Heterogenous group of disorders due to an imbalance of and globin chain synthesis
thalssemia: -globin chain production decreased
thalassemia: globin chain production decreased
The globin chains that are produced are normal
o thalassemia: No -globin chain is made
+ thalassemia: decreased -globin chain is made
With 4 genes and 2 genes there is wide phenotypic variation
Types of Thalassemia
thal : excess of globins , leading to formation of globin tetramers ( 4 ) that accumulate in the erythroblast , leading to ineffective erythropoiesis . Two types of mutations, the β0 in which no β globin chains are produced and β+, in which some β chains are produced but at a reduced rate.
thal : excess of globins , leading to the formation of globin tetramers ( 4 ) called hemoglobin H. Results in hemolysis, generally shortening the life span of the red cell. Hemoglobin H-Constant Spring disease is a more severe form of this hemolytic disorder. Most severe form is thalassemia major, in which fetus produces no globins, which is generally incompatible with life.
Found most frequently in the Mediterranean, Africa, Western and Southeast Asia, India and Burma
Distribution parallels that of Plasmodium falciparum
Genetics of Thalassemia
Inadequate production of alpha chains
Hemoglobin analysis normal; can be detected by globin gene analysis
Absence of 1-2 alpha chains
Does not require therapy
Absence of 3 alpha chains
Microcytic anemia (Hgb 7-10)
Absence of 4 alpha chains
Hydrops fetalis (non-viable)
Laboratory Findings in Alpha Thalassemia chains Hgb (g/dl) MCV (fl) RDW / Normal Normal Normal /- 12-14 75-85 Normal -/ - or - -/ 11-13 70-75 - -/- 7-10 50-60 - -/- - - - -
Minor (Trait) / + or / ° 10-13
Intermedia + / + 7-10
Major + / ° or °/ ° < 7
Beta Thalassemia Clinical Syndrome Genotype Hemoglobin (g/dl) Inadequate production of chains
Minor (Trait) / + or / ° 90-94 3.5-8 1-10
Intermedia + / + 5-60 2-8 20-80%
Major + / ° 2-10 1-6 >85
°/ ° 0 1-6 >94
Beta Thalassemia - Hgb analysis Clinical Syndrome Genotype A A2 F Hemoglobin analysis: Increased levels of Hgb A2 and Hgb F
Signs and symptoms
Thalassemia carriers (trait):
Usually no signs or symptoms are apparent, except for a mild anemia.
Carriers are usually initially detected through screening, or when performing routine CBC (complete blood count). Later it can be confirmed using hemoglobin electrophoresis.
Signs and symptoms- Cont
Signs such as paleness and growth retardation, are readily detectable since the first year of life. Those are mainly due to severe anemia. Later bone deformities and hepato-splenomegaly develops .
-Blood smear shows hypochromia and microcytosis (similar to Iron Deficiency Anemia).
-Hemoglobin A2 often elevated > 3%, sometimes reaching 7-8%.
Laboratory diagnosis- Cont
-Blood smear shows profound microcytic anemia, with extreme hypochromia, tear drop, target cells and nucleated RBCs.
-Hemoglobin may be very low at 3-4 g/dl.
Primary Laboratory Investigation Thalassemia
Severe cases present with
RBC counts higher than expected for the level of anemia
Early prenatal diagnosis can be done using first fetal blood sampling, and later chorion villus biopsy and direct analysis of the globin genes.
The error rate in experienced centers is now well under 1%.
Beta thalassemia major treatment
stem cell transplant
Management and treatment
Thalassemia minor (trait) :
No need for any treatment, since the carriers are usually symptomless.
The severe life-threatening anemia, requires regular life long blood transfusion, to compensate for damaged red blood cells.
Management and treatment- Cont
The continuous blood transfusion will eventually lead to iron overload, which must be treated with chelation therapy to avoid organ failure.
Source: Cooley’s Anemia Foundation
Management and treatment- Cont
Thalassemia Major -Continued:
Other novel treatments like bone-marrow transplantation are very costly.
New treatments includes the use of oral chelators, to replace the chelation treatment using Desferal delivered by infusion under the skin through a battery-operated pump.
Gene therapy is also an option still researched
Pre marital screening to make sure that the couple are not both carriers.
Provision of counseling and health education for the thalassemics, their families and the public .
Provision of prenatal testing for thalassemia.
Reduction of marriages between relatives.
Approach to Beta Thalassemia
RBC transfusion therapy
Agents to increase hemoglobin F (Hydroxyurea)
Bone marrow transplantation
Test partners of heterozygous or affected individuals
Antenatal diagnosis from DNA obtained by chorionic villus sampling, or by amniocentesis
Clinical Presentations of Abnormal Hemoglobins
Thalassemia or microcytic anemia
Asymptomatic (screening or family study)
Structural Haemoglobin Variants
Mostly: single AA substitution.
Over 300 variants.
Harmless, Accidently discovered (screening).
May alter Hb stability clinical disorders.
The Sickling Disorders
A group of disorders characterised by sickling of RBC on deoxygenation (unstable Hb).
Heterozygous state of Hb S (sickle cell trait , genotype A S ).
Homozygous state of Hb S (sickle disease, genotype S S).
Compound heterozygous state of Hb S with Hb SC, SD, SE and other structural variants.
Inheritance of sickle cell together with thalassemia.
Substitution of valine for Glutamic acid at position 6 in the B chain (B 6 Glut valine) = Hb S.
Replacement of adenine by thymine in the DNA code (GAG GTG).
Patho-physiology of sikle cell disease
Higher levels of Hb F in neonates protective 8 – 20 weeks.
Chronic hemolytic anaemia + Jaundice.
Growth & developmental retardation (skeletal deformities): Frontal bossing, short stature, inequalities between upper & lower segments, deformities ………
Anaemia & jaundice (ch. Haemolysis).
Splenomegaly resolves by infarcts (auto spelenectomy).
Fulminant pnuemococcal septicemia.
Chronic leg ulcers.
High fever ? Septicaemia.
Acute splenic sequestration.
Acute chest syndrome.
Pneumococcal septicaemia Prophylactic penicillin works but pneumococcal vaccine does not work well when it is most needed. Penicillin is given as monthly IM injections to ensure compliance. Given 4 months to 4 years when last injection is given with 23V vaccine. Protocol will need modifying with rapid emergence of penicillin resistance and conjugate vaccine.
Definition Sudden increase in spleen size, fall in Hb > 2g/dl, and reticulocytosis. The spleen size decreases spontaneously or post transfusion. Accounted for 24% deaths in first 10 years of study. Acute Splenic Sequestration
Aplastic crisis Human parvovirus B19 infection accounts for virtually all clinically defined episodes. High secondary infection rate so that siblings of affected cases should be closely monitored. Immunity appears to be life long with no recurrent episodes. Most cases can be safely treated by outpatient transfusion.
Mostly ischaemic in childhood associated with blockage of major cerebral vessels.
Mostly haemorrhagic in adults often associated with berry aneurysms at base of brain.