Session 4 Flashcards
What is anaemia?
Haemoglobin below the reference range for the normal population.
What are the general signs and symptoms of anaemia?
Symptoms: shortness of breath, tiredness, cardiac failure, palpitations, headache
Signs: pallor, tachycardia, tachypnoea, hypotension
Give examples of signs and symptoms specific to certain causes
Anaemia due to - The symptom/sign
Iron deficiency - Koilonychia - spooning of the nails
Vit B12 deficiency - Glossitis - enlarged shiny tongue
Thalassaemia - abnormal facial bone development
Iron deficiency - oesophageal webs (Plummer vinson syndrome)
Iron deficiency - angular stomatitis - inflammation of corners of the lips/mouth
What are the three general stages at which anaemia can be caused and how at each one?
In the bone marrow - issues in erythropoiesis or haemoglobin synthesis
In the peripheral red blood cells - the structure of the RBCs or issues with the metabolism within them
During removal - loss of red cells or issues in the reticuloendothelial system
Why might someone with chronic kidney disease have anaemia and how is this treated?
Loss of kidney function means kidneys aren’t as responsive in the haemostatic loop so produce less erythropoietin causing anaemia. these patients are given recombinant erythropoietin.
How may issues within bone marrow cause anaemia?
- Empty bone marrow unable to respond to stimulus from EPO eg after chemotherapy or toxic insult such as parvovirus infection or in aplastic anaemia
- Marrow infiltrated by cancer cells or fibrous tissue (myelofibrosis) means the normal haemopoieticcells are reduced
What is dyserythropoiesis?
Defective development of red blood cells
What is anaemia of inflammation / anaemia of chronic disease?
- due to inflammatory cytokines, iron is not released for use in bone marrow from macrophages (macrophages are involved in recycling iron)
- Cytokines also cause reduced lifespan of red cells
- The marrow shows a lack of response to erythropoietin
Often has raised CRP and ferritin
Seen in: Renal disease, inflammatory conditions such as Rheumatoid arthritis, SLE, Inflammatory bowel disease (Ulcerative Colitis or Crohn’s), chronic infections
What are Myelodysplastic syndromes (MDS) and how do they cause anaemia?
•Production of abnormal clones of marrow stem cells.
Pre cancer that can go on to develop into acute leukaemia. bone marrow produces lots of RBCs but because of acquired genetic changes they don’t develop properly so they are not allowed to enter the circulation.
How may haemoglobin production be affected resulting in anaemia?
- Deficiencies in essential nutrients:
•Lack of iron: deficiency in Haem synthesis due to:
Iron deficiency
Anaemia of chronic disease (functional lack of iron)
•Lack of B12/folate: Deficiency in the building blocks for DNA synthesis resulting in
megaloblastic anaemia
- Mutations in the proteins encoding the globin chains e.g thalassaemia and sickle cell disease
How might inherited defects in the red cell membrane lead to anaemia?
Some patients have inherited problems whereby the membrane isn’t formed properly for example in hereditary spherocytosis (RBCs become spherical), hereditary eliptocytosis (RBCs have elliptoid shape) and hereditary pyropoikilocytosis (very rare - multiple gene muations result in variety of shapes).
• The cells are less flexible and are damaged more easily and break up in the
circulation or are removed more quickly from the circulation by RES.
this results in a haemolytic anaemia.
How might acquired defects in the red cell membrane lead to anaemia?
–Mechanical damage to red cells
•Heart valves can damage RBCs as they pass through, shearing them resulting in schistiocytes.
•Vasculitis
•MAHA (microangiopathies)
•DIC –disseminated intravascular coagulopathy in this schistiocytes can also be seen.
–Heatdamage
•Burns
–Osmoticchange
•Drowning
Another cause of ‘haemolytic’ anaemia
How might anaemia develop from defects in red cell metabolism?
Red cell enzyme defects can lead to anaemia as energy is needed to maintain the membrane and cytoskeleton so if there’s not enough it cannot be fully maintain and is susceptible to damage or change in shape so recognised as abnormal by the spleen and removed.. this results in a haemolytic anaemia. energy also required to keep iron in its reduced state.
Best recognised are:
◦Glucose-6-phosphate dehydrogenase
◦Pyruvate kinase deficiency
How could injury cause anaemia?
Bad injury resulting in a large blood loss may cause anaemia. for example, stab wound, car crash.
How is the spleen adapted to help with large scale blood loss due to injury?
Blood can pool in the spleen to be utilised when needed.
When does the spleen remove RBCs in anaemia?
The spleen and other tissues of RES removes damaged or defective red cells
•It will do this in many of the causes of anaemia eg membrane disorders, enzyme disorders, haemoglobin disorders
What is a haemolytic anaemia?
red cells are destroyed more quickly as they are abnormal or damaged
What is the difference between intravascular and extravascular haemolytic anaemia?
- Within the blood vessels is intravascular
- Outside (within the RES macrophages in spleen. Liver, bone marrow) is extravascular
What is autoimmune haemolytic anaemia?
In this condition autoantibodies (ie Immunoglobulin -Ig – protein produced by own B lymphocytes) bind to the red cell membrane proteins
•Cells in the RES recognise part of the antibody, attach to it and remove it and the red cell from the circulation
Give two examples of when anaemia can be multifactorial
- In myelofibrosis, the bone marrow becomes fibrotic so there’s reduced space and sop reduced erythropoiesis. as a result erythropoiesis starts in the spleen by a lot of the RBCs pool there so there’s further anaemia.
- In thalassaemia there’s a mutation in one of the genes that codes for the chains in haemoglobin. as a result haemoglobin synthesis is ineffective so erythropoiesis spreads to the liver and spleen but the new RBCs also have structural deformities so are removed by the RES which further contributes to the anaemia.
what can we use to identify the type of anaemia in terms of evaluating it?
- By mechanism of anaemia
- By size –microcytic, normocytic, macrocytic
- By presence or absence of reticulocytosis
What can reticulocyte count tell us about a patient with anaemia?
Reticulocyte count can tell us about whether erythropoiesis is occurring correctly at the bone marrow. High reticulocyte count shows that the bone marrow is appropriately creating reticulocytes in response to the anaemia. If the reticulocyte count is low or not as high as expected in a patient with anaemia, it shows there’s an issue with erythropoiesis in the bone marrow.
What is the approach one should take when evaluating a patients anaemia when looking for a cause?
- is there an appropriate reticulocyte response?
If the answer to 1. is yes:
Is there evidence of haemolysis?
Yes - Cause?
No - Look for evidence of bleeding
If the answer to 1. is no:
what are the RBC indices?
(looking at whether anaemia is microcytic, normocytic or macrocytic)
what types of anaemia would come with reticulocytosis?
•Acute blood loss •Splenic sequestration •Haemolysis –Immune mediated eg autoimmune or drug related –Non-Immune *Mechanical ~Heart valves ~Microangiopathic haemolytic anaemia (MAHA) *Haemoglobinopathies *Enzyme defects *Membrane defects
What types of anaemia would be seen with a low reticulocyte count?
Low MCV (Microcytic) High MCV (Macrocytic) Normal MCV (Normocytic)
What anaemias have a low MCV (microcytic)?
•Low MCV (Microcytic) –Thalassaemia trait –Anaemia of chronic disease (though usually normocytic) –Iron deficiency –Lead poisoning –Sideroblastic anaemia (rare)
What anaemias have a high MCV (macrocytic)?
- Vitamin B12 deficiency
- Folate deficiency
- Myelodysplasia
- Liver disease
- Hypothyroidism
- Alcohol
what anaemias have a normal MCV (normocytic)?
Normal MCV (Normocytic) ◦Primary bone marrow failure -very rare Aplastic anaemia Red cell aplasia ◦Secondary bone marrow failure Anaemia of chronic disease Combined haematinic deficiencies (cause both macrocytic and microcytic so averages at normocytic) Uraemia Endocrine abnormalities HIV infection
Where do we get Vit B12 from?
From meat, eggs, fish and cheese?
How do we take Vit B12 into the body?
Vit B12 binds with Haptocorrin which is produced by our salivary glands. this complex then passes through the stomach and into the intestines. In the stomach there are parietal cells which produce hydrochloric acid and intrinsic factor (IF). this intrinsic factor exits the stomach and enters the small intestine. Pancreatic proteases in the small intestine break off the haptocorrin and the IF binds with the Vit B12 where it travels through the small intestine and IF-B12 complex binds with a receptor in the terminal ileum where the vitamin B12 is absorbed and IF destroyed.Once internalised B12 forms a complex with transcobalamin II and is released into the bloodstream for delivery to various tissues which possess specific receptors for the transcobalamin II-B12 complex
Why does vitamin B12 deficiency take so long to present?
Body stores can last from 3-6 years
What are the causes of low Vit B12
Dietary Deficiency: Vegan diet; poor diet
Lack of intrinsic factor : Pernicious anaemia (An autoimmune disease affecting gastric parietal cells causing lack of intrinsic
factor); gastrectomy
Disease of the ileum: Crohn’s disease; ileal resection; tropical sprue
Lack of Transcobalamin (transports B12 in the circulation): Congenital deficiency
Where does dietary folate come from?
Folate present in most foods, yeast, liver and leafy greens especially rich source
How long can we store folate for?
5mg stores for about 3-4 months
Where does absorption of folate occur?
Absorption occurs in the duodenum and jejunum
Where may a folate deficiency come from?
Dietary deficiency - poor diet
Increased use -
pregnancy, increased erythropoiesis eg haemolytic anaemia, severe skin disease (e.g psoriasis, exfoliative dermatitis)
Disease of the duodenum and jejunum - proximal small bowel disease eg coeliac disease, Crohn’s disease
Lack of methylTHF - drugs which inhibit dihydrofolate reductase enzyme (eg Methotrexate)
Others: alcoholism (multifactorial); urinary loss of folate in liver disease and heart failure; other drugs eg anticonvulsants
How are B12 and folate used in the body?
- Both B12 and folate play a role in converting homocysteine to methionine and the 2 vitamins are dependent on one another to do this.
- Vitamin B12 is responsible for reactivating folic acid, back into tetrahydrofolate, the form of folic acid which the body can use.-so low B12 causes a functional folate deficiency
- THF is essential for: serine-glycine conversion, histidine catabolism, purine synthesis, and most importantly, thymidylate synthesis which is needed throughout the body for DNA synthesis
- On the other hand, vitamin B12 needs folic acid to reduce homocysteine MTHF gives off its methyl group to vitamin B12 (cobalamin), which becomes methylcobalamin. At the same time, the MTHF folic acid is converted back into its bioactive form, tetrahydrofolate
- Methylcobalamin then gives off its methyl group to homocysteine, to create methionine
- Methionine is converted to S-adenosyl methionine (SAM) –one of the most important things for the production of various neurotransmitters and for DNA methylation.
Why does Vit B12 and folate deficiency cause a megaloblastic anaemia?
•So….both folate and Vit B12 deficiency ultimately lead to thymidylate deficiency
•In the absence of thymine, uracil is incorporated into DNA instead
•DNA repair enzymes detect the error and DNA strands are destroyed
•This causes asynchronous maturation between the nucleus and the cytoplasm.
–The nucleus (lacking DNA) does not fully mature,
–The cytoplasm ,in which RNA production and haemoglobin synthesis continues, matures at the normal rate.
Both B12 and folate necessary for nuclear divisions and nuclear maturation. When deficient, nuclear maturation and cell divisions lag behind cytoplasm development. This leads to large red cell precursors with
inappropriately large nuclei and open chromatin. The mature red cells are also large leading to a macrocytic anaemia
What megaloblastic features are shown in a peripheral blood film for someone with megaloblastic anaemia as a result of a B12/folate deficiency?
- macrocytic red cells
- anisopoikilocytosis with tear drops
- hypersegmented neutrophils
- Can see white cell precursors also
