Hemolytic anemias - Hemoglobinopathies

Part 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

Thalassemias

– Beta () 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

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.

Thalassemias

» The 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 leucopoenia 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

Thalassemias

» Therapy – 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 anemia

» Patients 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.

– Hgs S/ thalassemia – symptomless to moderate anemia

– 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.

Thalassemias

– Hemoglobin 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.