Red Cells Flashcards
what is anaemia?
the reduction in red cells or their haemoglobin content
main causes of anaemia
blood loss
increased destruction
lack of production
defective production
describe the development of red cells
see notes
what substances are required for red cell production?
metals - iron, copper, cobalt, manganease
vitamina -B12, folic acid,thiamine, B6, C, E
amino acids
hormones - erythropoietin, GM-CSF, androgens, thyroxine, SCF
normal life span of RBC
120 days
where does red cell breakdown take place?
in macrophages of reticuloendothial system
what happens to haem after red cell breakdown?
converted to biliverdin and bilirubin
what happens to globin and iron after red cell breakdown?
reutilised
describe the bilirubin cycle
see notes
defects in what parts of RBCs cause congenital anaemia
membrane
enzymes
haemoglobin
most congenital anemias result in what?
haemolysis
what are skeletal proteins in RBCs responsible for?
maintaining red cell shape and deformability
what can defects in the RBC cells membrane proteins caused?
increased cell destruction - haemolysis
what proteins are most commonly mutated in red cell membranes?
ankyrin
band 3
spectrin
draw a RBC membrane
see notes
Hereditary spherocytosis: inheritance
autosomal dominant
Hereditary spherocytosis: structural protein defects
ankyrin alpha spectrin beta spectrin band 3 protein 4.2
Hereditary spherocytosis: shape of cells
spherical
Hereditary spherocytosis: how are cells removed from circlulation?
haemolysis extravascular by spllen
Hereditary spherocytosis: clinical presentation
anaemia
jaundice (neonatal)
splenomegaly
pigment gallstones
Hereditary spherocytosis: treatment
folic acid
transfusion
splenectomy
name 3 rare membrane disorders
hereditary elliptocytosis
hereditary pyropoikilocytosis
South East Asian Ovalocytosis
name 2 cycles occuring in red cells. how are they linked?
gylcolysis
pentose phosphate shunt
glucose-6-phosphate dehydrogenase
in RBCs what is the purpose of glycolysis?
provides energy
in RBCs what is the purpose of the pentose dehydrogenase shunt?
protects from oxidative damage
what protects red cell proteins from oxidative damage?
glucose 6 phosphate dehydrogenase (G6PD)
what does G6PD produce?
NADPH
what is NADPH vital for?
reduction of glutathione
what does reduced glutathion do?
scavenges and detoxifies reactive oxygen species
what is the commonest disease causing enzymopathy in the world?
G6PD deficiency
what does G6PD deficiency result in?
cells vulnerable to oxidative damage
where is G6PD most common and why?
malarial areas as confers protection against severe falciparum
inheritance in G6PDdeficiency
x linked
what characteristics are there of RBCs in G6PD deficiency?
blister and bite cells
where does haemolysis occur in G6PD deficiency, what is the problem with this?
intravascular
haemoglobin can reach kidneys
clinical presentation of G6PD deficiency
neonatal jaundice
drug, broad bean or infection precipitated jaundice and anaemia
splenomegaly
pigment gall stones
triggers to haemolysis in G6PD deficiency
infection
acute illness e.g. DKA
broad beans “favism”
what drugs can cause G6PD deficiency?
o Antimalarials – primaquine, pamaquine o Sulphonamides and sulphones – salazopyrin, dapson, seprtin o Antibacterials – nitrofurantoin o Analgesics – aspirin o Antihelminths – B-naphthol o Vitamin K analogues o Probenecid o Methylene blue
name a rare enzyme deficiency disorder and briefly describe it
o Reduced ATP
o Increased 2,3,-DPG
o Cells rigid
o Variable severity – anaemia, jaundice, gallstones
o More liable to haemolysis in circulation
in deoxyhaemoglobin what enzyme holds it in the tight binding structure?
2,3-DPG
function of haemoglobin
gas exchange
affinity of foetal haemoglobin (HbF) for oxygen compared to HbA
higher
describe the structure of normal adult haemoglobin
2 alpha chains
4 alpha genes, Chr16
2 beta chains
2 beta genes, Chr11
describe the composition of haemoglobin in a normal adult
HbA (aabb) - 97%
HbA2 (aadd) - 2%
HbF (aayy) - 1%
what are haemoglobinopathies?
inherited abnormalities of haemoglobin synthesis
what is thalassaemia?
reduced or absent globin chain production
give examples of mutations that lead to structurally abnormal globin chains
HbS (sickle) HbC HbD HbE HbO Arab
inheritance of haemoglobinopathies
autosomal recessive
structure of sickle haemoglobin
haem
2 alpha chains
2 beta (sickle) chains
what mutation leads to sickle beta chains
point mutation - glutamate to valine
describe the consequences of sickle cell
red cell injury, cation loss, dehydration
describe the process of vaso-occlusion in sickle cell
haemolysis endothelial activation promotion of inflammation coagulation activation dysregulation of vasomotor tone by vasodilator mediations (NO) vaso occlusion
describe polymerisation in sickle cell
Some of the major complications of sickle cell disease (SCD) such as acute chest syndrome, stroke and pain episodes are attributed to vasoocclusive tissue damage. Cerebral vasculopathy is a major risk factor for stroke. The primary pathophysiologic mechanisms for lung disease are unknown. Pulmonary vasculopathy may be a risk factor for acute chest syndrome pulmonary hypertension. Both are leading causes of morbidity and mortality in adults with sickle cell disease.
sickle cell presentation
retinopathy cardiomegaly - congestive HF cholelithiasis renal infarcts - haematuria bone marrow hyperplasia aseptic bone necrosis - osteomyelitis ulcer vaso-occlusion infarcts of extremities splenomegaly - splenic atrophy pulmonary infarcts -pneumonia cerebral infarcts - stroke - mental retardation
complications of sickle cell
• Painful vaso-occlusive crises o Bone • Chest crisis • Stroke • Increased infection risk o Hyposplenism – splenic infarction and atrophy • Chronic haemolytic anaemia o Gallstones o Aplastic crisis – eyrthrovirus • Sequestration crises o Spleen – children, pooling of RBCs and not getting out, enlarged spleen o Liver – enlarged liver • Life expectancy o Males 42 o Females 48 o Childhood and perinatal mortality contribute to this reduction
treatment of a painful crisis in sickle cell
• Severe pain – often requires opiates o Analgesia should be given within 30 mins of presentation o Effective analgesia by 1 hour o Avoid pethidine • Hydration • Oxygen • Consider • Antibiotics • No routine role for transfusion
describe a chest crisis in sickle cell
- Life threatening
- Chest pain
- Fever
- Worsening hypoxia
- Infiltrates on CXR
- Respiratory support
- Antibiotics
- IV fluids
- Analgesia
- Transfusion – top up or exchange target HbS < 30%
- Incentive spirometry shown to reduce incidence
management of sickle cell
• Lifelong prophylaxis o Vaccination o Penicillin and malarial prophylaxis o Folic acid • Acute events o Hydration o Oxygenation o Prompt treatment of infection o Analgesia Opiates NSAIDs • Blood transfusion o Episodic and chronic o Alloimmunisation o Iron overload • Disease modifying drugs o Hydroxycarbamide • Bone marrow o Transplantation o Severe • Gene therapy o Severe
thalassaemia can result from mutations/delections in
alpha genes
beta genes
also gamma and delta but less important
thalassaemia results in
chain imbalance - chronic haemolysis and anaemia
spectrum of thalassaemia from fatal to minor
homozygous alpha zero thalassaemia
thalassaemia major
thalassaemia intermedia
thalassaemia minor
what is homozygous alpha zero thalassaemia
no alpha chains
hydrops fetalis - incompatible with life
what is beta thalassaemia major
no beta chains
transfusion dependent anaemia
when may someone with thalassaemia intermedia require transfusions?
times of stress
what is thalassaemia minor?
carrier
hypochromic microcytic cells
asymptomatic
severe anaemia in beta thalassaemia major results in
o Expansion of ineffective bone marrow
o Bony deformities
o Splenomegaly
o Growth retardation
when does beta thalassaemia major present?
3-6months
treatment of beta thalassaemia major
chronic transfusion
iron chelation therapy
bone marrow transplant
how often do those with beta thalassaemia major require blood transfusions? what can this cause?
4-6 weekly
iron overloading
consequences of iron overloading
death in 2nd/3rd decade due to heart/liver/endocrine failure if unteated
describe iron chelation therapy
s/c deferrioxamine infusions (Desferal)
Oral deferasirox (exjade)
If good adherence life expectancy >40
describe rare defects in haem synthesis
Defects in mitochondrial steps of haem synthesis result in sideroblastic anaemia. ALA synthase mutations. X linked inheritance. Acquired myelodysplasia. Defects in cytoplasmic steps result in porphyrias.
what factors influence normal haemoglobin?
age sex ethnic origin time of day time to analysis
normal haemoglobin: male 12-70
140-180
normal haemoglobin: male > 70
116-156
normal haemoglobin: female 12-70
120-160
normal haemoglobin: female >70
108-143
clinical features of acquired anaemia are due to?
reduced oxygen delivery to tissues
clinical features of acquired anaemia
tiredness/pallor breathlessness swelling of ankles dizziness chest pain
clinical features of acquired anaemia related to underlying cases
evidence of bleeding
symptoms of malabsorption - diarrhoea, weight loss
jaunice
splenomegaly/lymphadenopathy
potential causes of anaemia due to bleeding
menorrhagia
dyspepsia
PR bleeding
what further tests would you do in a hypochromic microcytic anaemia?
serum ferritin
what further tests would you do in a normochromic normocytic anaemia?
reticulocyte count
what further tests would you do in a macrocytic anaemia?
B12/folate
bone marrow
most common cause of hypochromic microcytic anaemia?
iron deficiency
hypochromic microcytic anaemia, serum ferritin = low
iron deficiency
hypochromic microcytic anaemia, serum ferritin = normal/increased
secondary anaemia
thalassaemia
sideroblastic anaemia
describe iron metabolism
Transferrin can contain up to two atoms of iron. Transferrin delivers iron to tissues that have transferrin receptors, especially erythroblasts in the bone marrow which incorporate the iron into haemoglobin. At the end of the red cell life cycle, the red cells are broken down in the macrophages of the reticuloendothelial system and the iron is released from haemoglobin, enters the plasma and is reutilised to provide most of the iron on transferrin. Only a small proportion of plasma transferrin iron comes from dietary iron, which comes in via the duodenum and jejunum. Some iron is stored in the macrophages as ferritin and haemosiderin, which varies depending on overall body iron status. Iron is also present in the muscle as myoglobin and in most other cells of the body in iron-containing enzymes e.g. cytochromes, succinic dehydrogenase, catalase. Body has no way of getting rid or iron hence why it builds up in transfusions
Hepcidin goes up in menstruation, inflammation and renal impairment to stop utilising iron. Iron absorbed in duodenum - Fe2+ > Fe3+. Transported from enterocytes and. macrophages by ferroportin. Transported in plasma bound to transferrin. Stored in cells as ferritin. Hepcidin synthesised in hepatocytes in response to inflammation (also renal failure and ↑iron levels)– blocks ferroportin so reduces intestinal iron absorption and mobilisation from reticuloendothelial cells.
causes of iron deficiency
dyspepsia, GI bleeding menorrhagia diet increased requirement e.g. pregnancy malabsorption
what may cause malabsorption of iron?
gastrectomy
coeliac disease
principles of management in iron deficiency
correct the deficiency
correct the cause
how to correct iron deficiency
oral iron
IV if intolerant of oral
transfusion rarely indicated
how to correct the cause of iron deficiency
diet
ulcer therapy
gynae interventions
surgery
nomochromic normocytic anaemia, reticulocyte count = increased
blood loss
haemolysis
nomochromic normocytic anaemia, reticulocyte count = normal/low
secondary anaemia
hypoplasia
marrow infiltration
results of haemolytic anaemia
accelerated red cell destruction - decreased haemoglobin
compensated by bone marrow - increased reticulocytes
causes of haemolytic anaemia: congenital
hereditary spherocytosis
enzyme deficiency G6PD def
haemoglobinopathy - sickle cell
causes of haemolytic anaemia: acquired
autoimmune haemolytic anaemia
mechanical e.g. artificial valve
sever infections/DIC
PET/HUS/TTP
extra vs intravascular. acquired haemolytic anaemia - immune related
extravascular
extra vs intravascular. acquired haemolytic anaemia - non-immune related
intravascular
in haemolytic anaemia what does it mean if DAGT is positive?
immune related
causes of acquired immune haemolysis + warm auto antibody
auto immune
drugs
CLL
causes of acquired immune haemolysis +cold autoantibody
CHAD
infections
lymphoma
causes of acquired immune haemolysis + alloantibody
transfusion reaction
how do you determine if a patient is haemolysing?
o FBC, reticulocyte count, blood film
o Serum bilirubin (direct/indirect), LDH
o Serum haptoglobin
how do you determine the cause of haemolysis?
o History and examination
o Blood film
o Direct antiglobulin test (Coombs’ test)
o Urine for haemosiderin/urobilinogen -intravascular haemolysis
management of haemolytic anaemia
• Support marrow function o Folic acid • Correct cause o Immunosuppression if autoimmune Treat trigger e.g. CLL , lymphoma o Remove site of red cell destruction Splenectomy o Treat sepsis, leaky prosthetic valve, malignancy etc if intravascular • Consider transfusion
secondary anaemia aka
anaemia of chronic disease
secondary anaemia is mostly what type?
normochromic normocytic
what causes secondary anaemia?
Defective iron utilisation as a result of increased hepcidin in inflammation. Ferritin is often elevated. Identifiable underlying disease – infection, inflammation, malignancy.
causes of megalblastic macrocytic anaemia
B12/folate deficiency
causes of non-megaloblastic macrocytc anaemia
myelodysplasia
marrow infiltration
drugs
causes of B12 deficiency
pernicious anaemia
gastric/ileal disease
causes of folate deficienc
dietary
increased requirements e.g. haemolysis
GI pathology e.g. coeliac
how is B12 absorped?
dietary B12 binds to intrinsic factor, secreted by gastric parietal cells. B12-IF complex attaches to specific IF receptors in distal ileum. Vit B12 bound by transcobalamin II in portal circulation for transport to marrow and other tissues
mechanism of pernicious anaemia
It is an autoimmune disease. Antibodies against intrinsic factor (diagnostic) and gastric parietal cells. There is malabsorption of dietary B12, but the signs and symptoms take around 1-2 years to develop.
causes of non-megaloblastic macrocytosis
• Alcohol • Drugs o Methotrexate, antiretrovirals, hydroxycarbamide • Disordered liver function • Hypothyroidism • Myelodysplasia
