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MEH > Haemolytic anaemias + Haemoglobinopathies > Flashcards

Haemolytic anaemias + Haemoglobinopathies Flashcards

1
Q

what are haemoglobinopathies

A

inherited disorders where expression of one or more of the globin chains of haemoglobin is abnormal

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2
Q

two main categories of haemoglobinopathies

A

abnormal haemoglobin variants
- result of mutations in genes for α or β chains
- alter stability and/or function of haemoglobin
- eg sickle cell disease

thalassaemias
- reduced or absent expression of normal globin chains
- imbalance in composition of haemoglobin tetramer
- reduced level of haemoglobin

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3
Q

inheritance pattern of haemoglobinopathies

A
  • typically autosomal recessive
  • heterozygotes show mild or no symptoms
  • homozygotes show symptoms of disease
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4
Q

structure of haemoglobin

A
  • tetramer of 4 globin polypeptide chains
  • 2 alpha (α) chains and 2 non-alpha chains (β
    , δ or γ)     held together by noncovalent interactions
  • each globin chain complexed with an oxygen binding haem group
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5
Q

changes in haemoglobin types

A
  • different haemoglobins expressed during developent as an adaptive response to variations in oxygen requirements
  • several embryonic forms expressed early in development
  • fetal haemoglobin (HbF) main form just before birth
  • HbA commences before birth and steadily increases to become dominant after birth
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6
Q

3 main types of haemoglobin in adults

A
  • HbA 2α+2β ~95%
  • HbA2 2α+2δ ~3%
  • HbF 2α+2γ <1%
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7
Q

where are the globin gene clusters located

A
  • α globin genes on chromosome 16
  • γ, δ, β globin genes on chromosome 11
  • humans have 4 α genes and 2 β genes
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8
Q

expression of globin genes

A
  • expression of these genes under tight control to ensure 1:1 ratio of α:non-α chains
  • defects in regulation of expression of globin genes can result in abnormalities in absolute and relative amounts of globin chains resulting in thalassaemia
  • defects in coding regions result in abnormal variants with structural defects that alter stability and/or function of haemoglobin
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9
Q

thalassaemias

A
  • heterogeneous group of genetic disorders
  • more prevalent in South Asian, Mediterranean, Middle east and Far east
  • result from decreased or absent α or β globin chain production resulting in an imbalance in composition of a2b2 tetramer
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10
Q

α thalassaemia

A

deletion or loss of function of one or more of the four α globin genes
1- silent carrier state
- asymptomatic
- carrier of disease

2- α thalassaemia trait
- minimal or no anaemia
- microcytosis and hypochromia
- resembles β thalassaemia minor

3- Haemoglobin H disease (HbH)
- moderately severe anaemia
- tetramers of β globin (HbH) form
- microcytic, hypochromic anaemia
- target cells and Heinz bodies
- resembles β thalassaemia intermedia

4- hydrops fetalis
- severe anaemia, in utero death
- excess γ globin forms tetramers in foetus (Hb Bart) that can’t deliver oxygen to tissues

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11
Q

β thalassaemia

A

mutation in one or both β globin genes leading to reduction or absence of β globin
β thalassaemia minor/trait
- asymptomatic with mild anaemia
- microcytic and hypochromic RBC
- resembles α thalassaemia trait
- heterozygous

β thalassaemia intermedia
- severe anaemia
- mild variants of homozygous (reduction)
- some compound heterozygous states

β thalassaemia major
- severe transfusion dependent anaemia
- manifests 6-9 months after birth when synthesis switches from HbF to HbA
- homozygous

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12
Q

thalassaemia phenotypes

A
  • thalassaemia major transfusion dependent
  • thalassaemia intermedia require transfusions intermittently
  • thalassaemia minor require no transfusions
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13
Q

peripheral blood smear results of thalassaemia

A
  • hypochromic and microcytic RBC
  • anisopoikilocytosis
  • frequent target cells
  • nucleated RBC
  • Heinz bodies
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14
Q

how is thalassaemia a form of haemolytic anaemia

A
  • relative excess of the unaffected globin chain contributes to defective nature of RBC eg. insoluble aggregates of α chains
  • haemoglobin aggregates get oxidised
  • premature death of erythroid precursors within bone marrow leading to ineffective eryhtropoiesis
  • excessive destruction of mature red cells in spleen leading to shortened RBC survival
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15
Q

consequences of thalassaemia

A
  • extramedullary haemopoiesis to compensate but results in splenomegaly, hepatomegaly and expansion of haemopoiesis into bone cortex imparing growth and skeletal abnormalities
  • reduced oxygen delivery leads to stimulation of EPO which further contributes to drive to make more defective RBC
  • iron overload due to repeated blood transfusions to treat anaemia and the excessive absorption of dietary iron due to ineffective haemopoiesis
  • reduced life expectancy
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16
Q

treatment for thalassaemias

A
  • red cell transfusion from childhood
  • iron chelation to delay iron overload
  • folic acid to support erythropoiesis
  • immunisation
  • holistic care - cardiology, endocrine, psychological, ophthalmology input to manage complications
  • stem cell transplantation to replace defective red cell production
  • pre-conception counselling for at risk couples and antenatal screening
17
Q

what is sickle cell disease

A
  • autosomal recessive disease due to mutation of β globin gene causing HbS variant
  • GAG changed to GTG so uncharged valine instead of charged glutamic acid at position 6 of β globin
  • HbS variant common in black africans, arab, mediterranean and south asian
  • heterozygous HbS (sickle cell trait) causes mild anaemia and resistance to malaria due to changes in RBC making it hard for Falciparum parasite to grow
  • homozygous HbSS develop sickle cell disease
  • HbS can be co-inherited with another abnormal Hb e.g. HbC or β thalassaemia
18
Q

mechanism of sickle cell anaemia

A
  • HbS forms** tetramers under normal oxygen tension** so readily gives up oxygen compared to HbA
  • HbS forms polymers under low oxygen tension causing cell to form sickle shape
  • repeated episodes of sickling causes red cell membrane to lose its elasticity causing irreversibly sickled red blood cells
19
Q

consequences of sickle cell formation

A

vaso-occlusive episodes due to occlusion of small capillaries from trapped sickle cells
- recurrent acute pain
- painful bone crises
- stroke
- acute chest syndrome
- chronic kidney disease
- avascular encrosis - joint damage

anaemia
- sickle cells undergoing haemolysis
- shortened erythrocyte lifespan from ~120 days to ~20-30 days

jaundice and gallstones
- increased bilirubin from chronic haemolysis

splenic atrophy
- splenic infarction
- susceptibility to infection by encapsulated bacteria (streptococcus pneumoniae, streptococcus meningitidis)

aplastic crises
- often triggered by parvovirus

20
Q

treatment for sickle cell anaemia

A

haemopoietic stem cell transplantation is only cure but rarely performed
treatment concentrated on reducing symptoms with regular medical care to prevent complications:
- folic acid
- penicilin
- vaccinations
- hydroxycarbamide - increases HbF levels
- red cell exchange

21
Q

what is haemolytic anaemia

A
  • results from abnormal breakdown of RBC in blood vessels (intravascular haemolysis) or spleen (extravascular haemolysis)
  • normal RBC lifespan ~120 days
  • bone marrow can compensate for decrease in lifespan by increasing production up to a point (5-6 fold)
  • if haemolysis exceeds capacity of marrow then rate of destruction exceeds rate of production and anaemia develops
22
Q

consequences of haemolytic anaemia

A
  • severity of anaemia typically worse than chronic disease if Hb very low or sudden fall in Hb
  • accumulation of bilirubin leading to jaundice and pigment gallstones
  • overworking of red pulp leading to splenomegaly
  • massive sudden haemolysis can cause cardiac arrest due to lack of oxygen delivery to tissues & hyperkalaemia due to release of intracellular contents
23
Q

key laboratory findings in haemolytic anaemias

A
  • raised reticulocytes as marrow tries to compensate
  • raised bilirubin due to breakdown of Haem
  • raised LDH as red cells rich in this enzyme
24
Q

types of haemolytic anaemis

A

inherited defective gene
- glycolysis defect (pyruvate kinase deficiency)
- pentose phosphate pathway (G6PDH deficiency)
- membrane protein (eg hereditary spherocytosis)
- haemoglobin defect (eg sickle cell)

acquired damage to cells
- mechanical damage (eg microangiopathic anaemia)
- antibody damage (autoimmune haemolytic damage)
- oxidant damage (exposure to chemicals or oxidants)
- heat damage (severe burns)
- enzymatic damage (snake venom)

25
Q

microangiopathic haemolytic anaemias (MAHA)

A

mechanical damage of red cells
- shear stress as cells pass through defective heart valve eg. in aortic valve stenosis
- cells snagging on fibrin strands in small vessels where there’s increased activation of clotting cascade eg. in DIC

heat damage from severe burns
osmotic damage

26
Q

what is disseminated intravascular coagulation (DIC)

A

bleeding and clotting occur at the same time in the patient eg. malignancy, obstetric complications, trauma, sepsis

27
Q

what is thrombotic thrombocytopenic purpura

A

syndrome where small thrombi form within the microvasculature

28
Q

what is haemolytic uraemic syndrome (HUS)

A

clots in vessels of kidney common in children after developing E coli diarrhoea

29
Q

what are schistocytes

A
  • fragments of RBC resulting from mechanical damage
  • good indicator that some form of pathology is present
30
Q

autoimmune haemolytic anaemias

A
  • caused by autoantibodies binding to red cell membrane proteins
  • result from infections, lymphoproliferative disorders and reactions to drugs (eg. cephalosporins)
  • classified as warm (IgG) or cold (IgM) based on the temperature the autoantibodies react best under laboratory conditions
  • macrophages in the spleen recognises antibody bound cells as abnormal and destroys them
  • red cell lifespan reduced resulting in anaemia
31
Q

warm (IgG) autoimmune haemolytic anaemia

A
  • IgG antibodies recognise epitopes on red cell membrane
  • leads to macrophages in spleen recognising antibody-coated red cells and destroying cell by phagocytosis or nibbling a bit off
  • some membrane is lost so red cells form a spherocyte
  • splenomegaly often occurs as spleen is doing extra work
32
Q

cold (IgM) autoimmune haemolytic anaemia

A
  • IgM autoantibodies recognise red cell epitopes and complement fixed to patient’s red cells
  • bind best at cooler temps so bind in distal parts of body like fingertips
  • IgM autoantibodies span several red cells creating large agglutinates that block small capillaries
  • creates ischaemic conditions in peripheral body parts causing numb fingertips, pallor, blue discolouration, gangrene
  • IgM falls off in warmer parts of body and agglutination disappears
  • complement binding to RBCs directly create holes in membrane and cause macrophages in spleen to recognise and destroy cells
33
Q

what is the direct Coombs test

A
  • used to detect antibodies or complement bound to surface of RBCs
  • patient’s red cells mixed with anti-human globulin antibody that will attach to antibodies on red cell making them clump together
  • suggests patient’s haemolysis is immune related
34
Q

how does pyruvate kinase deficiency cause haemolytic anaemia

A
  • mutations in PKLR gene causing deficiency in pyruvate kinase which catalyses final step in glycolysis and produces ATP
  • red blood cells lack mitochondria so deficiency inhibits their only metabolic pathway that supplies ATP for cellular processes
  • sodium potassium ATPase pump activity inhibited from insufficient ATP so red cells lose potassium to plasma
  • water moves down concentration gradient causing cells to shrink resulting in cellular death and haemolytic anaemia
  • mild deficiency doesn’t require treatment, severe deficiency require regular blood transfusions
35
Q

how does G6PDH deficiency cause haemolytic anaemia

A
  • G6PDH is rate limiting enzyme of pentose phosphate pathway which supplies reducing energy by maintaining NADPH levels
  • NADPH protects against oxidative stress by maintaining level of reduced glutathione
  • pentose phosphate pathway only source of reduced glutathione in RBCs
  • risk of haemolytic anaemia in states of oxidative stress such as infection or certain chemicals and medications
  • damaged red cells are phagocytosed in spleen and metabolism of excess Hb to bilirubin can lead to jaundice
36
Q

hereditary spherocytosis

A
  • inherited autosomal dominant disease
  • abnormalities in erythrocyte membrane proteins causing cells to be spherical which make cells less flexible and more easily damaged
  • ankyrin, spectrin, protein 4.2 or Band 3 defects disrupt vertical interactions between cytoskeleton and plasma membrane
  • poor deformability of spherocytes causes them to be trapped and damaged as they pass through spleen resulting in reduced lifespan and haemolytic anaemia
  • symptoms include anaemia, jaundice, splenomegaly and Howell-Jolly bodies in blood
  • severe symptoms improved with partial or full splenectomy
37
Q

hereditary eliptocytosis

A
  • many cells elliptical rather than biconcave disc shape
  • spectrin defect most common
  • also defects in band 4.1, band 3 and glycophorin C proteins
38
Q

hereditary pyropoikilocytosis

A
  • spectrin defect
  • severe form of hereditary elliptocytosis
  • abnormal sensitivity of red cells to heat
  • similar morphology to thermal burns

MEH (26 decks)

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