Anaemia, Vitamin B12, Polycthaemia

Question 1

Define anaemia

Answer 1

Inability for the body to deliver enough oxygen to tissues due to not enough red blood cells or not enough haemoglobin

Question 2

Are anaemia symptoms more serious in acute onset of long term

Answer 2

Long term anaemia less severe than acute onset anaemia, as body adjusts to low haemoglobin by increasing cardiac stroke volume to increase blood supply to tissues and increasing concentration of BPG to promote oxygen dissociation

Question 3

What are the symptoms and clinical features of anaemia

Answer 3

• Symptoms - fatigue, dyspnoea, palpitations, headache
  
  • Older patients - angina, intermittent claudication
• Clinical signs - pallor, tachycardia, systolic murmur

Question 4

Explain how reduced erythropoiesis leads to anaemia

Answer 4

• Reduced erythropoiesis - exposure of bone marrow to chemicals, ionising radiation, infection, parvovirus, autoimmunity
  
  • Pancytopenia - reduced production of red blood cells, white blood cells and platelets
  • Chronic kidney disease - cannot make enough erythropoietin to stimulate erythropoiesis
  • Marrow infiltrated by cancer cells or fibrous tissue - normal haemopoietic cells are reduced
  • Aplastic anaemia - inability of haematopoietic stem cells to generate mature red blood cells

Question 5

Define pancytopenia

Answer 5

Reduced production of red blood cells, white blood cells and platelets

Question 6

Define aplastic anaemia

Answer 6

Inability of haematopoietic stem cells to generate mature red blood cells

Question 7

What is dyserythropoiesis and give an example

Answer 7

• Producing non-functional erythrocytes

- Myelodysplastic syndromes (MDS) - production of abnormal clones of marrow stem cells

Question 8

What are the consequences of anaemia of chronic disease (ACD)

Answer 8

• Seen in inflammatory conditions such as Rheumatoid arthritis, chronic infections, malignancy
• Increased activity of macrophages reduce lifespan of erythrocytes
• Increase production of hepcidin - less iron absorption
• Lack of functional iron - restricted to within macrophages
• Often has increased CRP and ferritin

Question 9

What are the consequences of myelodysplasic syndromes (MSD)

Answer 9

• Production of abnormal clones of marrow stem cells
  
  • Since defective, they are targeted for destruction - leads to progressive anaemia
  • Treated by chronic transfusions of red cells

Question 10

How do haemoglobin synthesis abnormalities come about

Answer 10

• Iron deficiency anaemia
• Deficiency in building blocks for DNA synthesis - vitamin B12, folate
• Mutations in the genes that encode the globin proteins - thalassaemia, sickle cell disease

Question 11

What are the causes of iron deficient anaemia

Answer 11

• Once iron stores are used in tissues, iron deficiency anaemia will develop
• Caused by increased blood loss from bleeding
  
  • Increased requirements (pregnancy, growth)
  • Inadequate dietary supply
  • Decreased absorption
  • Lack of functional iron (anaemia of chronic disease)

Question 12

What are the effects of thalassaemia

Answer 12

• Reduced rate of synthesis of normal α,ß- globin chains
• Excess alpha globin form insoluble aggregates and become destroyed in the spleen
• Body tries to make blood in other areas - impairs growth and causes skeletal abnormalities
  
  • Premature cell death in bone marrow
• Blood cells released into circulation susceptible to oxidative damage of red cell membrane due to precipitated glbin chains leading to haemolysis
• Iron overload - iron not taken up by red blood cells
  - Transfusions increase iron concentration

Question 13

Differentiate between alpha and beta thalassaemia

Answer 13

• ß-thalassemia - decreased or absent ß-globin chain production
  
  • α-chains unable to form stable tetramers
  • Has only 1 gene per ß-chain
  • Symptoms appear after birth
• α-thalassemia - decreased or absent α-globin chain production
  
  • Several different levels of severity due to the multiple copies of α-chains present
  • Has 2 genes per alpha chain
  • 3 affected chains = severe, 4 = fatal
  • ß-chains can form stable tetramers with increased affinity for oxygen
  • Onset before birth

Question 14

What are the effects of sickle cell anaemia

Answer 14

• Abnormal synthesis of haemoglobin
  
  • Point mutation causes substitution of glutamate to valine on position 6 of ß-chain
  • Forms ‘sticky’ hydrophobic pocket in the ß-globin protein which allows deoxygenated haemoglobin to polymerise
  • Cause red cell membrane to lose elasticity
    
    • Lead to vessel occlusion and ischaemia

Question 15

What are the effects of deficiency in Vitamin B12 and folate

Answer 15

• Leads to megaloblastic anaemia - red cells cannot synthesise DNA and divide
• Macrocytic cells (insufficient haemoglobin) and hypersegmented neutrophils
• Cells released into bloodstream with inappropriately large nuclei and open chromatin
• Vitamin B12 used in synthesis of amino acid
• Folate used in synthesis of DNA bases

Question 16

Explain the importance of folate and how it may become deficient

Answer 16

• Present in most foods, yeast, liver, leafy greens
• Absorption in duodenum and jejunum
  
  • Converted to tetrahydrofolate (FH4) and enter portal circulation
  • Taken to liver and stored
  • Involved as a one-carbon carrier - oxidise reactions involved in DNA synthesis
• Dietary folates converted to methylTHF, which circulates the body and needed for synthesis of DNA bases
• Deficiency due to dietary deficiency, increased demands (pregnancy, lactation), proximal small bowel disease (can’t absorb), alcoholism

Question 17

Explain Vitamin B12 metabolism in the body

Answer 17

• Synthesised by microorganisms - obtained from eating foods of animal origin
• Free B12 and B12 released fro proteins by proteases for haptocorrins complex
• Digested by pancreatic proteases in small intestine, releasing B12 which binds to intrinsic factor produced by parietal cells in stomach
  
  • Allows B12-intrinsic factor complex to becomes internalised in ileum
• In the portal blood, B12 is bound to transcobalamin which delivers B12 to the bone marrow and other tissues
  
  • Involved in synthesis of amino acids
• Can be stored for a long time - years until become B12 deficient

Question 18

What is pernicious anaemia

Answer 18

Deficiency in intrinsic factor causes lack of B12 absorption

Question 19

What are the causes and effect of Vitamin B12 deficiency

Answer 19

• Deficiency causes neurological disease
  
  • Focal demyelination affecting the spinal cord, peripheral nerves, optic nerves
  • Dementia and depression may also develop
• Deficiency can be caused by Vitamin B12 dietary deficiency, factors affecting IF, IF-B12 complex and transcobalamin

Question 20

What are the shapes of abnormal red blood cells

Answer 20

• Spherocytes - sphere rather than bi-concave shape
• Elliptocytes - appear oval or elongated
• Acanthocyte - spiked cell membrane
• Target cells - look like bullseye target

Question 21

What are the effects of G6P deficiency

Answer 21

• Glucose-6-phosphate dehydrogenase deficiency
  
  • G6P rate limiting enzyme for pentose phosphate pathway
  • Pentose phosphate pathway supplies reducing energy by maintaining NADPH levels
    
    • NADPH required in maintaining glutathione level
  • Less protection against oxidative stress leading to haemolytic anaemia
  • Damaged red cells are phagocytose in spleen and metabolism of excessive haemoglobin can lead to jaundice

Question 22

What are the effects of pyruvate kinase deficiency

Answer 22

• Catalyses final step in glycolysis
• Pyruvate kinase deficiency blocks all production of ATP in RBC as no mitochondria
• Na/K ATPase stops working, causing Na to leave cell and shrink, leading to haemolytic anaemia

Question 23

How do defects in reticuloendothelial system lead to anaemia

Answer 23

• Spleen removes damaged and defective red cells
  
  • Many anaemia causes changes to membrane, enzyme and haemoglobin - recognized as defective
  • Haemolytic anaemia = increased red cell destruction
• Autoimmune haemolytic anaemia
  
  • Autoantibodies bind to the red cell membrane proteins
  • Clinical features - increased reticulocytes (bone marrow tries to compensate), raised bilirubin (breakdown of Haem)

Question 24

What are the main sites which can cause anaemia

Answer 24

• Bone marrow
  
  • Reduced erythropoiesis - pancytopenia, chronic kidney disease, aplastic anaemia
  • Haemoglobin synthesis defects - iron deficiency anaemia, deficiency in DNA synthesis (B12, folate), mutations (thalassaemia, sickle cell)
• Red cell metabolism - G6P, and pyruvate kinase deficiency
• Loss of red cells - injury
• Reticuloendothelial system defect

Question 25

What is myeloproliferative neoplasm

Answer 25

• Replacement of haematopoietic tissue by connective tissue leading to impairment of generation of all blood cells (pancytopenia)
  
  • Overproduction of one or several blood elements

Question 26

What is polycythaemia and its causes

Answer 26

• Volume percent of erythrocytes in blood (haematocrit) exceeds 55%
  
  • Due to increase in number of erythrocytes (absolute polychthaemia) or decrease in plasma volume (relative polychythaemia)
  • Can also be due to diuretics, smoking, causing chronic hypoxia

Question 27

What is polycythaemia vera and its cause

Answer 27

• Overproduction of red blood cells
  
  • High haematocrit (proportion of blood made up of cells)
  • Leads to higher concentration of erythrocytes compared to plasma, sticky blood, thrombosis
  • Due to myeloproliferative neoplasm in bone marrow resulting in overproduction of erythrocytes
    
    • Oncogenic mutations

Question 28

What are the clinical features and treatment of polycythaemia vera

Answer 28

• Clinical features - thrombosis, haemorrhage, burning pain in hands or feet, pruritus (itching), splenomegaly, gout, arthritis
• Treatment - phlebotomy (draw blood) to maintain haematocrit below 45%
  
  • Aspirin, cytoreduction of tumour

Question 29

How do you test for anaemia

Answer 29

• Red blood cell count
• Haemoglobin - amount of oxygen carried by haemoglobin in blood
• Mean corpuscular volume (MCV) - measure average volume of circulating red blood cells
• Mean cell haemoglobin (MCH) - measure of average haemoglobin content in RBC
• Platelets
• Reticulocyte count

Question 30

How do you analyse mean corpuscular volume (MCV)

Answer 30

• Measure average volume of circulating red blood cells
  
  • Low MCV = microcytic anaemia
    
    • Causes: iron deficiency, thalassemia
  • Normal MCV = normocytic anaemia
    
    • Causes: anaemia of chronic disease, haemolytic anaemia
  • High MCV = macrocytic anaemia
    
    • Causes: B12/folate deficiency

Question 31

How do you analyse mean cell haemoglobin (MCH)

Answer 31

• Measure of average haemoglobin content in RBC
  
  • Low MCH = hypochromia - red blood cells are paler
  • High MCH = hyperchromia - red blood cells are darker

Question 32

How do you analyse reticulocyte count

Answer 32

• High reticulocyte count - bone marrow functioning normally and all nutrients needed for RBC production are present
  
  • Bone marrow trying to replace deficient RBC
• Reticulocyte haemoglobin test - CHR
• Normal/low reticulocyte count - no response to low haemoglobin due to either a haematinic deficiency (iron/Vit B12/folate) or a primary bone marrow failure