Haematology I: Clinical Aspects of Haematological Disorders

• What is haematopoiesis and what does the process start with?

  The process through which all blood cells are derived.

  
  

  The process starts with a pluripotent stem cell, which is capable of both self-renewal & differentiation

  
• What is the haematopoietic system composed of?

  The bone marrow, spleen, liver, lymph nodes & thymus
• Where does haematopoiesis occur?

  Depends on the individual's age:

  Childhood= bone marrow of nearly all bones

  Adults= axial skeleton & proximal parts of the long bones
• What are the main functions of the mature cell lines?

  
• What are the normal red blood cell indices?


  Children 6mths–6yrs:110 – 145 g/LChildren 6yrs–14yrs:120 – 155 g/LAdult males:130–170 g/LAdult females:120–155 g/LPregnant females:110–140 g/LMean cell volume(MCV): 80–95 fL
• What is anaemia?


  Reduction in haemoglobin level below reference range for age and sex of individual
• What are some of the symptoms and signs of anaemia?

  Symptoms:LassitudeFatigueDyspnoea on exertionPalpitationsHeadacheChest pain

  Signs:PallorTachycardiaWide pulse pressuresSystolic flow murmursCongestive cardiac failure
• By what mechanisms can anaemia develop?

  Blood loss

  
  

  Decreased red cell life span (haemolytic)

  
  

  Congenital (sickle cell)

  
  

  Acquired (drugs,malaria)

  
  

  Impairment of red cell formation

  
  

  Insufficient erythropoiesis (process that provides a RBC)

  
  

  Ineffective erythropoiesis

  
  

  Pooling and destruction in spleen

  
  

  Increased plasma volume (pregnancy)

  
• How can the morphology of red blood cells be described?

  Microcytic(small hypochromic RBC)Normocytic(normal size and colour)Macrocytic(larger than normal RBC)

  (common reasons for this are listed below the words in the picture)

  
• What is the most common cause of anaemia worldwide?

  Iron deficiency

  
  

  (Excess iron is potentially toxic so the body tightly controls its absorption)
• What are the 3 main mechanisms by which iron deficiency can develop?

  Poor dietary intake(vegetarians and vegans)

  Malabsorption(duodenum in coeliac disease or jejunum in Crohn’s disease)

  Increased loss(commonly menorrhagia or gastrointestinal– peptic ulceration, inflammatory bowel disease, malignancy or hookworm infestation)
• How does iron deficiency typically manifest?

  Koilonychia(spoon shaped nails)Angular cheilitis(red cracking on mouth corners)Atrophic glossitis(thinning/redness of the tongue)Recurrent oral ulcerationBurning mouthOesophageal web(Plummer-Vinson/Patterson-Brown Kelly Syndrome
• How do you manage iron deficiency in a patient?

  Identify the cause and investigate by doingblood films&iron studies

  Treatment:1.Address underlying cause

  2. Oral supplementation (ferrous sulphate 200mg x3/day for 3 months)

  3. Parenteral available (fever, arthropathy, anaphylaxis)

  4.Blood transfusion (only in severe compromise)
• What are normocytic anaemias?

  The anaemias of chronic disease

  These can be associated with:

  -Chronic inflammatory/connective tissue conditions(rheumatoid arthritis)

  -Chronic infections(tuberculosis)

  -Chronic renal disease(due to reduction in erythropoietin)

  -Malignancies(bone marrow infiltration)
• What can macrocytic anaemia be divided into?

  Megaloblastic erythropoiesis-abnormal red cell development due to disordered DNA synthesis

  Normoblastic erythropoiesis–normal red cell maturation
• What are megaloblastic anaemias associated with?

  Folate deficiency

  folate is essential for DNA synthesis & is derived from many food sources
• What are the possible causes of folate deficiency?

  Inadequate intake(elderly, alcoholism)

  Malabsorption(Coeliac disease, Crohn’s disease, resection)

  Increased requirement(pregnancy, haemolytic anaemias, myelofibrosis)

  Increased loss(dialysis, liver disease, congestive heart failure)

  Drugs(methotrexate, phenytoin, trimethoprim)
• What is vitamin B12 required for and where is it found?

  It's required in a number of enzymatic reactions & its deficiency impacts on DNA synthesis

  
  

  It's found only in foods of animal origin
• What are the possible causes of vitamin B12 deficiency?


  Inadequate intake

  Inadequate secretion of intrinsic factor(pernicious anaemia, gastrectomy)

  Inadequate release from food(gastritis, PPI, EtOH abuse)

  Diversion of dietary B12(bacterial overgrowth, small intestinal strictures)

  Malabsorption(Crohn’s disease, ileal resection)
• What are the clinical features of folate & vitamin B12 deficiency?

  Folate & Vitamin B12-Generic symptoms & signs of anaemia-Occasionally mild jaundice-Glossitis-Oral ulceration

  Vitamin B12-Peripheral neuropathy(loss of proprioception and vibration sense)-Demyelination with subacute combined degeneration of spinal cord-Dementia

  
• How do you treat folate & B12 deficiency?

  Identify cause, and investigate by doing blood films & checking serum folate & B12 (low B12 can lead to low folate- always check together)

  Treat by addressing underlying cause, give oral supplementation (never folate only if B12 level not known); parenteral vitamin B12 (IM) required in pernicious anaemia
• What are some of the causes of normoblastic macrocytosis?

  Alcohol excess

  Liver dysfunction

  Hypothyroidism

  Drugs (methotrexate, azathioprine)
• How are haemolytic anaemias (RBC destroyed faster than made) classified?

  CongenitalMembrane defects:Number of proteins essential to maintain cell membrane integrityAny mutation leads to increased fragility and haemolysisHereditary spherocytosis most common congenitalEnzyme defects:Glucose-6-phosphate dehydrogenase (G6DP) deficiencyInvolved in glucose metabolismDeficiency results in increased sensitivity to oxidative stress

  AcquiredImmune:IgG coated red cells interacting with marcophages resulting in phagocytosisInclude autoimmune processes with antibodies against red cells (including idiopathic or secondary to infections, drugs, SLE, haematological malignancies)Alloimmune results from transfusion and production of antibodies to transfused red cellNon-immune:Include mechanical trauma (metallic valves), burns, infections (malaria) or drugs (dapsone)

  
• What are the clinical features of haemolytic anaemias?

  They vary greatly depending on cause but generally include:

  
  

  -Pallor

  -Jaundice (due to elevated bilirubin)

  -Splenomegaly

  -Expansion of erythropoiesis leading to bone deformities (frontal bossing) and pathological fractures
• What does adult Hb comprise?

  Hb A (97%)

  HbA2 (1.8-3.6%)

  HbF (<1.5%)

  
• What is thalassaemia?


  Common genetic disorder with significant associated morbidity and mortality

  
  

  There are 2 main groups depending on whether it's an alpha or beta chain defect

  
  

  1.a-Thalassaemia (alpha)

  2.B-Thalassaemia (beta)
• What are the potential implications of thalassaemia and how is thalassaemia diagnosed?


  Excess chains precipitate in precursor red cells leading to premature death

  
  

  Precipitated chains also result in oxidative damage to the cell membrane leading to haemolysis

  
  

  Severity depends on degree of globin chain imbalance

  
  

  Diagnosis made on Hb electrophoresis
• Where is alpha-thalassaemia most common?

  SE Asia (Thailand, Indonesia) & W Africa

  Prevalence is 20-30%
• What are the different forms of alpha-thalassaemia?

  
• How many people are affected by beta-thalassaemia and where is it most common?

  ~1.5% of the world population are beta-thalassaemia carriers

  Prevalent in Southern Europe (10-30%), especially Greece
• What are the forms of beta-thalassaemia?

  
• What are the clinical classifications of the different thalassaemias?


  Thalassaemia minima:Presence of mutation without clinical consequenceThalassaemia minor:Microcytosis and hypochromic red cellsThalassaemia intermedia:Microcytic hypochromic anaemiaExtramedullary haematopoiesis with splenomegaly (enlargement of spleen)Thalassaemia major:As above with severe anaemia and transfusion dependent
• What is the clinical presentation of someone with thalassaemia?


  Typically similar to those of anaemia unless it's severe

  If untreated, it can lead to growth retardation, splenomegaly & bony deformities due to marrow expansion

  Oral manifestations:Enlargement of maxilla (chipmunk facies)Migration and spacing of upper anterior teeth
• What is the main concern with a thalassaemia patient requiring transfusions?

  Iron overload- the repeated tranfusions can lead to iron accumulation in myocardium (cardiac failure), liver (cirrhosis), pancreas (DM) & salivary glands
• What is the most common structural variant of Hb and how does it arise?

  HbS

  Due to mutation inbeta-globin genewhich then leads to an interaction of the sickle beta-globin chains with normal alpha-globin chains= HbS

  This results in the deformation of cell into sickle shape
• Where is the prevalence of HbS greatest?

  Prevalence greatest in tropical Africa, Middle East & southern India and areas wherefalciparum malaria is endemic
• In what kind of individuals does sickle cell trait occur?

  Heterozygous individuals (20-40% HbS & remaining HbA)
• Do people with sickle cell trait have any symptoms?

  They're usually asymptomatic but can rarely experience spontaneous haematuria ( blood in urine)
• In what kind of individuals does sickle cell anaemia occur?

  Homozygous individuals (100% HbS)
• What are the clinical manifestations of sickle cell anaemia?

  Chronic haemolytic anaemia (60-90 g/L)

  
  

  Hyposplenism (due to infarcts = increased risk of infection)

  
  

  Splenic sequestration (too many blood cells stuck in spleen)

  
  

  Acute chest syndrome

  
  

  CVA / TIA

  
  

  Bone infarction & subsequent infections

  
  

  Chronic leg ulcers

  
  

  Haematuria (blood in urine) & chronic renal disease