Bio lecture 2

• Hemoglobinopathies


  Disorders where the production of normal adult hemoglobin is partly or completely suppressed or replaced by a variant hemoglobin

  
• Haemoglobin


  A conjugated protein, containing haem as prosthetic group and globin as the protein part-apoprotein
• The normal concentration of Hb in an adult male varies from 14.0 to 16.0 gms%
• Haemoglobin


  • Important in O2-binding and its transport and delivery to tissues

  
• Haem


  A Fe-porphyrin compound. The porphyrins are complex compounds with a tetrapyrrole structure
• Globin

  The protein part of Hb, is composed of four polypeptide chains, two identical α-chains and two identical β-chains
• Types of normal haemoglobins


  • Hb-A1
  • Hb-A2
  • Hb-F
  • Embryonic Hb
  • Hb-A1C (Glycosylated Hb)
• Hb-A1


  Normal adult Hb, commonly called Hb-A, consists of two α- and two β-chains and designated as α2 β2. 90 to 95 per cent of Hb of normal adult is of this type
• Hb-A2


  A minor component of normal adult Hb, present usually to the extent of 2.5 per cent. It contains two α-chains and two δ-chains and thus it is α2 δ2
• Hb-F


  Human foetal Hb, designated as Hb-F and it is α2γ2. Hb-F Present in foetal life, disappears after one year of birth. Persistence of Hb-F after one year is pathological
• Embryonic Hb

  Found in first three months of intrauterine life of the baby. It contains two α-chains and two ε-chains and thus it is α2 ε2. They include Gower I and Gower II Hbs
• Hb-A1C (Glycosylated Hb)

  In addition to Hb-A1 the major form of normal adult Hb, a minor glycosylated form is also found in adult red blood cells. In normal individuals, it is present in concentration of 3 to 5 per cent of total Hb. However, in patients with diabetes mellitus it may be increased to as much as 6 to 15 per cent of total Hb

  
• Haemoglobinopathies

  Disorders where the production of normal adult hemoglobin in partly or completely suppressed or replaced by a variant hemoglobin

  
• Types of abnormal haemoglobins and haemoglobinopathies

  • Qualitative: Mutation affects structural gene, results in replacement of a single amino acid residue of Hb-A1 by some other amino acid resulting into abnormal Hb (e.g. Hb-S, Hb-M, Hb-C, hemoglobin SC)
  • Quantitative: Mutation affects the regulator gene, affects the rate of synthesis of the peptide chains, producing thalassaemias (α-chain thalassaemias and β-chain thalassaemias)
• Qualitative abnormalities


  Abnormalities in globin structure, usually involving beta-chain. Heme portion is normal. Arise from single amino acid substitution or deletion
• Sickle Cell Anemia and Sickle Cell Trait


  Most common hemoglobinopathy. Autosomal recessive. AS is sickle cell trait, SS is sickle cell disease (patient is homozygous for HbS)
• Sickle cell disease occurs in 0.3-1.35% of African Americans, sickle cell trait occurs in 8-10%
• Sickle Cell Anemia


  Caused by a point mutation for the sixth amino acid in the Beta chain, where valine is substituted for glutamic acid
• One benefit for AS persons (sickle cell trait)

  Increased resistance to malaria
• Pathophysiology of Sickle Cell Anemia

  SS cells may look normal when fully oxygenated, sickling occurs when O2 decreased. Other causes of sickling include decrease in pH, High altitude, Increased pCO2, Increased concentration of 2,3 BPG and dehydration of patient. Cells become rigid, impeding blood flow to tissues. Tissue death, organ infarction, and pain result. Have both extravascular hemolysis and intravascular hemolysis
• Sickle Cell Anemia


  • Clinical signs appear at 6 months of age, have all physical symptoms of anemia, growth and sexual maturation slower, characterized by lifelong episodes of pain ("crises"), chronic hemolytic anemia, associated hyperbilirubinemia, and increased susceptibility to infections
• The lifetime of a RBC in sickle cell anemia is less than 20 days, compared with 120 days for normal RBC
• Organs affected in Sickle Cell Anemia


  • Liver: Enlarges, malfunctions, jaundice, hyperbilirubinemia
  • Heart: Cardiomegaly, iron deposits
  • Spleen: Enlarges leading to infarction and fibrosis
  • Skin: Develop ulcers, jaundice
  • Kidney: Hematuria and eventual failure
  • Lungs: Infarction
  • Brain: Strokes
• Sickle Cell Anemia - blood film


  • Sickle Cells
  • Erythroblasts
  • Howell-Jolly Body
• Special Hematology Tests in Sickle Cell Anemia

  • Osmotic Fragility - Decreased
  • Bilirubin - increased
  • Haptoglobin decreased
  • Electrophoresis
• Chemistry Tests in Sickle Cell Anemia

  • Hb A and Hb S (Hb S contains valine instead of glutamate)
• Sickle Cell Anemia


  • Leads to infarction and fibrosis
  • Skin: Develop ulcers, jaundice
  • Kidney: Hematuria and eventual failure
  • Lungs: Infarction
  • Brain: Strokes
  • Blood: Hemolytic anemia
• Sickle Cell Anemia

  • Hepatosplenomegaly
  • Bone marrow deformities
  • Hyperplastic and compensatory to produce more RBCs
• Sickle Cell Anemia


  1. Sickle RBCs stuck in small capillaries

  2. Tissue needs more blood

  3. Heart pumps more blood

  4. Hemolytic anemia and blood transfusion
• Sickle Cells

  RBCs that can't handle rigid cytoplasm and are fragile
• Sickle Cell Anemia leads to brain infarction in 24 hours
• Sickle Cell Anemia - blood film


  • Sickle Cells
  • Erythroblasts
  • Howell-Jolly Body
• Special Hematology Tests in Sickle Cell Anemia

  • Blood film
  • Osmotic Fragility - Decreased
  • Bilirubin - increased
  • Haptoglobin decreased
  • Electrophoresis
• Chemistry Tests in Sickle Cell Anemia

  • Hemoglobin electrophoresis
• Hemoglobin electrophoresis

  HbA has glutamate so migrates faster to cathode than HbS which has valine
• Sickle Cell Anemia: Treatment


  1. Adequate hydration

  2. Analgesics

  3. Aggressive antibiotic therapy if infection

  4. Transfusions for high risk occlusion

  5. Hydroxyurea to increase HbF and decrease sickling
• Sickle Cell Trait


  • Heterozygous AS with more HbA than HbS
  • Often has normal life span
  • Usually asymptomatic with occasional hematuria
  • Sickling can occur with low oxygen, exercise, etc.
• Sickle Cell Trait has a mild picture of the disease
• Hematuria in Sickle Cell Trait


  Can cause papillary necrosis or renal infarction
• Laboratory Features of Sickle Cell Trait

  • Normal CBC - Few target cells or sickle cells
  • Hb Electrophoresis - Both HbA and HbS present