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Metabolism, Endocrinology, Haematology > Haematology Session 3 > Flashcards

Haematology Session 3 Flashcards

1
Q

What is sickle cell disease?

A

Abnormal globin chain (alpha/beta) variants that affect stability and function of Hb.

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2
Q

What are thalassaemias?

A

Reduced/absent expression of normal alpha or beta globin chains, that leads to a reduced level of haemoglobin. Cause an imbalance in the composition of a tetramer.

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3
Q

Do carriers of haemoglobinopathies show symptoms?

A

No - usually autosomal recessive.

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4
Q

What is the makeup of haemoglobin?*

A
  • 2 alpha chains
  • 2 beta chains
    Each has an oxygen binding haem group
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5
Q

What are the 3 normal types of haemoglobin in the adult?

A 
Hb A (2 alpha 2 beta) - 95%
Hb A2 (2 alpha 2 delta) - 3%
Hb F (2 alpha 2 gamma) - less than 1%
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6
Q

Why is different haemoglobin expressed during development?*

A
  • Adaptive response to oxygen requirements
  • Hb F before birth
  • Hb A starts before birth and increases to be dominant after birth
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7
Q

What chromosome are the alpha globin genes encoded on?*

A
  • Chromosome 16
  • Each person has 2 copies on one chromosome
  • So 4 in total - one maternal, one paternal
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8
Q

What chromosome are the other globin genes on?

A
  • Chromosome 11
  • Single beta gene
  • So 2 copies in total, one maternal one paternal
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9
Q

What are thalassaemias?

A

Excess of chains of one certain type.
Alpha - alpha globin gene expression is affected
Beta - beta globin gene expression is affected

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10
Q

Where is thalassaemia most prevalent?

A

South Asian, mediterranean, Middle east and Far east.

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11
Q

What happens when one alpha globin gene is deleted?

A
  • Asymptomatic

- Patient is a silent carrier

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12
Q

What happens when 2 alpha globin genes are deleted?

A
  • Minimal/no anaemia
  • Both genes on 1 or 2 genes on one chromosome can be deleted
  • Microcytosis
  • Hypochromia
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13
Q

What happens when 3 alpha globin genes are deleted?

A
  • Hb H disease (moderately severe)
  • Beta globin tetramers
  • Microcytic, hypochromic cells
  • Target cells and Heinz bodies present
  • Haemolysis and splenomegaly
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14
Q

What happens when all 4 alpha globin genes are deleted?

A
  • Hydrops fetalis
  • Incompatible with life (intrauterine death)
  • Unable to deliver oxygen to tissues
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15
Q

What is beta thalassaemia caused by?

A

Most often mutation rather than deletion

B0 = no globin chain, B+ = reduced production

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16
Q

What is beta-thalassaemia minor?

A
  • Mild anaemia (microcytic, hypochromic)
  • Asymptomatic
  • Heterozygous, 1 normal and 1 abnormal gene
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17
Q

What is beta-thalassaemia intermedia?

A
  • Severe anaemia
  • Similar to Hb H disease
  • Can be mild variant of homozygous/severe variant of heterozygous
  • Genetically heterogeneous
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18
Q

What is beta-thalassaemia major?

A
  • Severe
  • Transfusion dependent
  • 6-9 months after birth, switches from Hb F to Hb A
  • Homozygous, Bo/Bo or B+/B+
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19
Q

What will a blood smear from a thalassaemic patient show?*

A
  • Hypochromic and microcytic cells
  • Anisopoikiloytosis (diff. sizes and shapes)
  • Target cells, nucleated RBCs (escape bone marrow when it’s working hard) Heinz bodies
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20
Q

Why is the excess of unaffected globin chain a problem?

A
  • Can form aggregates that get oxidised
  • Premature death of precursors and therefore ineffective erythropoiesis
  • Cells destroy spleen more - shorter RBC lifespan
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21
Q

What are the consequences of thalassaemia? ***!

A
  • Reduced lifespan
  • Iron overload from transfusions (not handled well) and from ineffective haematopoiesis
  • Reduced O2 delivery = erythropoietin stimulation, makes more defective red cells
  • Extramedullary haematopoiesis to compensate - splenomegaly, hepatomegaly (back to where it was as fetus)
  • Can cause skeletal abnormalities (eg. bowing and swelling)
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22
Q

What are the treatments for thalassaemias?

A
  • Red cell transfusion
  • Iron chelation (binding iron to reduce binding to tissues and lower iron overload)
  • Folic acid (erythropoiesis)
  • Immunisation (hyposplenic)
  • Holistic care to manage complications (eg. endocrinology, cardiac)
  • Stem cell transplants to replace defective red cell production
  • Pre conception counselling for couples at risk
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23
Q

What is sickle cell disease?*

A
  • Mutation of B-globin gene
  • Glutamic acid changed to valine at position 6
  • Mutant Hb is Hb S
  • Can be co-inherited with abnormal haemoglobin to cause disrorder
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24
Q

What are the symptoms of heterozygous carriers of sickle cell?

A

Mild asymptomatic anaemia

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25
Q

What are the symptoms of homozygous sickle cell anaemia?

A

Severe sickling syndrome

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26
Q

Why is the anaemia in sickle cell disease well tolerated, and why is there a problem?*

A

Hb S gives up oxygen more readily than Hb A, but cannot do so at low oxygen states (eg. cold, illness)

  • Deoxygenated Hb S forms polymers which give sickle cells
  • Sickle cells less deformable, cause occlusion of small vessels
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27
Q

Can sickled cells ‘bounce back’ to normal?*

A

Yes, however repeated sickling cycles will result in irreversibly sickled red blood cells.

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28
Q

What can occlusions in small blood vessels dues to sickle cell cause?

A
  • Acute chest symdrome
  • Stroke
  • Kidney infarcts
  • Splenic atrophy
  • Avascular necrosis
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29
Q

What are the types of sickle cell crises?

A
  • Vaso-occlusive: occlusion of capillaries - joint damage & pain (AVN) , stroke, acute chest syndrome
  • Aplastic (bone marrow stops working)
  • Haemolysis

End organ damage - thromboses, O2 deprivation

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30
Q

What are the consequences of sickle cell formation?

A
  • Anaemia (haemolysis - shorter lifespan)
  • Jaundice/gallstones (inc. bilirubin)
  • Splenic atrophy (splenic infarction)
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31
Q

What infections does hyposplenia make you more susceptible to?

A

Encapsulated bacteria:

  • Streptococcus pneumoniae
  • Streptococcus meningitidis
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32
Q

What are treatments for sickle cell disease?

A
  • Stem cell transplantation (rare to find match donors)
  • Red cell exchange
  • Vaccinations
  • Folic acid
  • Hydroxycarbamide to increase Hb F
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33
Q

What are inherited causes of haemolytic anaemias?*

A
  • Pyruvate kinase deficiency
  • G6PDH deficiency + oxidative damage
  • Hereditary spherocytosis
  • Haemoglobin defects
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34
Q

What are acquired causes of haemolytic anaemias?*

A

Mechanical, antibody, oxidant, heat and enzymatic damage.

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35
Q

Where can haemolysis occur?

A
  • Intravascular

- Extravascular (spleen/RES)

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36
Q

When does anaemia develop?

A

When rate of haemolysis exceeds rate of cell production.

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37
Q

How much does the RBC lifespan result to in haemolysis?

A

20-30 days.

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38
Q

What are some consequences of haemolytic anaemias?

A
  • Jaundice (high bilirubin)

- Splenomegaly (overwork)

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39
Q

Why can sudden haemolysis cause cardiac arrest?

A
  • Reduced O2 delivery

- Potassium leaves cells leading to hyperkalaemia

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40
Q

What is hereditary spherocytosis?*

A
  • Autosomal dominant
  • Spherical shape
  • Ankyrin, spectrin, protein 4.2 and band 3 defects
  • Easily damaged, less flexible cells
  • Disconnection of cytoskeleton
  • Reduction in membrane surface area
41
Q

What is a treatment of hereditary spherocytosis?

A

Splenectomy - improves anaemia as reduces removal

42
Q

What is hereditary elliptocytosis?*

A
  • Elliptical cells

- Spectrin defect most common

43
Q

What is hereditary pyropoikilocytosis?*

A
  • Spectrin defect

- Abnormal sensitivity to heat (similar to when burns damage)

44
Q

What is microangiopathic haemolytic anaemia?*

A
  • Acquired

- Damage by physical trauma

45
Q

How do microangiopathic anaemias occur?

A
  • Snagging on fibrin strands from clotting cascade (disseminated intravascular coagulation) - bleeding and clotting at same time
  • Shear stress from passing through a narrow heart valve
46
Q

What cell fragments are left behind and are an indication of microangiopathic haemolytic anaemia?*

A

Schistocytes

47
Q

Why does G6PDH deficiency cause anaemia?

A
  • Oxidative stress (NADPH depleted, no glutathione reformation)
  • Damage
  • Damaged cells removed by the spleen
  • Protein damage (Heinz bodies)
  • Should be screened for it before giving drugs causing haemolysis
48
Q

Why can pyruvate kinase deficiency cause anaemia?

A
  • RBCs have no mitochondria
  • Inhibits ATP supply to them by inhibiting glycolysis
  • Na/K ATPase activity halted
  • Shrinking/haemolytic anaemia
  • May need blood transfusion if severe
49
Q

What are autoimmune haemolytic anaemias?

A

Caused by antibodies binding to red cell membranes.

50
Q

What are the causes of autoimmune haemolytic anaemias?

A
  • Infections
  • Cancers of lymphoid system
  • Drug reactions
51
Q

What are those anaemias classified by and why?

A
  • Warm (IgG): react best at body temperature, recognise epitopes on red cell membrane
  • Cold (IgM): react best at colder temperatures, complement also fixed
52
Q

Why can IgM anaemia cause ischaemic conditions?

A
  • Create large agglutinates which block small capillaries

- Fall off at warmer temperatures

53
Q

Why does splenomegaly occur in autoimmune anaemias?

A

Spleen is working hard to replenish cells and there’s a high cell turnover

54
Q

What is the direct Coombe test?

A

Used to detect which antibody is bound to surfact

  • Mixed with anti-human globulin antibody
  • Will attach to any antibodies and cells will clump together
55
Q

What are myoproliferative neoplasms?

A
  • Diseases of the bone marrow in which excess cells are produced
  • Genetic mutations in precursors of myeloid lineage
56
Q

What are the 4 main types of myoproliferative neoplasms?

A
  • Polycythaemia vera (+ RBC)
  • Essential thrombocythaemia (+ Megakaryocytes)
  • Primary myelofibrosis (replacement by fibrous tissue + therefore pancytopenia)
  • Chronic myeloid leukaemia (+ Granulocytes)
57
Q

What are the diagnostic criteria for polycythaemia vera?*

A
  • Haematocrit above 52% (men) or 48% (women)
  • Can be caused by an increase in erythrocytes (absolute polycythaemia)
  • Decrease in plasma volume
58
Q

What is polycythaemia vera?

A
  • Arises from a myoproliferative neoplasm in BM

- Overproduction of erythrocytes (sometimes WBC and platelet too)

59
Q

What gene mutates to cause 95% of polycythaemia vera?

A
  • JAK2 (Janus kinase 2), a tyrosine kinase
  • Normal function is stimulate signalling pathways leading to increased erythropoiesis to respond to EPO
  • Continuous proliferation and survival with mutation
60
Q

What clinical features are associated with PV?

A
  • Venous and arterial thrombosis
  • Haemorrhage
  • Headache
  • Burning pain in hands/feet, erythromelagia
  • Arthritis
  • Gout

TRANSFORMATION TO MYELOFIBROSIS/ACUTE LEUKAEMIA

61
Q

What is the treatment for polycythaemia vera?

A
  • Phlebotomy (haematocrit below 45%)
  • Aspirin 75mg (anti-platelet, reduces risk of thrombosis)
  • Cytoreduction by hydroxycarbamide if patient has poor toleration of venesection or shows progression evidence
62
Q

What are secondary causes of polycythaemia?

A

Increased stimulation by EPO, caused by:

  • Living at high altitude (physiologically appropriate)
  • Chronic hypoxia (eg. COPD), pathological
  • Renal disease
  • Tumours secreting EPO
63
Q

What is relative polycythaemia?*

A

Decrease in plasma volume.

64
Q

What is absolute polycythaemia and what are its causes?

A

Increased number of erythrocytes.
Primary: polycythaemia vera
Secondary: responses & abnormal production of EPO

65
Q

What is essential thrombocythaemia?

A

Chronic blood cancer characterised by overproduction of platelets by large and excess megakaryocytes in bone marrow.

66
Q

What is thrombocythaemiea caused by?

A

Around 50% caused by JAK2 mutation or mutations in thrombopoietin receptor.

67
Q

What are the most common symptoms of thrombocythaemia?

A
  • Extremity numbness
  • Thrombosis (stroke, gangrene)
  • Hearing and vision disturbances
  • Headaches
  • Erythromelagia
68
Q

When is thrombocythaemia normal?

A
  • Response to infection
  • Response to inflammation
  • Hospitalised patients
69
Q

What are the reasons for thrombocytosis?

A
  • Primary: essential thrombocythaemia
  • Secondary: response to normal stimulus
  • Redistributional: platelets from splenic pool to bloodstream
70
Q

What is the management for patients with essential thrombocythaemia?

A
  • High risk of clotting: hydroxycarbamide to reduce platelet count
  • Low risk of clotting: aspirin
  • Managing any cardiovascular risk factors
71
Q

What are the other causes of a high platelet count?

A
  • Infection and inflammation
  • Tissue injury
  • Cancer
  • Haemorrhage
  • Redistribution post-splenectomy
72
Q

What is thrombocytopenia?*

A

Abnormally low platelet count.

73
Q

What are inherited reasons for thrombocytopenia?

A

Rare inherited syndromes, eg. Fanconi anaemia

74
Q

What are acquired causes for thrombocytopenia?

A
  • Decrease in platelet production (B12/folate, sepsis, leukaemia)
  • Increased consumption of platelets (DIC, haemorrhage)
  • Increased destruction of platelets (autoimmune thrombocytopenic purpura, splenic pooling)
  • NSAID/aspirin use
  • Myeloproliferative disorders
75
Q

What are the symptoms of a low platelet count?

A
  • Nosebleeds
  • Bleeding gums
  • Heavier periods
  • Spontaneous bleeding/petechiae
76
Q

What is immune thrombocytopenic purpura?

A
  • Autoimmune disease characterised by thrombocytopenia
  • Presents either due to symptoms or accidentally on a blood count
  • Mucosal bleeding, severe bleeding after trauma, easy bruising
77
Q

What are the causes of immune thrombocytopenic purpura?

A
  • Autoantibodies against platelets (Glycoprotein IIb/IIIa)
  • T cell activity against platelets and megakaryocytes
  • Secondary to autoimmune disorders, eg. rheumatoid arthritis or systemic lupus erythrematosus, leukaemia, HIV)
78
Q

What are the treatments for immune thrombocytopenic purpura?

A
  • Immunosuppression
  • Corticosteroids
  • Immunoglobulin
  • Splenectomy
  • Platelet transfusions don’t work as would also get destroyed
79
Q

What is a quantitative platelet disorder?

A

Low platelet count

80
Q

What is a qualitative platelet disorder?

A

Normal count but defective platelet function

81
Q

What is the key role of platelets?

A
  • Adhesion to damaged endothelial wall
  • Activation to change shape and release granules
  • Aggregation: clumping of more platelets to form plug
82
Q

What is primary myelofibrosis?*

A

Proliferation of mutated haematopoietic stem cells results in reactive bone marrow fibrosis, eventually leading to collagen deposition and therefore replacement with scar tissue.
(JAK2 association)

83
Q

Why do cells in a primary myelofibrosis blood film look like teardrops?

A

They got deformed trying to squeeze through the bone marrow.

84
Q

Why do patients with primary myelofibrosis present with hepatomegaly and massive splenomegaly?

A

Mutated progenitor cells colonise the liver and spleen, leading to extramedullary haematopoiesis.

85
Q

What is secondary myelofibrosis?

A

When the disease develops from polycythaemia vera or essential thrombocythaemia.

86
Q

What are clinical features of myelofibrosis?

A
  • Progressive pancytopenia due to fibrosis and hypersplenism
  • Fatigue, sweats when advanced
  • Pain, early satiety and splenic infarction due to splenomegaly
  • Progressive marrow failure
  • TRANSFORMATION TO LEUKAEMIA
  • Early death
87
Q

What are some treatments for myelofibrosis?

A
  • Hydroxycarbamide
  • Folic Acid
  • Blood transfusions
  • Splenectomy
  • JAK2 inhibitors
  • Poor prognosis
88
Q

What is the difference between chronic and acute leukaemias?

A
  • Acute leukaemias cause bone marrow failure due to many immature blast cells
  • Chronic leukaemias slower to cause symptoms, picked up by chance
89
Q

What is chronic myeloid leukaemia?

A

Unregulated growth of myeloid cells in bone marrow which leads to accumulation of mature granulocytes (neutrophils) in blood.

90
Q

What is associated with chronic myeloid leukaemia?**

A
  • Chromosomal translocation = PHILADELPHIA CHROMOSOME
  • Reciprocal translocation between chromosomes 9 and 22
  • Causes oncogenic gene fusion (BCR-ABL) with tyrosine kinase activity
91
Q

What does increased tyrosine kinase activity result in?*

A
  • Proliferation
  • Diferentiation
  • Inhibition of apoptosis
92
Q

What are tyrosine kinase inhibitors?*

A
  • Drugs that drastically improved survival rates in CML
  • IMATINIB binds to site and inhibits substrate binding
  • Cancer cell can’t proliferate
93
Q

What is pancytopenia?

A

Reduction in white cells, red cells and platelets

94
Q

How can pancytopenia be caused by increased removal of cells?

A
  • Splenic pooling (massive splenomegaly)
  • Haemophagocytosis (WBCs phagocytosing other blood components)
  • Immune destruction
95
Q

What can cause reduced red cell production?*

A
  • B12/folate deficiency
  • Bone marrow infiltration by cancer/fibrosis
  • Idiopathic aplastic anaemia
  • Radiation
  • Drugs
  • Viruses (eg. EBV, HIV)
  • Congenital bone marrow failure (eg. Fanconi’s anaemia)
96
Q

What is aplastic anaemia?

A

A rare disease resulting in damage to the bone marrow and haematopoietic stem cells, leading to pancytopenia.

Inability of the stem cells to generate mature blood cells.

97
Q

What are the features of aplastic anaemia?

A
  • Proneness to bleeding
  • No fibrosis
  • Fat deposits in marrow
  • Neutropenic infection (high mortality)
98
Q

What are the causes of aplastic anaemia?

A
  • Genetic
  • Autoimmunity
  • Chemical/drugs/radiation exposure

Metabolism, Endocrinology, Haematology (16 decks)

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