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Haematology > Inherited Haemolytic Anaemias and Heamoglobinopathies > Flashcards

Inherited Haemolytic Anaemias and Heamoglobinopathies Flashcards

1
Q

Red Blood Cell Compartments

A

Red Cell Membrane

Enzymes/Red Cell Metabolism

Heamoglobin

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2
Q

Red Cell Membrane

A

Lipid bilayer

Several integral proteins

Function
– Membrane stability
– Deformability

Horizontal vs vertical

Defects
– Abnormal red cell shape
– Haemolysis

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3
Q

Red Cell Metabolism/Enzymes:

Function

A
  1. Energy for red cell function
    • ATP via glycolytic pathway
  2. Prevent oxidative damage
    • G-6-PD & NADPH
  3. Regulate oxygen affinity of haemoglobin
    • Provides 2,3 – DPG
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4
Q

Haemoglobin

A

Consist of several components:

4 globin molecules
-2α + 2β

Haem molecule
-Protoporphyrin + Iron

Function
– Oxygen transport
– Carbon dioxide transport

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5
Q

Hereditary Haemolysis:

Classification according to the compartments of the Red Blood Cell

A

Problem with the RBC compartments/components:

1. Haemoglobin:
   Haemoglobinopathies:
   -Sickle Cell Disease
   -Thalassemias
   -Unstable Hb
  1. Membrane:
    Membrane defects:
    -Hereditary Spherocytosis
    -Hereditary Elliptocytosis
  2. Metabolic:
    Enzyme Deficiencies:
    -GDP6 Deficiency
    -Pyruvate Kinase Deficiency
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6
Q

Haemoglobinopathies

A

Can be categorised as Qualitative and Quantitative

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7
Q

Qualitative Haemoglobinopathies

A

Sickle Cell Anaemia

Haemoglobin C

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8
Q

Quantitative Haemoglobinopathies

A

Thalassemia(a/b)»>Hypochromic, Microcytic Aneamia

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9
Q

Haemoglobinopathies:

Syndromes/ Abnormality

A

Haemolysis:

  • Crystalline Hbs( Hb S, C, D etc)
  • Unstable Hb

Thalassaemia:
-a/b resulting from reduced globin chain synthesis

Familial Polycythemia:
-Altered Oxygen affinity

Methaemoglobinaemia:
-Failure of reduction(Hb Ms)

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10
Q

Sickle Cell Disease

A

Point mutation (single base change) in DNA coding for β-globin
– Substitution of glutamic acid with valine on position 6
– Form HbS instead of HbA

Sickle cell anaemia: Homozygous mutation
– Causes a severe syndrome

Sickle cell trait: Heterozygous
– Benign condition
– May have haematuria

Hb S is insoluble forms crystals at low oxygen tension
Oxygen dissociation curve shifted to the right

Initially reversible, but after several cycles the sickling becomes irreversible

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11
Q

Clinical features of Sickle Cell Anaemia

A

Chronic haemolytic anaemia

Infarctions/Painfull crises

Haemolytic crises

Aplastic crises

Spleen

Infections

Other

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12
Q

Chronic haemolytic anaemia

A

Sickle cells trapped in splenic microcirculation, premature RBC death Pigment gallstones

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13
Q

Infarctions/Painfull crises

A

Sickle cells trapped in small/medium blood vessels
Precipitating conditions: Hypoxia, infections, acidosis, dehydration, cold
Hand-foot syndrome: Infarction with subsequent infection of the
metacarpals/metatarsals in children
Chronic tissue/organ damage (bones, lung, kidneys, liver, brain etc.)

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14
Q

Haemolytic crises

A

Usually accompany infarctive crises: Anaemia+ Increased reticulocyte count

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15
Q

Aplastic crises

A

Parvovirus infection
Folate deficiency

Anaemia + decreased Reticulocyte count

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16
Q

Spleen

A

Enlarged due to trapped red cells

Subsequent infarction:Hyposplenism at 6 years

Prior to destruction of spleen: Risk of SPLENIC SEQUESTRATION (may be fatal)

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17
Q

Infections

A

Risk of overwhelming sepsis(early childhood)

Asplenic: infection by encapsulated organisms

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18
Q

Other

A

Priapism, chronic leg ulcers, proliferative retinopathy, pulmonary hypertension, acute chest syndrome

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19
Q

Sickle Cell Disease:

Effects of Vascular Occlusion

A

Retinopathy

Acute respiratory distress

Cor pulmonale

Hyposplenism (Autosplenectomy)

Haematuria and polyuria

Infections

Aseptic bone necrosis

Osteomyelitis

Leg ulcers

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20
Q

Sickle Cell Disease:

Effects of Chronic Haemolysis

A

Jaundice

Aneamia

Gall Stones

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21
Q

Sickle Cell Disease:

Other Features

A

Fatigue

Stunted Growth

Pain

Priapism

22
Q

Sickle Cell Disease:

Laboratory Diagnosis

A

Full blood count and peripheral smear

Screening

Specific
– Haemoglobin electrophoresis
– High performance liquid chromatography

23
Q

Sickle Cell Disease:

Treatment/Management

A

Vaccinate: Pneumococcus, meningococcus and Haemophillus influenza B

Penicillin prophylaxis

Folic acid supplements

Avoid precipitating factors

Prompt treatment of infections

Infarctive crises: Fluids, Analgesia, Warmth and Antibiotics

Blood transfusions / exchange transfusions

Prevent iron overload (rare)

24
Q

Other Haemoglobins

A

Haemoglobin C

  • β-globin
  • Form rhomboid crystals and target cells
  • Mild haemolytic anaemia

Haemoglobin D
– Homozygotes have a mild haemolytic anaemia

Haemoglobin E
– Homozygotes have a mild haemolytic anaemia

25
Thalassaemia
Deletion/mutation of haemoglobin genes leading to reduced production of haemoglobin. Causes a hypochromic microcytic anaemia Two main groups: - β-Thalassaemia: Chromosome 11- B globin gene - α-Thalassaemia: Chromosome 16- A globin gene
26
α-Thalassaemia: Diagnosis
Full blood count – Low MCV, MCH – May have high red cell count – Differentiate from iron deficiency Hb electrophoresis Genetic studies
27
α-Thalassaemia: Management
Transfusion as needed Genetic counselling
28
β-Thalassaemia Syndromes
β-thalassaemia major - 2 genes (Homozygous) - Severe disease - Onset 6-9 months β-thalassaemia intermedia - Different genotypes - Diagnosed based on clinical presentation - Onset 1-2 years - Moderate Anaemia β-thalassemia minor (trait) - 1 gene (Heterozygous) - Asymptomatic,Incidental finding - May have mild hypochromic microcytic aneamia(Hb 10-11 g/dL)
29
β-Thalassaemia Clinical Picture
Drawing on Page 102
30
β-Thalassaemia Diagnosis
FBC - Anaemia-β-thalassaemia major: Hb 2–3 g/dL - MCH & MCV low Peripheral smear - Target cells - Microcytes - Basophilic stippling Reticulocyte count -High Hb electrophoresis:HbA2 low High performance liquid chromatography
31
β-Thalassaemia Management
Blood transfusion Iron chelation Genetic counselling
32
Hb Electrophoresis
Electrophoresis: Separate molecules of similar size Passes electrical current through a medium containing the molecules Molecules travel at different rates according to the electrical charge and size Haemoglobin electrophoresis-Different types of haemoglobin= different structures – Electrophoresis produces a pattern of bands
33
Membrane Disorders
Hereditary Spherocytosis
34
Hereditary Spherocytosis
Common in northern Europeans -Autosomal dominant inheritance Defect of proteins involved in vertical interactions - Band 3 - Ankyrin - Protein 4.2 (Pallidin) - Deficiency of α- or β-spectrin Spherocytes formed when parts of lipid bilayer is lost during circulation through RE system - Loss of surface relative to volume - Decreased red cell survival
35
Hereditary Spherocytosis Pathogenesis
Drawing Page 104
36
Hereditary Spherocytosis: Clinical Picture
Present at any age Fluctuating jaundice -Increase during haemolysis Splenomegaly -Most patients Pigment gallstones Aplastic crises -Parvovirus or folate deficiency
37
Hereditary Spherocytosis: Diagnosis
Full blood count - Anaemia - High MCHC Peripheral smear -Microspherocytes Reticulocyte count raised Direct antiglobulin test (Coombs) negative Osmotic fragility -Increased fragility when incubated in dilute saline solution Flowcytometry Membrane protein analysis
38
Hereditary Spherocytosis: Management
Symptomatic management -Transfusions Prevent/Treat precipitating factors Splenectomy - Prevents haemolytic crises - Cholecystectomy = Splenectomy - Splenectomy ≠ Cholecystectomy
39
Enzymopathies/Enzyme Deficiencies
EMBDEN-MEYERHOF GLYCOLYTIC PATHWAY HEXOSE MONOPHOSPHATE SHUNT G6PD DEFICIENCY
40
HEXOSE MONOPHOSPHATE SHUNT
Glutathione = prevent oxidative damage to the red blood cell Red cell susceptible to oxidative damage if there is a deficiency of G6PD
41
G6PD DEFICIENCY
Wide variety of genetic variants - Over 400 variants - > 400 million people worldwide (most common enzyme deficiency in the world) Common variants - Type A - African type - Type B – Western type Sex-linked inheritance - Males affected, females carriers (50% normal activity) - Carriers have resistance to Falciparum malaria
42
Clinical Features of Enzymopathies
Usually asymptomatic 3 main syndromes: Acute haemolytic anaemia • Response to increased oxidant stress • Can be caused by medications, food (fava beans) or infections Neonatal jaundice Congenital non-spherocytic haemolytic anaemia • Rare
43
Increased Oxidant Stress
Infections Acute illness – E.g. Diabetic ketoacidosis Fava beans Drugs
44
Increased Oxidant Stress: Drugs
Antimalarial -Primaquine, pamaquine, chloroquine, Fansidar, Maloprim Sulphonamides/sulphones -Co-trimoxazole, sulfanilamide, dapsone, Salazopyrin Other antibacterials -Nitrofurans, chloramfenicol Analgesics -Aspirin (Moderate doses safe) Antihelminths -Β-naphtol, stibophen Miscellaneous - Vitamin K-analogues, naphthalene (mothballs) , probenecid
45
Enzymopathies: Diagnosis
Full blood count Peripheral smear Reticulocyte count Intravascular haemolysis Fluorescent screening Spectrometry
46
Enzymopthies: Dx-FBC
Normal between crises Anaemia Usually normocytic, normochromic
47
Enzymopathies: Dx-Peripheral Smear
Fragments, “bite”- and “blister”-cells
48
Enzymopathies: Dx-Reticulocyte Count
Increased in haemolytic crises Heinz bodies seen on smear: -Oxidized, denatured haemoglobin Fluorescent screening – False negative if haemolysing Spectrometry
49
Enzymopathies: Dx-Intravascular Haemolysis
Haemoglobinaemia and –uria, Raised unconjugated bilirubin Low haptoglobin Raised LDH Haemosiderin urea etc
50
Enzymopathies: Dx-Fluorescent Screening
False negative if hemolysing
51
Other Enzymopathies
Pyruvate kinase deficiency -Homozygotes has severe haemolytic anaemia Glutathione deficiency -Similar to G6PD Other glycolytic pathway defects -Congenital non-spherocytic haemolytic anaemia

Haematology (10 decks)

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