bp)
B(0)
Chinese Codon 6 (-1 bp)
B(0) Mediterranean Codon 114
(-2, 1 bp) B()
French Splice Junction Mutants IVS-1,
position 1 (G to A) B(0)
Mediterranean IVS-1, position 2 (T to G)
B(0) Indian,
Chinese New Splice Site IVS-1 110 (G to A)
B()
Mediterranean RNA Cleavage Defect AATAAA to
AACAAA B() Black
American
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• Severity of thalassemia based on type of mutation
• Thalassemia major- severe anemia and iron
  overload, chronic transfusions, short life span
• Thalassemia intermedia- less severe hemolytic
  anemia, transfusions not required, life into
  adulthood
• Thalassemia minor- abnormal erythrocytes, little
  or no anemia
• Thalassemia minima- detectable only by inference
  from family studies

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• Pathophysiology
• In the absence of complementary beta-globin
  chains with which to bind, alpha chains form
  aggregates, precipitate within the cytoplasm,
  damage cell membranes and lead to premature cell
  destruction
• Increase in membrane surface area causes amount
  of membrane phospholipids and cholesterol to
  increase in proportion
• Membrane rigidity and viscosity increased

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• Medical Complications
• Defective hemoglobin results in the lack of
  sufficient oxygen being carried through the body
  (severe anemia)
• Hemolysis and overactivity of bone marrow due to
  excess energy consumption in order to replace
  defective red blood cells

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Thalassemia
Study Design

• Areas of Research Interest
• Genetic
• Therapies
• Drug
• Transfusion
• Surgical
• Psychological Effects
• Others (associated diseases)

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Thalassemia
Study Design

• Recently Published Articles
• Agarwal, S., et al. Identification of a Novel
  Frameshift ß-Thalassemia Mutation in an Asian
  Indian. Clinical Genetics, April, 2000.
• Lacerra, G., et al. Restoration of HbA Synthesis
  in Erythroid Cells from Peripheral Blood of
  Thalassemia Patients. Proceedings of the NAS,
  August, 2000.
• Goussetis, E., et al. Combined Umbilical Cord
  Blood and Bone Marrow Transplantation in the
  Treatment of ß-Thalassemia. Pediatric Hematology
  and Oncology, June, 2000.
• Di Palma, A., et al. Psychosocial Integration of
  Adolescents and Young Adults with Thalassemia
  Major. Annals of the New York Academy of
  Sciences, June, 1998.

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Thalassemia
Study Design
ASSESSMENT OF INEFFECTIVE BONE MARROW
ERYTHROPOIESIS AND NEED FOR RED BLOOD CELL
TRANSFUSION IN PATIENTS WITH THALASSEMIA USING
EXHALED CARBON MONOXIDE Principal
Investigator Paul Harmatz, M.D.
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Thalassemia
Study Design

• Specific Aims

1) Determine carbon monoxide (CO) levels using
the CO-stat End Tidal Breath Analyzer prior to,
1-2 days, 7 days and 14 days after RBC
Transfusion in patients with Thalassemia
requiring routine transfusion.
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Thalassemia
Study Design
Natus Medical CO-Stat End Tidal Breath
Analyzer San Carlos, CA
(Pictures courtesy of Natus Medical Inc.)
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Thalassemia
Study Design
Natus Medical CO-Stat End Tidal Breath
Analyzer San Carlos, CA
(Pictures courtesy of Natus Medical Inc.)
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Thalassemia
Study Design

• Specific Aims

2) Compare measures of RBC destruction and
ineffective erythropoiesis to ETCO prior to and
1-2 days after RBC transfusion.
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Thalassemia
Study Design

• Preliminary Studies

• ETCO to Estimate Hemolysis in Children with
  Sickle Cell Anemia.
• Elevated ETCO in Patients with Thalassemia
  Receiving Routine Transfusions.

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Thalassemia
Study Design
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Thalassemia
Study Design
Study Control

• Red Blood Cell Aplastic Anemia patient tracked
  for two transfusion cycles.
• CO measurements were then compared with
  Thalassemia measurements.

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Thalassemia
Study Design
Preliminary Results
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Thalassemia
Study Design
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Thalassemia
Study Design
R0.73
R0.67
? Pre TfR ? Post TfR
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Thalassemia
Study Design
Conclusion

• Thalassemia patients do have an elevated CO level
  that can be followed and correlated with their
  level of ineffective erythropoiesis.

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Thalassemia
Study Design
Questions

• Can this be used to improve therapy?
• Are the results reliable enough?

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TAGS Mission is To promote a positive attitude
toward life. To stress the importance of
compliance and chelation therapy. To provide
patients a channel of communication and
information
Contact their TAG Line [phone]Contact
the Cooley's Anemia Foundation (CAF) at (800)
522-7222Or Email CAF at ncaf_at_aol.com http//www.
thalassemia.org http//www.thalassemia.com
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TAG was started 13 years ago by a group of young
adults who realized that by helping and sharing
with each other, coping with the daily struggles
of life with Thalassemia were made a little
easier.
TAG Hosts an annual patient/parent conference
bringing together patients and families with
renowned researchers and physicians.
Patient incentive Program Sponsors awards for
Thalassemia patients to further their education
and career goals
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References