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Metabolism, Endocrinology and Haematology > Session 5 - Haemolytic Anaemias And Haemoglobinopathies > Flashcards

Session 5 - Haemolytic Anaemias And Haemoglobinopathies Flashcards

1
Q

What are haemoglobinopathies?

A

Expression of one or more globin chains is abnormal

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2
Q

What are 2 main categories of haemoglobinopathies?

A

Abnormal haemoglobin variants

Thalassaemia

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3
Q

What are abnormal haemoglobin variants?

A

Result from mutations in the genes for alpha or beta chains that alter the stability and/or function of haemoglobin

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4
Q

What are thalassaemias?

A

Result from reduced or absent expression of normal alpha or beta globin chains leading to reduced level of haemoglobin rather than presence of abnormal haemoglobin

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5
Q

What kind of inheritance are haemoglobinopathies?

A

Usually autosomal recessive

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6
Q

What is the structure of normal haemoglobin?

A

Tetramer of four globin polypeptide chains (2 alpha and 2 non alpha) held together by non covalent interactions with each globin chain complexed with an oxygen binding haem group

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7
Q

What kind of haemoglobin is present in sickle cell disease?

A

Haemoglobin S (HbS)

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8
Q

How does HbS become sickle shaped?

A

Uncharged valine instead of charged glutamic acid, making haemoglobin S more prone to polymerase at low oxygen tension, leading to formation of long twisted polymers that can result in deformation in the membrane, causing a sickle shape

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9
Q

What are the 4 consequences of sickle cell formation?

A

Vaso occlusive episodes
Anaemia
Jaundice
Splenic atrophy

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10
Q

Why does sickle cell formation cause vaso occlusive episodes?

A

Occlusion of small capillaries from sickle cells getting trapped

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11
Q

How does sickle cell formation cause anaemia?

A

Sickle cells undergo haemolysis resulting in shortened erythrocyte lifespan to 20-30 days

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12
Q

How does sickle cell formation cause jaundice?

A

Increased bilirubin resulting from chronic haemolysis

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13
Q

How does sickle cell formation cause splenic atrophy?

A

Overwork of spleen

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14
Q

What is a cure for sickle cell disease?

A

Haematopoietic stem cell transplantation

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15
Q

What causes beta thalassaemia?

A

Mutation in one or both beta globin genes leading to reduced or absent beta globin polypeptide chain

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16
Q

What happens in heterozygous individuals where only one beta globin genes are mutated?

A

Rate of beta globin production is reduced so microcytosis - reduced blood cell size but more are produced

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17
Q

What happens in homozygous individuals where both beta globin genes are mutated?

A

Life threatening condition beta-thalassaemia major

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18
Q

What is beta thalassaemia major?

A

Synthesis of beta globin polypeptide chain is totally absent and are dependent on blood transfusions from first few months of life onwards

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19
Q

What is alpha thalassaemia?

A

Deletion or loss of function of one or more of the four alpha globin genes

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20
Q

What happens when one or two alpha globin genes are affected?

A

Normal with mild microcytosis

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21
Q

What happens if all 4 alpha globin genes are malfunctioning?

A

Death in utero

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22
Q

What happens if 3 of the 4 alpha globin genes lack function?

A

Haemoglobin H disease

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23
Q

What are 4 characteristics of haemoglobin H disease?

A

Severe microcytosis
Anaemia
Haemolysis
Splenomegaly

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24
Q

What is thalassaemia major?

A

Conditions where patients are transfusion dependent

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25
Q

What is thalassaemia intermedia?

A

When patients require transfusion intermittently

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26
Q

What is thalassaemia minor?

A

When patient require no transfusion

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27
Q

What is haemolytic anaemia?

A

Abnormal breakdown of red blood cells in blood vessels or spleen

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28
Q

What are 2 types of haemolytic anaemia?

A

Inherited

Acquired

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29
Q

What are inherited haemolytic anaemias?

A

When the gene is defective

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30
Q

What are acquired haemolytic anaemias?

A

Damage to cells

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31
Q

What is microangiopathic haemolytic anaemia?

A

Acquired haemolytic anaemias whee red cells are damaged by physical trauma as they try to passs through small vessels

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32
Q

What are 3 examples of microangiopathic haemolytic anaemia?

A

Disseminated intravascular coagulation
Thrombotic thrombocytopenic purpura
Haemolytic uraemic syndrome

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33
Q

What is disseminated intravascular coagulation?

A

Bleeding and clotting occurring at same time

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34
Q

What is thrombotic thrombocytopenic purpura?

A

Small thrombi form within micro vasculature

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35
Q

What is Haemolytic Uraemic syndrome?

A

Caused by E. coli in children

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36
Q

What are 2 ways microangiopathic haemolytic anaemias occur?

A

Red cells get snagged as they try to pass through small vessels laden with fibrin strands when there’s an increased activation of coagulation cascade or shear stress produced by defective heart valve

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37
Q

What are schistocytes?

A

RBC fragments resulting from mechanical damage

38
Q

What are autoimmune haemolytic anaemias?

A

Can result from infections, lymph proliferation disorders and reaction to drugs

39
Q

What are 2 classifications of autoimmune haemolytic anaemias?

A

Warm or cold

40
Q

What are warm autoimmune haemolytic anaemias?

A

IgG antibodies recognize epitomes on red cell membrane, leading to macrophages in spleen recognizing these antibody coated red cells and phagocytose it or nibbling a bit off to form a spherocyte

41
Q

What happens to the spleen of patients with warm autoimmune haemolytic anaemia?

A

Splenomegaly as it is doing extra work

42
Q

What are cold autoimmune haemolytic anaemias?

A

IgM autoantibodies recognize red cell epitomes and there is also complement fixed to the cells. As IgM autoantibodies bind best at cooler temperatures, they bind to cells in more distal parts of the body - as they span several red cells, they create large agglutinates which can block small capillaries creating ischaemic conditions in peripheral body parts

43
Q

What happens when red cells in cold autoimmune haemolytic anaemias return to more central part of body?

A

IgM falls off and agglutination disappears, the complement binding to the red cells causes more damage by creating holes in the membrane and causing macrophages in spleen to recognize and destroy cells

44
Q

What are 4 other causes of haemolysis?

A

Oxidants
Chemicals
Heat damage
Enzymatic action

45
Q

What is pyruvate kinase deficiency?

A

Inherited metabolic disorder due to mutations in PKLR gene

46
Q

What is the role of pyruvate kinase?

A

Catalyze final step in glycolysis, transferring phosphate form phosphoenolpyruvate to ADP to form ATP

47
Q

Why does pyruvate kinase deficiency affect RBCs a lot?

A

Red blood cells lack mitochondria so pyruvate kinase deficiency inhibits their only metabolic pathway that supplies ATP

48
Q

How does pyruvate kinase deficiency lead to haemolytic anaemia?

A

Na K ATPase is inhibited from insufficient ATP to provide energy and red cells lose potassium to plasma, water moves down its concentration gradient out of cells, causing them to shrink, die, causing haemolytic anaemia

49
Q

How to treat pyruvate kinase deficiency?

A

Regular blood transfusion

50
Q

What is the inheritance of G6PDH deficiency?

A

X linked recessive

51
Q

What is G6PDH?

A

Rate limiting enzyme of pentose phosphate pathway which supplies reducing energy by producing NADPH, which protects against oxidative stress by maintaining reduced glutathione

52
Q

Why are RBCs affected by G6PDH deficiency?

A

Pentose phosphate pathway is the only source of reduced glutathione

53
Q

What is the direct Coombs test?

A

Mix red cells with anti human globulin antibody, if red cells are coated with antibodies, the anti human globulin will attach to those antibodies making the red cells clump

54
Q

What does the direct Coombs test used for?

A

Detect antibodies or complement bound to surface of RBC

55
Q

What is the inheritance of hereditary spherocytosis?

A

Abnormalities in erythrocyte membrane proteins which impede the ability of cell to change shape

56
Q

What is the inheritance of hereditary spherocytosis?

A

Autosomal dominant

57
Q

What are the 4 proteins that are shown to cause hereditary spherocytosis?

A

Spectrin
Ankyrin
Band 3
Protein 4.2

58
Q

What is the common role of the 4 proteins?

A

Facilitate vertical interactions between cytoskeleton and the lipid bilayer

59
Q

How does the mutation of the 4 proteins lead to haemolytic anaemia?

A

Cytoskeleton and membrane disconnects, vesiculation of unsupported membrane components leading to progressive reduction in membrane surface area and production of a spherocyte shape, and becomes less deformable and becomes trapped and damaged as they pass through the spleen

60
Q

How to treat hereditary spherocytosis?

A

Splenectomy

61
Q

What are myeloproliferative neoplasms?

A

Group of diseases of the bone marrow in which excess cells are produced

62
Q

What are 4 major types of myeloproliferative neoplasms?

A

Polycythemia Vera
Essential thrombocythaemia
Primary myelofibrosis
Chronic myeloid leukemia

63
Q

What is polycythemia?

A

Volume percent of erythrocytes in blood exceed 52% males or 48% females

64
Q

What is absolute polycythemia?

A

Increase in number of erythrocytes leading to excessive percent of erythrocytes

65
Q

What is relative polycythemia?

A

Decrease in plasma volume causing excessive volume % of erythrocytes

66
Q

What is polycythemia Vera?

A

Myeloproliferative neoplasms in bone marrow results in overproduction of erythrocytes

67
Q

Wheat causes polycythemic Vera?

A

Mutation of gene coding for Janus Kinase 2

68
Q

What is the function of JAK2?

A

Stimulate signalling pathways leading to erythrocyte production in response to erythropoietin

69
Q

What happens when JAK2 is mutated?

A

Multi potent stem cells harboring the mutation survive longer and proliferate continuously

70
Q

What are 5 effects of polycythaemia Vera?

A 
Thrombosis
Haemorrhage
Headaches
Burning pain in hands or feet
Splenomegaly
71
Q

What is the treatment of polycythaemic Vera?

A

Phlebotomy to maintain the hematocrit below 45%
Aspirin anti platelet effects
Cytoreductive agents inhibit DNA synthesis

72
Q

What are secondary causes of polycythaemia?

A

Increased stimulation by erythropoietin like living at high altitude and chronic hypoxia

73
Q

What is thrombocytopenia?

A

Abnormally low level of platelets

74
Q

What are 5 symptoms of acquired thrombocytopenia?

A 
Bleeding gums
 Nosebleeds
Heavier menstrual periods
Bruises
Petechiae
75
Q

What are 3 reasons for thrombocytopenia?

A

Decreased platelet production
Increased platelet consumption
Increased platelet destruction

76
Q

What is immune thrombocytopenic purpura?

A

Autoimmune disease characterized by isolated thrombocytopenia which can take an acute or chronic course

77
Q

What happens during immune thrombocytopenic purpura?

A

Anti platelet auto antibodies

T cell activity against platelets and megakaryocytes

78
Q

What are 5 ways to treat immune thrombocytopenic purpura?

A 
Corticosteroids
Immunosuppressive drugs
Intravenous pooled human Immunoglobin
Splenectomy 
Thrombopoietin receptor agonists
79
Q

What is primary myelofibrosis?

A

Myeloproliferative neoplasm where proliferation of mutated haemopoietic stem cells result in reactive bone marrow fibrosis leading to replacement of marrow with scar tissues

80
Q

How does extramedullary haemopoiesis occur?

A

Mobilization of mutated progenitor cells from bone marrow, colonies liver and spleen

81
Q

What is secondary myelofibrosis?

A

When myelofibrosis developed as a consequence of polycythaemia Vera or essential thrombocythaemia

82
Q

What are 7 symptoms of primary myelofibrosis?

A 
Hepatosplenomegaly
Bruising 
Fatigue
Weight loss
Fever
Increased sweating 
Portal hypertension
83
Q

What are 6 treatment options for primary myelofibrosis?

A 
Hydroxycarbamide
Folic acid
Allopurinol
Blood transfusions
Splenectomy 
Ruxolitinib (JAK2 inhibitor reduces spleen volume and improves symptoms)
84
Q

What is acute leukaemia?

A

Cause bone marrow failure due to large numbers of immature blast cells overwhelming the ability of the tissue to produce mature blood cells

85
Q

What is chronic myeloid leukemia?

A

Unregulated growth of myeloid cells in the bone marrow leading to the accumulation of mature granulocytes and myelocytes in blood

86
Q

What leads to chronic myeloid leukaemia?

A

Philadelphia chromosome involving translocation between chromosomes 9 and 22 causing an oncogenes gene fusion with tyrosine kinase activity that results in proliferation, differentiation and inhibition of apoptosis

87
Q

What is aplastic anaemia?

A

Damage to bone marrow and haematopoietic stem cells leading to pancytopenia

88
Q

What is pancytopenia?

A

Deficiency of all 3 blood cell types (red, white blood cells and platelets)

89
Q

What is aplastic?

A

Inability of stem cells to generate mature blood cells

90
Q

What can aplastic anaemia be caused by?

A

Genetic causes, autoimmunity or exposure to chemicals, drugs or radiation

Metabolism, Endocrinology and Haematology (8 decks)

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