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Clinical Pathology > 6. Haemolytic Anaemias > Flashcards

6. Haemolytic Anaemias Flashcards

1
Q

Define anaemia and haemolytic anaemia.

A
  • ANAEMIA = reduced haemoglobin level for the age and gender of the individual
  • HAEMOLYTIC ANAEMIA = anaemia due to shortened RBC survival
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2
Q

Describe the variation in blood haemoglobin concentration from neonates to adults

A
  • Neonates have the highest Hb concentration. This decreases as they are infants and is at its lowest around 3 months. Then Hb concentration increases as they get older, until they are adults. When they are adults, it stays around the same level. Higher in men than in women. Slowly decreases in men over the age of 60.
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3
Q

Describe the normal red blood cell lifecycle

A

The RBC are produced in teh bone marrow and they are in circulation for about 120 days before they die.

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4
Q

Metabolic pathways in the mature RBC

A

1) Glycolytic pathway
- Na/K pump (3Na out and 2K in)
- ATP -> ADP+P

2) Hexose-monophosphate shunt ~ reducing power. (NADPH/GSH)
3) Rapoport Luebering shunt - 2,3 Bi-phosphoGlycerate (2,3 BPG) ~ modulates O2 binding to Hb

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5
Q

Describe the events of haemolysis.

A

1) Shortened red cell survival (30-80 days).
2) Bone marrow compensates with increased RBC 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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6
Q

Clinical findings of haemolysis.

A
  • Jaundice
  • Pallor/fatigue
  • Splenomegaly (site for abnormal RBCs)
  • Dark urine
  • Haemolytic crises-increased anaemia and jaundice with infections/ precipitants
  • Aplastic crises-anaemia, reticulocytopenia with parvovirus infection

CHRONIC FINDINGS:

  • Gallstones - pigment
  • Leg ulcers (NO scavenging)
  • Folate deficiency (increased use)
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7
Q

Haemolytic anaemia lab findings

A
  • Increased reticulocyte count
  • Increased unconjugated bilirubin
  • Increased LDH (lactate dehydrogenase)
  • Low serum haptoglobin ~ protein that binds free haemoglobin
  • Increased urobilinogen
  • Increased urinary haemosiderin
  • Abnormal blood film
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8
Q

Findings on a blood film for haemolytic anaemia

A
  • Reticulocytes
  • Polychromasia
  • Nucleated RBC
  • Poikilocytes - help point to a cause
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9
Q

Classifying haemolytic anaemias

A

INHERITANCE:
- Inherited ~ e.g. hereditary spherocytosis
- Acquired ~ e.g. paroxysmal nocturnal haemoglobinuria
SITE OF RBC DESTRUCTION:
- Intravascular ~ e.g. thrombotic thrombocytopenic pupura
- Extravascular ~ e.g. autoimmune haemolysis
ORIGIN OF RBC DAMAGE:
- Intrinsic ~ e.g. G6PD deficiency
- Extrinsic ~ e.g. delayed haemolytic transfusion reaction

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10
Q

Examples of inherited haemolytic disorders

A
  • MEMBRANE DISORDERS: Spherocytosis, Elliptocytosis
  • ENZYME DISORDERS: G6PD deficiency, Pyruvate Kinase deficiency
  • Hb DISORDERS: Sickle Cell Anaemia, Thalassaemias
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11
Q

Examples of how haemolysis is acquired

A
  • Immune
  • Drugs
  • Mechanical
  • Microangiopathic
  • Infections
  • Burns
  • Paroxysmal Nocturnal Hemoglobinuria
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12
Q

Describe extravascular haemolysis

A

• Occurs when RBCs phagocytosed by macrophages in reticuloendothelial system (the spleen, liver and bone marrow)
• Broken down to -> globin, iron, protoporphyrin
- Globin -> amino acids
- Iron -> binds to transferrin -> stored, taken to marrow to synthesise new Hb, some lost in bile
- Heme -> bilirubin (in macrophage) -> unconjugated bilirubin (peripheral blood) -> to liver and then bilirubin glucuronides form stercobilinogen (faeces) and urobilinogen (urine)

• Degradation in macrophages -> haemoglobin not released free into cytoplasm -> so no haemoglobinaemia or haemoglobinuria with extravascular haemolysis alone

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13
Q

Describe Intravascular haemolysis

A
  • Lysis of RBC within circulation -> release of haemoglobin into plasma
  • Leads to:
  • Haemoglobinaemia – excess Hb in blood plasma
  • Methaemalbuminaemia
  • Haemoglobinuria – haemoglobin in urine
  • Haemosiderinuria – haemosiderin in urine
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14
Q

What are the proteins that would be involved in defects in vertical and horizontal interactions in membranes? Give an example of a disorder for each disorder type.

A

• Defects in vertical interaction (hereditary spherocytosis)

  • Spectrin
  • Band 3
  • Protein 4.2
  • Ankyrin

• Defects in horizontal interaction (hereditary elliptocytosis)

  • Protein 4.1
  • Glycophorin C
  • (Spectrin – HPP)
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15
Q

Expand on hereditary spherocytosis.

A
  • 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
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16
Q

What are the clinical features hereditary spherocytosis?

A
  • 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
17
Q

What are management techniques of hereditary spherocytosis?

A
  • Monitor
  • Folic acid
  • Transfusion
  • Splenectomy
18
Q

What is the role of HMP shunt? What deficient molecule stops this shunt, and what are the consequences?

A

• Role of the HMP shunt:

  • Generates reduced glutathione
  • Protects the cell from oxidative stress
  • Glucose-6-phosphate deficiency
  • Effects of oxidative stress:
  • Oxidation of Hb by oxidant radicals
  • Resulting denatured Hb aggregates and forms Heinz bodies – bind to membrane
  • Oxidised membrane proteins – reduced RBC deformability
19
Q

Expand on G6PD deficiency.

A
  • Glucose-6-phosphate dehydrogenase deficiency
  • 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

• 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
20
Q

Expand on pyruvate kinase deficiency.

A 
• PK required to generate ATP - Essential for membrane cation pumps (deformability)
• Autosomal recessive
• Chronic anaemia
     - Mild to transfusion dependent
     - Improves with splenectomy
21
Q

What is the structure of Hb?

A

• HAEM -> protoporphyrin IX + iron; a prosthetic group in:

  • Haemoglobin
  • Myoglobin
  • Catalse
  • Peroxidase
  • Cytochrome C

• GLOBIN – globular protein, bind haem prosthetic group.
- Made of 2 alpha and 2 beta chains

22
Q

Expand on the globin gene loci, and describe the changes in pattern of globin gene expression during foetal development

A
  • Chromosome 16 (alpha-like): embryonic globin ~ alpha1/2
  • Chromosome 11 (beta-like): beta-globin cluster of genes found here! foetal (HbF - a2gamma2), adult (HbA2 - a2delta2, HbA - a2b2) ~ gamma, delta, beta
  • Alpha globin remain high
  • Beta globin rises after birth, whilst gamma (component of foetal haemoglobin) declines after birth
23
Q

How can you get haemoglobinopathies?

A

• Result from:

  • Synthesis of an abnormal haemoglobin, e.g. HbS (sickle cell disease), HbC, HbE
  • Reduced rate of synthesis of normal alpha or beta globin chains -> thalassaemia
24
Q

Expand on thalassaemias

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

25
Q

Expand on beta thalassaemia. Side effects if transfused and not transfused

A
  • Usually point mutations
  • Reduced or absent beta chains
  • Either no chain produced βo or small amounts β+
  • Beta thalassaemia trait: one chromosome (chromosome 11?)
  • Beta thalassaemia trait: both chromosomes
=> Beta thalassaemia major:
• 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
- Endocrinopathies
- Heart failure
- Liver cirrhosis
26
Q

Expand on the diagnosis of the 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-thalassaemia trait often by exclusion
  • Globin chain synthesis (rarely done now)
  • DNA studies (expensive)
27
Q

Expand on sickle cell disease

A
  • High incidence in tropical and sub tropical regions, esp sub Saharan Africa
  • Autosomal recessive, point mutation (substitution) in the beta globin chain ~ Β6 substitution glutamic acid -> valine
  • Alters solubility and stability of deoxy HbSS at low tissue oxygen levels
  • Hb polymerisation
  • Cell deformity -> sickle shape
  • Cell membrane interactions
  • Neutrophils implicated in vaso-occlusion -> can bind to sickle cells -> high WBC counts thus correlate with mortality
  • Sickle Hb shifts oxygen dissociation curve to the right -> decreased oxygen affinity
28
Q

Confirming diagnosis for sickle cell anaemia

A

• Diagnosis:

  • Normocytic, normochromic anaemia
  • Blood film: sickle cells present (note pointed ends), polychromatic cell present (reticulocyte)

• Confirming diagnosis of sickle cell anaemia:

  • Solubility test -> expose blood to reducing agent -> Hb S precipitated (can’t see black line) -> positive in trait and disease
  • Electrophoresis – structure
29
Q

Clinical and laboratory 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
30
Q

Immune haemolysis

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
31
Q

Non-immune acquired haemolysis

A 
• Paroxysmal nocturnal haemoglobinuria
• Fragmentation haemolysis:
 - Mechanical
 - Microangiopathic haemolysis
     * Disseminated intravascular coagulation
     * Thrombotic thrombocytopenic purpura
• Other:
 - Severe burns
 - Some infections: e.g. malaria
32
Q

Treatment for thalassaemia major

A

• Treatment for thalassaemia major:
- Regular blood transfusions
• Cure for thalassaemia major: BONE MARROW TRANSPLANT
- Must have matched donor (brother or sister)
- Most successful when performed early in life
- Has significant side effects – e.g. graft vs host disease (body recognises tissue as ‘foreign’), infetrtility

Clinical Pathology (62 decks)

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