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2A week 1 - anaemia, RBC metabolism etc. > the red blood cell and what can go wrong > Flashcards

the red blood cell and what can go wrong Flashcards

1
Q

what 5 things do RBCs need to function

A
  1. efficient production (synthesis)
  2. to be pliable (get through small vessels)
  3. haemoglobin to carry oxygen
  4. enzymes for metabolism
  5. removal of defective cells
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2
Q

what is erythropoiesis

A

synthesis of red cells

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3
Q

where does erythropoiesis happen

A

in the bone marrow - alongside production of other blood cell lines

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4
Q

what is the progenitor cell for RBCs

A

myeloid stem cell

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5
Q

erythropoiesis pathway

A

stem cell ->immature RBC -> erythroblast -> nucleated RBC -> reticulocyte (nucleus lost) -> erythrocyte

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6
Q

requirements for erythropoiesis (5)

A

normal stem cell; normal maturation; healthy bone marrow microenvironment; growth factors (erythropoietin, GM-CSF); essential components (iron, vit B12, folate, amino acids)

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7
Q

what gives RBCs their pliability

A

their structure - biconcave shape that arises due to Band-3 proteins and Spectrin in the membrane

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8
Q

fucntions of band-3 and spectrin

A

band-3 : provides a verticle scaffold for the cell membrane;
spectrin: comprises the main component of the cytoskeleton (provides a horizontal scaffold)

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9
Q

what is HbA comprised of

A

2 alpha and 2 beta globulin chains + 4 haem groups

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10
Q

where are the genes for the alpha globulin chains (chromosome)

A

chromosome 16

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11
Q

where are the genes for the beta-like globulin chains

A

chromosome 11

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12
Q

why are there twice as many alpha genes as beta genes

A

alpha chains are more important - they are present on all forms of haemoglobin from foetal stage onwards

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13
Q

what are the beta-like globulin chains and what Hb are they associated with

A

β - HbA (adult)
γ - HbF (foetal)
δ - HbA2 (low levels)

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14
Q

when is the switch from γ to β chain synthesis complete

A

3-6 months after birth; remains the same in adult life

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15
Q

why is it important to note the delay in switch from HbF to HbA (occurs at 3-6mo)

A

conditions with a β chain gene mutation will not present at birth as HbF (gamma chains) is still predominant

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16
Q

examples of β-chain mutations that may manifest 3-6mo after birth

A

sickle cell haemoglobin; β-thalassaemia

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17
Q

why is haemoglobin different in the foetus

A

HbF has a higher oxygen affinity and so O2 therefore flows from the maternal circulation to foetal and more readily across the placenta

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18
Q

why are enzymes essential to the function of RBCs

A

RBCs have no nucleus or mitochondria and so rely on enzymes to maintain the integrity of the cell membrane

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19
Q

primary functions of enzymes in RBCs + examples (2)

A
  1. protection against oxidative stress: G6PD -> involved in the pentose phosphate pathway -> generates NADPH which stabilises the RBC;
  2. ATP production: pyruvate kinase is involved in glycolysis (first step of ATP production)
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20
Q

what is the lifespan of a normal RBC and what are they removed by

A

120 days; removed by macrophages

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21
Q

what is anemia

A

a haemoglobin concentration below the reference range (specific to age and biological sex of the pt)

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22
Q

what 3 things does anaemia occur as a result of

A
  1. too few RBC;
  2. reduced Hb levels (on a normal/raised number of RBCs);
  3. abnormally low haematocrit;
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23
Q

what is a haematocrit

A

the term used for the percentage/ratio of blood made up of RBCs - packed cell volume

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24
Q

what can reduce the haematocrit

A

reduction of RBCs or increase in plasma volume

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25
Q

what do the symptoms of anaemia depend on and why

A

the speed of onset - acute will have more marked symptoms while chronic will have less severe as the body has had time to compensate for Hb reduction

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26
Q

what ar the 3 types of anaemia (according to MCV)

A

microcytic; normocytic; macrocytic

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27
Q

5 causes of microcytic anaemia

A

iron deficiency; thalassaemia; anaemia of chronic disease; lead poisoning; sideroblastic anaemia

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28
Q

5 causes of normocytic anaemia

A

anaemia of chronic disease; acute blood loss; chronic renal failure; mixed B12/folate and iron deficency; bone marrow disorders

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29
Q

7 causes of macrocytic anaemia

A

B12/folate deficency; liver disease; drugs/alcohol; reticulocytosis (haemolyis); hypothyroidism; myelodysplasia; pregnancy

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30
Q

how else can anaemia be classified (not MCV)

A

reduced RBC production; increases destruction (haemolysis) or loss

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31
Q

what may cause an RBC stem cell to be defective

A

inherited condition; acquired (drugs, infections, immune)

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32
Q

what may cause defect maturation of an RBC

A

lack of nutrients important for DNA synthesis; blood disorder causing impaired maturation e.g. myelodysplasia

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33
Q

what may cause an unhealthy microenvironment for RBCs to be produced

A

damage (radiation, infections etc.); lack of space (fibrosis, primary haem malignancy, secondary malignancy)

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34
Q

what is the effect of chronic renal impairment on RBC production

A

reduced erythropoietin levels resulting in decreased stimulation of RBCs

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35
Q

what kind of anaemia usually occurs due to decreased RBC production (not due to iron/B12 deficiency)

A

normocytic, normochromic

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36
Q

what does a low reticulocyte count indicate (and low RBCs)

A

bone marrow failure -> numbers should be higher is bone marrow is responding to a drop in RBC

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37
Q

what is aplastic anaemia

A

bone marrow cannot make enough new blood cells for your body to work normally

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38
Q

what is myelodysplastic syndrome

A

a group of cancers in which immature blood cells in the bone marrow do not mature or become healthy blood cells

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39
Q

what is anaemia of chronic disease

A

ineffective iron utiisation due to raised hepcidin -> result of a chronic inflammatory disease

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40
Q

what does raised hepcidin cause

A

functional iron deficiency - in ability to use iron effectively in the production of red blood cells

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41
Q

anaemia of chronic disease ferratin + transferrin saturation levels

A

ferratin - high
transferrin saturation - low

42
Q

what is haemolytic anaemia

A

anaemia due to RBC destruction > production

43
Q

what is haemolysis

A

the breakdown of RBCs before their normal lifespan (120 days)

44
Q

what happens to RBC production when haemolysis occurs and what cell will be increased in circulation due to this

A

production is increase, the bone marrow can increase production by 6-8x the normal rate; leads to increased number of reticulocytes circulating in the blood

45
Q

why are reticulocytes purple in colour (on a blood film)

A

it still contains some RNA within it

46
Q

3 signs of haemolysis

A

jaundice - when Hb breaks down, bilirubin is formed -> build up of it in the body causes jaundice;
dark urine - bilirubin -> urobilinogen which causes dark urine;
gallstones - when haemolysis is chronic
(possibly also haemoglobinuria and anaemia signs - fatigue etc.)

47
Q

blood results in haemolysis

A

MCV - normal or high (normocytic or macrocytic anaemia);
reticulocytes - raised;
unconjugated bilirubin - raised;
LDH - raised;
heptoglobin - low;

48
Q

what is LDH and when does it become raised

A

an intracellular enzyme that catalyzes the conversion of lactate to pyruvate and back, as it converts NAD⁺ to NADH and back; it becomes raised when cell turnover is increased

49
Q

intrinsic causes of haemolysis (3)

A
  1. membranopathy
  2. metabolism (enzymopathy)
  3. haemoglobinopathies
50
Q

3 inherited RBC membrane abnormalities and their consequence

A
  1. hereditary spherocytosis
  2. hereditary elliptocytosis
  3. herediatry stomatocytosis

leads to RBCs that cannot maintain their biconcave shape -> leads them to being more eaily damages and thus removed by macrophages earlier in their lifecycle

51
Q

what type of inheritance are RBC membrane defects usually

A

autosomal dominant

52
Q

4 conditions that may be caused by inherited RBC defects

A
  1. mild anaemia presenting at any age;
  2. jaundice fluctuations (usually worse during infections);
  3. gallstones;
  4. aplastic crises precipitated by parvo virus (B19) - temporary failure in RBC production
53
Q

what is an aplastic crisis

A

when the bone bone marrow suddenly stops making red blood cells so you develop severe and potentially life-threatening anemia

54
Q

what is the Coomb’s test

A

a test used to detect antibodies that act against the surface of your red blood cells - antibodies directed against human antibody is added to a sample of the pt’s RBCs and if they are coated in antigen they will agglutinate by cross linking with the antibody

55
Q

investigations for suspected inherited RBC membrane defect

A

FH, blood film, haemolysis screen, special tests (e.g. EMA binding, genetic testing)

56
Q

treatment for inherited RBC membrane defect

A

folic acid; splenectomy (severe cases)

57
Q

what is the most common enzymopathy associated with haemolysis

A

G6PD deficency

58
Q

why is G6PD essential to the RBC

A

allows the RBC to protect itself from oxidative stress -> produces NADPH via pentose phosphate pathway which is needed for glutathioe regenration (this detoxified H2O2);

without this RBC breakdown when exposed to oxidative stress

59
Q

what inheritance pattern is G6DP deficiency and how does this affect the epidemiology

A

X-linked recessive -> affects males more than females

60
Q

examples of oxidative stressors that may cause acute haemolysis episodes

A

drugs; infections; moth balls; fava beans

61
Q

what would a positive Coomb’s test indicate

A

autoimmune cause

62
Q

where in the world are haemoglobin abnormalities more common

A

areas with malaria -> shorter RBC life span would offer protections against some forms of malaria thus giving them an evolutionary advantage

63
Q

what is a cause of thalassaemia

A

reduced globin chain synthesis: α thalassaemia occurs due to reduce α chain synthesis and β due to reduce β chain synthesis

64
Q

what kind of people is thalassaemia most common in

A

people of asain, african or mediterranean

65
Q

consequences of thalassaemia pathway (4)

A
  1. chain imbalance
  2. excess α/β chains precipitate
  3. precipitated chains damage RBC membrane
  4. damaged cells destroyed prematurely by macrophages
66
Q

thalassaemia major vs trait

A

major - NO α/β chains produced;
trait - reduced α/β chains produced (person is largely unaffected);

67
Q

what is HbH disease

A

people who have 1/4 alpha genes functioning and produce Hb with four β chains instead -> variable phenotype, some require lifelong transfusion while others are mildly affected

68
Q

β thalassaemia train Hb composition in the body

A

greater proportion of Hb is made up by HbA2 (2α + 2 δ)

69
Q

what is important to know about with 2 gene deletion α thalassaemia trait (genetics) and why

A

whether the deletions are from the same chromosome (α-0-thalassaemia trait) or not (α-plus-thalassaemia trait) -> risk of conceiving a foetus with no α genes at all (if partner is also α-0-thalassaemic)

70
Q

what kind of anaemia is seen in pts w thalassaemia/thalassaemia trait and what must be excluded in diagnosis

A

hypochromic, microcytic anaemia - must rule out iron deficiency

71
Q

how can the relative quantities of each haemoglobin type be established

A

haemoglobin electrophoresis/ high performance liquid chromatography - separated the different haemoglobins according to their charge

72
Q

why is HbA2 higher in beta thalassaemia trait

A

some excess α chains pair with δ chains leading to raised HbA2 levels

73
Q

why does haemoglobin analysis not pick up alpha-thalassaemia trait?

A

there is a global reduction in Hb rather than just one specific type reduced

74
Q

what kind of anaemia is sickle cell disease

A

chronic haemolytic anaemia

75
Q

alongside HbS, what else might be seen in a blood test of a sickle cell anaemic

A

leucocytosis; thrombocytosis - common in pts with poor splenic function

76
Q

what is a compound heterozygote and what does it mean in terms of sickle cell anaemia

A

a type of germline variant that occurs when each parent donates one alternate allele and these alleles are located at different loci within the same gene - i.e. one parent donates a sickle cell allele and the other an absent β gene (β-thalassaemia trait) -> without this no β chains can be made so HbA cannot be produced, only HbS and HbA2

77
Q

what is paroxysmal nocturnal haemoglobinuria

A

a rare disease in which RBCs lyse prematurely (haemolysis) - due to inability of the RBCs to protect themselves from being attacked by compliment proteins

78
Q

4 extrinsic causes of haemolysis

A

antibody attack (against rbc memebrane); mechanical trauma to the rbc; infections; chemical + physical agents

79
Q

what is autoimmune haemolytic anaemia

A

haemolytic anaemia caused by the person’s own antibodies attacking the rbc -> leads to their premature removal by the spleen

80
Q

what test is used to detect autoimmune haemolytic anaemia

A

Coomb’s test

81
Q

warm vs cold antibodies (AIHA)

A

warm - antibodies that bind to RBCs at body temperature, usually IgG;
cold - antibodies that bind below body temperature, usually IgM

82
Q

4 causes of warm autoimmune haemolytic anaemia

A
  1. idiopathic (usually);
  2. autoimmune conditions e.g. SLE (secondary to);
  3. disordered immune system (low grade lymphoma, CLL etc.);
  4. drugs - antibodies agaisnt drug-RBC membrane complex (penicillin) or antibodies against the rbc membrane (methyldopa);
83
Q

where does rbc breakdown happen in warm autoimmune haemolytic anaemia

A

the reticuloendothelial system (live + spleen)

84
Q

4 causes of cold autoimmune haemolytic anaemia

A

IgM antibodies can activate complement and cause intravascular haemolysis;
1. idiopathic;
2. lymphoma (usually);
3. infections (EBV etc.);
4. paroxysmal cold haemoglobinura (rare, associated w siphylis);

85
Q

paroxysmal cold haemolgobinuria pathophys

A

IgG antibody is formed which is capable to binding to RBCs in the cold but only capable of causing haemolysis in the warm where it can activate complement

86
Q

AIHA lab findings

A

anaemia; reticulocytosis; raised LDH; raised unconjugated bilirubin; positive Coombs

87
Q

warm autoimmune haemolytic anaemia blood film

A

spherocytes (red cells with no central pallor)

88
Q

cold autoimmune haemolytic anaemia blood film

A

red cell agglutination

89
Q

autoimmune haemolytic anaemia management

A
  1. treat any underlying cause;
  2. keep pt warm if cold AIHA and consider warming any blood for transfusion;
  3. folic acid supplements (otherwise anaemia would be worsened);
  4. tranfusion;
  5. immune suppression (coticosteroids for warm, rituximab (anti- CD20) for both);
  6. splenectomy if resistant
90
Q

what can mechanical trauma cause to the rbc

A

intravascular haemolysis

91
Q

3 examples of mechanical trauma causes

A
  1. microangiopathic haemolytic anaemia;
  2. fault mechanical heart valves;
  3. march harmoglobinuria (repeated mechanical force on capillaries in feet e.g. during marching or marathon running);
    4.
92
Q

Coomb’s and urine test results for mechanical rbc trauma haemolysis

A

Coomb’s -ve; urine +ve for Hb (as haemolysis occurs in BVs)

93
Q

blood film of mechanical trauma haemolysis

A

schistocytes - fragmented red blood cells

94
Q

what infections can cause haemolysis

A

malaria;

95
Q

what chemical/physical agents can cause haemolysis (5)

A

drugs (dapsone); copper; lead; burns; snake/spider bites etc.

96
Q

what condition is an acquired cause of instrinsic haemolysis

A

paroxysmal nocturnal haemoglobinuria

97
Q

where is there a defect in PNH

A

bone marrow stem cells -> defect in the anchoage of surface proteins because of the absence of glycoslyphoshatidylinositol (GPI)

98
Q

why do rbcs lyse in PNH

A

the lack of GPI means that the red cell is not protected form lysis by compliment

99
Q

findings in a PNH pt (bloods, urine)

A

blood - high levels of free Hb;
urine - dark

100
Q

what are PNH pts at an increased risk of

A

clot formation esp at unusal sites e.g. hepatic veins

2A week 1 - anaemia, RBC metabolism etc. (5 decks)

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