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Haematology > Haemolytic Anaemias > Flashcards

Haemolytic Anaemias Flashcards

1
Q

What is anaemia?

A

A reduced haemoglobin level for the age and gender of the individual

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2
Q

What is haemolytic anaemia?

A

anaemia due to shortened RBC survival

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3
Q

Describe the variation in blood haemoglobin concentration throughout life

A

Babies when they’re born have HbF which is very high in concentration [180-190 g/dl] which falls in the first few months of life

Children have lower Hb than adults and females have lower Hbs than men

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4
Q

Where are RBCs produced?

A

RBCs produced in bone marrow along with all the factors required for their production (iron, B12/folate, Globin chains, protoporphyrins to carry haem)

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5
Q

What stimulates RBC growth?

A

Erythropoietin (EPO hormone) signals RBC production

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6
Q

How are RBCs released into circulation?

A

RBCs lose their nucleus as they exit bone marrow into circulation where they survive for ~120days

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7
Q

What is the fate of RBCs after 120 days?

A

As RBCs mature, changes occur to their red cell membranes identified by macrophages in the liver & spleen. These organs remove the older RBCs from circulation

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8
Q

Describe the structure of mature RBCs in circulation

A

Seen in peripheral circulation

Biconcave disc shape; comply able to fit through small capillaries

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9
Q

What are the metabolic pathways taking place within RBCs?

A
  • glycolytic pathway

- hexose-monophosphate shunt

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10
Q

What is the role of the metabolic pathways in RBCs?

A

Hb delivers O2 to tissues

Metabolic pathways maintain energy in RBC and keep it running

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11
Q

What is the consequence of incorrect functioning of RBC metabolic pathways?

A

Problems with these factors or external factors can reduce no. of RBCs

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12
Q

What is haemolysis?

A

Destruction of RBCs

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13
Q

How odes haemolysis affect the lifespan of RBCs?

A

Shortened red cell survival 30 - 80 days

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14
Q

How does the bone marrow compensate for haemolysis?

A

Bone marrow compensates with increased EPO ⇒ increased red blood cell production

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15
Q

What effect does haemolysis have on RBCs in circulation?

A

Increased young cells in circulation = Reticulocytosis +/- nucleated RBC

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16
Q

What is compesated haemolysis?

A

RBC production able to compensate for decreased RBC life span = normal Hb

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17
Q

What is Incompletely compensated haemolysis?

A

RBC production unable to keep up with decreased RBC life span = decreased Hb

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18
Q

Describe the clinical findings of haemolysis

A
  • Jaundice (unconjugated bilirubin)
  • Pallor/fatigue
  • Splenomegaly
  • Dark urine
  • Haemolytic crises-increased anaemia and jaundice with
    infections/ precipitants
  • Aplastic crises-anaemia, reticulocytopenia with parvovirus
    infection
    (causes rash & red cheeks, affects erythroblasts)
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19
Q

What are the chronic clinical findings of haemolysis?

A
  • Gallstones; pigment due to breakdown of bilirubin
  • Splenomegaly; abnormal RBCs detected by
    macrophages from the spleen
  • Leg ulcers (Nitric Oxide scavenging)
  • Folate deficiency (increased use to produce more RBCs)
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20
Q

Describe the clinical findings of haemolytic anaemia identified in the lab?

A
  • Increased reticulocyte count
    (exceptions: parvovirus / an inability to produce RBCs)
  • Increased unconjugated bilirubin
  • Increased LDH (lactate dehydrogenase)
  • Low serum haptoglobin (protein that binds free
    haemoglobin)
  • Increased urobilinogen
  • Increased urinary haemosiderin
    (Fe from Hb picked up by urinary tract epithelial cells,
    excreted in urine)
  • Abnormal blood film
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21
Q

What is a blood film?

A

A thin layer of blood smeared on a glass microscope slide and then stained in such a way as to allow the various blood cells to be examined microscopically

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22
Q

What blood film stain allows us to the reticular network?

A

Supravital stain used to see reticular network

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23
Q

What are polychromatic cells?

A

olychromasia is a disorder where there is an abnormally high number of immature red blood cells found in the bloodstream as a result of being prematurely released from the bone marrow during blood formation

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24
Q

Describe the blood film of polychromatic cells

A

These cells are often shades of grayish blue

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25
Q

What are poikilocytes?

A

abnormally shaped RBCs

their shape helps identify cause

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26
Q

Summarise the clinical features of haemolytic anaemia

A 
Jaundice
Pallor
Splenomegaly
Pigment gallstones (chronic)
Risk of aplastic crisis from parvovirus B19
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27
Q

Summarise the lab findings of haemolytic anaemia

A 
Normal/ low haemoglobin
Reticulocytosis +/- NRBC
Raised LDH
Raised unconjugated bilirubin
Decreased haptoglobin
Increased urobilinogen +/- haemoglobinuria
Abnormal blood film
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28
Q

How is haemolytic anaemia classified?

A

Anaemia may be classified by
Inheritance
- genetic or acquired

Site of RBC destruction
- intravascular or extravascular

Origin of RBC damage
- intrinsic or extrinsic

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29
Q

Give an example of a inherited and acquired haemolytic anaemia

A

Inherited: Hereditary spherocytosis

Acquired: Paroxysmal noctural haemoglobiuria

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30
Q

Name haemolytic anaemias based on their site of RBC destruction

A

Intravascular: thrombotic thrombocytopenic purpura

Extravascular: Autoimmune Haemolysis

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31
Q

Give examples of haemolytic anaemias depending on the origin of RBC destruction

A

Intrinsic: G6PD

extrinsic: delayed haemolytic transfusion reaction

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32
Q

How do inherited haemolytic anaemias cause haemolysis?

A

Hereditary anaemias affect RBC membranes or enzyme function (G6PD etc.)

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33
Q

What are the inherited types of haemolytic anaemia?

A

Membrane Disorder

  • Spherocytosis
  • Elliptocytosis

Enzyme Disorders

  • G6PD deficiency
  • Pyruvate Kinase Deficiency

Haemoglobin DIsorders

  • Sickle Cell Anaemia
  • Thalassaemia
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34
Q

What are the acquired haemolytic anaemias?

A 
Immune 
Drugs
Mechanical
Microangiopathic
Inections
Burns
Paroxysmal Nocturnal
Hemoglobinuria
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35
Q

What is the most common site of RBC destruction?

A

Most commonly extravascular haemolysis

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36
Q

Outline how extravascular haemolysis occurs

A
  1. Macrophage engulfs and destroys abnormal RBC into its
    constituents
  2. Bilirubin excreted, Fe stored and released back into
    liver where globin chains are degraded into amino acids
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37
Q

Explain what occurs in intravascular haemolysis

A

Intravascular haemolysis

RBC not systematically broken down: all Hb released and pre-Hb in blood and urine

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38
Q

Describe the normal red cell membrane structure

A

Lipid bilayer

Integral proteins anchor membrane to cytoskeleton

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39
Q

Outline the protein defects in hereditary spherocytosis

A 
Defects in vertical interaction 
(hereditary spherocytosis)
- Spectrin
- Band 3
- Protein 4.2
- Ankyrin
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40
Q

Describe the protein defects in hereditary elliptocytosis

A 
Defects in horizontal interaction 
(hereditary elliptocytosis)
- Protein 4.1
- Glycophorin C
- (Spectrin – HPP)
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41
Q

What is the inheritance pattern for membrane disorders?

A

Most of these disorders are autosomal dominant, phenotypes run in families

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42
Q

What are spheorcytes?

A

Problems with vertical anchors = spherocytes

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43
Q

What are elliptocytes?

A

Horizontal stabilities = elliptocytes as cells elongate

44
Q

Describe the features of hereditary spherocytosis

A

Common hereditary haemolytic anemia
- Inherited in autosomal dominant fashion (75%)
- Defects in proteins involved in vertical interactions
between the membrane skeleton and the lipid bilayer
- Decreased membrane deformability
- Bone marrow makes biconcave RBC, but as they
circulate membrane is lost, the RBC become spherical

45
Q

How would a blood film differ between normal and spherocytosis RBCs?

A

Central pallor seen on blood film in normal RBCs

Spherocytosis blood film shows rounder RBCs with no central pallor and some polychromatic cells

46
Q

How is hereditary spherocytosis diagnosed?

A

Diagnose using DAT (direct antiglobulin test): identifies Ab on RBC membrane
-ve in hereditary spherocytosis
+ve in autoimmune haemolysis

47
Q

Outline the clinical features of hereditary spherocytosis

A
  • Asymptomatic to severe haemolysis
  • Neonatal jaundice
  • Jaundice, splenomegaly, pigment gallstones
  • Reduced eosin-5-maleimide (EMA) binding – binds to
    band 3 membrane protein
  • Positive family history
  • Negative direct antibody test
48
Q

How is Hereditary spherocytosis managed?

A

Monitor
Folic acid
Transfusion (~1-2%)
Splenectomy

49
Q

What are enzymopathies?

A

Defects within RBC Metabolic Pathways

50
Q

What is the significance of glycolysis?

A

Glycolysis required for energy- ATP
Na/K pump
3 Na+ out 2 K+ in
ATP ADP+Pi

51
Q

What is the significance of the hexose monophosphate shunt?

A

HMS – reducing power -NADPH/GSH

52
Q

What is the isgnificance of the 2,3 BPG pathway?

A

2,3 Bi-PhosphoGlycerate (2,3 BPG) – modulates O2 binding to Haemoglobin

53
Q

What are the most common enzyme abnormalities?

A

G6PD

Pyruvate Kinase

54
Q

What is the role of the HMP shunt?

A

Role of the HMP shunt:

  • Generates reduced glutathione
  • Protects the cell from oxidative stress
55
Q

When do G6PD patients experiece problems?

A

G6PD patients RBCs are normal but when exposed to oxidative stress can cause problems

56
Q

What are the effects of oxidative stress on G6PD patients

A
  • Oxidation of Hb by oxidant radicals
  • Resulting denatured Hb aggregates & forms Heinz
    bodies; bind to membrane
  • Oxidised membrane proteins; reduced RBC deformability
57
Q

Describe the inheritance pattern of G6PD

A

Hereditary, X-linked disorder
Common in African, Asian, Mediterranean and Middle Eastern populations
Mild in African (type A), more severe in Mediterraneans (type B
Clinical features range from asymptomatic to acute episodes to chronic haemolysis

58
Q

What are teh oxidative precipitants of G6PD pateints

A 
Oxidative Precipitants
Infections
Fava/ broad beans
Many drugs
Dapsone
Nitrofurantoin
Ciprofloxacin
Primaquine
59
Q

Name examples of oxidative precipitant drugs

A
  • Dapsone
  • Nitrofurantoin
  • Ciprofloxacin
  • Primaquine
60
Q

Describe the blood film of G6PD patients

A

Bite cells were chunks have been taken out of RBCs

Blister cells & ghost cells from where membranes have blistered away from Hb

Heinz bodies (methylene blue)

61
Q

Why may an enzyme assay of a G6PD patient come back normal?

A

Reduced G6PD activity on enzyme assay

May be falsely normal if reticulocytosis

62
Q

What is the significance of pyruvate kinase?

A

PK required to generate ATP

Essential for membrane cation pumps (deformability)

63
Q

Describe the inheritance pattern of PKD

A

Autosomal recessive (rarer)

64
Q

What are the effects of PKD ?

A

Chronic anaemia
Mild to transfusion dependent
Improves with splenectomy

65
Q

Describe the blood film of PKD patiets

A

Blood film shows prickle cells - RBCs with pricks coming off the surface
Polychromasia also visible

66
Q

Describe the normal structure of Haemoglobin

A

Haem = Fe2+ ad protoporphyrin IX
Globin (protein)
2alpha and 2beta globin chains

67
Q

What is the normal Hb composition in adults?

A

There are alpha-like and beta-like chains

Lots of HbA (2alpha, 2beta) - adult Hb 
Some HbA2 (2alpha 2delta)
68
Q

Describe the structure of foetal Hb

A

Foetal Hb is designed to extract O2 from placenta rather than air and consists of 2alpha, 2gamma chains

69
Q

What is the Hb composition at birth

A

When you’re born Hb consist of ~20-30% HbA and rest is HbF

70
Q

What is the composition of Hb during early embryonic life?

A

During early embryonic life we mostly require alpha chains, beta chains are produced mainly postnatally

71
Q

Which Hb globin chain defects is responsible for most haemoglobinopathies

A

Haemoglobinopathies usually due to problems with beta chains so patients are fine during neonatal period

72
Q

Give an example of a alpha chain pathology

A

Alpha thalassemia 0 which causes problems in utero

73
Q

What are the two types of causes of haemoglobinopathies?

A
  • Quantitative

- Qualitative

74
Q

What are quantitative haemoglobinopathies?

A

Quantitative - thalassaemias:

Production increased/ decreased amount of a globin chain (structurally normal)

75
Q

What are qualitative haemoglobinopathies?

A

Qualitative – variant haemoglobins:

Production of a structurally abnormal globin chain

76
Q

What are the features of sickle cell?

A

HbS: autosomal recessive
sickle cell point mutations cause Hb changes

RBCs polymerise producing long spindly cells rather than normal round RBCs

77
Q

What are the features of Hb Koln?

A

Hb Koln: autosomal dominant

Alters Oxygen binding and becomes unstable

78
Q

What are the features of HbC?

A

HbC: autosomal recessive, RBCs crystalise

79
Q

What are thalassaemias?

A

Imbalanced alpha and beta chain production; too much of one causes issues

80
Q

Why are excess unpaired Hb globin chains problematic?

A
  • Precipitate and damage RBC and their precursors
    (erythroblasts)
  • Ineffective erythropoiesis in bone marrow
  • Haemolytic anaemia
81
Q

Which is the most common of the thalassaemias

A

Beta thalassaemia

82
Q

Describe the inheritance pattern of beta thalassaemia

A

Autosomal recessive: both parents would carry thalassaemia trait (small RBCs, low MCV) but are fine
¼ chance of having a child with both mutations

83
Q

How can parents detect if their baby will be a carrier of thalassaemia?

A

Antenatal screening offered in UK - blood test carried out to assess if baby is a carrier - can get prenatal diagnosis

84
Q

How is SCA tested in babies?

A

All babies are tested for SCA using a newborn blood spot which also detects thalassaemia

85
Q

Describe the blood film of a transfused patient

A

Normal RBCs as well as abnormal RBCs with precipitated Hb and ghost cells

86
Q

Describe the symptoms used to diagnose thalassaemia trait

A
  • Asymptomatic
  • Microcytic hypochromic anaemia
  • Low Hb, MCV, MCH
  • Increased RBC
  • Often confused with Fe deficiency
  • Compensatory increased HbA2; more delta chains in β-
    thal trait – (diagnostic)
  • a-thal trait often by exclusion
  • Globin chain synthesis (rarely done now)
  • DNA studies (expensive)
87
Q

Why is beta thalassaemia major so dangerous in children?

A

As children stop producing HbF and are unable to form correct HbA thalassemia patients become increasingly anaemic

88
Q

What are the effects of beta thalassaemia major?

A

Patients still try making Hb but it isn’t picked up so get enlarged spleen and liver

Transfusion dependent in 1st year of life

89
Q

What are the consequences of beta thalassaemia major if patients aren’t transfused?

A

If not transfused:

  • Failure to thrive
  • Progressive hepatosplenomegaly
  • Bone marrow expansion; skeletal abnormalities
  • Death in 1st 5 years of life from anaemia
90
Q

What are the side effects of transfusion in beta thalassaemia major patients?

A

Iron overload

  • Endocrinopathies
  • Heart failure
  • Liver cirrhosis
91
Q

What causes SCA?

A

Different combinations of genetic mutations can cause SCA

e. g. Clinically significant sickling syndromes:
- HbSS
- HbSC
- HbS-D Punjab
- HbS- O Arab
- HbS- β thalassaemia

92
Q

Outline how SCA arises

A
  1. point mutation in Beta globin gene: glutamic acid ->
    valine
  2. insoluble Hb tetramer when deoxygenated ->
    polymerisation
  3. sickle cell shaped cells
93
Q

Describe the pathophysiology of SCD

A

SCD causes a huge spectrum of problems due to intravascular haemolysis causing changes to NO

RBCs have abnormal membranes which alters the vasculature

94
Q

What are the acute complications of haemolytic anaemias?

A
  • Stroke: ischaemic + haemorrhagic
  • cholecystitis
  • hepatic sequestration
  • dactylitis
  • bone pain + infarcts
  • osteomyelitis
  • retinal detachment
  • vitreous haemorrhage
  • chest syndrome
  • splenic sequestration
  • haematuria papillary necrosis
  • priapism
  • aplastic crisis
  • leg ulcers
95
Q

Outline the chronic complications of haemolytic anaemias

A
  • silent infarcts
  • pulmonary hypertension
  • chronic lung disease, bronchiectasis
  • erectile dysfunction
  • chronic pain syndromes
  • Azoospermia
  • delayed puberty
  • moya-moya
  • retinopathy, visual loss
  • chronic renal failure
  • avascular necrosis
  • leg ulcers
96
Q

What are the clinical features of SCD?

A

Painful crises
Aplastic crises
Infections

97
Q

Outline the acute sickling features

A

Acute sickling:

  • Chest syndrome
  • Splenic sequestration
  • Stroke
98
Q

Outline the chronic sickling effects

A

Chronic sickling effects:

  • Renal failure
  • Avascular necrosis bone
99
Q

What are the lab features of SCD?

A 
Anaemia
Hb often 65-85
Reticulocytosis
Increased NRBC
Raised bilirubin
Low creatinine
100
Q

How is SCD diagnosis confirmed?

A

Solubility test
Expose blood to reducing agent
Hb S precipitated
Positive in trait and disease

electrophoresis to confirm
HPLC is not definitive – need sickle solubility test

101
Q

What are the 2 types of immune haemolysis?

A
  • autoimmune

- alloimmune

102
Q

What are the causes of autoimmune haemolysis?

A

Autoimmune (immune / ab mediated) - ab produced against own cells

Idiopathic

  • Usually warm
  • IgG, IgM

Drug-mediated (mainly antibiotics)
Cancer associated
- LPDs

103
Q

What are the causes of alloimmune haemolysis?

A

Alloimmune

Transplacental transfer:

  • Haemolytic disease of the newborn: D, c, L
  • ABO incompatibility

Transfusion related
- Acute haemolytic transfusion reaction; ABO
- Delayed haemolytic transfusion reaction E.g Rh groups,
Duffy

104
Q

Give examples of non-immune acquired haemolysis

A
  • Paroxysmal nocturnal haemoglobinuria

- fragmentation haemolysis

105
Q

What is paroxysmal nocturnal haemoglobinuria

A

Red cells have proteins protecting them from complement mediated lysis

Acquired mutations in these cause cells to become vulnerable to complements within the plasma causing lysis → haemoglobinuria; intravascular haemolysis

106
Q

What is fragmentation haemolysis?

A 
Red cell fragments on blood film due to:
Mechanical
Microangiopathic haemolysis
- Disseminated intravascular coagulation
- Thrombotic thrombocytopenic purpura
107
Q

What other ways can we acquire haemolysis?

A

Severe burns

Some infections: e.g. malaria

Haematology (8 decks)

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