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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
Q

Thalassaemia

A

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
Q

α-Thalassaemia:

Diagnosis

A

Full blood count – Low MCV, MCH
– May have high red cell count
– Differentiate from iron deficiency

Hb electrophoresis

Genetic studies

27
Q

α-Thalassaemia:

Management

A

Transfusion as needed

Genetic counselling

28
Q

β-Thalassaemia

Syndromes

A

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
Q

β-Thalassaemia

Clinical Picture

A

Drawing on Page 102

30
Q

β-Thalassaemia

Diagnosis

A

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
Q

β-Thalassaemia

Management

A

Blood transfusion

Iron chelation

Genetic counselling

32
Q

Hb Electrophoresis

A

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
Q

Membrane Disorders

A

Hereditary Spherocytosis

34
Q

Hereditary Spherocytosis

A

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
Q

Hereditary Spherocytosis

Pathogenesis

A

Drawing Page 104

36
Q

Hereditary Spherocytosis:

Clinical Picture

A

Present at any age

Fluctuating jaundice
-Increase during haemolysis

Splenomegaly
-Most patients

Pigment gallstones

Aplastic crises
-Parvovirus or folate deficiency

37
Q

Hereditary Spherocytosis:

Diagnosis

A

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
Q

Hereditary Spherocytosis:

Management

A

Symptomatic management
-Transfusions

Prevent/Treat precipitating factors

Splenectomy

  • Prevents haemolytic crises
  • Cholecystectomy = Splenectomy
  • Splenectomy ≠ Cholecystectomy
39
Q

Enzymopathies/Enzyme Deficiencies

A

EMBDEN-MEYERHOF GLYCOLYTIC PATHWAY

HEXOSE MONOPHOSPHATE SHUNT

G6PD DEFICIENCY

40
Q

HEXOSE MONOPHOSPHATE SHUNT

A

Glutathione = prevent
oxidative damage to the red
blood cell Red cell susceptible to oxidative
damage if there is a deficiency of G6PD

41
Q

G6PD DEFICIENCY

A

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
Q

Clinical Features of Enzymopathies

A

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
Q

Increased Oxidant Stress

A

Infections

Acute illness
– E.g. Diabetic ketoacidosis

Fava beans

Drugs

44
Q

Increased Oxidant Stress:

Drugs

A

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
Q

Enzymopathies:

Diagnosis

A

Full blood count

Peripheral smear

Reticulocyte count

Intravascular haemolysis

Fluorescent screening

Spectrometry

46
Q

Enzymopthies:

Dx-FBC

A

Normal between crises

Anaemia

Usually normocytic, normochromic

47
Q

Enzymopathies:

Dx-Peripheral Smear

A

Fragments, “bite”- and “blister”-cells

48
Q

Enzymopathies:

Dx-Reticulocyte Count

A

Increased in haemolytic crises

Heinz bodies seen on smear:
-Oxidized, denatured haemoglobin

Fluorescent screening
– False negative if haemolysing

Spectrometry

49
Q

Enzymopathies:

Dx-Intravascular Haemolysis

A

Haemoglobinaemia and –uria,

Raised unconjugated bilirubin

Low haptoglobin

Raised LDH

Haemosiderin urea etc

50
Q

Enzymopathies:

Dx-Fluorescent Screening

A

False negative if hemolysing

51
Q

Other Enzymopathies

A

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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