Types of Anaemia

Symptoms and signs of Anaemia

• Pallor  oral mucosa (gets pale when the Hb is less than 9g/dL) and conjunctiva
• Lethargy, tiredness, weakness
• SOB, tachycardia, palpitations
• Angular stomitis, painless glossitis
• In older patients there may be symptoms of cardiac failure, angina pectoris, intermittent claudication or confusion

Causes of anaemia

• Due to either decreased production of Hb or increased loss/destruction

Reduced bone marrow function;

• Primary
  • BM failure
  • Red cell aplasia
• Secondary
  • Infection
  • Drugs
  • Infiltration
  • Absence of ‘ingredients’
  • BM hypoxia
  • Ineffective erythropoesis

Increased red cell loss;

• Bleeding
• Haemolysis

Classification of Types of Anaemia based on MCV

Microcytosis (<80fL) Anaemia

• Iron deficiency
• Haemoglobinopathies e.g. Thalasaemia and Sickle cell
• Anaemia of chronic disease

Normocytic Anaemia

• Blood loss
• Haemolytic
• Stem cell defects

Macrocytosis (>80fL) Anaemia

• Megaloblastic
• Alcohol
• Liver disease
• Reticulocytosis
• Drug therapy e.g. methotrexate, hydroxyurea
• Marrow failure

Laboratory Investigation of Anaemia

FBC

• Gives HB, white cell count, platelet count and MCV

Leukocyte and platelet counts

• Helps to distinguish pure anaemia from pancytopenia (reduced RBC, platelets and granulocytes)

Reticulocyte count

• The normal count is 0.5 to 2%. This should be higher in anaemia because of erythopoetin increase and should be higher the more severe the anaemia
• After an acute haemorrhage, the reticulocyte count rises within 2-3 days, reaches a max at 5-10 days and remains raised until the Hb returns to normal
• If it is not raised it suggests impaired bone marrow function of a lack of EPO stimulus

Blood film

• Provides info on the size, shape, colour of RBC, if there are any inclusions

Bone marrow biopsy

• May be preformed by aspiration or trephine
• Aspiration is the best way to assess cellular characteristics
• Trephine biopsy is the best way to assess the overall cellularity and any architectural changes

Iron deficiency anaemia

• Causes;
  • Poor iron intake – common in paeds
  • Poor iron absorption – Coeliac’s gastrectomy
  • Chronic blood loss – GI or menorrhagia
  • Increased iron utilisation – neonates, puberty, pregnancy
• Results in a microcytic hypochromic anaemia with occasional target cells and pencil shaped poikilocytes
• Maybe associated with a mild thrombocytosis
• Generally associated with a reduced serum ferritin
• Serum iron falls and total iron binding capacity increased
• In the BM there is reduced erythopoesis and reduced iron stores

Megaloblastic anaemia

• Associated with defective DNA synthesis
• Causes;
  • Vit B12 (pernicious anaemia, associated with intrinsic factor autoantibodies) or folate deficiency
  • Abnormalities in Vit B12 or folate metabolism, transcobalamin deficiency, nitrous oxide, anti-folate drugs
• May be associated with a Vit B12 neuropathy
• Causes an oval macrocytosis with hypersegmented neutrophils (6 or more lobes)
• Associated with mild haemolysis and raised bilirubin
• In severe cases there may be a pancytopenia with decreased platelets and white cell count
• Associated with hypercellular bone marrow

Haemolytic Anaemias

• Mean lifespan of an RBC is 120 days. Haemolytic anaemias are due to an increased rate of RBC destruction
• Classification
  • Intrinsic red cell defect
    • Membrane
      • Hereditary spherocytosis – autosomal dominant. Defect in RBC membrane proteins, spectrin, actin and band 3. Causes splenomegaly and gallstones
      • Hereditary elliptocytosis – autosomal dominant
    • Metabolism
      • Glucose-6-phosphate dehydrogenase deficiency – haemolysis when the RBC is exposed to oxidative stress
      • Pyruvate kinase deficiency – autosomal recessive
    • Haemoglobin
      • HbS, HbC
  • Extrinsic defect
    • Severe hepatic dysfunction
    • Red cell fragmentation – DIC, Thrombotic thrombocytopenic purpura, haemolytic uraemic syndrome
• Results in;
  • Red cell destruction
  • Increased bilirubin
  • Increased LDH
  • Reduced haptoglobin (bind free haemoglobin) as the reticulo-endothelial system removes free Hb-haptoglobulin complexes
  • Evidence of damaged cells
  • Spherocytes
  • Fragmented red cells
  • Increased RBC production and reticulocytosis

• Immune haemolytic anaemia
  • Autoimmune haemolytic anaemia
    • Due to autoantibody production against RBC
    • Characterised by a positive direct antiglobulin test (DAT)
    • Can be divided into warm and cold types depending on whether the antibody reacts best with the RBC at 37 or 4 degrees
    • Treated by immunosuppression and splenectomy
  • Alloimmune haemolytic anaemia
    • Haemolytic disease of the newborn
  • Drugs
    • e.g. antibiotics (cephalosporins), albumin and immunoglobulins

Anaemia of Chronic Disease

• Associated with chronic infections, inflammations and malignancies
• Microcytic or normocytic anaemia
• Mostly normal morphology but may be hypochromic
• Low serum iron and iron binding capacity
• Reduced erythropoesis due to reduced iron release to the BM but increased iron in reticulo-endothelial stores
• Normal or raised serum ferritin concentrations
• Caused by a reduction in renal production of EPO caused by the action of IL-1, TNF and IFN-γ
• The cytokines also stimulate the synthesis of hepcidin by the liver which inhibits the release of iron from the storage pool

Thalassaemia

• Heterogenous groups of genetic disorders of haemoglobin synthesis
• Result from reduced production of one or more of the globin chains of Hb
• Divided into  a-,  b-,  d b-,  g d b- thalassaemia depending on which globin chain is being produced in reduced amounts
• May produce no chain and therefore be termed, for example,  a⁰ or reduced amounts and be termed  a₊
• Severity of disease ranges from intrauterine death to mild symptomless anaemia
• Inherited in a simple Mendelian co-dominant fashion
• Heterozygotes are usually symptomless, homozygotes are more severely affected
• Clinical disease is classified into major, intermediate and minor forms

• Thalassaemia major is a severe transfusion dependant disorder
• Thalassaemia intermediate is characterised by anaemia and splenomegaly
• Thalassaemia minor is the symptomless carrier stage

 b-Thalassaemia

• Common.
• Cause severe anaemia in homozygotes
• Can be caused by over 100 different mutations
• Therefore individuals who are homozygotes are rather compound heterozygotes for two different mutations

Pathology of Anaemia

• Absent or reduced  b-chain production whilst  a-chain production continues at a normal rate
• Excessive unpartnered  a-chains are unstable and precipitate in the red-cell precursor to form large intracellular inclusions
• This results in increased intramedullary destruction of red cell precursor and, if cells do enter the periphery their  a-chain inclusions interfere with their passage through the microcirculation and results in increased breakdown in the spleen – causes splenomegaly
• This leads to a marked anaemia
• The anaemia stimulates increased EPO production which causes a massive expansion of the bone marrow – thus leading to deformities of the skull and long bones
• The splenomegaly causes an increase in plasma vol which also contributes to anaemia
• Patients have a raised fetal haemoglobin.
• This is due to the fact that some adult red cell precursors retain the ability to produce a small amount of  g-chain.  g-chain can pair with  a-chain and these cells have a selective advantage
• There is also an increase in production of HbA₂ ( a₂ d₂ as  d-chain synthesis remains unaffected)
• Treatment is with blood transfusion
• However every unit of blood contains 200mg of iron which can result in accumulation in the liver, heart and endocrine glands. This results in iron overload

Clinical features of homozygous or compound heterozygous  b-Thalassaemia

• Presents in first year of life as failure to thrive
• In the well transfused child early growth is normal and splenomegaly is minimal
• However tissue siderosis start to appear from the age of 10
• Normal adolescent growth spurt fails to occur and patient develops a variety of complications due to iron overload. These are;
  • Diabetes
  • Hypoparathyroidism
  • Adrenal insufficiency
  • Liver failure
  • Delayed/absent secondary sexual development
• Death occurs at the end of 2^nd decade due to cardiac failure or acute arrhythmia
• May be delayed with chelation therapy
• In children who are not well transfused, the picture differs
  • Splenomegaly
  • Worsening anaemia
  • Bleeding tendency (as the also develop thrombocytopenia)
  • Deformities of the skull (marked radiological changes)
  • Increases susceptibility to infection
• Generally these children die by the age of two

Haematological changes

• Red cells are hypochromic and microcytic
• There is reduced MCV and MCH
• White cell and platelet counts are normal unless there is hypersplenomegaly in which case they are reduced
• Transfusion dependant children have high ferritin levels
• Often folic acid depleted

Heterozygous  b-Thalassaemia

• Normally asymptomatic except in periods of stress such as pregnancy when they can become anaemic

 db-Thalassaemia

• Much less common than disorders due to defective b-chain production alone
• Genetic defect heterogenous, may be an outright deletion or a db fusion.
• This results in db-fusion chains called Lepore haemoglobulins     
• In the homozygous state this results in a mild degree of anaemia that is only symptomatic during stress (pregnancy)
• Hb analysis shows 100% HbF or HbF and Lepore in the case of Lepore haemoglobulins

gdb-Thalassaemia

• Rare disorder whereby there are large deletions of the b-gene cluster which removes not just the b-genes but also the g- and d- genes
• Homozygotes are incompatible with life
• Heterozygotes suffer severe haemolytic disease of the newborn with anaemia and hyperbilirubinaemia
• If they survive to adult life they have a haematological picture similar to heterozygous b-thalassaemia

a-Thalassaemia

• More common than b-thalassaemia
• Severe homozygous forms are incompatible with life whilst milder forms don’t produce major disease
• a⁰-thalassaemia is due to a complete absence of the a-chain and heterozygotes have a mild hypochromic anaemia
• a⁺-thalassaemia has a partial reduction in a-chains. This is completely silent in carriers with only a possibility that their RBC might be slightly hypochromic
• There are two symptomatic types of a-thalassaemia, haemoglobin Bart’s hydrops and haemoglobin H disease
• Bart’s hydrops syndrome is due to homozygous inheritance of a⁰-thalassaemia and occurs in the fetus. The deficiency in a-chains results in excess g-chains which form g4 tertramers called Bart’s Hb
• Hb H disease usually results from co-inheritance of both a⁰- and a⁺-thalassaemia. Whereby the deficiency in a-chains results in an excess of b-chains which form b4 tetramers called haemoglobin H