Anaemia Flashcards
Define anaemia
Haemoglobin concentration lower than the normal range
(normal range varies with gender, age and ethnicity so the point at which a patient becomes anaemic depends on those parameters)
Key clinical point about anaemia
It is NOT a diagnosis
It is a clinical manifestation of an underlying disease state
It is important to ESTABLISH CAUSE
Symptoms of anaemia (7)
Shortness of breath Headaches Angina Weakness/lethargy Confusion Palpitations Claudication
Signs of anaemia
Pallor Tachycardia Systolic flow murmur Tachypnoea (fast breathing) Hypotension
Specific signs associated with the cause of anaemia
Koilonychia (spoon nails, iron deficiency)
Angular Stomatitis (inflammation around mouth, iron deficiency)
Glossitis (inflammation and smooth tongue, Vit B12 deficiency)
Abnormal facial bone development (Thalassaemia)
Reasons anaemia can develop (bone marrow)
Reduced or dysfunctional erythropoesis
Abnormal Haem synthesis
Abnormal globin chain synthesis
Reasons anaemia can develop (RBC)
Abnormal structure
Mechanical damage
Abnormal metabolism
Reasons anaemia can develop (removal)
Excessive bleeding
Increased removal by reticuloendothelial system
Reduced/dysfunctional erythropoesis reasons explained (5)
Lack of erythropoietin (chronic kidney disease as kidney produces it)
Bone marrow cannot respond to erythropoietin (eg after chemo)
If marrow is infiltrated by cancer cells or fibrous tissue (myelofibrosis), the number of normal haemopoeitic cells is reduced
Anaemia of chronic disease = no iron available to marrow for bc production
Myelodysplastic syndromes (rare forms of blood cancer) = abnormal clones of stem cells so no capacity to make RBC or WBC
Role of erythropoetin
- It works in a negative feedback loop
- Pericytes in kidney detect low O2 of blood (hypoxia)
- Kidney produces erythropoietin
- EPO binds to receptors on erythroblasts in bone marrow and stimulates RBC production
- Number of RBC increases
- High blood oxygen
- This is sensed by the kidney and EPO production goes down
What is defect in haem pathway called?
Sideroblastic anaemia
Reasons haemoglobin synthesis can be affected
Sideroblastic anaemia
Iron deficiency anaemia
Anaemia of chronic disease - results in a lack of functional iron
Mutations in genes encoding gloin chain proteins ( we see that in patients with a and b thalassaemia and sickle cell disease)
Inherited reasons for haemolytic anaemia
- Mutations in genes coding for proteins in membrane and cytoskeleton of RBC
- Cause cells to be less deformable and more fragile
- They break up in circulation and removed by RES
= haemolytic anaemia (eg Hereditary spherocytosis)
Acquired reasons for haemolytic anaemia
Microangiopathic haemolytic anaemia (MAHA) from mechanical damage
Heat damage from severe burns
Osmotic damage (drowning in fresh water)
Reasons for mechanical damage in patients with MAHA (Microangiopathic haemolytic anaemia) occurs
Shear stress as cells pass through defective heart valve
Cells snag on fibrin strands in small vessels where clots have been formed and they break down (eg in Disseminated Intravascular Coagulation)
Blood film blood cells mechanical damage
Schistocytes - fragments of RBC resulting from mechanical damage
Causes of defect in RBC metabolism
G6PDH deficiency
Pyruvate kinase deficiency
Why does G6PDH deficiency cause anaemia?
- Mature RBC’s don’t have mitochondria to give energy, they rely on certain glycolytic pathways
- Decreased G6PDH = Lack of NADPH
- Lack of NADPH = lower GSH (glutathione)
- lower GSH = less protection of RBC from oxidative stress
- Oxidative stress
- Oxidative stress (eg from infection, drugs like anti malaria, and broad beans)
- Oxidative stress leads to
Lipid peroxidation (leads to cell membrane damage) and protein damage to RBC
=
Heinz bodies (aggregates of cross linked haemoglobin)
Red cells recognised by RES as defective and removed
Why does pyruvate kinase deficiency cause anaemia?
- RBC have no mitochondria so depend on glycolysis for energy production
- Pyruvate kinase is final enzyme of glycolysis
- Some patients may have rare genetic defects in this enzyme
- A defective glycolytic pathway causes RBC’s become deficient in ATP and undergo haemolysis
What are the 3 excessive bleeding causes of anaemia?
- Acute blood loss
- Chronic NSAID’s (Nonsteroidal anti-inflammatory drugs)
- Chronic bleeding (most common)
Acute blood loss causes of anaemia
Injury
Childbirth
Surgery
Ruptured vessel
Chronic excessive bleeding causes of anaemia
- Heavy menstrual bleeding
- Repeated nosebleeds
- Haemorrhoids
- GI bleeding (blood loss in stool)
- Kidney/bladder tumours (blood loss in urine)
Causes of GI bleeding
Ulcers (stomach or intestine) Polyps in large intestine Intestinal cancer NSAIDS Diverticulotis
How can NSAID usage lead to anaemia?
Nonsteroidal anti-inflammatory drugs treat conditions with pain and inflammation:
- Asprin
- Ibruprofen
- Naproxen
They Induce GI bleeding by:
- Inhibit cyclooxygenase activity
- Direct cytotoxic effects to epithelium
Describe the role of the Reticuloendothelial system in causing anaemia and
Describe what happens in autoimmune haemolytic anaemias
What can occur as a result of haemolytic anaemias?
Haemolytic anaemia = RBC destroyed more quickly due to abnormality or damage
Autoimmune haemolytic anaemia:
- Autoantibodies bind to RBC membrane proteins causing them to be recognised by macrophages in spleen and destroyed
(splenomegaly often occurs with haemolytic anaemias as the spleen is doing extra work)
In haemolytic anaemias, blood cells are destroyed more quickly as they are abnormal or damaged. Where can the damage occur?
- Within the blood vessels (intravascular haemolysis)
- Within the RES (extravascular haemolysis)
Organs involved in RES
Spleen
Liver
Myelofibrosis explained
- Mutated haemopoetic stem cells results in reactive bone marrow fibrosis
- Fibrotic marrow with little space for haemopoesis
- Mutated Progenitor cells from marrow then colonise liver and spleen leading to extramedullary haemopoesis
(such patients often have hepatomegaly
and splenomegaly)
Thalassaemia explained
- Inherited disorder
- Results from Decreased/absent alpha and beta globin chain production
- Results in defective Microcytic and hypochromic RBC
(can result in splenomegaly if haemoglobin H disease)
How to work out the cause of an anaemia/evaluate it
1) Size of RBC - macrocytic, microcytic, normocytic (big, small or normal)
2) Presence/absence of reticulocytes - is there a reticulocytosis or not? (is bone marrow responding to anaemia by pumping out immature cells?)
What are reticulocytes?
Immature RBC
No nucleus
Take about 1 day to mature into erythrocytes
Slightly larger than mature RBC
What do you bear n mind when measuring MCV?
Reticulocytes are Larger than RBC so an increase in reticulocyte number can increase MCV when measuring
What do reticulocytes show?
If marrow is able to respond to anaemia (you would expect increased reticulocyte count if marrow was responding to anaemia/working normally)
Evaluate the Causes of anaemia if the reticulocyte is high/increased
1) If there is an increased in reticulocyte count, the Bone Marrow if functioning normally
2) Is there evidence of Haemolysis? (we would know because there would be high bilirubin and high LDH - lacate dehydrogenase)
If YES, determine the cause of Haemolysis:
Autoimmune, MAHA, Membrane defects, enzyme defect, haemonoglobinopathies
3) If no, look for evidence of bleeding:
Acute blood loss
Chronic bleeding
Use of NSAID’s
Evaluate the Causes of anaemia if the reticulocyte is low/no increase
1) If the reticulocyte is low/no increase, there is a problem in the bone marrow
2) We look at the RBC indices/MCV - Mean cell volume
Microcytic: TAILS Thalassaemia Anaemia of chronic disease Iron deficiency Lead poisoning Sideroblastic anaemia
Macrocytic: Vit B12 deficiency Folate deficiency Liver disease Alcohol toxicity Myelodysplasia
Normocytic:
Could be because they have got a combo of microcytic and microcytic cells
Primary bone marrow failure (e.g. aplastic anaemia)
Secondary bone marrow failure (HIV)
Macrocytic anaemia types
Megaloblastic
Maconormoblastic
Stress erythropoesis
Megaloblastic macrocytic anaemia
- The reticulocyte count is low but the cells are large
- Interreference with DNA synthesis during erythropoeisis and nucleus isn’t maturing at the same rate as cytoplasm
- Cell division is delayed and erythroblasts continue to grow to form megaloblasts
Megaloblastic macrocytic anaemia causes
Vit B12/Folate deficiency
Drugs that interfere with DNA synthesis (anti-cancer)
Macronormoblastic macrocytic anaemia
Normal nucleus and cytoplasm relationship
Cells just larger than normal
Macronormoblastic macrocytic anaemia causes
Liver disease
Alcohol toxicity
Stress erythropoesis
High reticulocyte count
High levels of erythropoetin = accelerated erythropoesis
Causes of stress erythropoesis
Recent blood loss from haemorrhage
Recovery from haemolytic anaemia
Megaloblasts appearance
Larger than normal erythroblasts
Large immature nuclei
What is folate synthesised from?
Bacteria and plants
Where is folate found?
Animal and veg food
Particularly LEAFY GREENS
Where is folate absorbed
Duodenum and jejenum
What happens to folate when absorbed?
Coverted to tetrahydrofolate by intestinal cells
Then taken up by liver - acts as a store
Role of folate
Provides carbons for other reactions
Synthesis of nucleotide bases for DNA and RNA synthesis
Store of folate in body
3-4 months
Causes of folate deficiency
Poor diet
Increased requirements - pregnancy, haemolytic anaemia, severe skin disease (psoriasis)
Disease of duodenum or jejunum (coeliac, crohns)
Drugs that inhibit dihydrofolate reductase (Methotrexate)
Alcoholism
Liver disease/Heart failure
Symptoms of folate deficiency
Anaemia symptoms Reduced sense of taste Diarrhoea Numbness and tingling in hands/feet Muscle weakness Depression
Key point babies and folate
Need 400 micrograms per day of folate before conception to 12 weeks of pregnancy
Deficiency can result in neural tube defects for babies
Vitamin B12 function
Water soluble
Co-factor for DNA synthesis
Needed for erythropoesis
Normal function and development of CNS
What produces Vitamin B12
Bacteria (found in foods of animal origin)
Vitamin B12 sources
Meat Fish Eggs Milk Cheese Yeast extract
Vitamin B12 supplements
People on vegan diet need to eat foods with fortified B12 or 10 micrograms a day supplements
What does vitamin b12 bind to in stomach
Haptocorrin
What happens to haptocorrin vitamin b12 complex?
Digested by pancreatic proteases
Releasing B12
What does the released B12 then bind to?
Intrinsic factor
What does intrinsic factor vitamin B12 complex bind to?
Cubam receptor
= receptor mediated endocytosis into enterocytes
How does vitamin B12 exit basolateral membrane?
Through MDR1
How is Vitamin B12 transported in blood?
Binds to transcoalbumin
Where is B12 stored?
Mostly liver - 3-6 years worth of storage
Causes of Vitamin B12 deficiency
Dietary deficiency (vegan)
Lack of intrinsic factor - Pernicious anaemia
Disease of ileum (Crohns)
Lack of transcoalbumin (congenital)
Chemical inactivation of B12 (nitrious oxide gas use)
Parasitic infestation (tapeworm traps B12)
Some drugs chelate Vit B12 (hypercholestrolaemia drug Cholestyramine)
What is pernicious anaemia?
Decreased/absent intrinsic factor causing low Vitamin B12
Autoimmune disease
Antibodies involved with pernicious anaemia
Blocking Ab blocks binding of B12 to IF
Binding Ab prevents receptor mediated endocytosis
Symptoms of Vit B12 deficiency
Anaemia Glossitis / mouth ulcers Diaarrhoea Paraesthesia Disturbed vision Irritability
What defieciencies cause defects in CNS
Vit B12 - demyelination*
and Folate - neural tube
*which then can cause subacute combined degeneration of the cord
What is subacute combined degeneration of the cord?
Degeneration of the posterior and lateral columns of spinal cord - need urgent haematologist if neurological involvement
Symptoms of subacute combined degeneration of the cord
Gradual onset - weakness, numbness and tingling in arms legs and trunk
Progressively worsens
Changes in mental state
What does lack of B12 do?
Traps folate in methyltetrahydrofolate form
Prevents synthesis of thymidine
B12 and Folate cycles are linked
How do Vitamin B12 and folate cause megaloblastic anaemia?
Thymidine deficiency
Uracil incorporated instead
DNA repair enzymes detect and repair via excision
Asynchronous maturation of nucleus and cytoplasm
(nucleus doesnt fully mature, cytoplasm matures at normal rate)
RBC in folate and Vit b12 deficiency
Large red cell precursors
Inappropriate large nuclei
Open chromatin
Megaloblastic blood film
Anisopoikilocytosis (varied shape and size) Tear drop Ovalocytes Hyper segmented neutrophils Macrocytic red cells
- progressively becomes pancytopenia in B12/folate deficiency
Treatment of folate deficiency
Oral folic acid
Treatment of vitamin B12 deficiency
Pernicious: Hydroxycobalamine intramuscular (NOT ORAL)
Other causes: Oral cyancobalamine
What can happen at start of treatment of pernicious anaemia?
Hypokalaemia - increased K+ requirement as erythropoesis is using it
What happens if you blood transfuse someone with vitamin B12 deficiency?
High output cardiac failure
Heart has adjusted to low O2 and then is working too hard
