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SEM 4: Haematology > Haemolytic Anaemias > Flashcards

Haemolytic Anaemias Flashcards

1
Q

What is the difference between haemolytic anaemia and normal anaemia?

A

Haemolytic anaemia is due to shortened RBC survival compared to reduced Hb level for the age and gender of the individual

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2
Q

Describe the normal Hb variation according to age

A

Babies have more foetal Hb
Children have less than adults
Women have less than men

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3
Q

What is the normal RBC lifecycle?

A
  1. RBC are produced in the bone marrow using Iron, B12 folate, Globin chains, and protoporphyrins
  2. Then, RBC are circulating for 120 days where they lose their nucleus.
  3. Next, the removal senescent RBC where there are changes on the RC membrane identified by liver and spleen removing RBC.
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4
Q

What does the mature RBC look like?

A

The membrane is a biconcave disc
There is haemoglobin which supplies oxygen
RBC carry out metabolic pathways: glycolytic pathway and hexose-monophosphate shunt

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5
Q

How is haemolysis combated in haemolytic anaemia?

A
  1. Shortened red cell survival 30-80 days -> This is when changes are noticed.
  2. Bone marrow compensates with increased red blood cell production
  3. Increased young cells in circulation = reticulocytes +/- nucleated RBC
    Compensated haemolysis: RBC production is able to compensate for decreased RB life span = normal Hb which need a reticulocyte count to tell
    Incompletely compensated haemolysis: RBC production unable to keep up with decreased RBC life span = decreased Hb which causes anaemia
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6
Q

What are the clinical findings of haemolytic anaemia?

A
  • Jaundice
  • Pallor/fatigue
  • Splenomegaly
  • Dark urine = increased bilirubin or free haemoglobin
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7
Q

What are the characteristics of congenital haemolysis?

A

Increased anaemia and jaundice with infections/precipitants

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8
Q

What are the characteristics of aplastic anaemia crisis?

A
  • Reticulocytopenia with parvovirus infection
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9
Q

What are the chronic clinical findings of haemolytic anaemias?

A
  • Gallstones: pigment -> pigment gallstones common in young teens
  • Splenomegaly
  • Leg ulcers (NO scavenging) -> pre-hemoglobin damages NO
  • Folate deficiency (increased use) -> seen in acute haemolysis using more folate
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10
Q

What are the haemolytic anaemia lab findings?

A
  • Increased reticulocyte count
  • Increased unconjugated bilirubin
  • Increased LDH (lactate dehydrogenase)
  • Low serum haptoglobin
  • Increased urobilinogen (bilirubin in urine)
  • Increased urinary haemosiderin
  • Abnormal blood film
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11
Q

Why is there increased lactate dehydrogenase?

A

Released from haemolysed RBC

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12
Q

What is haptoglobin?

A

Protein that binds free haemoglobin and there is less of it in haemoglobin anaemia

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13
Q

What is urinary haemosiderin?

A

When iron is picked up by cells in the urinary tract so in the urine.

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14
Q

What is polychromasia?

A

Purple -> reticulocytes on normal blood film

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15
Q

What are the different types of poikilocytes and what do they help us do?

A
  • Fragments
  • Irregularly contracted
  • Blister
  • Bite
  • Spherocytes
  • Elliptocytes
    Changes in RBC that can help with diagnosis
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16
Q

How are haemolytic anaemias classified?

A
  • Inheritance: Inherited (hereditary spherocytosis) and Acquired (paroxysmal nocturnal haemoglobinuria)
  • Site of RBC destruction: Intravascular - “pop” inside the bloodstream (thrombotic thrombocytopenic purpura) and Extravascular - mostly in the spleen not in the bloodstream (autoimmune haemolysis)
    Origin of RBC damage: Intrinsic (G6PD deficiency) and Extrinsic (Delayed haemolytic transfusion reaction)
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17
Q

Give examples of inherited anaemia

A
  • Sickle cell anaemia
  • Hereditary spherocytosis
  • G6PD deficiency
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18
Q

Examples of acquired anaemia (not born with)

A
  • Paroxysmal nocturnal haemoglobinuria

- Autoimmune haemolysis

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19
Q

Why is G6PD deficiency an intrinsic RBC damage?

A

There is not enough G6P production as there is an enzyme problem -> Intrinsic inside the cell itself

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20
Q

What are the inherited anaemias divided into?

A

Membrane disorders: spherocytes and elliptocytes -> anchor proteins on phospholipid bilayer change which changes the shape
Enzyme disorders: G6PD deficiency (glycolysis) and Pyruvate Kinase deficiency
Haemoglobin disorders: Sickle Cell anaemia and Thalassaemias

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21
Q

What can cause acquired anaemia?

A
  • The immune system can attack the RBC
  • Drugs can also attack the RBC
  • Mechanical (leaky value)
  • Microangiopathic causes hypertension
  • Infections such as malaria
  • Burns damage the RBC membranes
  • Paroxysmal Nocturnal Haemoglobinuria as the RBC are susceptible to complement-mediated haemolysis
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22
Q

How are RBC destroyed extravascularly?

A
  • Absorbed by macrophages that have enzymes which breakdown the RBC -> release the components such as iron, bilirubin, etc
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23
Q

How are RBC destroyed intravascularly?

A
  • RBC isn’t broken down but all the Hb is released into the blood and urine.
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24
Q

What are two membrane disorders?

A 
Hereditary spherocytosis (defects in vertical interaction) 
Hereditary elliptocytosis (defects in horizontal interaction)
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25
Q

What is the structure of the normal red cell membrane structure?

A
  • Lipid bilayer
  • Integral proteins
  • Membrane skeletons
  • Anchored to the cytoskeleton by proteins
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26
Q

What happens if there is a mutation in the cytoskeleton of the protein?

A

Mutations in the proteins affect the connection to the cytoskeleton. Most are autosomal dominant - phenotype runs in families.

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27
Q

What are the proteins affected in hereditary spherocytosis?

A
  • Spectrin
  • Band 3
  • Protein 4.2
  • Ankyrin
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28
Q

What are the proteins affected in hereditary elliptocytosis?

A
  • Protein 4.1
  • Glycophorin C
  • (Spectrin - HPP)
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29
Q

What is the most common hereditary haemolytic anaemia?

A

Hereditary spherocytosis

30
Q

What is hereditary spherocytosis?

A
  • Normal like RBC are deformed and shed as it travels in the blood.
  • 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 the membrane is lost, the RBC becomes spherical.
31
Q

What is DAT?

A

It is a direct antiglobulin test that detects red blood cells (RBCs) that are coated with complement and/or antibodies in-vivo (in the body).

32
Q

What is the DAT score in spherocytosis?

A

Hereditary spherocytosis = negative

Autoimmune spherocytosis = positive

33
Q

What is autoimmune spherocytosis?

A

Antibodies bind and remove parts of the membrane. Get these from the clinical history or do a DAT.

34
Q

What are spherocytes?

A
  • Small central pallor when normal but spherocytes have no central pallor and are rounder.
35
Q

What are the clinical features of HS?

A
  • Asymptomatic to severe haemolysis
  • Neonatal jaundice (may need to exchange transfusion -> more severe in babies as bilirubin can cross the BBB)
  • Jaundice, splenomegaly, pigment gallstones
  • Reduced eosin-5-maleimide (EMA) binding - binds to band 3
  • Positive family history
  • Negative direct antibody test
36
Q

How is HS managed?

A
  • Monitoring the patient
  • Folic acid to make more RBC quickly
  • Transfusion but mostly for children
  • Splenectomy (removal of the spleen)
37
Q

What is hereditary pyropoikilocytosis?

A

Autosomal recessive - more than one mutation

38
Q

What are the main RBC metabolic pathways?

A

Glycolysis: energy- ATP is produced
HMS: reducing power - NADPH/GSH
Rapoport Luebering Shunt: 2,3 Bi-phosphoGlycerate (2,3-BPG) - modulates O2 binding to haemoglobin

39
Q

What is the role of the Hexose Monophosphate Shunt (HMP)?

A
  • Generates reduced glutathione

- Protects the cell from oxidative stress

40
Q

What is G6PD? Where is G6PD common? What are the effects of G6PD?

A
  • An X-linked hereditary disorder that can be inherited by women so 50% of cells will be G6PD.
  • Clinical features range from asymptomatic to acute (become acutely jaundice) episodes to chronic haemolysis.
    Common in the Mediterranean
  • High rates of G6PD in Africa, the Caribbean, and parts of Africa
    RBC will look fine and lives to 120 days but if exposed to oxidizing agents e.g. foods - fibre and broad beans and drugs such as antimalarials. A cell cannot protect itself so oxidation of membrane proteins and Hb.
41
Q

What is the management of G6PD?

A
  • Inform pt to avoid foods and drugs
42
Q

What are the features of G6PD?

A
  • Haemolysis
  • Blood films: Bite cells, Blister cells as Hb away from the membrane; Heinz bodies (see the oxidising Hb - Methylene blue)
  • Reduced G6PD activity on enzyme assay: may be falsely normal if reticulocytosis as reticulocytes have higher enzyme levels than RBC
43
Q

What is the function of pyruvate kinase?

A

Required to generate ATP

Essential for membrane cation pumps (deformability)

44
Q

What is pyruvate kinase deficiency?

A

An autosomal recessive disorder that causes chronic anaemia. It is rarer than G6PD.

45
Q

What is the treatment of PKD?

A
  • Mild to transfusion-dependent

- Improves with splenectomy -> 1-2g rise in PKP when the spleen is removed

46
Q

What is the blood film of PKD look like?

A
  • Show smaller with spikes cells
  • Can see polychromasia
  • Only one lab in the UK that tests for the rare enzyme disorders
47
Q

Hb structure

A
  • Ferrous iron (Fe2+)
  • Protoporphyrin IX
    These form Haem
  • Globin (protein)
48
Q

What are haemoglobinopathies?

A

There is a problem with the globin protein chain.

49
Q

Structure of normal Hb

A

HbA - 2 alpha 2 beta
HbA2 - 2 alpha 2 delta
HbF - 2 alpha 2 gamma - designed to extract O2 from the placenta, not air.

50
Q

Describe the pattern of globin gene expression during foetal development

A
  1. Early in embryo life make embryonic haemoglobin which is different from HbA, HbF and HbA2. These contain alpha chains.
  2. Beta chains develop at about 4-5 weeks
51
Q

Why are beta chains important for diagnosing haemoglobinpathies?

A

Almost all haemoglobinpathies affect beta chains

52
Q

Why does alpha-thalassaemia 0 cause problems in utero?

A

Alpha chains are important in AT0

53
Q

What are thalassaemias?

A
  • Production increased/decreased amount of a globin chain (structurally normal)
  • Quantitative
  • Imbalanced alpha and beta chain production
  • Excess unpaired globin chains are unstable:
    • > Precipitate and damage RBC and their precursors
    • > Ineffective erythropoiesis in bone marrow
    • > Haemolytic anaemia
54
Q

What are other variant haemoglobins?

A
  • Production of a structurally abnormal globin chain

- Make enough but abnormal = variant haemoglobins

55
Q

What can cause variant haemoglobins?

A
  • Point Mutations: HbS -> decrease in solubility polymerisation
  • Alter O2 binding: Hb Koln -> decrease instability leading to the formation of Heinz body formation
  • Autosomal Recessive: HbC -> decrease solubility, crystallisation
56
Q

Stats of Beta Thalassaemia

A
  • Most common autosomal recessive

- 1/4 chance of the child having severe beta thalassaemia if both parents are carriers

57
Q

Blood film of beta thalassemia trait

A

Bit small blood cells

58
Q

Blood film of beta thalassaemia major

A

Abnormal blood cells

59
Q

Diagnosis of thalassaemia trait

A
  • Asymptomatic
  • Microcytic hypochromic anaemia
  • Low Hb, MCV, MCH
  • Increased RBC
  • Often confused with Fe deficiency
  • HbA2 increased in Beta-thal trait - (diagnostic)
  • A-thal trait often by exclusion
  • Globin chain synthesis (rarely done now)
  • DNA studies (expensive)
60
Q

Symptoms of beta thalassaemia trait

A
  • Transfusion dependent in 1st year of life
  • If not transfused: failure to thrive, progressive hepatosplenomegaly; bone marrow expansion - skeletal abnormalities; death in 1st 5 years of life from anaemia
  • Side effects of transfusion: iron overload leading to endocrinopathies, heart failure, and cirrhosis.
  • Stop making HbF can’t make beta chains and become progressively anaemic
  • Big liver and spleen -> changes to facial shape
  • After screening, it can be treated but without this, die early.
61
Q

What is sickle cell disease?

A
  1. Point mutation in the beta-globin gene; glutamic acid -> valine
  2. Insoluble haemoglobin tetramer when deoxygenated -> polymerisation.
  3. “Sickle” shaped cells
62
Q

Pathophysiology of SCA

A
  • Intravascular haemolysis
  • NO
  • Abnormal membranes affect vascularity
63
Q

What the complications of acute SCA?

A
  • Retinal detachment
  • Vitreous haemorrhage
  • chest syndrome
  • splenic sequestration -> BC blocks blood flow through spleen and spleen enlarges
  • haematuria: papillary necrosis
  • priapism
  • aplastic crisis
  • leg ulcers
  • osteomyelitis
  • bone pain and infarcts
  • dactylitis
  • hepatic sequestration
  • cholecystitis
  • stroke: ischaemia and haemorrhagic
64
Q

What is the complications of chronic SCA?

A
  • Silent infarcts
  • Pulmonary hypertension
  • Chronic lung disease, bronchiectasis
  • Erectile dysfunction
  • Azoospermia
  • Chronic pain syndromes
  • Delayed puberty
  • Moya-moya (blood vessels in the brain)
  • Retinopathy, visual loss
  • Chronic renal failure
  • Avascular necrosis
  • Leg ulcers
65
Q

What are the clinical features of SCD?

A
  • Painful crises
  • Aplastic crises
  • Infections
  • Acute sickling: chest syndrome, splenic sequestration, and stroke
  • Chronic sickling effects: renal failure and avascular necrosis bone
66
Q

How does SCA present in the lab?

A
  • Anaemia: Hb often 65-85
  • Reticulocytosis
  • Increased NRBC
  • Raised bilirubin
  • Low creatinine
67
Q

What tests are done to confirm diagnosis of SCA?

A
  • Solubility test
  • Expose blood to reducing agent
  • Hb S precipitated
  • Electrophoresis-structure
68
Q

What does the electrophoresis of a patient with SCA show?

A
  • Separation to show the levels of Hn in SS patients compared to trait and normal.
69
Q

What can cause autoimmune acquired haemolytic anaemias?

A
  • Usually idiopathic: usually warm, IgG and IgM
  • Drug-mediated
  • Cancer-associated: LPDs
70
Q

What can cause alloimmune acquired haemolytic anaemias?

A
  • Transplacental transfer: haemolytic disease of the newborn - D, c, L and ABO incompatibility
  • Transfusion-related: acute haemolytic transfusion reaction (ABO) and Delayed haemolytic transfusion reaction e.g. Rh groups, Duffy
71
Q

What are some examples of non-immune acquired haemolysis?

A
  • Paroxysmal nocturnal haemoglobinuria -> proteins mutated which means RBC are vulnerable to complement in plasma and get haemoglobinuria
  • Fragmentation haemolysis: can be mechanical and microangiopathic haemolysis (disseminated intravascular coagulation and thrombotic thrombocytopenic purpura)
  • Other: severe burns and some infections e.g. malaria

SEM 4: Haematology (8 decks)

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