My Clinical Notes

Symptoms and signs

• 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 Anaemia based on MCV

 

Microcytosis (<80fL)

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

Normocytic

• Blood loss
• Haemolytic
• Stem cell defects

Macrocytosis (>80fL)

• 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

 

Index

Comments

 

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-, db-, gdb- 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

• 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 (a₂d₂ 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

 

Sickle cell anaemia

• Main mutation is a point mutation in the sixth position of the β-haemoglobin chain leading to the substitution of a valine for a glutamic acid
• Results in HbS or Sickle cell haemoglobin
• In heterozygotes about 40% of the Hb is HbS
• 8% of black Americans are heterozygotes
• In Africa, where malaria is endemic, 30% of the population is heterozygous

 

Pathogenesis

• When deoxygenated HbS aggregates and polymerises
• Initially the red cell cytoplasm becomes more viscous until needle-like fibres are assembled
• Initially sickling is reversible with oxygenation but with continuous sickling membrane damage occurs making it irreversible
• With membrane damage, calcium accumulates within the cell resulting in potassium and water efflux and intracellular dehydration. The cell membrane also becomes increasingly sticky
• Factors that affect the rate and degree of sickling;
  • The amount of HbS and its interaction with other Hb molecules
    • HbA only weakly aggregates with HbS so heterozygotes only sickle under extreme hypoxia
    • Fetal Hb also inhibits the polymerisation of HbS therefore new borns don’t manifest symptoms until 5-6 months
  • Haemoglobin concentration per cell i.e. the mean corpuscular haemoglobin concentration (MCHC). The higher the concentration the more likely sickling occurrence is
  • A decrease in pH
    • Decreases the oxygen affinity for Hb therefore increasing the fraction of deoxygenated Hb
  • The length of time RBC are exposed to low oxygen tension
    • Increased if microvascular blood flow is sluggish e.g. in inflammation

 

The clinical manifestations are due to;

• Haemolysis – sticky rigid cells get stuck in the spleen and get phagocytosed. Some intravascular haemolysis also occurs as the cells are more fragile
• Microvascular occlusion – the increased stickiness of cells makes them more likely to stop in the microvascular. This is enhanced by inflammation which increased adhesion molecule expression on endothelial cells

 

Morphology

• Bone marrow is hyperplastic and can result in bone reabsorption and secondary bone formation may cause facial deformities
• Extramedullary haematopoiesis may occur
• Splenic enlargement – due to congestion of the red pulp. The erythrostasis of the spleen can cause hypoxia, infarction and thrombosis which can lead to progressive splenic shrinkage
• Infarction due to vascular occlusions can occur in the bones, brain, kidney, liver, retina and pulmonary vessels
• Lug ulcers can occur
• Increased breakdown of Hb can cause pigment gallstones
• Patients develop hyperbilirubinaemia during periods of haemolysis

 

Clinical course

• Problems stem from;
• Severe anaemia
• Vascular occlusion
• Chronic hyperbilirubinaemia
• Increased susceptibility to infection due to sluggish blood flow through the spleen/ adult splenic infarction. There are also defects in the alterative complement pathway impairing opsonisation of capsulated bacteria. There is therefore increased incidence of septicaemia and meningitis
• Vaso-occlusive crises precipitated by hypoxia and infarction cause severe pain. The most common sites are the bones, lungs, liver, spleen and penis
• Sequestration crisis occur in children with intact spleens – sequestration of sickled red cells results in splenic enlargement, hypovolaemia and sometimes shock
• Aplastic crisis – parvovirus B19 causes transient cessation in erythropoesis , this can cause a sudden worsening of anaemia
• Chronic hypoxia can cause generalised impaired growth and development as well as organi damage to the spleen, heart, kidneys and lungs

 

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This entry was posted on Monday, January 21st, 2008 at 5:13 pm and is filed under Haematology. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.