5.18 - Anaemia and transfusion Flashcards
What are the four underlying mechanisms of anaemia?
- reduced production of red cells/haemoglobin by the bone marrow
- reduced survival of red cells in circulation (haemolysis)
- loss of blood from the body
- pooling of red cells in a very large spleen
What are spherocytes?
Very round cells without the usual central pallor (which reflects the disc shape of a normal RBC)
What is hereditary spherocytosis?
- due to an inherited defect in red cell membrane
- disruption of vertical linkages in membrane, usually ankyrin/spectrin
- defect in membrane can lead to haemolysis
What is the difference between haemolysis and haemolytic anaemia?
- haemolysis - increased destruction of red blood cells (reduced RBC survival)
- haemolytic anaemias - group of anaemias due to reduced red cell lifespan (haemolysis that leads to a reduction in Hb)
- haemolytic anaemia is the result of haemolysis
What term describes a patient with anaemia due to haemolysis?
Haemolytic anaemia
How is haemolytic anaemia treated? (2)
- folic acid (because of the increased requirement for erythropoiesis to replace lost RBCs)
- splenectomy (if severe) to increase red cell life span
What is the bone marrow response to haemolysis?
Reticulocytosis - increases production of young red cells - reticulocytes (seen as larger and bluer polychromatic macrocytes due to increased RNA content)
How do we interpret an increase in unconjugated bilirubin?
Haemolytic jaundice - RBC breakdown causes increased unconjugated BR in bloodstream
What is formed as a result of increased breakdown of haemoglobin to bilirubin?
Gallstones
What is it called when a gallstone obstructs the common bile duct?
Obstructive jaundice - liver still able to conjugate bilirubin but not passing from bile ducts and gall bladder into the duodenum (high conjugated bilirubin)
What finding is common in haemolytic anaemia?
Pigment gallstones
What are the differences between unconjugated vs conjugated bilirubin? (5)
- insoluble in blood vs water soluble
- largely attached to albumin in blood vs small amounts are loosely bound to albumin in blood
- accumulates in pre-hepatic jaundice vs accumulates in post-hepatic jaundice
- toxic to tissues and organs e.g. brain vs relatively non-toxic
- cannot be excreted in urine vs can be excreted in urine (dark urine)
What is DAT?
Direct antiglobulin test (i) - detects antibodies bound to antigen on RBC membrane in a patient who has developed an autoantibody
What is autoimmune haemolytic anaemia (AIHA)?
- DAT positive
- can be idiopathic
- or, associated with disorders of immune system:
- systemic autoimmune disease (SLE)
- underlying lymphoid cancers (lymphoma)
Host immune response against RBC antigens
What are the blood count abnormalities in autoimmune haemolytic anaemia? (7)
- low Hb
- high MCV
- high reticulocytes
- high unconjugated bilirubin
- high LDH
- +++ DAT
- spherocytes on blood film
High MCV is due to reticulocytosis
What is laboratory evidence of haemolysis? (3 + 1)
- LDH raised
- unconjugated hyperbilirubinaemia (anaemia with raised bilirubin)
- reduced haptoglobins
- (raised reticulocytes)
Are acquired anaemias due to a defect in the RBC or a problem/defect in the RBC environment?
RBC environment defect - plasma/vasculature
What are non-immune environmental factors that can damage RBCs? (5)
- microangiopathic
- haemolytic uraemic syndrome
- malaria
- snake venom
- drugs
What are immune mediated (DAT +ve) environmental factors that can damage RBCs? (2)
- autoimmune
- alloimmune (post blood transfusion)
What two blood disorders are spherocytes present in?
- hereditary spherocytosis
- acquired autoimmune haemolytic anaemia
- (distinguished by DAT test)
When do we consider haemolysis?
- anaemia with raised bilirubin
- elevated reticulocytes/LDH/unconjugated BR
- blood film
- clinical history and examination may point to acquired or inherited (e.g. sickle cell)
In acquired haemolysis, what does DAT positive confirm?
- confirms immune mechanism
- systemic autoimmune disease
- underlying lymphoid cancer (lymphoma)
- idiopathic
e.g. autoimmune haemolytic anaemia
What are examples of acquired red cell defects? (3)
- damage to red cell membrane e.g. AIHA or snake bite
- damage to whole red cell e.g. MAHA (microangiopathic haemolytic anaemia)
- oxidant exposure, damage to red cell membrane and Hb e.g. dapsone or primaquine
What are examples of inherited red cell defects? (4)
- abnormal RBC membrane e.g. hereditary spherocytosis
- abnormal Hb e.g. sickle cell anaemia
- defects in glycolytic pathway e.g. pyruvate kinase deficiency
- defect in enzymes of pentose shunt e.g. G6PD deficiency
What does the glycolytic pathway do?
Provides energy for the cell
What does the pentose shunt do?
Protects the cell from oxidant damage - G6PD is a key enzyme (deficiency is very common)
What are the similarities and differences between irregularly contracted cells and spherocytes?
- both have lost their central pallor
- but they differ as irregularly contracted cells are more irregularly shaped
What is visible in a blood film of G6PD deficiency? (4)
- ghost cells
- hemighost cells
- Heinz bodies
- irregularly contracted cells
What features on a blood film shows oxidant damage? (2)
- irregularly contracted cells
- Heinz bodies
What are Heinz bodies?
Precipitated oxidised haemoglobin
What do ‘ghost cells’ show us?
‘Ghost cells’ show that there has been intravascular haemolysis
What should a patient with G6PD deficiency be advised to do? (4)
- avoid oxidant drugs
- avoid eating broad beans (fava beans)
- avoid naphthalene
- be aware that haemolysis can result from infection
How can G6PD deficiency cause haemolysis?
- G6PD is an important enzyme in the hexose monophosphate shunt, which is tightly coupled to glutathione metabolism, which protects red cells from oxidant damage
- oxidants may be generated in the bloodstream, e.g. during infection, or may be exogeneous e.g. drugs, broad beans
- a deficiency in G6PD causes red cells to be vulnerable to oxidant damage, resulting in haemolysis
What is haemolytic anaemia?
Anaemia resulting from shortened survival of red cells in the circulation
What two types of abnormalities can haemolysis result from?
- haemolysis can result from an intrinsic abnormality of the red cells
- haemolysis can result from extrinsic factors acting on normal red cells
How can haemolytic anaemia be classified? (4)
- inherited
- acquired
- intravascular
- extravascular
What is the difference between inherited and acquired haemolytic anaemia?
- inherited haemolytic anaemia can result from abnormalities in the cell membrane, the haemoglobin or the enzymes in the red cell
- acquired haemolytic anaemia usually results from extrinsic factors such as microorganisms, chemicals or drugs that damage the red cell
- extrinsic factors can interact with red cells that have an intrinsic abnormality
What is the difference between intravascular and extravascular haemolytic anaemia?
- intravascular haemolysis occurs if there is very acute damage to the cell
- extravascular haemolysis occurs when defective red cells are removed by the spleen
- often haemolysis is partly intravascular and partly extravascular
What can oxidant exposure to red cells cause?
Oxidant exposure (acquired cause) –> precipitation of episodic haemolysis in individuals with enzyme G6PD deficiency (inherited cause)
What makes us think a diagnosis is haemolytic anaemia? (4)
- otherwise unexplained anaemia, which is normochromic and usually either normocytic/macrocytic (severe)
- evidence of morphologically abnormal red cells (e.g. ghost cells)
- evidence of increased red cell breakdown (e.g. jaundice due to increased BR)
- evidence of increased bone marrow activity (reticulocytosis, increased polychromatic macrocytes)
Inherited haemolytic anaemia - what condition is caused by a membrane defect?
Hereditary spherocytosis
Inherited haemolytic anaemia - what condition is caused by a haemoglobin defect?
Sickle cell anaemia
Inherited haemolytic anaemia - what condition is caused by a glycolytic pathway defect?
Pyruvate kinase deficiency (rare)
Inherited haemolytic anaemia - what condition is caused by a pentose shunt defect?
Glucose-6-phosphate dehydrogenase deficiency
Acquired haemolytic anaemia - what condition is caused by a membrane defect (immune)?
Autoimmune haemolytic anaemia (AIHA)
Acquired haemolytic anaemia - what condition is caused by a whole red cell defect (mechanical)?
Microangiopathic haemolytic anaemia (MAHA)
Acquired haemolytic anaemia - what condition is caused by a whole red cell defect (oxidant)?
Drugs and chemicals
Acquired haemolytic anaemia - what condition is caused by a whole red cell defect (microbiological)?
Malaria
What are the blood count abnormalities in someone with iron deficiency anaemia? (11)
- low Hb
- low MCV
- low MCH
- low MCHC
- low RBC
- high platelets
- low ferritin
- low serum iron
- high transferrin
- low transferrin saturation
- Hb electrophoresis - no increase in HbA2 (not beta thalassaemia)
What are some further questions to ask someone with iron deficiency anaemia? (5)
- diet - vegetarian/vegan
- gastrointestinal symptoms - dysphagia/dyspepsia/abdominal pain/change in bowel habit/haematemesis/rectal bleeding/melaena
- menstrual history/post-menopausal bleeding
- weight loss
- medication - e.g. aspirin/NSAIDs
What are three clinical signs of iron deficiency anaemia?
- koilonychia
- glossitis
- angular stomatitis
Angular stomatitis/cheilitis = irritated corners of mouth
What further tests can be done after diagnosis of iron deficiency anaemia? (3)
- investigating for blood in stool - faecal immunochemical test (FIT)
- gastrointestinal (GI) investigations - upper GI endoscopy (oesophagus, stomach, duodenum), take duodenal biopsy, colonoscopy
- coeliac antibody testing
What are the causes of iron deficiency anaemia? (3)
- increased blood loss - commonest cause in adults
- hookworm commonest cause worldwide
- menstrual (menorrhagia)
- GI (often occult)
- insufficient iron intake
- dietary - vegetarians
- malabsorption - coeliac disease (gluten-induced enteropathy), H.pyloris gastritis
- increased iron requirements
- physiological - pregnancy, infancy
What are blood film features of iron deficiency anaemia? (4)
- microcytosis (low MCV, small cells)
- hypochromia (low MCHC, pale cells)
- occasional target cells
- elliptocytes (pencil cells)
What does reduced ferritin cause? (2)
- reduces hepcidin production
- increases iron supply
What is absorption of iron from the gut and release of storage iron increased by?
Reduced hepcidin
How do you treat iron deficiency anaemia?
Iron replacement therapy (e.g. ferrous sulphate tablets)
What differential diagnoses are available for anaemia associated with low MCV? (3)
- iron deficiency anaemia
- thalassaemia
- anaemia of chronic disease
What is the difference in blood count results between iron deficiency anaemia vs anaemia of chronic disease?
- MCV: low vs low/normal
- ferritin: low vs high
- transferrin: high vs low/normal
- transferrin saturation: low vs normal
- ESR: may be high (due to low Hct) vs high
What are the features on a blood film of someone with anaemia of chronic disease? (3)
- hypochromic
- microcytic
- Rouleaux (stacks of RBCs)
Does a normal ferritin always exclude iron deficiency?
No - ferritin can be normal if you have both iron deficiency anaemia and anaemia of chronic disease
Why does anaemia of chronic disease happen?
- hepcidin is usually secreted by liver in response to high iron states
- hepcidin production is also increased in inflammatory states, reducing iron supply (blocks absorption of iron from gut and release of storage iron)
What are some common causes of anaemia of chronic disease? (3)
- infections such as TB and HIV
- rheumatoid arthritis and other autoimmune disorders
- malignancy
How do you treat anaemia of chronic disease?
Treat the underlying cause (no obvious cause except the patient is ill)
What are the megaloblastic features in the bone marrow in megaloblastic anaemia due to B12 deficiency? (3)
- megaloblasts are large with nucleocytoplasmic dissociation
- impaired DNA synthesis, nuclear maturation and cell division
- adequate cytoplasmic maturation and cell growth
What can cause megaloblastic change in the bone marrow?
- vitamin B12 and folate
- required for DNA synthesis
- absence leads to severe anaemia which can be fatal
- secondary to agents/mutations that impair DNA synthesis
- drugs - azathioprine, cytotoxic chemotherapy
- folate antagonists - methotrexate
- BM cancers - myelodysplastic syndrome
What is vitamin B12 required for? (2)
- DNA synthesis
- integrity of the nervous system
What is folic acid required for? (2)
- DNA synthesis
- homocysteine metabolism
What are the dietary causes of vitamin B12 deficiency and how is this treated?
- B12 present in animal products
- inadequate diet, veganism
- treated with oral supplements
What are the gastric causes of vitamin B12 deficiency and how is this treated?
- intrinsic factor needed for B12 metabolism
- gastrectomy (some bariatric procedures); autoimmune (pernicious anaemia - anti-GPC and IF antibodies)
- treated with hydroxocobalamin injections (IM)
What are the bowel causes of vitamin B12 deficiency and how is this treated?
- terminal ileum needed for B12 metabolism
- Crohn’s disease; ileal resection
- treated with hydroxocobalamin injections (IM)
What are the reduced availability causes of folic acid deficiency and how is this treated?
- dietary - poverty, alcoholism
- malabsorption - coeliac disease, jejunal resection
- treated with oral supplements
What are the increased demand causes of folic acid deficiency and how is this treated?
- pregnancy
- lactation
- increased cell turnover - haemolysis
- treated with oral supplements
What neurological disorders can cause megaloblastic anaemia?
- vitamin B12 - dementia and sub-acute combined degeneration (SACD) of spinal cord
- folic acid - developmental neural tube defects
What is megaloblastic anaemia?
Anaemia associated with megaloblastic morphological changes in the bone marrow due to asynchronous nucleocytoplasmic maturation
What are the two most common causes of megaloblastic anaemia?
- vitamin B12 deficiency
- folic acid deficiency
What is the general relationship between cell sizes and colours in anaemia?
- microcytic usually hypochromic
- normocytic and macrocytic usually normochromic
What are the common causes of a microcytic anaemia? (2)
- defect in haem synthesis - iron deficiency anaemia, anaemia of chronic disease
- defect in globin synthesis (thalassaemia) - defect in alpha chain synthesis (a-thalassaemia), defect in beta chain synthesis (b-thalassaemia)
What are the mechanisms of normocytic anaemia? (3)
- recent blood loss - GI haemorrhage, trauma
- failure of production of RBCs - early stages of iron deficiency, BM failure/suppression (e.g. chemo), BM infiltration (e.g. leukaemia)
- pooling of RBC in spleen - hypersplenism (e.g. liver cirrhosis), splenic sequestration in sickle cell anaemia
What are some common causes of macrocytic anaemia? (4)
- lack of vitamin B12/folic acid (megaloblastic anaemia)
- use of drugs interfering with DNA synthesis
- liver disease and ethanol toxicity
- haemolytic anaemia (reticulocytes increased)
