Haemolytic anaemias

• Haemolysis can occur in the circulation (intravascularly) or in the reticulendothelial system (extravascularly)
• When trying to diagnose a haemolytic anaemia ask yourself the following questions;
  • Is there increased red cell breakdown?
    • Increased bilirubin?
    • Increased urine bilinogen?
    • Increased serum LDH as released from RBCs?
  • Is there increased red cell production?
    • Increased reticulocytes causing increased MCV
  • Is the haemolysis mainly extra or intravascular?
    • Extravascular haemolysis can lead to splenomegaly
    • Intravascular haemolysis can lead to;
      • Free plasma haemoglobin
      • Methaemalbuminaemia – some free Hb is broken down in the circulation to haem and globin, haem can combine with albumin to make methaemalbuminaemia
      • Haemoglobinuria
      • Haemosiderinuria – when haptoglobin binding capacity is exceeded, free Hb is filtered by the renal glomeruli and absorbed by the renal tubules as haemosiderin, these sloughed off tubular cells can be detected in the urine by Prussian blue staining, implying a chronic intravascular haemolysis

Examination

• Jaundice
• Hepatosplenomegaly
• Gallstones (pigmented)
• Leg ulcers (due to poor blood flow)

Investigations

• FBC
• Reticulocytes
• Bilirubin
• LDH
• Haptoglobin
• Urinary urobilinogen
• Thick and thin films for malaria if there has been a history of travel
• Things that might be seen in the blood film;
  • Hypochromic microcytic anaemia – thalassaemia
  • Sickle cells – Sickle cell anaemia
  • Schistocytes – microangiopathic haemolytic anaemia
  • Abnormal cells in haematological malignancy
  • Spherocytes – hereditary spherocytosis or autoimmune haemolytic anaemia
  • Elliptocytes – hereditary elliptocytosis
  • Heinz bodies and bite cell – Glucose 6 phosphate dehydrogenase deficiency

Further tests

• Coombs – direct antiglobulin test
• Chromium labelling – determines RBC lifespan and major site of breakdown

Causes of haemolytic anaemia

• Can be acquired or hereditary

Acquired causes

• These can be divided into immune mediated and non-immune causes

Immune mediated

• Drug induced
  • Causing formation of RBC autoantibodies from binding to the red cell membrane e.g. penicillin or forming immune complexes e.g. quinine
• Autoimmune haemolytic anaemia
  • Mediated by autoantibodies causing mainly extravascular haemolysis and spherocytosis
  • There are divided by the optimum temperature they bind to RBC
  • Warm AHA – IgG mediated. Treat with steroid and splenectomy
  • Cold AHA – IgM mediated, chronic anaemia made worse by the cold
  • May be idiopathic or caused by drugs, infections or lymphoproliferative disease
• Paroxysmal cold haemoglobinuria
  • Seen with viruses/syphilis
  • Caused by Donath-Landsteiner antibodies which stick to RBCs in the cold and cause complement mediated lysis on rewarming

Isoimmune mediated

• Acute transfusion reaction
• Haemolytic disease of the newborn

Microangiopathic haemolytic anaemia

• A mechanical disruption of RBCs in the circulation causing intravascular haemolysis and schistocytes
• Causes include;
  • Haemolytic uraemia syndrome
  • Thrombotic thrombocytopenic purpura
  • DIC
  • Pre-eclampsia/eclampsia
  • Intravascular devices e.g. prosthetic valves

Infection

• Malaria

Paroxysmal nocturnal haemoglobinuria

• RBCs are sensitive to complement mediated lysis due to an inherited loss of glycosylphosphatidylinositol (GPI)
• There is chronic intravascular haemolysis particularly at night, pancytopenia and thrombosis

Hereditary causes

• These can occur if there is a defect in RBC enzymes, membrane or haemoglobinopathies

Enzyme defects

• Glucose-6-phosphate dehydrogenase deficiency
  • Commonest enzyme defect
  • It is X-linked
  • Most are asymptomatic but oxidative crises can be precipitated by drugs e.g. sulphonamides, aspirin, exposure to broad beans or illness
  • During an attack there is rapid anaemia and jaundice with bite or blister cells on the blood film
• Pyruvate kinase deficiency
  • This is autosomal recessive
  • Reduced ATP production causes shortened red cell survival

Membrane defects

• Hereditary spherocytosis
  • This is autosomal dominant
  • Results in less deformable RBCs which get trapped in the spleen results in extravascular haemolysis
• Hereditary elliptocytosis
  • Autosomal dominant
  • Mostly asymptomatic

Haemoglobinopathies

• Sickle cell disease
• Thalassaemia

Sickle cell anaemia

• Autosomal recessive disorder
• Amino acid substitution in the gene coding the ?-chain (glu-val at position 6) results in the production of HbS rather than HbA
• Common in people of African origin
• Homozygotes have sickle cell disease
• Heterozygotes have sickle cell trait – no disability unless in hypoxia
• HbS polymerises when deoxygenated causing RBCs to deform, these produce sickle cells which are fragile and haemolyse and so block small vessels

Tests

• Increased reticulocytes
• Increased bilirubin
• Blood film – sickle cells and target cells
• Hb electrophoresis

Symptoms and signs

• Chronic haemolytic anaemia
• Vaso-occlusive ‘painful’crisis
  • Can affect the BM causing severe pain, hands and feet are affected in children
  • This is precipitated by the cold, dehydration, infection or hypoxia
  • May cause mesenteric ischaemia
• Cerebral infarction
• Priapism
• Anaplastic crisis
  • Due to parovirus B19 resulting in sudden reduction in marrow production
  • Usually self limiting but may require transfusions
• Sequestration crisis
  • Most commonly affects children in whom the spleen has not yet atrophied
  • There is pooling of blood in the liver and spleen
  • Results in organomegaly, anaemia and shock and may require transfusion

Complications

• Splenic infarction leading to increased susceptibility to infection
• Growth impairment
  • Bone necrosis especially femoral head
• Chronic renal failure
• Chronic leg ulcers
• Gallstones
• Retinal disease and visual impairment
• Iron overload due to multiple transfusions
• Long term lung damage – hypoxia, fibrosis, pulmonary hypertension

Management of chronic disease

• Hydroxycarbamide (hydroxyurea) – this causes increased production of fetal Hb and decreased polymerisation
• Antibiotic and immunisation prophylaxis
• BM transplant

Prevention

• Genetic counselling and pre-natal tests

Thalassaemia

• This is a defect in haemoglobin synthesis due to an underproduction or lack of one globin chain
• Unmatched globins precipitate damaging RBC membranes and causing haemolysis
• Can be split into ? and ? thalassaemias depending on whether there is reduced production of ? or ? Hb

? thalassaemia

• Caused by a point mutation in the ? globin genes on chromosome 11

? thalassaemia minor

• This is the carrier state which is usually asymptomatic
• Causes mild well tolerated anaemia which may get worse in pregnancy

? thalassaemia intermedia

• Describes an intermediate state with moderate anaemia but not requiring transfusions
• May be due to co-inheritance of the thalassaemia trait with another haemaglobinopathy

? thalassaemia major

• Cooley’s anaemia
• There are abnormalities in both ? genes and presents within the 1^st year with severe anaemia and FTT
• Results in extramedullary haematopoesis and frontal skull bossing and hepatosplenomegaly
• Life long transfusions are required which can result in iron overload and endocrine failure, liver disease and cardiac toxicity
• This can be helped by desferrioxamine
• Test results;
  • Hypochromic microcytic anaemia with target cells and nucleated RBCs
  • HbF­, HbA2 variable and absent HbA

Treatment

• Folate supplements
• Regular blood transfusions
• Iron chelators e.g. desferrioxamine
• Large doses of ascorbic acid also increase urinary excretion of iron
• Splenectomy
• Hormone replacement for endocrine complications
• BM transplant

The ? thalassaemias

• There are 4 separate ? genes, 2 on each chromosome 16
• If all 4 genes are deleted Bart’s hydrops occurs and there is death in utero
• HbH disease occurs in 3 genes are deleted, there is moderate anaemia and haemolysis. The ? chains form tetramers (HbH)
• If 2 genes are deleted this results in an asymptomatic carrier state with a low MCV