S5) Anaemia, B12 & Folate and Polycythaemia Flashcards
What is anaemia?
- Anaemia is defined as a haemoglobin concentration lower than the normal range
- It is not a diagnosis but a manifestation of an underlying disease state
Why are symptoms mild in anaemia that has developed slowly over a long period of time?
Body has time to adjust to the lower concentration of haemoglobin:
- Increase cardiac stroke volume to increase blood supply to tissues
- Increase [2,3-BPG] in erythrocytes to promote oxygen dissociation
In acute onset anaemia, the symptoms are more severe.
Identify some symptoms
- Fatigue
- Dyspnoea
- Palpitations
- Headache
- Angina & intermittent claudication (older patients)
Identify some clinical signs of anaemia
- Pallor
- Tachycardia
- Systolic murmur
Why might anaemia develop?
Anaemias can develop due to abnormalities in the production, function or removal of RBCs or because of excessive blood loss
Explain how abnormalities in the production, function or removal of red blood cells can lead to anaemia
Abnormal erythropoiesis is a deficiency in red cell production.
Identify some possible causes of this
- Exposure of the bone marrow to certain chemicals e.g. chemotherapy, ionising radiation
- Infection with parvovirus
- Autoimmunity
- Chronic kidney disease (insufficient production of EPO)
What is aplastic anaemia?
Aplastic anaemia refers to an inability of haematopoietic stem cells to generate mature blood cells
What is iron deficiency anaemia?
Iron deficiency anaemia is the type of anaemia which develops if the supply of iron is inadequate for the requirements of haemoglobin synthesis
Identify and describe five causes of iron deficiency anaemia
- Increased blood loss from bleeding (uterine, GI, renal tract, nose, lungs)
- Increased requirements (growth spurts, pregnancy, lactation)
- Inadequate dietary supply (financial constraints, anorexia, poor dentition)
- Decreased absorption (gastrectomy, coeliac disease)
- Anaemia of chronic disease (functional lack of iron)
What is anaemia of chronic disease?
Anaemia of chronic disease is a condition characterised by a functional lack of iron and is commonly associated with chronic inflammatory conditions, chronic infections and malignancy
Explain why chronic, inflammatory and malignant conditions lead to anaemia of chronic disease
- Increased activity of macrophages in underlying conditions reduces lifespan of RBCs and blunts signalling through the EPO receptor
- Chronic release of cytokines, e.g. IL-6, increases hepcidin production by the liver resulting in less iron absorption
Mutations in the genes that encode the globin proteins can also lead to anaemia.
Identify two examples
- Thalassaemia
- Sickle cell anaemia
In 6 steps, explain why thalassaemia leads to anaemia
⇒ Decreased/absent α or β globin chain production
⇒ Imbalance in the composition of the α2β2 tetramer
⇒ Precipitation of chain remaining in excess
⇒ Premature cell death prior to release from bone marrow
⇒ Released cells susceptible to oxidative damage due to precipitated globin chains
⇒ Haemolysis occurs
In 5 steps, explain why sickle cell disease leads to anaemia
⇒ Mutation of glutamate → valine in the β globin gene
⇒ Sticky hydrophobic pocket forms in β globin protein
⇒ Deoxygenated haemoglobin polymerises
⇒ RBCs sickle under low O2 tension and damage cell membrane
⇒ Cells are unable to deform & are removed by spleen
What are the building blocks for DNA synthesis?
- Vitamin B12 (cobalamin)
- Folate (vitamin B9)
What is megaloblastic anaemia?
Megaloblastic anaemia is a form of anaemia arising due to deficiencies in Vitamin B12 and folate as RBC precursor cells are unable to synthesise DNA and therefore divide
What is observed in the blood film of a patient with megaloblastic anaemia?
- Large, partially replicated red cell precursors are released into the bloodstream with inappropriately large nuclei and open chromatin
- This is due to the fact that nuclear maturation and cell division lag behind cytoplasm development
Where can folate be found?
Folate is synthesised in bacteria and plants and is present in a variety of animal and vegetable food sources
Where can vitamin B12 be found?
Vitamin B12 can only be obtained from food of animal origin so it is essential that people on a vegan diet eat foods fortified with vitamin B12 or take a B12 supplement daily/weakly
What is pernicious anaemia?
- Pernicious anaemia is a deficiency in intrinsic factor which results in anaemia from a lack of B12 absorption
- The B12-intrinsic factor complex needs to form to be internalised by receptors in the ileum
How can one treat pernicious anaemia?
- Intramuscular injection of a B12 supplement
- Nasal spray with a B12 supplement
What is haemolytic anaemia?
Haemolytic anemia is a form of anaemia due to hemolysis either in the blood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular, spleen)
How does one treat anaemia due to haematinic deficiency?
- Always replacement therapy
- Only use red cell transfusion if there is cardiac compromise
What is Glucose-6-phosphate dehydrogenase deficiency?
- G6PDH deficiency is an X-linked recessive inborn error of metabolism wherein the G6PDH enzyme in the pentose phosphate pathway is deficient
- It presents with RBC defects as NADPH cannot be produced by the pentose phosphate in the erythrocytes to reduce glutathione and protect against oxidative damage
Illustrate the mechanism by which G6PDH deficiency can lead to haemolytic anaemia
What is pyruvate kinase deficiency?
Pyruvate kinase deficiency is an inherited disorder due to the lack of the enzyme pyruvate kinase, which is used by red blood cells to form ATP in the final step of glycolysis
In 6 steps, explain why a pyruvate kinase deficiency will lead to haemolytic anaemia
⇒ No pyruvate kinase to perform glycolysis
⇒ No ATP for cellular processes
⇒ NA K ATPase pump stops
⇒ RBCs lose potassium to plasma
⇒ H2O moves out of cells causing them to shrink
⇒ Cellular death → haemolytic anaemia
What are myeloproliferative neoplasms?
- Myeloproliferative neoplasms are a group of diseases of the bone marrow in which excess cells are produced
- They arise from genetic mutations in the precursors of the myeloid lineage, specifically the gene coding for JAK2
What is essential thrombocythaemia?
Essential thrombocythaemia is a condition characterised by the overproduction of platelets by megakaryocytes
What is myelofibrosis?
Myelofibrosis is characterised by replacement of the hematopoietic tissue by connective tissue leading to impairment of the generation of all blood cells (pancytopenia)
What is polycythaemia?
Polycythaemia is a disease state in which the volume percent of erythrocytes in the blood (the haematocrit) exceeds 55%
What are the two forms of polycythaemia?
- Absolute polycythaemia: increase in the number erythrocytes
- Relative polycythaemia: decrease in the plasma volume
What is polycythaemia vera?
- Polycythaemia vera is a specific form of polycythaemia which arises from a myeloproliferative neoplasm in the bone marrow resulting in overproduction of erythrocytes
- In most cases, it is driven by oncogenic mutations that constitutively activate the JAK-STAT signalling pathway
The clinical features associated with polycythemia vera essentially result from the blood being thicker.
Identify 5 of these features
- Thrombosis (venous & arterial)
- Haemorrhage (skin or GI tract)
- Burning pain in the hands or feet
- Pruritis
- Splenomegaly
Identify two complications of polycythaemia vera
- Myelofibrosis
- Acute leukaemia
How can polycythaemia vera be treated?
- Phlebotomy – maintain the haematocrit below 45%
- Aspirin – anti-platelet effects
- Hydroxyurea – cytoreduction, use if poor tolerance of venesection, symptomatic/progressive splenomegaly
What is measured by a direct Coombs test?
- The direct Coombs test is used when immune-mediated haemolytic anemia is suspected
- The test determines if antibodies/complement system factors have bound to RBCs surface antigens in vivo
What is a schistocyte?
A schistocyte is a fragmented part of a red blood cell, often seen in patients with haemolytic anemia
What is microcytic anaemia?
- Microcytic anemia is a form of anaemia wherein there is a presence of small, hypochromic red blood cells in a peripheral blood smear
- It is usually characterised by a low MCV
Identify the causes for microcytic anaemia
- Thalassaemia
- Anaemia of chronic disease
- Iron deficiency anaemia
- Lead poisoning
- Sideroblastic anaemia
What is normocytic anaemia?
Normocytic anemia is a form of anaemia with a normal MCV but a decreased haematocrit and haemoglobin
Identify the causes of normocytic anaemia
- Acute blood loss
- Bone marrow failure
- Anaemia of Chronic Disease
- Destruction (haemolysis)
What is macrocytic anaemia?
- Macrocytic anaemia is a form of anaemia in which the red blood cells are larger than their normal volume
- It is usually characterised by a high MCV
Identify the causes of macrocytic anaemia
- Foetus (pregnancy)
- Alcohol
- Thyroid (hypothyroidism)
- Reticulocytosis
- B12/folate deficiency
- Cirrhosis
