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Molecular basis of disease > Haemolytic Anaemias > Flashcards

Haemolytic Anaemias Flashcards

1
Q

Define Anaemia

Define Haemolytic Anameia

A

Reduced Hgb level for the age and gender of the individual

Anaemia due to shortened RBC survival

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2
Q

Factors which affect anaemia

A

Age and Gender

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3
Q

Normal RBC lifecycle

A

RBC production (in bone marrow):

  • iron
  • B12/folate
  • globin chains
  • protoporphyrins

Circulating RBC
-120 days

Removal/Senescent RBC
-as red blood cells age, they accumulate changes on their membrane, recognised by macrophages in the liver and spleen which then remove those red blood cells

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4
Q

RBC lifecycle with Haemolysis

A

Haemolysis= shortened red cell survival (30-80 days)

  • Bone marrow compensates with increased red blood cell production via EPO action
  • Increased young cells in circulation= reticulocytosis/ increase of nucleated RBC
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5
Q

Compensated haemolysis

A

when RBC production is able to compensate for the decreased RBC life span, maintaining a normal haemoglobin level

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6
Q

Incompletely compensated haemolysis

A

when RBC production is unable to keep up with the decreased RBC life span, resulting in decreased haemoglobin levels (anaemia)

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7
Q

Clinical findings of haemolytic anaemia

A

· Jaundice:
-due to breakdown of red blood cells, producing unconjugated bilirubin

· Pallor (unnatural lack of colour in skin)
· fatigue
· Splenomegaly (enlarged spleen)
· Dark urine

· Haemolytic crisis:
-increased anaemia and jaundice with infections/precipitants

· Aplastic crisis:
-anaemia, reticulocytopenia and parvovirus infection

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8
Q

Chronic clinical findings of haemolytic anaemia

A

· Gallstones- pigment
· Leg ulcers (Nitric Oxide scavenging)
· Folate deficiency (increased use to make more RBC

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9
Q

Laboratory findings in haemolytic anaemia

A
  • Normal/low haemoglobin
  • Increased reticulocyte count
  • Increased unconjugated bilirubin
  • Increased LDH (lactate dehydrogenase) which is released from haemolysed RBCs
  • Low serum haptoglobin (protein that binds free haemoglobin)
  • Increased urobilinogen +/- haemoglobinuria
  • Increased urinary haemosiderin
  • Abnormal blood film
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10
Q

Where is the majority of red cell destruction?

A

in the spleen (extravascular)

*but there is some intravascular haemolysis (inside bloodstream)

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11
Q

Classifying haemolytic anaemias

A

Inheritance

  • Hereditary
  • acquired

Site of RBC Destruction

  • intravascular
  • extravascular

Origin of RBC Damage

  • intrinsic
  • extrinsic
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12
Q

Classification of haemolytic anaemia: Inheritance

A

Haemolytic anaemias can either be inherited or acquired.

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13
Q

Classification of haemolytic anaemia: Site of Red Blood Cell Destruction

A

Red blood cell destruction is mostly extravascular, but there also is intravascular destruction.

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14
Q

Extravascular haemolysis

A

1) Macrophage of reticuloendothelial system digests RBC

2) RBC is broken down into its constituents (globin, iron & protoporphyrin) which are further broken down

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15
Q

What happens to the RBC constituents after extravascular haemolysis?

A
  • globin broken down into amino acids
  • iron binds trasnferrin in plasma to be transported to liver for storage
  • protoporphyrin broken down into bilirubin and released into peripheral blood (unconjugated) to be transported to the liver for further metabolism
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16
Q

Intravascular haemolysis

A

During intravascular haemolysis, the red blood cell is not systematically broken down, haemoglobin is just released as free haemoglobin into the blood and urine.

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17
Q

Red cell membrane structure

A

lipid bilayer anchored to the cytoskeleton by a number of different proteins (e.g. integral proteins)

mutations in proteins affecting the anchoring of the lipid bilayer to the cytoskeleton will affect the stability of the membrane (most of these are autosomal dominant)

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18
Q

Inherited membrane disorders which cause haemolytic anaemia

A

Hereditary spherocytosis

Hereditary elliptocytosis

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19
Q

Hereditary spherocytosis

A

Defects in proteins involved in VERTICAL interactions between the lipid bilayer and cytoskeleton:

  • Spectrin
  • Band 3
  • Protein 4.2
  • Ankyrin
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20
Q

Effect of hereditary spherocytosis on RBC membrane

A

decreased membrane deformability
-as the RBCs go around the circulation & spleen and are required to deform to do that, the membrane is lost, and the red blood cells become spherical

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21
Q

Hereditary spherocytosis blood film

A

rounder RBCs

polychromasia (no central pallor)

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22
Q

Clinical features of hereditary spherocytosis

A

· Asymptomatic to severe haemolysis
· Neonatal jaundice
· Jaundice, splenomegaly, pigment gallstones
· Reduced eosin-5-maleimide (EMA) binding (usually binds to band 3 membrane protein- test for hereditary spherocytosis)
· Positive family history
· Negative direct antibody test

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23
Q

Management of hereditary spherocytosis

A
  • Monitor
  • Folic acid
  • Blood transfusion
  • Splenectomy
24
Q

Hereditary Elliptocytosis

A

Defects in proteins involved in HORIZONTAL interactions between the lipid bilayer and cytoskeleton:

  • Protein 4.1
  • Glycophorin C
  • Spectrin-HPP
25
Q

Inherited enzymopathies which cause haemolytic anaemia

A

Glucose-6-Phosphate Deficiency

Pyruvate Kinase Deficiency

26
Q

Metabolic pathways in the RBC

A

Glycolysis

Hexose-monophosphate shunt

Rapaport Lubering shunt

27
Q

Role of the hexose-monophosphate shunt

A

Generates NADPH and reduced glutathione which protects the cell from oxidative stress

28
Q

What is the effect of oxidative stress on RBC?

A

Oxidant radicals oxidise Hb, denaturing and aggregating it to form Heinz bodies which bind to the membrane. Oxidised membrane proteins reduce RBC deformability

29
Q

Glucose-6-Phosphate Dehydrogenase Deficiency

A

Hereditary, X-linked disorder

Common in African, Asian, Mediterranean and Middle Eastern populations

Mild in African (type A), more severe in Mediterranean (type B)

Clinical features range from asymptomatic to acute episodes to chronic haemolysis

30
Q

What can trigger oxidative precipitants in G6PD Deficiency?

A

Infections

Fava/broad beans

Many drugs (e.g. Dapsone, Nitrofurantoin, Ciprofloxacin, Primaquine)

31
Q

Features of G6PD deficiency

A
  • Haemolysis
  • Film:
    >bite cells
    >blister cells & ghost cells
    >heinz bodies (methylene blue stain)
  • Reduced G6PD activity on enzyme assay
    >may be falsely normal if reticulocytosis
32
Q

Why would G6PD activity on an enzyme assay be falsely normal if there is reticulocytosis?

A

because reticulocytes have high enzyme levels

33
Q

Pyruvate Kinase Deficiency

A

Autosomal recessive disease causing chronic haemolytic anaemia
>mild to transfusion dependent
>improves with splenectomy

34
Q

Role of pyruvate kinase in RBC metabolism

A

required to generate ATP, essential for membrane cation pumps - Na/K pump (deformability)

35
Q

Features of pyruvate kinase deficiency

A

Prickle cells on blood film

36
Q

Inherited haemoglobinopathies which cause haemolytic anaemia

A

Sickle Cell Disease

Thalassaemias

37
Q

Normal Haemoglobin

A

HbA:
-Two alpha chains (gene on chromosome 16)

-Two beta chains (gene on chromosome 11)

HbA2:
-Two alpha chains (gene on chromosome 16)

-Two delta chains (gene on chromosome 11)

HbF:
-Two alpha chains (gene on chromosome 16)

-Two gamma chains (gene on chromosome 11)

38
Q

Clinical significance of globin gene expression during neonatal period

A

Alpha chains are needed early on in embryonic life, but beta chains are really more vital after birth at about 4-5 weeks old.

This is important when diagnosing haemoglobinopathies because almost all the clinically significant ones affect beta chains, meaning the foetus is unharmed in the neonatal period (less than 4 weeks old).

39
Q

Which haemoglobinopathy causes problems in utero?

A

Alpha thalassemia 0 because it causes problems in alpha chains and therefore causes problems in utero because alpha chains are needed early on in foetal life.

40
Q

Types of haemoglobinopathies

A

Quantitative haemoglobinopathies: Thalassaemias
-production increase/decrease in amount of a globin chain (but structurally normal)

Qualitative haemoglobinopathies: Variant Haemoglobins
-production of a structurally abnormal globin chain (e.g. SCD)

41
Q

Thalassaemia

A

Imbalance between alpha and beta chain production, resulting in an excess of unpaired globin chains which are unstable.

42
Q

Effect of excess unpaired globin chains in thalassaemias

A

The excess unpaired globin chains are unstable:
>precipitate and damage RBC and their precursors
>ineffective erythropoiesis in bone marrow
>haemolytic anaemia

43
Q

What is the most common thalassaemia?

A

Beta Thalassaemia major is the most common thalassaemia.

- autosomal recessive

44
Q

Clinical features of Beta Thalassaemia Major

A
  • severe anaemia
  • progressive hepatosplenomegaly
  • iron overload
  • mild jaundice
  • bone marrow expansion - facial bone abnormalities
  • intermittent infections, pallor
45
Q

Peripheral blood in Beta thalassaemia major

A
  • reticulocytes >2%
  • Microcytic hypochromic with decreased MCV, MCH, MCHC
  • Anisopoikilocytosis: target cells, nucleated RBC, tear drop cells
46
Q

Side effect of transfusion in beta thalassaemia major

A 
Side effects of transfusion:
>Iron overload
>Endocrinopathies
>Heart failure
>Liver cirrhosis
47
Q

Diagnosis of Thalassaemia trait (minor)

A
  • Asymptomatic
  • often confused with Fe deficiency
    · HbA2 increased in beta thalassaemia trait: this is a diagnostic test done for it
    · Alpha thalassaemia trait often by exclusion
48
Q

What are the 3 alpha thalassaemias?

A

Hb Barts hydrops syndrome

  • deletion of all 4 globin genes
  • incompatible with life, so foetus dies in utero or after birth

HbH disease

  • deletion of 3/4 alpha globin genes
  • common in SE Asia
  • Clin Features:
    • splenomegaly, hepatomegaly
    • electrophoresis -diagnostic
    • Moderate chronic HA
    • hypochromic microcytic, poikilocytosis, polychromasia, target cells

Thal trait (minor)

  • Normal or mild HA
  • MCV and MCH low
49
Q

Beta thalassaemia major treatment

A

Transfusion dependent in 1st year of life

If not transfused:
>Failure to thrive
>Progressive hepatosplenomegaly
>Bone marrow expansion causing skeletal abnormalities
>Death in 1st 5 years of life from anaemia

50
Q

Thalassaemia Intermediate

A

Disorder with clinical manifestation between manjor and minor:

  • Transfusion independent
  • diverse clinical phenotype
  • varying symptoms
  • increased bilirubin level
  • diagnosis - largely clinical
51
Q

Sickle cell disease

A

Autosomal recessive

  • point mutation in β globin gene (glutamic acid–> valine)
  • insoluble haemoglobin tetramer when deoxygenated causing polymerisation
  • resulting in ‘sickle’ shaped cells
HbSS = sickle cell anaemia (homozygous)
HbAS = sickle cell trait (heterozygous)
52
Q

Pathophysiology of SCD

A
  • Issues are partly because there is intravascular haemolysis and changes in nitric oxide, and because the abnormally shaped red cells have abnormal membranes (loss of deformability/morphology of RBC)
53
Q

Clinical features of SCD

A
  • painful crisis
  • aplastic crisis
  • infections
  • acute sickling (chest syndrome (occlusion of pulmonary vasculature), splenic sequestration, stroke)
  • chronic sickling effects (renal failure, avascular necrosis bone)
54
Q

Laboratory features of SCD

A
  • Anaemia (Hb = 60-90)
  • Reticulocytosis
  • Increased NRBC
  • Raised Bilirubin
  • Low creatinine levels
55
Q

Confirming diagnosis of SCD

A

Solubility test:

  • Expose blood to reducing agent
  • HbS precipitated
  • Positive in trait and disease

Electrophoresis
-analyse structure of Hb

HPLC Test
-not definitive, need sickle solubility test

56
Q

Disorders causing acquired haemolytic anaemia

A

Immune haemolysis
>autoimmune
>alloimmune

Non-immmune acquired haemolysis

57
Q

Autoimmune haemolysis

A
  • Idiopathic (usually warm; IgG, IgM)
  • Drug-mediated (e.g. antibiotics)
  • Cancer associated (lympho-proliferative disorders)

Molecular basis of disease (31 decks)

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