Abnormal types of hemoglobin, Sickling of RBCs, Types and causes of methemoglobinemia

There are abnormal types of hemoglobin such as Sickle cell disease (HbS), Thalassemias, and Methemoglobinaemia, Sickle-shaped RBCs are fragile and easily hemolysed so anemia will occur (sickle cell anemia), The abnormal hemoglobin does not function as normal hemoglobin and has an abnormal O₂ dissociation curve.

Abnormal types of hemoglobin

• Sickle cell disease (HbS)
• Thalassemias
• Methemoglobinaemia

Sickle cell disease (HbS)

The glutamic amino acid is replaced by valine amino acid at position number 6 of the beta chain due to mutation in the structured gene (α₂ S₂).

Pathogenesis

The presence of valine (nonpolar amino acid) instead of glutamic (polar amino acid) at position 6 of β-chain will lead to the formation of sticky patches on the surface of hemoglobins of both oxyhemoglobin S and deoxyhemoglobin S. However both the deoxyhemoglobin S and A contains complementary patches (grooves). When the blood is deoxygenated, the sticky patches of deoxyhemoglobin S bind to the complementary patches of deoxyhemoglobin S, leading to polymerization of deoxyhemoglobin S leading to the formation of long fibrous precipitates leading to sicking of RBCs.

Effects of sickling of RBCs

Sickle-shaped RBCs are fragile and easily hemolysed so anemia will occur (sickle cell anemia). Sickle-shaped RBCs are easily trapped in small blood vessels leading to thrombus formation and damage of organs like brain, bone spleen, etc.

Diagnosis

• Reticulocyte count between 10-20%.
• Sickle-shaped RBCs by microscopic examination.
• Electrophoresis. Shows HBS, no HbA. HbS moves slowly due to less negative charges on its molecules, so, it appears in paper electrophoresis nearer to the cathode than normal hemoglobin.

Thalassemias

These are hereditary hemolytic diseases in which the synthesis of either α- or β- globin chain is defective due to mutation affecting the regulatory gene.

Types of Thalassemias

• α-Thalassemias: is characterized by the decreased or absent synthesis of α- chains of hemoglobin with a compensatory increase in the synthesis of other chains. Include 2 types: Pure β- chain HbH: Where there are 4 β- chains (HbH disease). and Pure γ- chain-Hb Bart’s Where there are 4 γ- chains.

• β-Thalassemias: Synthesis of β- chains is decreased or absent, whereas synthesis of α- chains is normal and will combine with δ- chains giving an excess of HbA2 (α2δ2) or it may combine with γ- chains producing an excess of HbF (α2γ2).
  

The abnormal hemoglobin does not function as normal hemoglobin and has an abnormal O₂ dissociation curve.

Diagnosis

• Anemia: called Cooley’s anemia or Mediterranian sea anemia.
• Electrophoresis: shows HbF, HbH, HbA2.

Methemoglobinaemia

This is oxidized Hb, the Fe²⁺ normally present in heme being replaced by Fe³⁺. The ability to react as an  O₂ carrier is lost. The normal erythrocyte contains small amounts of met-Hb, formed by spontaneous oxidation of Hb. Met-Hb is normally reconverted to Hb by reducing systems in the RBC, the most important of which is NADH-methemoglobin reductase. Excess met-Hb may be present in blood because of increased production or diminished ability to convert it back to Hb.

Types and causes of methemoglobinemia

Congenital methemoglobinemia

Hemoglobin M (Hb-M): A congenital condition due to mutation in globin biosynthesis in which distal or proximal histidine is replaced by tyrosine so, heme iron is stabilized in the ferric state. Treatment with reducing agents as methylene blue is ineffective. The treatment is only conservative as a blood transfusion.

Deficiency of NADH cytochrome b5 methemoglobin reductase system: This is required for reducing heme Fe³⁺ back to the Fe²⁺ state. This system consists of NADH generated by glycolysis), a flavoprotein named cytochrome b5 reductase (also known as met Hb reductase), and cytochrome b5. Treatment with reducing agents is effective in converting met Hb back to Hb in those patients.

Acquired (toxic) methemoglobinemea

Usually arises following the ingestion of large amounts of drugs e.g. phenacetin or the sulphonamides, excess of nitrites or certain oxidizing agents present in the diet may also cause it. Treatment with the injection of reducing agents like vitamin C or glucose or methylene blue is effective in reversing acquired methemoglobinemea.

Diagnosis

1. Cyanosis.
2. Using a spectroscope, a dark band is found in C-line.

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