THALASSEMIA
Hope Y. Agbemenyah
Thalassemia syndromes
• The hemoglobin is critical for gaseous exchange and transportation between
tissues.
• Hemoglobins are encoded in two tightly linked gene clusters;
• the α-like globin genes are clustered on chromosome 16, and the β-like genes
on chromosome 11.
• The α-like cluster consists of two α-globin genes and a single copy of the ζgene.
• The non-α gene cluster consists of a single ε gene, the Gγ and Aγ fetal globin
genes, and the adult δ and β genes.
• Thalassemias are heterogeneous group of inherited haemoglobinopathies due
to mutations leading impaired α- or β- globin biosynthesis.
-diminished production of adult haemoglobin tetramers HbA (α2β2): hypochromic
and microcytic anemia.
-increased cell membrane damage or ineffective erythropoiesis or both
Demographics and Epidemiology
Certain ancestry: endemic in the Mediterranean basin, Middle East, Asian and tropical
Africa and the Indian subcontinent ancestry. Distribution parallels that of Plasmodium
falciparum
Molecular Pathogenesis
• Mutations
• Trancriptional: Promoter region mutations
– Inability to recruit transcription factors eg GATA-1, NFE-2, the SWI/SNF-like
protein called ATRX
• Posttranscriptional: mRNA processing
– Splicing mutations some normal beta globin
– β+- Thalassemia (reduced but detectable β-globin synthesis)
• Translational: Chain termination mutation
– de-novo stop codon and indel blocking translation
– βo- Thalassemia (absent β-globin)
– Deletion: α-Thalassemia
• Deletion: α-Thalassemia
• Other causes
• α-protein stabilizing protein (AHSP)
Classifications
• α-Thalassemias
• due to deletions that cause reduced or lack of synthesis of alpha
globin chain.
• hence unpaired gamma globins (fetal) or beta (adults)
• these are soluble so hemolysis and ineffective erythropoiesis is less
severe than beta thalassemia.
Thalassemia
Genetic mutation
Remarks
Silent carrier
-α/αα
No effect
α-Thalassemia trait
Minor
-α/-α
--/αα
Slight anemia
Hb H, β4
--/-α
Severely anemic and
susceptible to oxidation
Barts hydrops fetalis, γ4
--/--
Lethal
Classifications
β-Thalassemias
variable mutations leading to increased levels of alpha globin proteins
Thalassemia
Genetic mutation
Remarks
β-Thalassemia trait
β/βo or β/β+
Mild anemia and small
RBCs due to lack of Hb
β-Thalassemia intermedia
Milder variant of β+/β+ or
βo/β+
Significant lack of Hb,
Moderate anemia
β-Thalassemia major
βo/βo, βo/β+
or β+/β+
Severe anemia
• accumulation of highly insoluble unpaired α chains. They form toxic inclusion bodies
that kill developing erythroblasts in the marrow, few escape with membrane
damaging insoluble α chains that undergo extravascular lyses
• Provoking compensatory erythroid hyperplasia but the marrow is
sabotaged by ineffective erythropoiesis.
Persistence of anemia causes exuberant extramedullary erythropoietic tissues
recruitment
Clinical presentations
Despite differences in the molecular mechanisms underlying the cause of the disease
patients generally present common symptoms of
•
severe tissue hypoxia, hemolytic anemia, marked hepatomegaly, marked
erythroid hyperplasia, iron overload
Other symptoms include fatigue, weakness, pale appearance, excessive hemolysis
leading to yellowish discoloration of skin (jaundice), facial bone deformities, dark
urine. The signs and symptoms the patient experiences depend on the type and
severity of thalassemia.
Hyperplasia of bone marrow and extramedullary erythropoiesis
Diagnosis
•
β-Thalassemia major: basis of severe microcytic anemia, ineffective erythropoiesishepatosplenomegaly, and elevated levels of HbF, HbA2 or both
•
Intermedia exhibit similar stigmata but can survive without chronic
hypertransfusion
•
Minor: profound microcytosis and hypochromia with target cells, but only minimal
or mild anemia. Mean corpuscular volume is rarely >75fL; hematocrit is rarely <3033%. Hb electrophoresis reveals normal/elevated HbA2 or normal/elevated HbF
•
•
•
•
•
α-thalassemia trait- mild hypochromia and microcytosis usually without anemia
Hb electrophoresis
Microcytosis and hypochromia
Reduction in HbA and increase in Hb F
Increased RBC count for such level of anemia
Diagnosis
• Blood smear shows
– Anisocytosis (marked variation in size)
– Poikilocytosis (variation in shape)
– Target cells ( accumulation of Hb in the center of the cell)
• Basophilic stippling
• Enlargement of cheekbones and other bony prominence
Treatment
•
Blood transfusion and as complication you treat iron overload iron chelatordeferoxamine or deferasirox
–
Cardiac disease resulting from progressive iron overload and secondary hemochromatosis- an
important cause of death
•
Regular monitoring of extramedullary hematopoiesis and spleen size
(Splenectomy)
•
Hydroxyurea (established) and HDACi (worth testing experimentally) indicated in
patients with extramedullary hematopoiesis and leg ulcers
•
Allogenic stem cells transplantation is the only curative therapy
•
Vitamin D supplementation
•
Gene therapy, lentiviral constructs expressing corresponding correct gene
•
Premature Termination Codon treatment by the use of aminoglycosides
Prevention
Antenatal diagnosis
DNA diagnosis by PCR amplification of fetal DNA obtained by amniocentesis or
chorionic villus biopsy which is then hybridized to allele-specific oligonucleotide
probes
This examination is only appropriate if both parents are known to be carriers (βThalassemia minor) and will accept a termination
Seek genetic counseling if a carrier of α-Thalassemia gene
Assisted reproductive therapy
Differential Diagnoses
Anemia of Chronic Disease and Renal Failure
Lead Nephropathy
Lead poisoning
Sideroblastic Anemias
Case
• A 10-month-old boy of Arabic extraction is brought to
the physician by his parents who complain that their
child is failing to thrive. Physical examination reveals
splenomegaly and jaundice. A CBC shows a microcytic,
hypochromic anemia (hemoglobin = 7.4 g/dL). Fetal
hemoglobin accounts for most of the hemoglobin. A
peripheral blood smear is shown in the image. Which
of the following is the appropriate diagnosis?
• What is the pathogenesis of splenomegaly seen in the
patient described above
• Adriana is a 7-year-old who lives with her parents in a surburban
community. Her parents brought her to the united states from their
homeland in Greece when she was 1 year old. At the of 3, she was in the
10th percentile for her height and weight, pale and her hemoglobin was
5.8 g/dL. Following further diagnostic studies, she was diagnosed with
beta-thalassemia major. Over the course of the next 4 years, Adriana was
hospitalized every 1-2 months so she could be transfused with packed red
blood cells.
• Case study
• During a routine follow-up visit at the hematology clinic, Adriana’s
laboratory results were as follows:
• Hemoglobin: 10 g/dL
• Total serum iron: 150 g/L
• As hematologist, you discuss planned treatment with Adriana and her
parents
• What are the clinical manifestations of bThalassemia?
• What are the priorities of care for Adriana?
• Which options are available for Adriana to
prevent life-long blood transfusion?
References
• http://www.ncbi.nlm.nih.gov/pubmed/7290983
• http://www.sciencedirect.com/science/article/pii/S089
1584914001907
• http://www.thalassemia.com
• http://www.thalassemia.org
• http://www.thalassemia.org.cy
• Pathology by Kumar and Robbins
• Harrison’s principles of internal medicine 17th ed
McGraw-Hill
• Davidson’s principles and practice of internal medicine
20th ed McGraw-Hill
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