HEMOLYTIC ANEMIAS - HEMOGLOBINOPATHIESPart 2

THALASSEMIAS

Thalassemias are a heterogenous group of genetic disorders Individuals with homozygous forms are

severely affected and die early in childhood without treatment

Heterozygous individuals exhibit varying levels of severity

The disorders are due to mutations that decrease the rate of synthesis of one of the two globin chains ( or ). The genetic defect may be the result of:

THALASSEMIAS A mutation in the noncoding introns of the gene

resulting in inefficient RNA splicing to produce mRNA, and therefore, decreased mRNA production

The partial or total deletion of a globin gene A mutation in the promoter leading to decreased

expression A mutation at the termination site leading to

production of longer, unstable mRNA A nonsense mutation

Any of these defects lead to: An excess of the other normal globin chain A decrease in the normal amount of physiologic

hemoglobin made Development of a hypochromic, microcytic

anemia

WORLD DISTRIBUTION OF THALASSEMIAS

THALASSEMIASBeta () thalassemia

The disease manifests itself when the switch from to chain synthesis occurs several months after birth

There may be a compensatory increase in and chain synthesis resulting in increased levels of hgb F and A2.

The genetic background of thalassemia is heterogenous and may be roughly divided into two types: 0 in which there is complete absence of chain

production. This is common in the Mediterranean. + in which there is a partial block in chain

synthesis. At least three different mutant genes are involved:+1 – 10% of normal chain synthesis occurs+2 – 50% of normal chain synthesis occurs+3 - > 50% of normal chain synthesis occurs

ALPHA AND BETA THALASSEMIAS

THALASSEMIAS The clinical expression of the different gene

combinations (1 from mom and 1 from dad) are as follows: 0/0, +1/ +1, or 0/ +1,+2,or +3 = thalassemia major,

the most severe form of the disease. Imbalanced synthesis leads to decreased total

RBC hemoglobin production and a hypochromic, microcytic anemia.

Excess chains precipitate causing hemolysis of RBC precursors in the bone marrow leading to ineffective erythropoiesis

In circulating RBCs, chains may also precipitate leading to pitting in the spleen and decreased RBC survival via a chronic hemolytic process.

The major cause of the severe anemia is the ineffective erythropoiesis.

THALASSEMIASThe severe, chronic anemia early in life leads to

marked expansion of the marrow space and skeletal changes due to the increased erythropoiesis.

Untreated individuals die early, usually of cardiac failure (due to overwork and hemochromatosis).

Individuals may have massive splenomegaly leading to secondary leukopoenia and thrombocytopenia. This can lead to infections and bleeding problems.

Lab findings include: - hypochromic, microcytic anemia - marked anisocytosis and poikilocytosis - schistocytes, ovalocytes, and target cells - basophilic stippling from chain precipitation - increased reticulocytes and nucleated RBCs

THALASSEMIAS

- serum iron and ferritin are normal to increased and there is increased saturation

- chronic hemolysis leads to increased bilirubin and gallstones

- hemoglobin electrophoresis shows increased hgb F, variable amounts of hgb A2, and no to very little A

THALASSEMIA MAJOR

THALASSEMIASTherapy – transfusions plus iron chelators to

prevent hemochromatosis and tissue damage from iron overload; Gene therapy?

+2, or 3 homozygous = thalassemia intermedia Heterozygosity of 0, or + = thalassemia minor

Mild hypochromic, microcytic anemiaPatients are usually asymptomatic with symptoms

occurring under stressful conditions such as pregnancy

thalassemia may also be found in combination with any of the hemoglobinopathies (S, C, or E) leading to a mild to severe anemia depending upon the particular combination.

THALASSEMIA MINOR

THALASSEMIAS Alpha () thalassemia

The disease is manifested immediately at birth There are normally four alpha chains, so there is a

great variety in the severity of the disease. At birth there are excess chains and later there are

excess chains. These form stable, nonfunctional tetramers that precipitate as the RBCs age leading to decreased RBC survival.

The disease is usually due to deletions of the gene and occasionally to a functionally abnormal gene.

THALASSEMIAS The normal haploid genotype is / If one gene is deleted, the haploid phenotype is

thal 2 If both genes are deleted, the haploid phenotype

is thal 1 Since one gets two genes from each parent,

there are four types of thalassemia: / thal 2 = silent carrier / thal 1, or thal 2/ thal 2 = thal trait with

mild anemia thal 1/ thal 2 = hemoglobin H disease (4 = hgb

H) Hgb H has a higher affinity for O2 and precipitates in older cells. Anemia may be chronic to moderate to severe.

THALASSEMIAS thal 1/ thal 1 = hydrops fetalis which is fatal with

stillbirth or death within hours of birth. Hemoglobin Barts (4) forms and has such a high affinity for O2 that no O2 is delivered to the tissues.

Hgb S/ thalassemia – symptomless to moderate anemia

ALPHA THALASSEMIAS

THALASSEMIAS

Delta/beta (/) thalassemia – both and chains are absent with no or little compensatory increase in chain synthesis. This leads to 100% hgb F and mild hypochromic, microcytic anemia

Hereditary persistence of hgb F – are a group of heterogenous disorders with the absence of and chain synthesis which is compensated for by an increase in chain synthesis leading to 100% hgb F. Since hgb F has an increased affinity for O2, this results in polycythemia.

THALASSEMIASHemoglobin Constant Spring – formed by a

combination of two structurally abnormal chains (each elongated by 31 amino acids at the COOH end) and two normal chains. The abnormal chains are inefficiently

synthesized resulting in an thal 1 like phenotype (excess chains)

Homozygous individuals have mild hypochromic, microcytic anemia similar to a mild a thalassemia.

Hemoglobin Lepore – a normal chain plus a - hybrid (N-terminal , and C-terminal ).

There is ineffective synthesis of the hybrid chain leading to chain excess and the same problems seen in thalassemia.

THALASSEMIAS Homozygous individuals have a mild to severe

hypochromic, microcytic anemia Heterozygous individuals are asymptomatic.