Haematology

• Where does haemoglobin production occur in the embryo?

  Yolk sac
• Where does haemoglobin production occur in neonates and adults?

  Bone marrow
• Relate the sites of globin chain production to the age-stages of development and the genes involved.

  • Embryo: Yolk sac
  • Neonate and adult: Bone marrow
  • Genes: α, β, γ, δ
• List the normal globin chains seen in hemoglobin.

  • α
  • β
  • δ
  • γ
• Name the sites of haemoglobin production in the body.

  • Yolk sac
  • Liver
  • Bone marrow
• Which type of cells in the bone marrow produce haemoglobin?

  Erythroblasts
• What do reticulocytes contain that indicates they are still producing haemoglobin?

  A little mRNA
• Describe the different stages of haemoglobin production and the factors involved.

  • Mitochondria
  • Formation of Hb tetramers
  • Allosterism
• List the components of a precursor cell used in haemoglobin production.

  • Pyrrole ring
  • Methylene bridges
  • Iron atom
• What are the two main components of haemoglobin?

  • Haem (iron-containing porphyrin ring)
  • Globin (2 α and 2 other chains)
• What property does haemoglobin exhibit?

  • Allosterism
• What are the normal adult haemoglobins and their compositions?

  • HbA: $\alpha_2\beta_2,$ 96%
  • HbA2: $\alpha_2\delta_2,$ 3%
  • HbF: $\alpha_2\gamma_2,$ <1%
• Which haemoglobin is predominant during foetal development?

  • HbF: $\alpha_2\gamma_2$
• What is the major component of haemoglobin after birth?

  HbA: $\alpha_2\beta_2$
• What is the difference between the formation of Hb variants and thalassaemia?

  Hb variants are structural changes in globin chains, whereas thalassaemia involves globin chain imbalances caused by gene defects
• List the ‘thalassaemic’ red cell indices.

  • Increased RBC > $5.5 \times 10^{12}/L$
  • Normal Hb: $110-130 g/l$
  • Decreased MCV: <78 fl
  • Decreased MCH: <27 pg
  • Normal MCHC: >300 g/l
• What is the normal MCHC range?

  >300 g/l
• How do structural variants of haemoglobin arise and what are some common clinically significant variants?

  • Substitution of one or more amino acids
  • >800 different variants
  • HbS (sickle cell haemoglobin) is the most clinically significant variant
  • Mutation at position 6: Glutamine to Valine
• What is the most clinically significant structural variant of haemoglobin?

  HbS (sickle cell haemoglobin)
• What are the best methods to detect structural variants and why?

  Position of the variant is paramount as it impacts the structure-function relationship
• List some common external variants of haemoglobin and their mutations.

  • HbE: point mutation at E26, Glutamic acid to Lysine
  • HbS: point mutation at position six, Glutamic acid to Valine
  • HbC: amino acid substitution at position six, Glutamic acid to Lysine
  • Hb D-Punjab: Position 121, GAA→CAA, Glutamine for Glutamic acid
  • Hb G Philadelphia: alpha chain variant, deletion and mutation at alpha 68, Lysine for Asparagine
• How can the position of deletion or variant substitution affect haemoglobin function and cells?

  • Inefficient oxygen carrying
  • High affinity haemoglobins
  • Cell instability
  • Early death of cells
  • Removal of abnormal cells
• What are the major haemoglobinopathies?

  • Alpha Thalassaemia
  • Beta Thalassaemia
  • Sickling Disorders
• What are the main learning outcomes for this topic?

  • Non-Malignant leukocyte disorders
  • Overview of malignant leukocyte disorders
  • Overview of classification
  • Laboratory analysis
• How many copies of the alpha globin gene are normally located on Chromosome 11?

  • Two copies
• Are disorders of neutrophils more or less common than malignant leukemias and lymphomas?

  More common
• What are the main categories of non-malignant leukocyte disorders?

  • Disorders of Neutrophils
  • Disorders of Eosinophils and Basophils
  • Disorders of Mononuclear phagocytes
  • Disorders of Lymphocytes
• How do circulating neutrophil counts vary with age in newborns?

  Higher in newborns until 6-9 years of age
• At what age ratio are lymphocytes greater than neutrophils?

  After 9 years, the ratio is 60:40 (lymphocytes to neutrophils)
• What are the common genotypes for alpha thalassaemia and in which populations are they prevalent?

  • Heterozygous forms:
  • $-α/αα:$ 1 gene deletion, common in African, Afro-Caribbean, Indian, Pakistani and Bangladeshi populations
  • $α0/αα:$ 1 allele deletion, prevalent in Far East Asians, Chinese, Greeks, Turkish, and some Mediterranean and Middle Eastern populations
  • Homozygous forms:
  • $α_/α_:$ 2 gene deletion, as above
  • $--/αα:$ 2 allele deletion, heterozygous form, prevalent in Far East Asians, Chinese, Greeks, Turkish, and some Mediterranean and Middle Eastern populations
• What are the two most common abnormalities in disorders of neutrophils?

  • Neutrophilia (increased number of neutrophils)
  • Neutropenia (reduced number of neutrophils)
• What are other causes of neutrophilia?

  Inflammatory conditions, neoplasia, and hemolysis
• What is neutrophilia and its mimic in extreme cases?

  Neutrophilia is an increased number of neutrophils; in extreme cases, it can mimic leukemia as a leukaemoid reaction.
• Describe the modes of inheritance for alpha thalassaemia and their associated conditions.

  • $α_/αα:$ 1 gene deletion, alpha+, heterozygous form
  • $α_/α_:$ 2 gene deletion, alpha+, homozygous form
  • αα/_ _: 2 gene deletion, alphao, heterozygous form
  • α_/_ _: 3 gene deletion, HbH disease, excess β4
  • __/__: 4 gene deletion, Hb Barts ϒ4, intrauterine death (IUD)
• What condition results from a 3 gene deletion in alpha thalassaemia and what is the excess globin chain?

  HbH disease, excess β4
• How is neutropenia defined?

  A reduction in the absolute number of neutrophils in the peripheral blood.
• What are the classifications of neutropenia?

  • Mild
  • Moderate
  • Severe
• What are the common genotypes for beta-thalassaemia and their associated terminology?

  • $β/β$ or β_/β:</latex> one beta globin gene partially deleted
  • $β0/β:$ one beta globin gene is absent, Beta thalassaemia trait/minor
• What are some acquired causes of neutropenia?

  • Infections
  • Drugs
  • Micronutrient deficiency
  • Hematological malignancy
  • Inflammation
  • Splenomegaly
• How is beta thalassaemia trait diagnosed and which populations does it affect?

  • Clinically asymptomatic
  • Normal ferritin
  • Raised HbA2: >3.5%
  • ‘Thalassaemic’ red cell indices
  • Hypochromic, microcytic, <MCH
  • Affects Asian, Bangladeshi, Pakistani and Mediterranean populations