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Molecular basis of disease > Haemolytic anaemias > Flashcards

Haemolytic anaemias Flashcards

1
Q

What is haemolytic anaemia

A

anemia due to shortened RBC survival

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2
Q

What is the lifespan of an RBC with HA?

A

80 days

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3
Q

Describe variation in blood Hb concentration

A
  • High foetal haemoglobin at birth
  • Falls during first few months of life
  • Children have lower levels than adults
  • Lower for women than men
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4
Q

What is haemolysis?

How can the body compensate?

A
  1. Shortened red cell survival 30 - 80 days
  2. Bone marrow compensates with increased red blood cell production
  3. Increased young cells in circulation = Reticulocytosis +/- nucleated RBC
    • Compensated haemolysis: RBC production able to compensate for decreased RBC life span = normal Hb
    • Incompletely compensated haemolysis: RBC production unable to keep up with decreased RBC life span = decreased Hb
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5
Q

What are the clinical findings of hemolysis?

A
  • When red blood cell are broken down thye form haem which then is broken down into porphoprhin and ions which is then broken down into bilirubin which causes the Jaundice
  • Pallor due to lack of haemoglobin, so less o2 to tissues/fatigue
  • Splenomegaly
  • ?Dark urine
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6
Q

Define Haemolytic crises and Aplastic crises

A

Haemolytic crises-increased anaemia and jaundice with infections/ precipitants

Aplastic crises-anaemia, reticulocytopenia (low reticulocyte levels) with parvovirus infection

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7
Q

What are the chronic clinical findings?

A
  • Gallstones – pigment (bilirubin)
  • Leg ulcers (NO scavenging)
  • Folate deficiency - (increased use to make red blood cells)
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8
Q

What are the lab findings of haemolytic anaemia?

A
  • Increased reticulocyte count
  • Increased unconjugated bilirubin
  • Increased LDH (lactate dehydrogenase)
  • Low serum haptoglobin protein that binds free haemoglobin
  • Increased urobilinogen from breakdown of red blood cells
  • Increased urinary haemosiderin (ion)
  • Abnormal blood film
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9
Q

Identify the blood film of HA

A

On image

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10
Q

How can HA be classified?

A

On table

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11
Q

How is RBC broken down?

A
  • Most commonly extravacular
  • Macrophage eats RBC
  • Bilirubin released
  • Iron stored for a little then back to liver
  • Globin chains break down to amino acids
  • Intravascular: RBC not systematically broken down, release haemoglobin so free Hb in blood and urine and iron in urine too
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12
Q

Describe the structure of the membrane in relation to the cytoskeleton

What can occur if there are problems with the proteins?

A
  • Red cell membrane is a lipid bilayer and it has some proteins that anchor the membrane onto the cytoskeleton to keep it stable
  • Red cells come as biconcave discs as they have to deform as they go through capillaries
  • It is important that they are mobile and have a flexible membrane
  • You can get problems in the proteins that anchor the membrane
  • This can cause the red cells to lose part of the membrane and so change their shape
  • e.g. can become spherocytes or elliptocytes
  • Usually due to autosomal dominant genetics
  • Usually occurs if you have inherited abnormalities in one of the proteins that is part of the lipid bilayer
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13
Q

Describe the structure of a normal RBC membrane?

A

Normal red cell membrane structure
• Lipid bilayer – enables it to be mobile
• Integral proteins
• Membrane skeleton

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14
Q

What are the defects in hereditary spherocytosis?

A
  • Round shaped cells rather than biconcave = SPHEROCYTES
  • Spectrin
  • Band 3
  • Protein 4.2
  • Ankyrin
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15
Q

What are the defects in hereditary elliptocytosis?

A
  • Elongated cells = ELLIPTOCYTES
  • Protein 4.1
  • Glycophorin C
  • (spectrin – HPP)
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16
Q

Describe hereditary spherocytosis, its clinical features and management of HS

A

Hereditary Spherocytosis
• 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 membrane is lost, the RBC become spherical
Clinical Features
• Asymptomatic to severe haemolysis
• Neonatal jaundice
• Jaundice, splenomegaly, pigment gallstones
• Reduced eosin-5-maleimide (EMA) binding – binds to band 3
• Positive family history
• Negative direct antibody test
Management of HS
• Monitor
• Folic acid
• Transfusion- if severe
• Splenectomy- if severe

17
Q

What are the RBC metabolic pathways?

A
  • RBC don’t have nuclei
  • They have several metabolic pathways that keep them going
  • Glycolytic pathway
  • HMS (protects from oxidative stress)
  • 2,3 BPG
  • Modulates O2 binding to Hb
  • Problems in any of these pathways can cause haemolytic anaemias
  • Once the RBC leaves the bone marrow, it can’t make new things.
18
Q

What does G6P deff cause?

A
  • G6PD the most common
  • Protects from oxidative stress
  • This occurs due to certain drugs, infections
  • If you can’t protect yourself, then you get denatured Hb, which precipitates out and oxidises membrane proteins
  • This is when you get very specific changes in the red cell
  • Blister cells, bite cells etc.
  • Hereditary, X-linked disorder
  • Common in African, Asian, Mediterranean and Middle Eastern populations
  • Mild in African (type A), more severe in Mediterranean’s (type B)
  • Clinical features range from asymptomatic to acute episodes of chronic haemolysis
19
Q

What is the function of the HMP shunt?

A
  • Generates reduced glutathione

* Protects the cell from oxidative stress

20
Q

What happens when Hb is oxidized?

A

Effects of oxidative stress
• Oxidation of Hb by oxidant radicals
• Resulting denatured Hb aggregates & forms Heinz bodies – bind to membrane
• Oxidised membrane proteins – reduced RBC deformability

21
Q

What is G6PD Deficiency caused by?

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
22
Q

What are the oxidative precipitants and features?

A 
Oxidative precipitants
•	Infections
•	Fava/ broad beans
•	Many drugs e.g.:
•	Dapsone
•	Nitrofurantoin
•	Ciprofloxacin
•	Primaquine
Features
•	Haemolysis
•	Film:
•	Bite cells
•	Blister cells & ghost cells
•	Heinz bodies (methylene blue)
•	Reduced G6PD activity on enzyme assay
•	May be falsely normal if reticulocytosis
23
Q

Describe Pyruvate Kinase Deficiency

A
  • PK required to generate ATP
  • Essential for membrane cation pumps (deformability)
  • Autosomal recessive
  • Variable
  • Chronic anaemia
  • Mild to transfusion dependent
  • Improves with splenectomy
24
Q

Describe the structure of hemoglobin

A

On image

25
Q

What can go wrong with the structure of hemoglobin?

A

What can go wrong?
• Quantitative - thalassaemias:
• Production increased/ decreased amount of a globin chain (structurally normal)
• Qualitative – variant haemoglobins:
• Production of a structurally abnormal globin chain

26
Q

What are thalassamais and what does this cause?

A
  • 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
27
Q

What is Beta thalassaemias?

A
  • Beta thalassemia is a blood disorder that reduces the production of haemoglobin
  • Low levels of hemoglobin lead to a lack of oxygen in many parts of the body
  • People with beta thalassemia trait have both normal hemoglobin A and the abnormal beta thalassemia(β) hemoglobin in their red blood cells. Beta thalassemia is common in people of African, Mediterranean, Asian and Middle Eastern descent
  • Beta thalassemia major (also called Cooley’s anemia). People with beta thalassemia major have severe symptoms and life-threatening anemia. They need regular blood transfusions and other medical treatment
28
Q

How can we diagnose thalassamias?

A
  • Asymptomatic
  • Microcytic hypochromic anaemia
  • Low Hb, MCV, MCH
  • Increased RBC
  • Often confused with Fe deficiency
  • HbA2 increased in b-thal trait –(diagnostic)
  • a-thal trait often by exclusion
  • globin chain synthesis (rarely done now)
  • DNA studies (expensive)
29
Q

What is Beta Thalassaemia Major?

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: Get 200mg from a single blood transfusion
  • Iron overload
  • Endocrinopathies
  • Heart failure
  • Liver cirrhosis
  • But iron chelators bind excess iron in the circulation and in organs from blood transfusions
30
Q

What is SCD and describe the blood film of it?

A

Sickle Cell Disease (SCD)
• Lot of different genes that can cause it
• Commonest are SS and SC
• You get an insoluble Hb that wants to polymerise, and it distorts the shape of the RBC
Blood film
• Some normal cells
• Some sickle cells
• Nucleated red ells
• Howell-jolly bodies as they are hypersplenic
• Some polychromasia
• More common than thalassaemia in the UK
• Autosomal recessive

31
Q

Describe the pathophysiology of SCD

A
  • A vascular disease
  • Abnormal shaped RBCs irritate the lining of the capillaries
  • Changes on the surfaces of the White cells
  • Problems due to the intravascular haemolysis  alters the vascular tone
  • SC disease is the commonest cause of child stroke
  • They get narrowing of main arteries in the brain
  • Older patients will have pulmonary hypertension and leg ulceration
  • Pain is the most well-known symptom
  • Sickling in the chest causes problem with oxygenation
  • Also, effects in blood supply to the bone, causing necrosis
  • Well known for causing acute pain or vaso-occlusive crises – most common symptom, has biggest impact of quality of life in patients
  • Get occlusion in blood vessels of sickle cell disease. Particularly in places like bones where you get infarction of small areas of the bone
  • Can cause sickling in many organs, e.g. in the chest, getting acute chest syndrome. In the tissue, can get leg ulcers. Sickling in blood vessel in penis causing priapism. Sickling in brain causing stroke
  • These are associated with other blood cell abnormalities particularly the stenosis or vasodilatation due to NO and increased changes in the tone of blood ve
32
Q

What are the acute complications of SCD?

A
  • Children get dactylitis first (sickling of the small bones in the hand)
  • Also have painful, puffy hands
  • Trouble with blood flow through the spleen in children
  • Spleen enlarges largely and can cause death
  • As they get older the vessels in the back of the eye change, they can bleed and cause a hemorrhage or a retinal detachment
33
Q

What are the chronic complications of SCD?

A
  • Changes to blood vessels means you produce new blood vessels which are prone to bleeding  intra-cranial bleeds
  • Chronic changes to vessels at the back of the eye that can results in a loss of vision
  • Pulmonary hypertension
  • Chronic renal failure is quite common
34
Q

What are the clinical and lab features of SCD?

A 
Clinical
•	Painful crises
•	Aplastic crises
•	Infections
•	Acute sickling:
•	Chest syndrome
•	Splenic sequestration
•	Stroke
•	Chronic sickling effects:
•	Renal failure
•	Avascular necrosis bone
Laboratory
•	Anaemia
•	Hb often 65-85
•	Reticulocytosis
•	Increased NRBC
•	Raised bilirubin
•	Low creatinine
35
Q

How do we confirm SCD?

A
  • Sickle Hb is insoluble
  • Solubility test
  • Expose blood to reducing agent
  • Hb S precipitated
  • Positive in trait and disease
  • Electrophoresis
  • Structure
  • Separate out Hb over an electric current
36
Q

Describe the principle of HPLC

A
  • HPLC is not definitive
  • Need a sickle solubility test
  • Because other Hbs can run at exactly the same time point
  • Many different mutations you can get in beta chains, most of which aren’t clinically significant and that’s the problems with these assays as you pick up stuff which interfere with what you’re looking for
  • Separates out the Hb, hPLC
  • Different proteins can also separate out where we expect to see sickle Hb, so we always do a second test just to make sure
37
Q

Describe Acquired Haemolytic Anaemias

A 
Autoimmune
•	Idiopathic
•	Usually warm
•	IgG, IgM
•	Drug-mediated
•	Cancer associated
•	LPDs
Alloimmune
•	Transplacental transfer:
•	Haemolytic disease of the newborn:
•	D, c, L
•	ABO incompatability
•	Transfusion related
•	Acute haemolytic transfusion reaction
•	ABO
•	Delayed haemolytic transfusion reaction
•	E.g Rh groups, Duffy
Non-immune acquired haemolysis
•	Paroxysmal nocturnal haemoglobinuria
•	Fragmentation haemolysis:
•	Mechanical
•	Microangiopathic haemolysis
•	Disseminated intravascular coagulation
•	Thrombotic thrombocytopenic purpura
•	Other:
•	Severe burns
•	Some infections: e.g. malaria

Molecular basis of disease (30 decks)

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