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Year 5 - Pathology > HAEM: Haemolytic anaemias > Flashcards

HAEM: Haemolytic anaemias Flashcards

1
Q

What is the normal RBC lifespan?

A

120 days

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2
Q

Define haemolysis. How is it categorised?

A

Shortened RBC survival, may be predominantly:

  • Intravascular - within circulation
  • Extravascular - removal/destruction by reticuloendothelial (RE) system
  • Inherited or acquired
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3
Q

What are the causes of extravascular haemolysis?

A
  • Autoimmune
  • Alloimmune
  • Hereditary spherocytosis
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4
Q

What are 4 intravascular causes of haemolysis?

A
  • Malaria (most common worldwide)
  • G6PD deficiency
  • Mismatched blood transfusion (ABO)
  • Cold antibody haemolytic syndromes
  • Drugs
  • Microangiopathic haemolytic anaemia e.g. haemolytic uraemic syndrome, thrombotic thrombocytopenic purpura
  • Paroxysmal nocturnal haemoglobinuria
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5
Q

What are the main causes of herediatry haemolytic anaemias? Divide these into categories.

A

Membrane

  • Cytoskeletal proteins
  • Cation permeability

Red cell metabolism

Haemoglobin

  • Thalassaemia
  • Sickle cell syndromes
  • Unstable Hb variants
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6
Q

What are the consequences of haemolysis?

A
  • Anaemia(+/-)
  • Erythroid hyperplasia with increased rate of RBC production and circulating reticulocytes
  • Folate demand increased
  • Parvovirus B19 susceptibility
  • Gallstones(cholelithiasis)

Increased risk of:

  • Iron overload - due to increased intestinal iron absorption
  • Osteoporosis
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7
Q

What is shown in this BM slide?

A

Parvovirus B19 infection - presents as an aplastic crisis.

Erythroid progenitors in the bone marrow shown which are early forms with no differentiation.

Immunity is lifelong after infection .

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8
Q

This shows a liver slide of pyruvate kinase deficiency with Pearls stain. There is an increased amount of iron in the parenchyma of the liver and Kupffer cells.

A
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9
Q

What is the genotype of Gilbert’s?

A

UGT 1A1 TA7/TA7 genotype

The UGT1A1 gene belongs to a family of genes that provide instructions for making enzymes called UDP-glucuronosyltransferases

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10
Q

In haemolytic anaemia, what is the patient more at risk of if they also have Gilbert’s?

A

Coinheritance of Gilbert syndrome further increases risk of cholelithiasis in chronic haemolytic anaemia

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11
Q

What are the clinical features of haemolytic anaemia?

A
  • Pallor
  • Jaundice
  • Splenomegaly
  • Pigmenturia
  • Family history
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12
Q

What are the laboratory findings in a haemolytic anaemia?

A
  • Anaemia
  • Increased reticulocytes - esp in PB19 infection
  • Polychromasia
  • Hyperbilirubinaemia
  • Increased LDH
  • Reduced/absent haptoglobins
  • Haemoglobinuria
  • Haemosiderinuria
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13
Q

RBC membrane - what are labels A, B, C and D?

A

A (band 3) and B (rhesus) = transmembrane proteins

C (junctional) and D (spectrin) = skeletal proteins

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14
Q

What are defects in RBC membrane categorised into?

A
  1. Hereditary spherocytosis
  2. Hereditary elliptocytosis
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15
Q

What is the pathophsyiology of most herditary spherocytosis vs elliptocytosis? Name 3 locations of defects that may cause each.

A

Spherocytosis = Vertical interaction

  • Band 3
  • Protein 4.2
  • Ankyrin
  • b Spectrin

Elliptocytosis = Horizontal interaction

  • b Spectrin
  • Protein 4.1
  • a Spectrin
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16
Q

What is the pattern of inheritance in hereditary spherocytosis?

A

FH in 75% - typically autosomal dominant

25% recessive or de novo mutation

17
Q

How do RBCs react to hypotonic saline in vitro in hereditary spherocytosis?

A

Osmotic fragilty test - In vitro red cells show increased sensitivity to lysis in hypotonic saline

Reduced binding of dye eosin-5-maleimide

18
Q

What is shown in this slide of hereditary spherocytosis?

A
  • RBCs ack central pallor which usually arises from the biconcave shape of RBCs
  • Smaller than normal
  • MCHC is increased (seen on blood count) so you see hyperchromic cells with higher Hb concentration
  • Polychromatic cells (indicative of young RBCs)
19
Q

What does this dye binding test in hereditary spherocytosis show?

A

Dye binding test uses flow cytometry to look at the mean cell fluorescence after incubation with the dye

You can see that the second plot shows that of a patient with herediatry spherocytosis (cut off used is 0.8, 97% sensitive test)

20
Q

What condition is shown?

A

Hereditary elliptocytosis

21
Q

What condition is shown? What is seen? What is the inheritance of this condition?

A

Hereditary pyropoikilocytosis - fragmentation of RBCs, budding or vesciculation of the membrane, large variation in shape of the RBC (poikilocytosis)

NB: this is the homozygous state for hereditary elliptocytosis i.e. more severe which may sometimes require transfusion.

22
Q

What is the most common haemolytic anaemia caused by problems affecting RBC metabolism?

A

Glucose-6-phosphate dehydrogenase deficiency

23
Q

Where is G6PD most common? What is the inheritance pattern?

A

Prevalent in areas of malarial endemicity - selection as there is some protection against plasmodium falciparum malaria

X-linked - clinical effects seen predominantly in hemizygous males and homozygous females

24
Q

What is the role of G6PD?

A

Enzyme catalyses first step in pentose phosphate(hexose monophosphate) pathway - generates NADPH required to maintain intracellular glutathione(GSH) which is needed to protect the cell against oxidative stress

So G6PD deficiency causes haemolytic anaemia in response to oxidative stress.

25
Q

What are the clinical manifestations of G6PD deficiency?

A
  1. Neonatal jaundice - probably most common cause of kernicterus worldwide
  2. Acute haemolysis(triggered by oxidants/infection)
  3. Chronic haemolytic anaemia(rare)
26
Q

What can trigger acute haemolysis in G6PD?

A

Drugs:

  • Anti-malarials - Primaquine
  • Antibiotics - Sulphonamides, ciprofloxacin, nitrofurantoin
  • Other drugs - dapsone, Vitamin k

Infections

Fava beans

Moth balls

27
Q

What is the condition shown? What is seen?

A

G6PD deficiency

  • Contracted RBCs
  • Nucleated RBCs
  • Bite cells - some cytoplasm removed
  • Hemi ghosts - haemoglobin retracted to one side of the cell
28
Q

The G6PD slide has been stained with Methylviolet. What is now seen?

A

Peripheral inclusions within the RBC called ‘Heinz bodies’ formed from deformed haemoglobin.

Usually only transiently seen as the spleen will remove these cells.

29
Q

Apart from G6PD, name some other metabolic pathways within the RBC that may cause haemlytic anaemia if defective.

A

Defects in nucleotide and glutathione metabolism etc:

Embden-Meyerhof = ATP, NADH

Hexose monophosphate shunt = NADPH (pentose phosphate)

Rapoport-Luebering shuttle = 2,3-DPG

Nucleotide metabolism

  • Adenine salvage
  • Adenosine phosphate equilibrium
  • Removal of pyrimidine nucleotides

Glutathione biosynthesis = GSH

Cytochrome b5 reductase = Methemoglobin reduction

30
Q

What is the most common defect in tye glycolytic pathway of RBC metabolism causing haemolytic anaemia? (condition shown below - what features are seen?)

A

Pyruvate kinase deficiency (post splenectomy shown)

  • Echinocytes- RBCs have short projections. The number of these increases post-splenectomy
  • Spherocytes/spheroechinocytes - as there is shrinkage due to dehydration there

Pyruvate kinase enzyme is near the end of the pathway

31
Q

What condition is shown below?

A

Pyrimidine 5’-nucleotidase deficiency - defect in a nucleotide metabolism pathway. Pyrimidine is toxic to the RBC if it accumulates. But purines need to be retained so there should be a mechanims for retaining these which invovles the above enzyme.

Relatively uncommon

Basophilic stippling - basophilic inclusions in RBCs; also seen in lead poisoning as lead is a potent inhibitor of this enzyme.

32
Q

What investigations are important in patients presenting with haemolysis?

A
  • Direct antiglobulin test (DAT) - detects Ig on surface of RBC in AI disease
  • Urinary haemosiderin/haemoglobin - tells us whether intravascular haemolysis is present; haptoglobin levels low in intravascular haemolysis
  • Osmotic fragility - if considering membrane defect
  • G6PD +/- PK activity- if considering enzyme deficiency; but G6PD is acute and PK chronic usually.
  • Haemoglobin separation A and F% - electrophoresis or HPLC
  • Heinz body stain - for oxidative haemolysis
  • Ham’s test/Flow cytometry of GPI-linked proteins - for paroxysmal nocturnal haemoglobinuria
  • Thick and thin blood film - Malaria
33
Q

What are the principles of management of haemolytic anaemia?

A

Conservative:

  • Avoidance of precipitating factors e.g. oxidants in G6PD deficiency
  • Immunisation against blood borne viruses e.g. hepatitis A and B
  • Monitor for chronic complications

Medical:

  • Folic acid supplementation
  • Red cell transfusion/exchange

Surgical:

  • Cholecystectomy for symptomatic gallstones
  • Splenectomy if indicated
34
Q

What are the conditions in which splenectomy may be indicated?

A

Beneficial in:

  • PK deficiency and some other enzymopathies
  • Hereditary spherocytosis
  • Severe elliptocytosis/pyropoikilocytosis
  • Thalassaemia syndromes
  • Immune haemolytic anaemia
35
Q

What are the complications/risks of splenectomy?

A
  • Capsulated bacteria eg Pneumococcus
  • Penicillin prophylaxis and immunisation
36
Q

What clinical features are indications for splenectomy in haemolytic anaemia?

A

Criteria

  • Transfusion dependence
  • Growth delay
  • Physical limitation Hb
  • Hypersplenism
37
Q

When can splenectomy be carried out i.e. age? What age is it most beneficial?

A

After 3 years only - as spleen is important in immune function in infants and toddlers

But before 10 years - most beneficial as helps to maximise prepubertal growth

38
Q

Do not learn

Case: Haemoglobin Hammersmith discover 1967

  • Female infant aged18 months from UAE; Presented at 6 months of age - anaemia jaundice and pigmenturia; Sudden onset after respiratory illness; Chronic haemolysis ensued; Parents (first cousins) and 2 siblings well
  • Examination - pale and icteric with palpable spleen tip
  • Hb 7.0 reticulocytes 880 (37.4%) i.e. raised; Film shown with supravital stain - methyl violet
  • Heat stability and isopropanol precipitation tests strongly positive - 17% Hb precipitation (less than 1% in parental and control samples)
  • Cellulose acetate electrophoresis testing did not show anything which is not unusual but HPLC showed other peaks so new Hb variant and this was done for the rest of the family.
  • Mass spectrometry was then used to separate molecules based on their mass - named Hb Hammersmith
A
  • G6PD deficiency suspected based on blood film
  • Unstable Hb variant seen by heat stability testing
  • Haemoglobin Hammersmith - severe electrophoretically silent, Heinz bodies present, mutation disrupts haem contact, reduced oxygen affinity

Year 5 - Pathology (89 decks)

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