Hemoglobin A is a Tetramer Composed of One Pair of Alpha Globin Chains and One Pair of Beta Globin Chains
Globin Chain Synthesis is Normally Tightly Regulated
Ratio of Alpha/Non-Alpha Chains: 1.00 ± 0.05
Alpha Globin Chains are Very Insoluble
Beta Globin Chains are Soluble: they can assemble to form homotetrameric HbH
Normal Hemoglobin Electrophoresis
HbA: 95–98%
HbS: 0%
HbC: 0%
HbF: <1%
HbA2: 2.5%
Thalassemias
Thalassemias is a Spectrum of Diseases Where There is Decreased or Absent Production of One or More of the Globin Chains, Resulting in an Alteration in the Normal Alpha/Non-Alpha Chain Ratio
Can Occur with Individual Who Carries this Allele and Mates with a Partner Carrying the Alpha Thalassemia-1 Allele
Alpha Thalassemia Minor
Physiology
Loss of Two of the Four Alpha Globin Genes
Heterozygous for Alpha Thalassemia-1 Trait (Heterozygous for Alpha (0) Thalassemia): both alpha genes on one chromsome have been deleted -> aa/– (“cis” deletion)
This Genetic Type Occurs More Commonly in Asians
Homozygous for Alpha Thalassemia-2 Trait (Homozygous for Alpha (+) Thalassemia): one alpha gene has been deleted from each chromsome -> a-/a- (“trans” deletion)
This is the Most Common Genetic Type in Patients of African Origin (“cis” Deletion is Rare in this Population)
Usually Involves the Less Active Alpha Globin Allele, Leading to Milder Disease than that Seen in Asian Populations (Where the “cis” Deletion is More Common)
General Comments: likely related to selective pressure from Plasmodium Falciparum malaria (over which the beta thalassemia trait is believed to offer some survival advantage)
Africa
Central Asia
Far East/Southeast Asia
Indian Subcontinent
Mediterranean
Cyprus: prevalence is 14%
Sardinia: prevalence is 12%
Middle East
Transcaucasus
Armenia
Georgia
Azerbaijan
Physiology
Genetics: Heterozygous State with One Normal Beta Globin Allele and One Beta Globin Thalassemic Allele (Tt)
Mild Microcytic Anemia (see Anemia): Hct usually >30%
Mean Corpuscular Volume (MCV) Usually <75 fL: microcytosis is usually more severe (and anemia less severe) than that observed in iron deficiency anemia
In Contrast, in Iron Deficiency Anemia, MCV Doesn’t Fall <80 fL Until the Hematocrit Decreases to <30%
HbA2: elevated (usually 3.5–78%) -> however, a normal HbA2 does not rule out beta thalassemia (due to some cases with delta-beta or gamma-delta-beta thalassemia trait or when the beta thalassemia trait is co-inherited with a delta globin gene mutation)
HbF: increased in 50% of patients
Clinical Manifestations
General Comments
Usually Asymptomatic
Cardiovascular Manifestations
Protection Against Arterial Thromboembolic Events: studies indicate that beta thalassemia trait confers a protective effect against arterial cardiovascular and cerebrovascular disease in male patients
Likely Due to Low Serum Cholesterol, Slight Anemia, Microcytosis, and a Decrease in Blood Viscosity
Diagnosis: splenic volume (by ultrasound) is 29–67% greater in those with beta thalassemia minor as compared to controls
Clinical: however, the spleen is palpable in <20% of patients
Beta Thalassemia Intermedia
Epidemiology
Highest Population Risk Groups
General Comments
Likely Related to Selective Pressure from Plasmodium Falciparum Malaria (Over Which the Beta Thalassemia Trait is Believed to Offer Some Survival Advantage)
HbA2: elevated (usually 3.5–78%) -> however, a normal HbA2 does not rule out beta thalassemia (due to some cases with delta-beta or gamma-delta-beta thalassemia trait or when the beta thalassemia trait is co-inherited with a delta globin gene mutation)
HbF: increased in 50% of patients
Clinical Manifestations
General Comments
Definition
Beta Thalassemia Intermedia is Defined as Patient with Symptomatic Beta Thalassemia Who Does Not Require Transfusion During at Least the First Few Years of Life
Beta Thalassemia Intermedia Patients are Generally Able to Survive into the Second Decade of Life without Chronic Hypertransfusion Therapy (ie: They Have Non-Transfusion-Dependent Thalassemia)
However, There is Considerable Variability in the Clinical Manifestations
These Patients Usually Only Require Packed Red Blood Cell Transfusion When Red Blood Cell Production is Impaired Due to an Acute Event Which Impairs Erythropoiesis (Such as Infection, etc)
Beta Thalassemia Major (Cooley’s Anemia)
Epidemiology
Highest Population Risk Groups
General Comments
Population Risk is Likely Related to Selective Pressure from Plasmodium Falciparum Malaria (Over Which the Beta Thalassemia Trait is Believed to Offer Some Survival Advantage) (see Malaria)
Africa
Central Asia
Far East/Southeast Asia
Indian Subcontinent
Mediterranean
Cyprus: prevalence is 14%
Sardinia: prevalence is 12%
Middle East
Transcaucasus
Armenia
Georgia
Azerbaijan
Physiology
Genetics
Inheritance of Recessive Thalassemia Trait from Both Parents
Beta Globin Gene is a Single Copy on Chromosome 11
Inheritance Follows Mendelian Genetics
Parents Would Both Be Tt: where T = normal allele, t = thalassemia trait
Therefore, the Probability of These Parents Giving Birth to Homozygous Child (tt) with Beta Thalassemia Major Would Be 25%
Although Both Parents Would Be Phenotypically “Normal”, They Would Have Normal-Near Normal Hemoglobin Levels with Low MCV (Usually 60–70’s)
Absent or Significantly Impaired Beta Globin Chain Synthesis with Presence of Excess Alpha Globin Chains
Excess Alpha Globin Chains are Unstable and Precipitate Within the Cell
Results in Increased Synthesis of Reactive Oxygen Species, Causing Erythroid Membrane Damage, Ineffective Erythropoiesis (with Extramedullary Hematopoiesis), and Hemolysis
Results in Iron Overload
Degree of Alpha Globin Chain Excess Determines the Severity of Clinical Manifestations
Note: the major non-alpha globin produced at the time of birth is gamma globin
Therefore, the Major Hemoglobin Synthesized in Early Postnatal Life is Fetal Hemoglobin: it is not until fetal hemoglobin production wanes, in the second 6 months of life, that the symptoms of beta thalassemia occur
Infants are Normal at Birth: as beta globin synthesis is not essential during fetal life or during the immediate perinatal period during which the production of fetal hemoglobin predominates
Infants Begin to Manifest Clinical Symptoms During the Second 6 Months of Life: when gamma globin chain production normally decreases and is usually replaced with the production of beta globin to form adult hemoglobin -> however, patients with beta thalassemia major are unable to produce beta globin
Variability of Clinical Manifestations
Clinical Manifestations are Highly Variable Between Patients (Possibly Related to Differences in Mutations with Regard to Beta Globin Production or Co-Existing Alpha Thalassemia)
Occurs Early in the Course of Disease: due to increased red cell destruction and splenic extramedullary hematopoiesis
Clinical
May Be Massive
Infectious Manifestations
Increased Risk of Infection (Especially Encapsulated Organisms)
Physiology
Due to Loss of Splenic Immune Function
Neurologic Manifestations
Chronic Pain
Pulmonary Manifestations
Abnormal Pulmonary Function Tests (PFT’s)/Exercise Testing: for unclear reasons -> these defects correct with transfusion and do not correlate with the iron burden, blood counts, or degree of hemolysis
Preferred Donor: HLA-matched sibling marrow or cord blood stem cells
Allogeneic BMT: being studied
Pharmacologic Manipulation of Fetal Hemoglobin Levels
Experimental
Gene Therapy
Experimental
Prognosis
Mortality in Untreated Cases: 80% of untreated children will die within the first 5 years of life (usually due to severe anemia, high output congestive heart failure, failure to thrive, and unsusual susceptibility to infection)
Mortality in Treated Cases: survival into 50’s and beyond can be achieved with appropriate transfusion and iron chelation treatment
References
The beta-thalassemias. N Engl J Med. 1999;341(2):99 [MEDLINE]
The definition and epidemiology of non-transfusion-dependent thalassemia. Blood Rev. 2012;26 Suppl 1:S3 [MEDLINE]
Thalassemias. Pediatr Clin North Am. 2013;60(6):1383 [MEDLINE]
