PBL 7 - anaemia: types and causes Flashcards
what does blood distribute?
- oxygen and nutrients (removes waste products)
- hormones delivered to target organs
- blood cells and platelets
what does blood regulate?
- body temp
- pH
- solutes
- restricts osmosis into tissues
what does blood protect against?
- blood/fluid loss via haemostasis (coagulation)
- infection via contribution to inflammatory and immune responses
if the cellular components of blood are removed, what remains?
plasma
what is the buffy coat?
everything but the RBCs which will centrifuge out at this layer — WBCs + platelets
what is roughly the circulating volume of blood?
4-5l
where are the remnants of RBCs broken down?
liver and spleen
describe production of EPO
produced by kidney in response to low O2 levels
how can acute kidney disease affect EPO production?
often have anaemia with acute kidney disease — reduced production of EPO
how does testosterone affect EPO production?
enhances production
how many haem groups are there per Hb molecule?
4
how many iron atoms are there in 1 molecule of Hb?
4
each Hb can bind how many molecules of O2?
4
Hb holds iron in what form?
ferrous form = Fe++
what does proliferation of RBC precursors require?
- DNA synthesis (ie. precursors have a nucleus)
- protein synthesis (synthesis of some amino acids)
what 2 B-complex vitamins play a critical role in RBCs?
- folate (50-100ug/day) = vitamin B9 — required for synthesis of purines and pyrimidines
- vitamin B12 (approx 3ug/day) — required for synthesis of some amino acids
what is anaemia?
= reduction in Hb conc
- men < 13.5 g/dl
- women < 11.5 g/dl
what are some symptoms of anaemia?
- breathlessness
- fatigue
- palpitations
- related to cause
what are some signs of anaemia?
- pallor (pale) — not always
- related to cause — eg. jaundice if liver disease, cachexic if malnourished/cancer, sallow complexion if renal disease due to increased urea
what are the 2 different classifications of anaemia?
based on cause:
- failure of production
- defective red cells
- loss/destruction of red cells
based on red cell size:
- macrocytic
- normocytic
- microcytic
impaired vs. excessive erythrocyte production/destruction
- impaired erythrocyte production
- caused by deficiencies (diet)
- not caused by deficiencies - excessive erythrocyte destruction
- extracorpuscular defects, usually acquired eg.
autoimmune disease
- intracorpuscular defects, usually inherited
what is looked at in a FBC for anaemia?
- normal ranges change with age, sex
- look at MCV (mean cell volume)
- look at other aspects of the FBC; WCC and differential and platelets
- blood film comments
- compare with previous results, if available
what are the 2 different types of blood loss that can lead to anaemia?
- acute = dilution to maintain circulatory volume
- chronic = slow and ongoing but profound — peptic ulcers, menorrhagia, piles, worms etc.
what deficiencies can cause impaired erythrocyte production?
- iron
- vitamin B12
- folate
- protein — malnutrition, liver disease, malabsorption, carcinoma
- vitamin C (vital for protein synthesis)
what is the most common cause of anaemia?
iron deficiency anaemia
what can cause iron deficiency anaemia? (5)
- increased physiological demands eg. pregnancy, metastatic cancer
- chronic blood loss (70% of body iron is in red cells)
- inadequate intake
- dietary
- malabsorption
what are some causes of impaired erythrocyte production NOT caused by deficiencies? (8)
- general disorders of metabolism eg. endocrine disorders
- chronic inflammation eg. rheumatoid arthritis
- chronic renal disease
- reduced EPO
- increased blood urea
- liver failure
- marrow replacement
- cancers, such as leukaemia
what are some causes of excessive erythrocyte destruction with intracorpuscular defects?
- abnormal haemoglobins: abnormal chains eg. sickle cell anaemia OR normal chains but genes for a or b not expressed eg. thalassaemias
- erythrocyte membrane defects eg. spherocytosis, elliptocytosis
- enzyme defects eg. glucose-6-phosphate dehydrogenase deficiency
what are some causes of excessive erythrocyte destruction with extracorpuscular defects?
- immune: haemolytic disease of the newborn, incompatible blood transfusion, drug-induced eg. methyldopa
- idiopathic
- non-immune — normally dye to really severe trauma (mechanical such as cytokine storm and inflammatory reaction (autoimmune destruction of RBCs) or burns)
what should be included in clinical history of patient when trying to diagnose anaemia?
- age/sex of patients
- past or family history of anaemia
- GI symptoms
- diet
- bleeding history
- co-morbid conditions (eg. liver/renal disease)
- drug history (alcohol)
- transfusion history
- other symtpoms eg. neurological, bone pains
what does a microcytic appearance of RBCs indicate?
- Fe deficiency
- thalassaemia
- anaemia of chronic disease
what does a macrocytic appearance of RBCs indicate?
- alcohol
- liver disease
- B12/folate deficiency
- pernicious anaemia (autoimmune disease which causes reduced B12 absorption)
- megaloblastic anaemia (due to B12/folate def, drugs)
what does appearance of elliptocytes indicate?
Fe def
what does appearance of spherocytosis indicate?
immune haemolysis
what does appearance of nucleated red cells indicate?
severe anaemia, marrow infiltration
what does appearance of tear drop cells indicate?
myelofibrosis (a bone marrow cancer)
what is a reticulocyte?
a RBC where nucleus/part of nucleus is still present
what is presence of reticulocytes a sign of?
very high proliferation of precursors to overcome severe anaemia
presence of what is an indication of liver disease?
bilirubin
what are some typical causes of microcytic anaemia?
- Fe deficiency
- thalassaemia
- anaemia of chronic inflammation
> childhood
- iron deficiency anaemia is by far the most common cause of anaemia in general and of microcytic anaemia in particular
- thalassemia
> adulthood
- blood loss
- iron deficiency anaemia
- sideroblastic anaemia, congenital or acquired (myelodysplasia) (bone marrow if filled with abnormal, non-functioning cells)
- anaemia of chronic disease although this more typical causes normocytic anaemia
what is sideroblastic anaemia??
when the body produces enough iron but is unable to put it into the HB
what is myelodysplasa considered to be?
pre-leukaemia
what does iron deficiency cause a drop in?
drop in MCV in proportion to the degree of anaemia
what are haemoglobinopathies?
- inherited disorders of Hb structure and/or function
- thalassaemias
- sickle cell disorders
- unstable haemoglobins
- abnormal O2 affinity Hbs
what is thalassaemia?
= a group of inherited disorders resulting in reduced production of one or more globin chains
- results in an imbalance of globin chains with the excess chain producing the pathological effects
what are the pathological effects of thalassaemia?
- damage to red cell precursors — ineffective erythropoiesis
- damage to mature red cells — haemolytic anaemia (RBCs are destroyed faster than they can be made)
what type of anaemia is thalassaemia?
microcytic
what are the 2 main types of thalassaemia? how many genes are they controlled by?
- alpha thalassaemia — alpha chains — controlled by 4 genes (2 from each parent)
- beta thalassaemia — beta chains — controlled by2 genes (1 from each parent)
alpha/beta chain imbalance leads to haemolysis and anaemia
what are the different clinical classifications of thalassaemia?
> thalassaemia major
- transfusion dependent
> thalassaemia intermedia
- less severe anaemia and can survive without regular
blood transfusion
> thalassaemia minor or carrier
- asymptomatic carrierwhat are the clinical features of thalassaemia due to anaemia?
- failure to grow and develop
- gross enlargement of liver and spleen
- skull deformities
- death in childhood/teens (if untreated)
what are the clinical features of thalassaemia due to iron overload?
- failure to grow and mature
- organ damage due to iron deposition — cardiac, liver, endocrine
- death in early adulthood due to cardiac/liver disease
what is sickle cell disease?
= genetic variation of B globin chain of Hb molecule (HbS)
- homozygosity (2 identical genes) or compound heterozygosity (2 different B chain variants) produces clinical disease eg.
- Hb SS
- Hb SC
- HB S/bthal
- Hb SD - Hb molecule becomes unstable in low oxygen conditions leading to formation of insoluble rigid chains — hard, brittle, break easily
- produces vaso-occlusion (“sickling”) and destruction of the red cell (haemolysis)
- drop in oxygen can cause sickle cell crisis eg. covid, cold, high altitude
- vaso-occlusion causes microinfarcts all over the body in organs such as liver, kidney eyes, and also bones - bone necrosis causing bone pain (only relived by morphine)
what are some clinical problems of sickle cell disease?
- anaemia
- infections
- painful crises
- stroke
- leg ulcers
- visual loss
- chronic organ damage — kidneys, lungs, joints, heart
what questions would be asked to diagnose macrocytic anaemia?
- is it due to alcohol?
- is it due to diet/haematinic deficiency?
- is it due to drugs?
- is it due to hypothyroidism?
- is it due to marrow failure (aplastic anaemia or infiltration by cancer or haematological malignancy)?
what are causes of vitamin B12 deficiency anaemia?
> malabsorption - coeliac disease, cystic fibrosis, inflammatory bowel disease
gastric disease with loss of intrinsic factor (vital for B12 absorption)
pernicious anaemia (destruction of intrinsic factor)
gastrectomy (no stomach so no intrinsic factor)
small intestinal disease with failure to absorb (terminal ileum is where B12 is absorbed)
increased demands
growth
pregnancy
inadequate diet (no eggs, meat etc)
small intestinal infection or infestation
binding by drugs preventing absorption eg. neomycin, colchicine
describe intrinsic factor
- aka castle factor
- required for B12 absorption
- produced by parietal cells of the stomach
what are some causes of folic acid deficiency anaemia?
> malabsoprtion - small intestinal disease
increased demands
pregnancy
haemolytic anaemia (required for DNA synthesis - massive increase in requirement for RBC production, can’t keep up with synthesis of DNA)
leukaemia (hyperanabolic state)
hyperthyroidism
inadequate diet (no green vegetables)
anti folate drugs eg. trimethoprim, methotrexate
anticonvulsants
summarise the approach to the investigation of anaemia
what is the MCV in Fe def anaemia?
< 90 Fl
what does B12 bind to in order to be absorbed?
intrinsic factor
what kind of anaemia is it where there is an autoimmune reaction against intrinsic factor?
pernicious
what is B12 needed for?
for DNA to mature and condense — not enough Hb made
what type of anaemia is B12 def?
macrocytic
what is the MCV in macrocytic anaemia?
> 90 Fl
what is there a mutation in in spherocytotic anaemia?
ankyrin and spectrin
what is a symptom of hereditary spherocytosis?
splenomegaly — spherical RBCs get caught in capillaries and undergo haemolysis
what is a G6PDH deficiency? what type of does it cause? what test can be done?
glucose 6-phosphate dehydrogenase deficiency — reactive oxygen species damage the Hb — haemolytic anaemia (RBCs can’t squeeze through capillaries, causing haemolysis, due to reduced flexibility of RBC membrane due to Heinz bodies — see Heinz bodies in blood test
what test can be done for hereditary spherocytosis?
Coombs test
what type of mutation causes HbS?
missense mutation (Glu —> Val)
what is the sickle shape of RBCs in sickle cell disease due to?
due to the polymerisation of Hb molecules because of the missense mutation
when does Hb polymerise in sickle cell disease?
lack of O2
what can the sickling of Hb cause?
vaso-occlusive crisis
what is the benefit of having HbS?
resistance to malaria
what are destroyed in aplastic anaemia?
destruction of bone marrow —> destruction of myeloid stem cell, resulting in low RBCs, WBCs and platelets — pancytopenia
who is thalassemia more common in?
Mediterranean ancestry
what is the MCV in thalassaemia?
<90Fl — microcytic
what is the ideal treatment for thalassaemia?
bone stem cell transplant
what type of anaemia is thalassaemia?
microcytic, haemolytic
