Anaemia Flashcards
C - iron deficiency anaemia
- hypochromic RBCs
- pencil cells
- anisopoikilocytosis
What is the definition of anaemia?
How do you clinically check whether someone is anaemic?
- anaemia describes a low blood haemoglobin
- check for anaemia by looking for conjunctival pallor
- patients will often also have pale skin, but this can be difficult to identify
What is meant by “symptomatic anaemia”?
Why does this develop?
- symptomatic anaemia occurs when a patient’s respiratory rate and heart rate are raised
- anaemic patient is not oxygenating their tissues effectively due to less Hb present in the blood
- RR and HR are increased to compensate for the lack of oxygenation
- anaemia can be a cause of acute breathlessness
What are the 3 features that help to identify iron-deficiency anaemia on a blood film?
- there is anisopoikilocytosis
- RBCs are both hypochromic and microcytic
- a cell is hypochromic when > 1/3 of the cell is pale in colour (central pallor)
- pencil cells are present
What is meant by “anisopoikilocytosis”?
this is a combination of 2 words:
- poikilocytosis means different shapes are present within the blood film
- anisocytosis means that different sizes are present within the blood film
What are the 3 different categories of causes of iron-deficiency anaemia and examples of each?
Reduced uptake:
- malnutrition
- coeliac disease
- IBD
Increased loss:
- GI malignancy
- peptic ulcer
- IBD
- menstruation
Increased requirement:
- pregnancy
- breastfeeding
What is the biggest concern in older patients (>55) with iron deficiency anaemia?
What other associated symptoms would heighten concern?
- in older patients with unexplained IDA, think colon cancer until proven otherwise
- colon cancer presents with a triad of symptoms:
- unexplained iron-deficiency anaemia
- PR bleeding
- change in bowel habit
What type of anaemia is anaemia of chronic disease?
What is the main “chemical” that is responsible for this?
- it is often normocytic, but can also be microcytic
- the presence of a chronic disease causes increased release of cytokines due to presence of chronic inflammation
- cytokines increase the amount of hepcidin in the body
What is involved in removing iron from the gut and what happens to it after this has happened?
- iron is loaded via ferroportin in the gut
- iron comes out into the blood via transferrin
- OR it is stored as ferritin
How does hepcidin interfere with iron storage and transport?
- hepcidin decreases the activity of ferroportin
- this reduces the uptake of iron from the gut
- it also decreases the activity of transferrin
- if some iron manages to come in from the gut, the hepcidin then stops it from getting out of cells and into the blood
- hepcidin causes iron to clump in the interstitial cells and be converted to ferritin
- this makes the iron useless as it is just being stored and can’t be used
Why is the production of hepcidin useful in acute inflammation?
How do its actions lead to anaemia of chronic disease?
- in acute inflammation, the body wants to ensure bacteria are not provided with iron that they can use for nutrition
- hepcidin prevents iron from being available by storing it as ferritin
- starving an infection of iron will stop it from replicating
- in a chronic state this results in anaemia as there is decreased iron in the blood
How can ferritin be used to distinguish between IDA and ACD?
Why is this not the best marker to use?
- ferritin is REDUCED in iron-deficiency anaemia (IDA)
- ferritin is unchanged or INCREASED in anaemia of chronic disease (ACD)
ferritin is upregulated due to hepcidin production
- ferritin is an acute phase protein so can also be raised in acute infections
What is the best marker to use for distinguishing between IDA and ACD on blood test?
Total Iron Binding Capacity (TIBC)
- this relates to the raw level of transferrin in the blood
- there is HIGH transferrin in IDA as you are trying to get as much iron as possible into the blood from the gut
- there is LOW transferrin in ACD as it is inhibited by hepcidin
What is thalassaemia?
What type of anaemia does this produce?
- inherited blood disorders characterised by decreased haemoglobin production
- these are autosomal recessive globin chain mutations
- they produce a microcytic anaemia
What are the 2 different types of thalassaemia?
In which country are both these types relatively common?
- alpha thalassaemia is more rare than beta thalassaemia
- in alpha - there is a defect affecting chromosome 16
- in beta - there is a defect affecting chromosome 11
- Cyprus has one of the highest levels of thalassaemia in the world
What are the different subtypes of alpha thalassaemia?
How does the severity differ?
- alpha+
- alphao
- Hb H
- Hb Barts
- there are 4 alpha genes, 2 from your father and 2 from your mother
- different subtypes arise depending on how many genes are knocked out
- the more genes that are knocked out, the increased severity of disease
(someone with Hb H has only 1 alpha gene and needs blood transfusions for life
in Hb Barts there are no alpha genes at all and it produces death in utero)
What are the different types of beta-thalassaemia?
How does their severity vary?
- beta minor
- beta intermedia
- beta major
- beta minor involves only one allele bearing a mutation, and sufferers have microcytic anaemia
- beta intermedia involves the need for occasional transfusions e.g. in pregnancy
- beta major occurs when both alleles have mutations and requires blood transfusions for life
What are the investigations involved in thalassaemia?
- diagnosis involves identification of microcytic anaemia but with normal iron studies
- normal levels of iron show it is not IDA or ACD
-
gel electrophoresis is performed to confirm the diagnosis
- different sized proteins depend on the number of genes present
What is a benefit of having thalassaemia minor?
- it is associated with resistance to falciparum Malaria
Around what age do alpha and beta thalassaemia present?
- at birth the child has foetal Hb (blue line) which decreases with age
- B-Hb compensates for foetal Hb and increases in the first 3 months of life
- if you are lacking a B-globin chain in B-thalassaemia, it will present here
- A-thalassaemia will present from birth
What causes sickle cell disease?
In what population is it common and why?
- caused by a point mutation on the B globin gene on chromosome 11
- it is an autosomal recessive condition
- 20% of tropical Africa population have sickle cell trait as it has resistance to Falciparum Malaria
What factors predispose to sickling of RBCs?
- hypoxia
- dehydration
- acidosis
- infection (particularly encapsulated bacteria)
- these all upset the membrane potential of the cell and make it more predisposed to sickling
- sickle cells can then go on to cause occlusion of blood vessels
How is sickle cell anaemia identified on blood film?
- sickled cells are present
-
Howell-Jolly bodies are present, which are nuclear remnants
- they would usually be taken up and removed by the spleen
What are the 4 different types of sickle cell crises?
What causes these?
- acute painful crisis
- stroke
- sequestration crisis
- chronic cholecystitis
- these all occur due to sickle cells entering small, narrow vessels and causing vessel occlusion
What happens during a sequestration crisis?
- sickle cells can become lodged in the spleen
- the spleen decides whether RBCs are functional or not, so attempts to remove the sickle cells
- there are so many sickle cells, that as the spleen tries to remove them it becomes massively enlarged
- the sequestration crisis occurs due to all the RBCs getting stuck inside the spleen
Are Howell-Jolly bodies typically seen in older or younger patients and why is this the case?
- in younger patients, the spleen is still functioning so they will get sequestration crisis (and splenomegaly)
- the presence of Howell-Jolly bodies tells you that the spleen is no longer functioning as it would’ve removed these if it could
- older patients will have Howell-Jolly bodies and hyposplenism as their spleen is no longer functioning
How is sickle cell anaemia diagnosed and treated?
- it is diagnosed by Hb electrophoresis + blood film
- management involves preventing problems related to sickling from happening before they occur
Conservative:
- avoid triggers
Medical:
- hydroxyurea
- prophylactic antibiotics - as patients are susceptible to certain infections
- vaccination - to prevent infection, which can cause sickling
Surgical:
- bone marrow transplant
What are the 5 most severe consequences of sickle cell anaemia?
Dactylitis:
- RBCs enter vessels of the hands and cause swelling of the fingers, which is very painful
Acute chest syndrome
Priapism:
- sickle cells clog up vessels in the penis and cause an erection that lasts for 4-5 hours and is painful
Haemolytic anaemia:
- the cells break apart and haemolysis occurs
- this leads to jaundice due to the build-up of bilirubin
Aplastic crisis:
- this occurs due to infection by parvovirus B19
What type of anaemia is produced from folate or B12 deficiency?
How can this be identified on blood film?
- it is a megaloblastic anaemia (macrocytic)
- folate helps the nucleus to develop, so in megaloblastic anaemia there is a problem with nuclear development
- this produces hypersegmented neutrophils
- the cells become very large as the cytoplasm carries on growing, whilst the nucleus cannot
What are the different causes of megaloblastic anaemia caused by vitamin B12 and folate deficiency?
Vitamin B12 deficiency:
- alcohol
- IBD and coeliac disease
- malnutrition
-
pernicious anaemia
- this is the autoimmune cause of B12 deficiency
Folate deficiency:
- alcohol
- IBD and coeliac disease
- anti-folate drugs
-
pregnancy
- folic acid supplements are given to women who are planning on getting pregnant
Why does B12 deficiency produce neurological signs?
What are these signs?
- B12 is important for preserving the myelin sheath in the nervous system, so deficiency produces neurological symptoms
- these symptoms are referred to as “subacute combined degeneration of the cord” and include:
- glove and stocking parasthesiae
- hyporeflexia
- Romberg’s positive
What is glove and stocking paraesthesia?
- numbness or tingling sensations
- the distal portions of the nerves are affected, meaning that this affects the hands and feet
When do the symptoms of B12 deficiency typically arise?
B12 reserves last for 3-4 years
symptoms of deficiency do not arise until after this time
What is meant by a positive Romberg’s sign?
- the patient stands upright and is asked to close their eyes
- a loss of balance is interpreted as a positive Romberg’s test
- this is a test of proprioception (body’s sense of positioning), which requires healthy functioning of the dorsal columns of the spinal cord
What is meant by the phrase “subacute combined degeneration of the cord”?
- this is progressive degeneration of the spinal cord due to vitamin B12 deficiency
- there is damage to nerve fibres that control movement and sensation
- there is tingling / numbness in the hands / feet, stiff limbs and confusion / irritability
What is pernicious anaemia?
- autoimmune condition which produces autoantibodies against intrinsic factor or cells in the stomach (parietal cells) that produce intrinsic factor
- intrinsic factor binds vitamin B12 so that it can be absorbed
- the body cannot produce enough RBCs due to lack of vitamin B12
What are the 4 main causes of non-megaloblastic macrocytic anaemia?
remember Alcoholics May Have Liver failure
- A - Alcohol
- M - Myelodysplasia
- H - Hypothyroidism
- L - Liver disease
What is haemolytic anaemia?
What are the 2 different mechanisms by which this can occur?
- anaemia resulting from RBCs being destroyed faster than they can be reproduced
Intravascular haemolysis:
- RBCs lyse / rupture within the blood vessels
- this occurs due to rupture of the RBC membrane
Extravascular haemolysis:
- this is haemolysis occurring in the liver, spleen, bone marrow and lymph nodes
- the spleen removes RBCs that are not functioning properly
What are the clinical features of haemolytic anaemia?
- scleral icterus (jaundice)
- pale conjunctivae & skin
What will blood tests show in haemolytic anaemia and why?
- low haemoglobin
-
low haptoglobin
- this is the molecule that mops up Hb in the blood
- you would expect Hb levels to be high as it leaks out of RBCs, but it is not as haptoglobin mops it up
- eventually levels drop as haptoglobin is exhausted
- this is a sign of intravascular haemolysis
- raised unconjugated bilirubin
-
raised LDH
- this leaks out of RBCs
What are the 4 different hereditary haemolytic anaemias?
Which parts of the RBC are affected in each type?
- hereditary spherocytosis affects the RBC membrane
- G-6-PD deficiency affects enzymes within the RBC
- sickle cell anaemia and thalassaemia result from haemoglobin defects
Why do broad beans (fava beans) predispose to glucose-6-phosphate deficiency?
- G6P is an enzyme that is involved in making glutathione, which helps the body to deal with oxidative stress
- if there is a G6P deficiency, the person may run out of glutathione
- they cannot respond to oxidative stress and the cell becomes damaged
- things that are oxidative stressors, such as fava beans, are more likely to cause problems
How is glucose-6-phosphate deficiency contracted?
it is an X-linked recessive condition
What 2 signs on blood film will be present in G6PD?
What do these result from?
Heinz bodies:
- these are small bits of oxidative damage from the nucleus
- they are detected by the spleen which attempts to remove them
- the spleen literally “takes a bite” out of the cell producing…
Bite cells:
- these indicate previous haemolysis as the spleen takes time to respond
How can hereditary spherocytosis be identified on blood film?
What causes it?
- this is an autosomal dominant inherited condition
- the blood film shows spherocytes
- these cells are shaped like a sphere so have no central pallor
What is involved in the pathogenesis of hereditary spherocytosis?
- it is caused by a beta spectrin or ankyrin deficiency
- these proteins usually anchor the centre of the cell to make it a biconcave shape
- when these proteins are defected, the cell loses its shape and becomes spherical
What is the investigation for hereditary spherocytosis?
How does it work?
osmotic fragility test
- hypotonic fluid is given, which puts stress on the RBC
- a normal RBC can expand in response to the extra fluid
- when fluid enters a spherocyte, they are more prone to breaking apart, so lysis occurs
- this test identifies whether there are spherocytes
How does an aplastic crisis occur in hereditary spherocytosis and sickle cell anaemia?
- parvovirus B19 infects children (usually) and enters the bone marrow
- it prevents the bone marrow from making RBCs, so you need to rely on the current store of RBCs circulating in the body
- if someone has HS or SCD, RBCs in the body are prone to lysis
- this leads to very few RBCs in the periphery as they are breaking apart and none are being made in the bone marrow
- this is an aplastic crisis
What type of “sheared cell” is associated with haemolytic-uraemic syndrome?
How are they formed?
- schitsocytes are seen in HUS
- they occur as a result of mechanical destruction of a normal RBC
- RBCs get trapped in fibrin strands
- the sheer force of the blood flow produces a “cheese grater” effect that causes the RBC to break
What type of anaemia is seen in haemolytic uraemic syndrome?
What is the triad of symptoms associated with this condition?
- this is a disease of early childhood that is characterised by microangiopathic haemolytic anaemia (MAHA)
- the triad of HUS includes:
- thrombocytopenia
- AKI
- MAHA
- it presents with jaundice and conjunctival pallor
What type of infection is the main cause of HUS in children aged 4-5?
EHEC O157:H7
- this is a nasty haemorrhagic E. coli infection that can be acquired through eating dodgy food
- it is a gastric infection so also causes abdominal pain and bloody diarrhoea
What is disseminated intravascular coagulation?
DIC involves concurrent clotting and bleeding
- there is an underlying problem that activates the clotting cascade
- no proper clots are formed as there is no specific problem/injury
- the supply of clotting factors is eventually exhausted
- there are lots of small ineffective clots that are not doing anything, and now clots can not be formed when needed
- bleeding occurs very easily as clotting factors have been depleted
What are the 6 most common causes of DIC?
- pancreatitis
- sepsis
- obstetric complications
- cancer
- trauma
- ABO reaction
What are the bleeding features, clotting features and haemolytic features associated with DIC?
Bleeding features:
- petechiae
- ecchymoses (bruising)
- haematuria
Clotting features:
- prolonged APTT
- prolonged PT
Haemolytic features:
- jaundice
- conjunctival pallor
What blood test results would you expect to see in DIC?
- decreased platelets
-
decreased fibrinogen
- this has all been exhausted as it is part of the clotting cascade
- increased FDPs
-
increased D-dimer
- this indicates that excess thrombolysis is occurring
Why does thrombotic thrombocytopaenic purpura occur?
- there is a defect of the ADAMTS-13 enzyme
- ADAMSTS-13 enzyme cleaves vWF, decreasing the activity of vWF multimers
- without this enzyme, platelets bind vWF as they spontaneously aggregate in small blood vessels
- this is a form of microangiopathic haemolytic anaemia (MAHA)
- the platelet-vWF complexes form small blood clots that shear RBCS, leading to their rupture and formation of schistocytes
What are the features of the clinical pentad associated with thrombotic thrombocytopenic purpura?
How can this be remembered?
remember there is a defunct ADAMSTS-13 enzyme:
- A - Antiglobulin negative
- D - Decreased platelets
- A - AKI
- M - MAHA
- T - Temperature
- S - Swinging CNS signs
- decreased platelets, AKI and MAHA are all signs of HUS
- temperature and swinging CNS signs are not present in other MAHAs
What test is negative in all 3 MAHAs?
DAT / Coombs test is negative
How does the Direct Antiglobulin Test (DAT) / Coombs test work?
In what type of condition will it be positive?
- it is used to detect the presence of autoimmune haemolytic anaemias by detecting the presence of antibody bound to the red cell surface
- if it is autoimmune, there will be antibodies bound to the RBC antigen
- DAT test uses antibodies to human globin
- these will bind to the autoantibodies anchored to the RBC and cause RBC agglutination
What is meant by warm and cold types of autoimmune haemolytic anaemias?
What can cause these?
Warm:
- agglutination occurs at > 37oC
- associated with IgG antibodies attacking the RBC
- idiopathic
- SLE
- CLL
Cold:
- agglutination occurs at < 37oC
- associated with IgM antibodies attacking the RBC
- idiopathic
- Mycoplasma
- Mononucleosis
both of these will be DAT / Coombs positive as there are anti-RBC antigen antibodies
myelofibrosis
What is primary myelofibrosis?
What causes it?
fibrosis in response to a bone marrow malignancy
- myelofibrosis means fibrosis of the bone marrow
- fibroblasts are very overactive
- the interior of the bone marrow is destroyed by fibroblast tissue, leading to formation of scar tissue
- the scar tissue crowds the bone marrow so it cannot work properly, leading to anaemia and low WCC
What are the risk factors for primary myelofibrosis?
What would you expect to see on blood film?
- increased risk with radiation exposure and >65 years old
- tear drop cells (dacrocytes) are seen on blood film
these occur when there is fibrosis as the RBCs have to squeeze out of the bone marrow, which distorts their shape
What would you expect to see on bone marrow aspirate in primary myelofibrosis?
“dry tap” fibrosis
- bone marrow is usually highly vascularised and will bleed
- when there is scarring and fibrosis, it has all dried up so you won’t be able to extract anything out of it
What might be found on examination in someone with primary myelofibrosis?
massive splenomegaly
- this is due to extramedullary haematopoiesis
- the bone marrow is ruined so the rest of the body tries to compensate and form new blood cells
- as the spleen tries to compensate for the BM, it increases in size
