7. Anaemia Flashcards
Define the term anaemia and the factors that can affect the range value
The term anemia refers to a haemoglobin concentration lower than the normal range.
Normal range will vary with age, sex and ethnicity.
Importantly, anaemia isn’t a diagnosis, it is a manifestation of an underlying disease
Give the respective signs and symptoms of anaemia
As haemoglobin carries O2 in blood, the signs and symptoms will be related to the insufficient delivery of oxygen to tissues. Symptoms: 1. Shortness of breath 2. Palpitations 3. Headaches 4. Claudication (pain in limbs at rest) 5. Angina (pain in the chest due to an inadequate blood supply to the heart ) 6. Weakness & Lethargy 7. Confusion
Signs:
- Pallor
- Tachycardia
- Systolic flow murmur (heart mummurs heard during systole)
- Tachypnoea (increased respiratory rate to try and compensate for low oxygen levels)
- Hypotensio
Give the 4 specific signs that can help identify the CAUSE of anaemia
• Koilonychia - (Spoon shaped nails) - Iron deficiency • Glossitis - (inflammation & depapillation of tongue) - Vitamin B12 deficiency • Angular stomatitis - (Inflammation of corners of the mouth) - Iron deficiency • Abnormal facial bone development - Rare in recent times as preventable with early diagnosis - Thalassaemia
What can cause abnormal facial bone development?
Thalassaemia - increase of Haemopoiesis in areas we wouldn’t normally see an increase
Why might symptoms of anaemia be mild if it develops over time?
Body has had time to adjust to the lower concentration of Hb by increasing cardiac stroke volume to increase blood supply to tissues and increasing the conc of 2,3- Bisphosphoglycerate in RBCs to promote oxygen dissociation
Give the 3 main categories of problems that can cause anaemia to develop
- Problem in the bone marrow
- There’s reduced or dysfunctional erythropoiesis
- Abnormal haem synthesis
- Abnormal globin chain synthesis
(This means that a proper haemoglobin molecule isn’t being formed) - Problems with the RBCs
- Abnormal structure of the RBCs
(E.g the membrane structure is not right)
- Mechanical damage to the RBCs
- Abnormal metabolism of the RBCs - Excessive bleeding
E.g because if bowel cancer which causes an increase in blood loss meaning you’ll have lower levels of haemoglobin present - Increased removal by reticuloendothelial system
E.g by the spleen or liver
What is the role of erythropoietin?
It’s a hormone that’s produced and released by the pericytes in kidney when there are low levels of oxygen.
It’s used to trigger an increase in the synthesis and release of RBCs in the bone marrow by binding to receptord on erythroblasts in bone marrow
This leads to high blood oxygen so negatively feeds back to the kidney to reduce the release of erythropoietin.
Discuss how reduced or dysfunctional erythropoiesis might develop anaemia
• Anaemia can result from lack of response in the haemostatic loop e.g. in chronic kidney disease the kidney stops making erythropoietin
• Anaemia can result from marrow being unable to respond to EPO e.g. after chemotherapy, toxic insult or parvovirus infection
• If marrow is infiltrated by cancer cells or fibrous tissue (myelofibrosis) the number of normal haemopoietic cells is reduced
• In Anaemia of chronic disease e.g. in rheumatoid arthritis, iron is not made
available to marrow for rbc production
• In rare forms of blood cancer called myelodysplastic syndromes abnormal clones of marrow stem cells limit the capacity to make both red and white blood cells
Why might defects in Hb synthesis come about?
- Defects in the haem synthetic pathway can lead to Sideroblastic anaemia
- An insufficient level of iron in the diet can lead to iron deficiency anaemia (this is because not enough iron is present to make Haem)
- Anaemia of chronic disease can result in a functional iron deficiency (there’s sufficient amount of iron in the body but it’s not made available for erythropoiesis).
Give the examples of diseases caused by mutations in the genes encoding the globin chain proteins
- α Thalassaemia
- β Thalassaemia
- Sickle cell disease
Why might abnormal structure and mechanical damage to RBCs come about that is inherited? What does this cause?
- mutations in genes coding for the proteins involved in interactions between the plasma membrane and cytoskeleton
- causes cells to become LESS flexible and more susceptible to damage.
- RBCs are broken up in the circulation or removed more quickly by the RES
E.g. hereditary spherocytosis
Why might abnormal structure and mechanical damage to RBCs come about that is acquired? What does this cause?
- mechanical damage: shear stress as cells pass through defective heart valve e.g. MAHA in aortic valve stenosis
- cells snagging on fibrin strands in small vessels where increased activation of clotting cascade has occurred e.g. in disseminated intravascular coagulation
- heat damage from severe burns
- osmotic damage - drowning in freshwater
What type of anaemia does abnormal structure and mechanical damage to RBCs result in?
abnormal structure and mechanical damage to RBCs causes haemolytical anaemias. Microangiopathic haemolytic anaemias are caused by the mechanical damage aspect
What are schistocytes?
- Fragments resulting from mechanical damage to RBCs
* The presence of schistocytes is agood indicator that some form of pathology is present
Why does G6PDH deficiency cause defects in RBC metabolism?
• decrease in G6PDH activity limits amount of NADPH which is required for the reduction of oxidised GSSG back —> reduced glutathione (GSH).
• Less GSH means less protection against damage from oxidative stress
• Oxidative stress from infection, drugs, broad beans causes:
- lipid peroxidation
(cell membrane damage, lack of deformability leads to mechanical stress)
- protein damage - causes aggregates of cross-linked haemoglobin called Heinz bodies
• These are recognised as defective by RES and are removed by haemolysis
Why does pyruvate kinase deficiency cause defects in RBC metabolism?
- pyruvate kinase: final enzyme in glycolysis
- Rare genetic defects in this enzyme occur in some patients
- RBCs lack mitochondria so depend on glycolysis for energy production
- defective glycolytic pathway causes RBCs to rapidly become deficient in ATP and they undergo haemolysis
What are causes of acute blood loss?
- injury
- surgery
- childbirth
- ruptured blood vessel
What are NSAIDs used for and how can they induce GI injury/ bleeding?
- nonsteroidal anti-inflammatory drugs are used for treatment of conditions with pain and inflammation e.g. aspirin, ibuprofen, naproxen
- induce GI injury/ bleeding via inhibition of cyclooxygenase activity and via direct cytotoxic effects on epithelium
What is chronic bleeding?
A small amount of bleeding continuing over a long time may result in a significant blood loss
What are the most common causes of chronic bleeding?
• Heavy menstrual bleeding • Repeated nosebleeds • Haemorrhoids • Occult gastrointestinal bleeding (blood lost in stool) - Ulcers (stomach or small intestine) - Diverticulosis - Polyps in large intestine - Intestinal cancer • Kidney or bladder tumours (blood lost in urine)
In which two general sites can damage to RBCs occur?
- within blood vessels (intravascular haemolysis)
- within the RES system (extravascular haemolysis)
What happens in autoimmune haemolytic anaemias?
Autoantibodies bind to the RBC membrane proteins causing them to be recognised by macrophages in the spleen and become destroyed
Symptom of splenomegaly as the spleen is doing extra work
What is haemolytic anaemia?
In haemolytic anaemias red cells are destroyed more quickly as they are abnormal or damaged
Why can haemolytic anaemias result in splenomegaly?
as the spleen is doing
extra work to remove the extra damaged blood cells
What is the Role of the reticuloendothelial system?
Macrophages in spleen and other tissues of RES remove damaged or defective red cells e.g. in membrane,
enzyme & haemoglobin disorders.
How can myelofibrosis result in the development of anaemia?
- proliferation of mutated haemopoetic stem cells results in reactive bone marrow fibrosis
- Fibrotic marrow with little space for haemopoiesis
- mutated progenitor cells from marrow can also colonise liver and spleen —> extramedullary haemopoiesis. Results in enlarged liver and spleen
How can Thalassemia result in the development of anaemia?
- inherited disorders resulting from decreased/ absent alpha or beta globin chain production
- imbalance in composition of haemoglobin a2 or beta2 tetramer results in defective microcytic hypochromic RCs (small, pale)
- severity depends on type e.g. lack of 3 of 4 alpha globin genes leads to Hb H disease —> severe splenomegaly, microcytosis, haemolysis
What are two key features that can help to work out the cause of an anaemia?
- the RBC size - macrocytic (> 100 fl), microcytic (< 80 fl) normocytic (8-100 fl)
- the presence/ absence of reticulocytosis —> should be increased if BM has responded normally to anaemia
What are reticulocytes?
- immature RBCS - just released from BM —> blood
- no nucleus and eliminate remaining mitochondria
- compose of 1% of all RBCs and take about a day to mature
- slightly larger than mature RBCs so increase MCV
What can cause macrocytic RBCs ?
Vitamin B12 deficiency Folate deficiency Myelodysplasia Liver disease Alcohol toxicity
What can cause normocytic RBCs?
Primary bone marrow failure e.g. aplastic anaemia
Secondary bone marrow failure e.g. ACD, uraemia (high levels of urea in blood) HIV
What can cause microcytic RBCs?
Thalassaemia Anaemia of chonic disease Iron deficiency Lead poisoning Sideroblastic anaemia
What indicates haemolysis?
High bilirubin
High LDH
What can cause anaemias involving haemolysis?
- autoimmune
- MAHA (microangiopathic haemolytic anaemia)
- haemoglobinopathies
- enzyme defects
- membrane defects
What are the 3 types of macrocytic anaemias?
- Megaloblastic anaemias
- Macronoromoblastic erythropoiesis
- ‘Stress’ erythropoeisis
What are megaloblastic anaemias caused by? Give examples
- interference with DNA synthesis during erythropoeisis causes development of retatded nucleus in relation to maturation of cytoplasm
- cell division is delayed and erythroblasts continue to grow to form megalobasts (big, large immature nuclei) which give rise to larger RBCS
Examples: • Vitamin B12 / folate deficiency • Drugs that interfere with DNA synthesis (e.g. some anticancer) • Some erythroid leukaemias where DNA synthesis is retarded
What does macrocytic anaemias mean?
Anaemias where the average
red cell size is greater than
normal (↑ MCV)
What is macronormoblastic erythropoiesis? Give examples
- normal relationship between development of nucleus and cytoplasm but erythroblasts are larger than normal —> larger RBCs
E.g. liver disease, alcohol toxicity, some myelodysplastic syndromes (involving lipid content of membrane), hypothyroidism
Why can chronic excess alcohol consumption cause macrocytosis and mild anaemia?
Alcohol has a weak anti-folate effect and a poor dietary intake of folate is often common in alcoholic patients
What is stress erythropoiesis? Give examples
- conditions associated with a high reticulocyte count which are larger than RBCs
- high level of erythropoietin leads to an expanded and accelerated erythropoiesis
E.g. recovery from haemorrhage/ haemolytic anaemia
Describe the appearance of megaloblasts
Megaloblasts are much larger than the usual erythroblast cells in bone
marrow and have very large
immature nuclei
Why is folate needed?
- Converted to tetrahydrofolate by intestinal cells before entering the circulation
- Stored in liver
- Tetrahydrofolate acts as a one-carbon carrier, accepting carbon units from sources such as serine, glycine, histidine and formate
- Once these carbons are attached they can be oxidised/ reduced and used to provide carbons for other metabolic reactions including the synthesis of thymidine for DNA synthesis, synthesis of the purine bases adenine and guanine and RNA synthesis and transfer of methyl groups to B12
Where is folate found?
- synthesised in bacteria and plants
* present in wide range of animal/ vegetable (especially green leafy vegetable) sources
What are causes of folate deficiency?
- poor diet
- increased requirement: pregnancy, increased erythropoeisis e.g. haemolytic anaemia, severe skin disease e.g. psoriasis, exfoliative dermatitis
- disease of duodenum and jejunum e.g. coeliac, crohns
- drugs which inhibit dihydrofolate reductase
- alcoholism: poor diet/ damage to intestinal cells
- urinary loss in liver disease/ heart failure
What are symptoms of folate deficiency?
- Those related to anaemia
- Reduced sense of taste
- Diarrhoea
- Numbness and tingling in feet and hands
- Muscle weakness
- Depression
If folic acid is taken before conception/ during the first 12 weeks of pregnancy what can it prevent? How much should be taken?
Majority of neural tube defects in babies e.g. spina bifida
400 micro grams per day
What is vitamin B12 needed for?
- cofactors for DNA synthesis(due to its role in folate metabolism)
- normal erythropoiesis
- normal function and development of CNS
How is vitamin B12 obtained?
- produced by bacteria (NOT plants or animals)
- largely obtained from foods of animal origin - meat, fish, eggs, cheese, yeast extract, milk (produced by commensal bacteria)
How much B12 supplement should vegans take?
10 micro grams daily or 2mg weekly
How is vitamin B12 absorbed?
• B12 released from food proteins by proteolysis in stomach where it then binds to haptocorrin ( produced by salivary glands to protect B12 from acid degradation in stomach)
• Haptocorrin B12 complex digested by pancreatic proteases in small
intestine releasing B12 which then binds intrinsic factor (produced by
gastric parietal cells).
• Intrinsic factor–B12 complex binds to cubam receptor which mediates
uptake of complex by receptor- mediated endocytosis into enterocytes
• After lysosomal release in enterocytes, B12 exits via basolateral membrane through MDR1
• Binds to transcobalamin in blood and transported around bloodstream
What is the required dietary B12 intake?
5-10 micro grams per day
Where is B12 stored?
Liver
Can last 3-6 years
What are causes of B12 deficiency?
• Dietary deficiency (Vegan diet lacking B12 supplementation)
• lack of intrinsic factor - pernicious anaemia
• ileum diseases - B12/ intrinsic factor complex cant be absorbed e.g. crohns, ileal resection, tropical sprue
• congenital lack of transcobalamin
- chemical inactivation of B12 e.g. anaesthetic nitrous oxide
• parasitic infestation - trap B12 e.g. rare tapeworm
• drugs that chelate intrinsic factor e.g. hypercholesterolaemia drug cholestyramine
What is pernicious anaemia? What is it caused by?
• Decreased or absent Intrinsic factor (IF) causes progressive exhaustion of B12 reserves. • Autoimmune disease • 2 types of Antibody (Ab) : - Blocking Ab (more common) blocks binding of B12 to IF. - Binding Ab prevents receptor mediated endocytosis.
What are symptoms of vitamin B12 deficiency?
- Those related to anaemia
- Glossitis & mouth ulcers
- Diarrhoea
- Paraesthesia
- Disturbed vision
- Irritability
How can vitamin B12/ folate deficiency affect the CNS?
- folate defiance in pregnancy —> neural tube defects in baby
- vitamin B12 defiency —> focal demyelination (reversible)
- B12 deficiency more often results in a reversible peripheral neuropathy
- vitamin B12 defiency —> subacute combined degeneration of the cord - degeneration of posterior and lateral columns of spinal cord (irreversible damage)`
What are symptoms of subacute combined degeneration of the spinal cord?
- gradual onset weakness, numbness and tingling in arms, legs and trunk which worsens
- changes in mental state
How are vitamin B12 and folate linked?
- lack of B12 will trap folate in the stable methyltetrahydrofolate form
- B12 usually needed to accept that methyl group - hence removing it from the methyltetrahydrofolate
- folate therefore cannot be used to convert deoxyridine —> thymidine for DNA synthesis
- uridyl inserts into DNA —> abnormal DNA!
Why do B12 and folate deficiency cause a megaloblastic anaemia?
Vitamin B12 and folate are both necessary for nuclear division and maturation.
- both lead to thymidine deficiency
- uracil incorporates into DNA
- DNA repair enzymes detect this and constantly repair by excision
- results in ansynchronous maturation between nucleus and cytoplasm —> nucleus doesn’t fully mature, cytoplasm matures at normal rate
- leads to large red cell precursors with large nuclei and open chromatin —> macrocytic RBCs
How can megaloblastic anaemia be detected?
- low Hb
- raised MCV
- low RBC and reticulocyte count
- low/ normal neutrophil and platelet count
- raised serum ferritin
- raised plasma lactate dehydrogenase due to increased cell destruction/ production
- raised bilirubin as cells are broken down in BM
- increased cellularity and megaloblastic changes in BM
If there is no evidence of clear cause e.g. food malabsorption of megaloblastic anaemia, what should be checked for?
Anti-intrinsic factor Abs
How is folate deficiency treated?
Oral folic acid
check B12 levels as improvement in patient due to treatment could mask underlying B12 deficiency and allow neurological diseases to develop
How is vitamin B12 defiency treated?
Oral cynanocobalamine
For pernicious anaemia: lifetime regular intramuscular hydroxycobalamine injection (not oral as cannot be absorbed anyway!)
Why are blood transfusions dangerous for someone with B12 deficiency?
- can cause high output cardiac failure
- heart already hypertrophic (enlarged) from working harder due to defiency
Why can hypokalaemia arise at the start of treating severe pernicious anaemia?
Increased potassium requirement as erythropoiesis returns to normal rate
Why does anaemia lead to an increase in the concentration of 2,3- bisphosphoglycerate?
In order to shift the Hb oxygen dissociation curve to the right meaning that Hb will give up its oxygen more readily to tissues
Why is haemoglobinaemia a symptom of intravascular haemolysis?
Excess Hb in the blood:
If the normal reticuloendothelial pathway for removal of RBCs is overwhelmed or haemolysis is very sever, a direct breakdown of RBCs results in release of Hb into the circulation
Normally, free Hb in the blood is picked up by the protein haptoglobin (produced in liver) but there’s a imited amount and it can get saturated quickly
Why does hereditary spherocytosis increase red cell rigidity?
Mutations results in loss of function of proteins (ankryin, spectrin, band 3, band 4.2) involved in vertical interactions between the cytoskeleton and the lipid bilayer of the plasma membrane
Disruption of this interaction causes a local disconnection of the cytoskeleton and membrane resulting in vesiculation of unsupported membrane components and progressive reduction in membrane SA
Causes red cells to adopt a spherocyte shape which is more rigid and less deformable
Spherocytes haemolyze as they pass through vessels of the spleen
What is a direct Coombs test used to measure?
Aka direct antiglobulin test
Used when immune-mediated haemolytic anaemia is suspected - attacking the patients own RBCs
Test measures antibodies bound directly to the surface of RBCs to determine if ABs or complement system factors have bound to RBCs surface antigens
What is the cause of pernicious anemia?
Auto-antibodies interfering with the production/ function of intrinsic factor - needed for the absorption of vitamin B12 in the ileum - needed in turn to produce RBCs
Mnemonic for macrocytic anaemia
FAT RBC
Folate
Alcohol
Thyroid (hypothyroidism)
Reticulocytosis
B12 deficiency
Cirrhosis
Mnemonic for normocytic anaemia
BASE
Bleeding
Anaemia of chronic disease
Sickle cell disease
Early iron deficiency
