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Molecular Basis of Disease(Sem 4) > Haemolytic Anaemias > Flashcards

Haemolytic Anaemias Flashcards

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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 which is due to shortened RBC survival

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3
Q

Describe the variation in blood Hb concentration

A

The Hb level is high in neonates but starts to decrease infants , it then increases at around 1 years old an continues until adulthood (20 years old aprox ).
The men Hb level will plateau higher than woman at around 13.5g/dl compared to 11.5g/dl .

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4
Q

Describe the normal RBC lifecycle .

A

There are around 2x10 ^11 RBC/day in the bone marrow.

300 miles travelled through microcirculation.

7.8 microns diameter -They can go through capillaries which are as small as 3.5microns ( so they should be able to deform their shape)

RBC circulate for approx.120 days without nuclei or cytoplasmic organelles -mitochondria.

The energy required in RBC is produced by enzymes which is used to maintain their shape.

Senescent RBC removal by RES (reticuloendothelial system) -Liver /spleen

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5
Q

What is Haemolysis ?

A

It is the shortened red cell survival between 30-80 days ).
Bone marrow will compensate by increasing RBC production
Increased young cell circulation (Reticulocytes and nucleated RBC )

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6
Q

What is compensated haemolysis?

A

RBC production able to compensate for decreased RBC life span - normal HB

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7
Q

What is incompletely compensated haemolysis?

A

This is when the RBC production is unable to keep up with decreased RBC life span +decreased Hb

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8
Q

What are some clinical findings with haemolysis?

A

Jaundice
Pallor/Fatigue
Splenomegaly
Normal urine

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9
Q

Why does haemolyisis cause jaundice ?

A

The RBC are broken down into haem and globin.The haem is then further broken down into protoporphyrin and iron.The protoporphyrin is furthen broken down into bilurubin.This is what causes the yellow colour of skin and eyes .

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10
Q

What is Pallor and why does haemolysis cause this ?

A

Pale appearance linked with fatigue. This is caused because the lack of haemoglobin. Not carrying enough oxygen to the tissues.

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11
Q

What is splenomegaly and how is it caused ?

A

The spleen is the organ which removes damaged cells therefore it becomes enlarged.

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12
Q

What happens to the urine in clinical settings during haemolysis ?

A

It is usual normal however it can become darker because of increased urobilinogen

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13
Q

What is haemolytic crises ?

A

This is increased anaemia and jaundice with infections/precipitants.

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14
Q

What is aplastic crises ?

A

This is anaemia where there are other cells involved as well as RBC.Reticulocytopenia (low reticulocytes) and pavovirus infection.

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15
Q

What are some of the more chronic clinical findings ?

A 
Gallstones -pigment (increased breakdown of RBC -bilirubin )
Leg ulcers (haemoglobin is NO(nitric oxide ) scavenging )
Folate deficiency -increased demand due to RBC being broken down and more required
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16
Q

Describe the typical laboratory findings

A

Increased reticulocyte count

Increased unconjugated bilirubin

Increased LDH (lactate dehydrogenase) -released from lysed RBC

Low serum haptoglobin
protein that binds free haemoglobin

Increased urobilinogen

Increased urinary
hemosiderin

Abnormal blood film

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17
Q

What can we see on the blood film ?

A
  • Reticulocytes
  • Polychromasia (RBC have different colours)
  • Nucleated RBC -being broken down
  • Poikilocytes-Different shapes of RBC
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18
Q

What are the three categories we use to classify haemolytic anaemia ?

A
  • Inheritance
  • Site of RBC destruction
  • Origin of RBC damage
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19
Q

Expand on the inheritance classification of haemolytic anaemia

A
  • Hereditary

- Acquired

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20
Q

Expand on the site of RBC destruction classification of haemolytic anaemia

A

Intravascular -Thrombotic thrombocytopenic purpura
(Blood disorder which causes clots forming in blood vessels -low RBC ,platelets due to breakdown )

Extravascular -Autoimmune haemolysis (antibodies are directed against a persons own RBC causing them to burst)

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21
Q

Expand on the origin of RBC damage classification of haemolytic anaemia

A

Intrinsic-G6PD deficiency
(Genetic disorder that affects mostly males ,G6PD enzyme not enough - red bloods cells don’t work properly

Extrinsic -Delayed haemolytic transfusion reaction (present with RBC haemolysis following transfusion)

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22
Q

Describe Acquired RBC haemolysis

A

Immune
Autoimmune (immune system
Alloimmune (immune response to non self antigens

Non -immune
Paroxysmal Noctural haematuria (rare acquired disease which destroys RBC)-not by immune system

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23
Q

Describe Hereditary RBC haemolsis

A

Red Cell enzymopathies
G6PD deficiency
PK deficiency

Red Cell membrane disorders 
Hereditary spherocytosis (sphere shaped RBC instead of biconcave)
Hereditary elliptocytosis (elliptical rather than biconcave) 
Haemoglobinopathies 
(Problems with the actual haemoglobin )
Sickle cell diseases 
Thalassaemia
(no/little haemoglobin production)
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24
Q

Where is the normal site of RBC destruction?

A

This is mostly extravascular. Macrophages will ingest abnormal RBC and break it down into globin iron and protoporphyrin. Bilirubin becomes unconjugated bilirubin and will be carried to the liver where it becomes bilurubin glucoronides and enters faeces where it is stercobilinogen.

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25
Describe intravascular RBC breakdown
RBC will not be systematically broken down .The Hb will be released into the blood to get free Hb in blood , urine and iron in the urine as well. Some of the haemoglobin will enter the kidney and this causes haemoglobinuria or haemosiderinuria
26
What is the pathway that protoporphyrin will undergo following RBC break down extravascularl ?
Protoporphyrin will become Bilirubin following expulsion of CO. This will then become unconjugated bilirubin (peripheral blood ) and will be carried to the liver where it becomes bilirubin glucuronides (enters the gut ) and enters faeces where it is stercobilinogen or (reabsorbed and travels to kidneys ) urobilinogen in the urine.
27
Describe the pathway followed by Iron following RBC being broken down extravascular
The iron will be converted into transferrin.
28
Describe the pathway followed by globin following RBC being broken down extravascular
The Globin will be broken down into amino acids
29
What is haemoglobinuria ?
The presence of excess haemoglobin in the urine
30
What is haemosiderinuria
This is the presence of hemosiderin in the urine. This is the protein compound which stores iron in tissues. When the haemoglobin breaks down it releases iron.
31
What is Methaemalbumin ?
This is found when degraded haemoglobin enters the plasma and binds to albumin.
32
What is haptoglobin ?
This is a protein which is encoded by the HP gene. In blood plasma haptoglobin will bind to free haemoglobin.
33
Describe the normal structure of a red cell membrane
- Lipid bilayer - Integral proteins - Membrane skeleton
34
What are some defects which may arise in the vertical interaction and what can this cause?
This is called hereditary speherocytosis. ``` These problems can occour in the following proteins : Spectrin Band 3 Protein 4.2 Ankyrin ```
35
What are some proteins in which defects in horizontal interactions may result in and what can this cause ?
This is caled hereditary elliptocytosis. These problems can occour in the following proteins : Protein 4.1 Glycophorin C Specitrin -HPP
36
Describe how hereditary spherocytosis may arise
Common hereditary haemolytic anaemia 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 becomes spherical
37
How is Haemolytic spherocytosis managed ?
Monitored Folic Acid Transfusion Splenectomy
38
What are the clinical features of haemolytic spherocytosis ?
Asymptomatic to severe haemolysis Neonatal jaundice Jaundice ,splenomegaly ,pigment gall stones (Caused by constant bilurubin breakdown ) Reduced eosin-5-maleimide (EMA) bindin bind to band 3 Positive family history Negative direct antibody test
39
What are enzymopathies ?
These are enzymes which are responsible for producing energy in the glycolytic pathway. This is used to maintain the RBC size and haemoglobin
40
What are the RBC metabolic pathways?
- Glycolysis - HMS - Rapoport Leubering shunt
41
How do RBC generate energy ?
They do this through Glycolysis *Emden-Meyerhof pathway),Hexose Monophosphate shunt , Rapoport Luebering Shunt.
42
What are the two most common enzyme abnormalities ?
Glucose -6-Phosphate deficiency | Pyruvate Kinase deficiency
43
Describe G6P deficiency
- Hereditary, X-linked disorder (if its in the X chromosome, men have it and it can also occur in women-In cells they randomly switch off 1 of the genes and so 50% of cells will be G6P Deficient) - 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 (except for neonatal jaundice)until they get exposed to things to acute episodes to chronic haemolysis (which is less common)
44
What are the roles of HMP shunt ?
-Generates reduced glutathione -Protects the cell from oxidative stress So RBC that are G6P deficient look fine and live a normal amount of time but only when exposed to oxidizing precipitants e.g. drugs, fava beans etc. you get oxidation of membrane proteins and Hb.
45
What are the effects of oxidative stress?
Oxidation of Hb by oxidant radicals - Resulting in denatured Hb aggregates and forms Heinz bodies (bind to membrane) - Oxidised membrane proteins-Reduced RBC deformability
46
What are some oxidative precipitants ?
-Infections -Fava/broad beans -Drugs : Anti-biotics /Malarial Dapsone Nitroflurantoin Ciprofloxacin Primaquine
47
What exactly does the HMP shunt do ?
The HMP shunt extends the life span of RBC by maintaining membrane proteins and lipids. It diverts Glucose-6-phosphate to 6-phosphogluconate through Gluycose-6-phosphate dehydrogenase
48
What are the features of G6PD deficiency ?
- Haemolysis | - Film (bite cells, blister cells ,ghost cells , Heinz bodies (with methylene blue ).
49
How can you make a diagnosis of G6PD deficiency?
This can be done using an enzyme assay. - May be falsely normal if reticlocytosis is occurring after a recent episode as reticulocytes usually have high enzyme levels . - Wait for the reticlocytes to decrease or check ratios between enzyme levels .
50
What happens to patients who are having a acute Haemolytic episode ?
- They will be come acutely jaundiced. - May have intravascular Haemolysis, dark urine from Hb in the urine. - Anaemic
51
What is the morphology of oxidative haemolysis ?
The presence of Heinz bodies and bite cells
52
What are bite cells?
These are abnomrally shaped mature RBC with one or more semicircular portions removed from the cell margin.
53
What are Heinz bodies?
These are inclusions within RBC composed of denatured Hb
54
Describe Pyruvate Kinase deficiency
-Pyruvate kinase is required to generate ATP. -This is essential for membrane cation pumps (deformability) -Autosomal recessive and much rarer. -Can cause chronic haemolytic anaemia Mild to transfusion dependent (Depends on genetics do you make a tiny bit less or do you make no PK) Improves with splenectomy (HS goes to normal Hb remember) what you see characteristically on a blood film are prickle cells (small and spikey), polychromasia.
55
What are Haemoglobinopathies ?
This is a group of disorders which are inherited. They cause a abnormal production or structure of Hb. Example is SCD
56
What is the normal structure of Haemoglobin ?
Ferrous iron + Protoporphoryin IX =Haem Globin protein Haem + Globin = Haemoglobin
57
Describe normal Haemoglobin
HbA -Adult which consists of α2β2 (97%)with some α2 delta2 e (2-3.5%) and alpha2 gamma 2 (foetal Hb)
58
Describe the globin gene expression during foetal development
Alpha chains are expressed from the beginning and if problems occur in utero , alpha chains are required. For e.g. Alpha thalassemia zero Beta chains are not expressed until a few weeks old during the neonatal period. The most common haemoglobinopathies are Beta chains.
59
What are the globin disorders?
Quantitative =thalassaemias (The production of increased/decreased amount of globin chain) Qualitative =variant haemoglobins (Production of a structurally abnormal globin chain.
60
Describe the different Haemoglobin disorders
HbS =This decrease solubility and causes polymerisation Hb Koln=Decreases stability and increases Heinz body formation HbC=Decreases solubility and increases crystallisation
61
What are Thalassaemias?
This is an imbalanced alpha and beta chain production Excess unpaired globin chains are unstable -Precipitate and damage RBC and precursors -Ineffective erythropoiesis in bone marrow -Haemolytic anaemia
62
What are the two types of Beta thalassaemia that can be inherited?
Beta thalassaemia trait | Beta Thalassaemia major
63
How do we diagnose the thalassaemia trait ?
-Asymptomatic -Microcytic hypochromic anaemia -Low Hb, MCV, MCH -Increased RBC -Often confused with Fe deficiency Because your making less β chains, HbA2 is increased in b-thal trait –(diagnostic test) a-thal trait often by exclusion -globin chain synthesis (rarely done now) -DNA studies (expensive)
64
Describe Beta Thalassaemia major
- Transfusion dependent in 1st year of life - When they stop making Foetal Hb they become progressively anaemic -If not transfused: Failure to thrive Progressive hepatosplenomegaly (big liver and spleen and so have big tummies) Bone marrow expansion – skeletal abnormalities (facial shape changes aswell) Death in 1st 5 years of life from anaemia Side effects of transfusion: Iron overload from the excess iron in the transfused blood - usually treated through medication (iron chelators help iron be excreted in urine) if not can cause: Endocrinopathies Heart failure Liver cirrhosis And so Treated with transfusions and iron chelators
65
Describe Sickle cell disease
Tested for in newborn babies in the UK Clinically significant sickling syndromes: HbSS HbSC HbS-D Punjab (started in india) HbS- O Arab (started in arab peninsula) HbS- β thalassaemia – ( the other gene can’t make beta chains and so you get SC) And so as you can see you can get a sickle cell disease by having one S mutation on a beta gene matched up with other mutations on the other gene. Point mutation in the β globin gene: glutamic acid → valine Insoluble haemoglobin tetramer when deoxygenated → polymerisation “Sickle” shaped cells SC cause a huge spectrum of problems; intravascular haemolysis and so changes in NO, Abnormal shaped RBC have abnormal membranes which effect vasculature.
66
What are the acute complications of SCD?
``` Stroke-Ischaemia and 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 ```
67
What are the chronic complications of SCD?
``` Silent infarcts Pulmonary hypertension Chronic lung disease, bronchiectasis Erectile dysfunction Azoospermia Chronic pain syndromes Delayed puberty Avascular necrosis Moya-moya Retinopathy, visual loss ```
68
What are the clinical features of SCD
Painful crises Aplastic crises Infections Acute sickling: Chest syndrome Splenic sequestration Stroke Chronic sickling effects: - Renal failure - Avascular necrosis bone
69
What are the laboratory features of SCD?
``` Anaemia (Hb often 65-85) Reticulocytosis Increased NRBC (nucleated RBC) Raised Bilurubin Low creatinine ```
70
How can we confirm the diagnosis of SCD ?
-Through a solubility test Expose blood to reducing agent HbS precipitated Positive in trait and disease -Using electrophoresis structure A-C =SCT D-E = HbC trait F= SCD -HPLC The extra portion at the end of the trait machine result when compared to normal. SS patient= no HbA.
71
What are the two types of acquired Haemolytic anaemia ?
Autoimmune | Alloimmune
72
Describe Autoimmune Haemolytic Anaemia
``` Idiopathic (Usually warm) (IgG, IgM) Drug mediated Cancer associated (LPDs) ```
73
Describe Alloimmune Haemolytic Anaemia
``` 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 ```
74
Describe Non-Immune acquired haemolysis
Paroxysmal nocturnal haemoglobinuria RBC become vulnerable through a mutation in proteins which protects the cell normally from the complement mediated lysis. And so there is intravascular Haemolysis through the lysis of the RBC. ``` Fragmentation haemolysis: Mechanical Microangiopathic haemolysis Disseminated intravascular coagulation – fibrin strands from clotting factors because of sepsis in the capillaries, damage the red cells Thrombotic thrombocytopenic purpura ``` Other: Severe burns Some infections: e.g. malaria

Molecular Basis of Disease(Sem 4) (28 decks)

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