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Clinical Immunology & Haematology > Clinical Haematology (1-6) > Flashcards

Clinical Haematology (1-6) Flashcards

1
Q

Where does haematopoiesis occur?

A

as embryo matures, stem cells migrate to the liver which serves as a niche for blood stem cell production

production the moves to the bone marrow
- in infants all bone marrow contains stem cells
- in adults this is reduced to certain bones

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2
Q

What are the two types of stem cell renewal?

A

symmetric
- give rise to either two daughter cells or two more differentiated cells (in which case pluripotency is lost)

asymmetric
- differentiate into one stem cell and one differentiated cell

~ 1 billion cells produced each day in a healthy adult
1 HSC can produce ~10^6 mature blood cells after 20 divisions
1 HSC per 10 000 BM cells

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3
Q

Why do erythrocytes not have a nucleus?

A

to make space for more haemoglobin

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4
Q

What types of signals are required for differentiation of stem cells?

A

extrinsic signals
- growth factors (cell survival, proliferation, differentiation, maturation, activation
- adhesion molecules (interact w extracellular matrix)

intrinsic signals
- transcription signals

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5
Q

Give examples of different growth factors?

A

myelopoiesis
- G-CSF: granulocytes
- M-CSF: macrophages
- IL-5: eosinophils

thrombopoiesis
- thrombopoietin from liver
- feedback mechanism controls platelet count

erythropoiesis
- regulated by renal erythropoietin which is stimulated by tissue oxygen

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6
Q

What is the haematocrit parameter?

A

proportion of blood that is cells

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7
Q

What is the reticulocyte parameter?

A

number of immature red blood cells

a high count means that the bone marrow is producing a lot

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8
Q

What is the nomenclature for blood conditions?

A

too much (-cytosis)
- known as cytoses
can be malignant or benign

too little (-cytopenia)
- failure of production
- excess loss/ consumption
- both
a primary cytopenia is a problem w the bone marrow
secondary is other

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9
Q

What can cause anaemia?

A

blood loss
- menstruation
- gastrointestinal bleeding

reduced RBC production
- iron deficiency
- B12/folate deficiency
–> malabsorption eg coeliac disease
- malignancy
- thalassaemia

increased RBC destruction
- haemolysis eg autoimmune
- sickle cell disease

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10
Q

How is iron deficiency anaemia diagnosed?

A

easily by looking at a blood film
RBCs are:
- paler
- smaller

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11
Q

What is megaloblastic anaemiaand how is it caused?

A

defective DNA synthesis during RBC production causing cell growth without division
–> increased mean cell volume (MCV)
–> usually due to B12/folate deficiency
–> also causes hyper-lobed
neutrophils

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12
Q

What is pernicious anaemia?

A
  • intrinsic factors released by parietal cells in the stomach are required for B12 absorption
  • if antibodies target theses cells or the intrinsic factors, B12 cannot be absorbed
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13
Q

What is spherocytosis?

A

inherited genetic disorder characterized by defects in the red blood cell membrane proteins, such as spectrin, leading to spherical-shaped red blood cells (spherocytes) that are prone to premature destruction and haemolysis

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14
Q

What is Autoimmune Hemolytic Anemia (AIHA) and how can it be tested for?

A

acquired disorder characterized by the production of autoantibodies that target and destroy red blood cells, leading to hemolysis and anemia

direct Coombs test tests if RBCs are coated in Igs or complement in vivo
Coombs reagent - antibody against human Igs, this crosslinks autoantibodies

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15
Q

What is leucopenia?

A

low white blood cell counts

most common is neutropenia
- recurrent bacterial skin infections
- mouth ulcers
- sepsis
- unusual infections

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16
Q

What is thrombocytopenia?

A

low platelet counts
- bruising
- gum bleeding
- nose bleeds
- petechiae
–> pinpoint spots on skin and mucous membranes
–> associated w brain bleeds
- prolonged bleeding from cuts

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17
Q

What is meant if a patient is “left-shifted”?

A

if there are precursors of cells in the blood
as it is further left of cell line

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18
Q

What are functional disorders?

A

where cell count is normal but function is inhibited for some reason

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19
Q

Where are lymphocytes produced and where do they mature?

A
  • produced in the bone marrow
  • T cell maturation in the thymus
  • B cell maturation in lymph nodes and spleen
  • circulation to secondary lymphoid organs
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20
Q

What is multiple myeloma?

A

clonal proliferation of plasma cells in the bone marrow
make up >10% of cells in bone marrow

detected by presence of paraprotein in blood, a monoclonal Ig fragment produced by malignant clone of plasma cells

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21
Q

What is the difference between acute and chronic haematological malignancy?

A

acute
- overproliferation of immature cells
- sub/acute aggressive

chronic
- overproliferation of mature cells
- long history/ indolent disease

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22
Q

What is the difference between myeloid and lymphoid haematological malignancy?

A

myeloid
- proliferative disease in the blood/bone marrow
- an increase in mature and immature myeloid cells, including granulocytes, erythrocytes, and platelets

lymphoid
- clonal proliferation of lymphoid cells derived from B-cells, T-cells, or natural killer (NK) cells
- accumulation of lymphocytes in lymphoid tissues, lymph nodes, spleen, or other organs

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23
Q

What are the CD antigens?

A

cluster of differentiation antigens on cell surface
- some are lineage specific
- change as cell matures
eg CD45: common leukocyte antigen

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24
Q

What is flow cytometry?

A

detection of fluorescently labelled antibodies which stick to different surface markers on cells
eg CD receptors

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25
Q

What are the genetics of haematological maligancies?

A

mutation in a tumour suppressor gene leading to malfunction or upregulation of proto-oncogene through exposure of carcinogens
eg chemicals, radiation, drugs, virus translocation

leads to excess proliferation and failure of apoptosis

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26
Q

How are genetic investigations conducted?

A

cytogenetics
- karyotype analysis of cells in metaphase
- translocations, deletions, monosomies

molecular studies
- PCR: sensitive
- FISH: dividing or non-dividing cells

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27
Q

What is acute leukaemia?

A

overproliferation of immature blast cells
- myeloid (AML)
- lymphoid (ALL)
–> usually determined through genetic rather than morphological

variable cytopenias, leucocytosis, or leucopenia

bone marrow >20% blasts (can be diagnosis)
- blasts can spill into periphery giving higher blood counts

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28
Q

What causes chronic myeloid leukaemia?

A

Philadelphia chromosome (9:22)
- BCR-ABLS fusion gene encoding a tyrosine kinase signalling molecule w enhanced activity

clonal disorder of bone marrow stem cell

usually asymptomatic w high WCC

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29
Q

What is myelodysplasia?

A
  • progressive bone marrow failure due to quantitative and qualitative abnormalities or any or all myeloid cell lines
  • disease of older age
  • may precede or transform to AML
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30
Q

What is acute lymphoblastic leukaemia?

A

overproliferationof immature lymphocytes

most common malignancy of childhood
- ages 3-7
- second rise after 40

  • causes cytopenias, infiltration of marrow or other organs
  • 80-90% cure in children
    –> research is now more focussed on how to make it less harmful to the patient
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31
Q

What is chronic lymphocytic leukaemia (CLL)?

A

B cell lymphocytosis in peripheral blood

cytopenias
- marrow infiltration

incidence increases w age

increased frequency/severity of infections - low Ig level common

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32
Q

How is CLL diagnosed?

A

Flow cytometry
- CD markers differentiate from other low grade lymphoproliferative disorders

Genetics
- chromosomal abnormalities
- p53 deletion

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33
Q

What are lymphomas

A
  • B cell vs T cell
  • low grade vs high grade

accumulation of malignant lymphocytes in lymphoid tissues
can invade other tissues eg brain
–> invasion of bone marrow leads to low blood count

34
Q

How can different blood disorders be treated?

A

RBC transfusion
- anaemia
- thalassemias
- accidents
- surgery
–> short term fix

Platelet transfusion
- clotting disorders
- following BM transplant
- chemotherapy
–> short term fix

Stem Cell Transplant
- cancer/leukaemia
- immune disorders
–> long term cure

35
Q

What are the different categories of stem cells?

A
  1. totipotent
    - give rise to ALL cell types including extraembryonic lineages
    –> fertilised egg, cells of early morula
  2. pluripotent
    - give rise to all cell types found in the embryo proper
    –> embryonic SCs, induced pluripotent cells
  3. multipotent
    - give rise to more than one lineage
    –> lineage specific tissue stem cells
    eg Haematopoietic stem cells (HSC)
36
Q

How are HSCs identified?

A

expression of surface markers
- lack of lineage surface marker (lin-)
–> tested for first
- presence of Sca1
- presence of Kit

together are referred as LSK

can be sorted automatically via expression of surface markers fluorescently tagged

37
Q

How are induced pluripotent stem cells made?

A

incubation of skin cells with a variety of transcription factors
eg Oct4, Sox2, Klf4, Myc

can provide patient derived cell types for:
- drug testing
- disease modelling
- cell therapy

38
Q

What are some problems w blood transfusion?

A
  • donor dependent
  • transfusion transmitted infection
  • limited storage time
  • blood group matching/compatibility
  • no blood transfusion service in developing world
39
Q

What are some pros and cons to PSC derived blood cells?

A

Pro:
would solve a lot of problems w current blood transfusion

Con:
high cost for low amount of blood, more from donation

40
Q

What are some features of in vitro derived blood cells?

A
  • few lymphocytes
  • nucleated RBCs
  • no bona-fide HSCs
41
Q

What is the intrinsic tenase coagulation pathway?

A

Activation: Triggered by contact between blood and foreign surfaces, exposure to collagen, or activation of the Hageman factor (Factor XII).

Cascade: Sequential activation of Factor XII → Factor XI → Factor IX → Factor VIII.

Amplification: Enhancement of the coagulation process through the formation of the intrinsic tenase complex (Factor IXa, Factor VIIIa) and the activation of Factor X.

this pathway is faster

42
Q

What is the extrinsic tenase coagulation pathway?

A

Activation: Initiated by tissue damage or exposure to tissue factor (TF, also known as Factor III) released from injured endothelial cells.

Cascade: Activation of Factor VII → Factor VIIa.

Conversion: Factor VIIa complexed with tissue factor activates Factor X

this pathway is slower

43
Q

Both the intrinsic and extrinsic tenase pathways converge at Factor X activation. What happens next (common pathway)?

A

Conversion: Factor Xa, in the presence of Factor Va, calcium ions (Ca^2+), and phospholipids, forms the prothrombinase complex, which converts prothrombin (Factor II) into thrombin (Factor IIa).

Fibrin Formation: Thrombin catalyzes the conversion of fibrinogen (Factor I) into fibrin strands, which polymerize and form a stable blood clot.

Stabilization: Factor XIII (fibrin-stabilizing factor) crosslinks and stabilizes the fibrin clot, contributing to clot strength and stability.

44
Q

What is the catalytic advantage associated with prothrombinase?

A

relative rates of prothrombinase activity catalysed by different combinations of components of the enzyme complex

  • Xa, Ca, PL, Va = 100%
  • Xa, Ca, Va = 0.13%
  • Xa, Ca, PL = 0.008&
  • Xa Ca = 0.0007%
  • Xa = 0.0003%%
45
Q

What is the intrinsic tenase complex?

A

Components
- Factor IXa:
–> Activated form of Factor IX, a serine protease
–> activates Factor X (X –> Xa), which is required for the conversion of prothrombin to thrombin and the subsequent formation of a fibrin clot

  • Factor VIIIa:
    –> Activated form of Factor VIII, a co-factor protein
    –> stabilizes Factor IXa and facilitates its interaction with Factor X
46
Q

How is Emicizumab used to treat haemophilia?

A

a humanised antibody that binds to and bridges IXa and X
- preventing formation

47
Q

What is prothrombin time?

A

PT
- measured in seconds
- reflects the extrinsic and common pathway

48
Q

What is activated partial thromboplastin time?

A

APTT
- measured in seconds
- reflects the intrinsic pathway and the common pathway
- Thromboplastin is TISSUE FACTOR

49
Q

How is fibrinogen measured?

A
  • measured in grams/L
  • reflects the functional activity of the fibrinogen protein
50
Q

What is haemophilia A?

A
  • X-linked recessive disorder
  • 1:8000 males, 30% cases are sporadic mutations
  • deficiency of fVIII (or dysfunction)
  • clinical severity correclates to fVIII level

severe (<1%) = spontaneous bleeding into weight bearing joints –> swelling –> muscle wasting due to low use

51
Q

What is thrombosis?

A

over clotting

Venous
- deep venous thrombosis
- pulmonary embolus (PE)
–> large blood clot that moves up to the lung and can be fatal
- cerebral, mesenteric, axillary, splanchnic, splenic

Arterial
- myocardial infarction
- CVA (stroke)

52
Q

How do blood-thinners work?

A

anticoagulants: inhibit different sites in the coagulation pathway

eg Draculin: blocks active site if IXa in intrinsic tenase complex

53
Q

What is DIC?

A

syndrome of Disseminated Intravascular Coagulation (DIC)

  • widespread deposition of fibrin in circulation
    –> tissue ischemia and multi-organ failure
  • consumption of platelets and coagulation factors to generate thrombin, may induce sever bleeding
  • to maintain vascular patency, plasmin generated in excess, leads to fibrinogenolysis
54
Q

How is DIC diagnosed?

A
  • prolonged prothrombin time (PT)
  • prolonged activated partial thromboplastin time (APTT)
  • low fibrinogen
  • Raised D-dimers
    –> small protein fragments generated by the proteolytic degradation of cross-linked fibrin by plasmin
    –> due to the increased formation and degradation of cross-linked fibrin clots within the microvasculature
55
Q

When would fresh frozen plasma be administered?

A

given to patients w deficiencies in coagulation factors

  • stored at -25C or below for a max of 26 months
  • use within 4 hours if maintained at 22C
  • maximum of 120 hours if stored at 4C
56
Q

What are the most important blood group antigens?

A

ABO and Rhesus are the most important in clinical practice

  • more than 300 different blood group antigens
  • minority cause clinically significant transfusion reactions
57
Q

What are the different blood types and what antibodies and antigens do they each possess?

A

Group A
RBC type: A
Ab in plasma: anti-B
Ag in RBC: A antigen

Group B
RBC type: B
Ab in plasma: anti-A
Ag in RBC: B antigen

Group AB
RBC type: AB
Ab in plasma: none
Ag in RBC: A + B antigens

Group O
RBC type: O
Ab in plasma: anti-A + anti-B
Ag in RBC: none

each of these can be positive or negative if the possess the Rh (D) antigen or not

58
Q

What classes of antibodies are the blood antibodies?

A

anti-A + anti-B are mainly of the IgM class
- cause visible agglutination of A or B cells in lab mixing tests
- antibodies to ABO antigens are naturally occurring and are found after 3 months of life

antibodies to rhesus (Rh) antigens are smaller IgG molecules
- do not directly cause agglutination of RBCs
- not naturally occurring (pregnacy, occuring)

59
Q

What is the universal donor and universal recipient?

A

recipient: individuals w type AB+ can receive blood from donors of type A, B, AB, or O
- no antibodies against blood antigens

donor: individuals from A, B, AB, and O can receive blood from donors of type O-
- no blood antigens

60
Q

Why is giving blood from the universal donor not completely safe?

A

due to other incompatible antigens but these cause much weaker reactions compared to AB antigen mismatch

61
Q

What are the results of ABO-incompatible transfusion?

A
  • Acute intravascular haemolysis
  • complement-mediated destruction of the transfused RBCs and release of inflammatory cytokines

–> may be life-threatening: shock, renal failure and DIC

62
Q

What is the Rhesus blood system?

A

refers to 5 main Rh antigens

IgG anti-D antibodies can cause
- acute or delayed haemolytic transfusion reaction
- haemolytic disease of the foetus and newborn (HDFN)

63
Q

What is HFDN?

A

Haemolytic Disease of the Foetus and Newborn

  • incompatibility between the blood type of mother and baby
  • feto-maternal transfusion during pregnancy
    eg trauma/injury, vaginal delivery

during subsequent pregnancy, maternal IgG antibodies may pass through placenta; if baby is RhD positive, this can lead to haemolysis

64
Q

What are allo-antibodies?

A

produced when an individual is exposed to blood of a different blood group either through transfusion or pregnancy

65
Q

How is blood compatibility done?

A
  1. group and screen
    - pre transfusion sample to check ABO and Rh type and screen for allo-antibodies
  2. further investigations if antibody screen indicates antibodies
  3. select appropriate blood
  4. crossmatch
    –> serological - patients plasma vs red cell donation
    –> electronic issue if certain criteria met
  5. label and issue
66
Q

In an emergency, what blood would be immediately given to a person before typing?

A

O Rh D negative
–> not 100% ‘compatible’ w everyone but the best chance

67
Q

What is the direct Coombs test/direct antiglobulin test?

A

DAT
used to detect antibodies present on circulating RBCs, as in autoimmune haemolytic anaemia or after mismatch blood transfusion

  1. blood sample taken w immune mediated haemolytic anaemia
    –> antibodies attached to blood
  2. patient’s washed RBCs incubated w anti-human antibodies (coombs reagent)
  3. RBCs agglutinate, anti-human antibodies form links between RBCs by binding to autoimmune antibodies
68
Q

What is the indirect Coombs test/indirect antiglobulin test?

A

IAT
blood group antibodies are demonstrated in serum

  1. recipients serum is obtained containing antibodies (IgG)
  2. donors blood sample is added to serum
  3. recipients Ig’s that target the donor’s RBCs for Ig-antigen complexes
  4. anti-human Ig’s are added to the solution
  5. agglutination of RBCs occurs because Ig’s are attached to RBCs
69
Q

What are some acute/immediate complications that can arise from blood transfusion?

A
  • acute haemolytic transfusion reaction
  • bacterial contamination - sepsis
  • allergic, mild to severe (anaphylaxis)
  • transfusion associated circulatory overload (TACO)
    –> give to much fluid to patient, can lead to fluid leaking into the lungs
  • transfusion associated lung injury (TALI)
    –> less common
70
Q

What are some delayed complications that can arise from blood transfusions?

A
  • delayed haemolytic transfusion reactions
  • transfusion associated grafts vs host disease
  • post transfusion purpura
    –> sudden and severe thrombocytopenia (a low platelet count) occurring within 5 to 10 days after a blood transfusion
71
Q

What is a long term complication from blood transfusion?

A

iron overload

72
Q

What are some alternatives to transfusion?

A
  • ESAs, erythropoietin stimulating agents
  • anti-fibrinolytic drugs
  • stopping anticoagulants/antiplatelet agents pre-operatively
  • maximising Hb pre-operatively eg iron replacement
73
Q

What is the genetic cause of leukaemia?

A

new constitutively active fusion protein present

switching off/on of wrong genes
= cells grow out of control

represents 5% of adult cancers
50% of childhood cancers

74
Q

Why are leukaemias easy to diagnose?

A
  • easy to obtain biopsy of blood
  • easy to do cytogenetics of blood cells compared to solid tumours
  • visible chromosomal changes are apparent in chromosome spread
75
Q

Give two examples of chromosomal translocations and the leukaemias they cause.

A

philadelphia chromosome, part of chromosome 22 translocated onto 9 and vice versa
–> generates fusion protein AB
–> BCR-ABL = CML
–> RUX-ETO = AML

chromosome 3 translocated onto chromosme 4
–> regulatory element from 3 upregulates gene B on 4 in inappropriate cell types
–> c-MYC in Burkitts lymphoma

76
Q

What ages are different acute leukaemias prevelant?

A

acute myeloid leukaemia (AML)
- common in old age

acute lymphoblastic leukaemia (ALL)
- common in children

77
Q

How does the BCR-ABLE fusion protein cause CML?

A

native c-ABLE tyrosine kinase is located partially in the nucleus and has tightly regulated kinase activity

BCR-ABL fusion protein results in production of constitutively active cytoplasmic tyrosine kinase:
- activates signalling pathways
- decreases apoptosis
- survival advantage
- abrogates growth factor dependency

78
Q

How do chromosomal translocations result in disease?

A
  • DNA from one chromosome is directly linked to the DNA of the other
  • some translocations result in a selective advantage to the cells
  • cells carrying the translocation are more likely to proliferate
79
Q

What is a treatment for CML?

A

Imatinib blocks the ATP binding site of the tyrosine kinase
= no downstream signalling

the BCR-ABL oncoprotein chronically activates many downstream signalling pathways to confer malignant transformation in hematopoietic cells
–> these can be inhibited by selective small molecules

80
Q

What is meant by resistant and refractory cancers?

A
  • cells are resistant if mutations are acquired
  • cells are refractory if they are non-responsive eg quiescent
  • most therapies target dividing cells
  • leukaemic stem cells are quiescent so, they cannot be targeted by drugs and the disease persists
81
Q

What are leukaemic stem cells?

A

a subpopulation of cells found within leukemic tissues, such as bone marrow or blood, that have the ability to self-renew and differentiate into various types of leukemic cells

arise from haematopoietic progenitor cells

82
Q

What is the difference between high grade and low grade lymphomas?

A

High-grade lymphomas:
- aggressive and fast-growing lymphomas
- may spread to other parts of the body early in the disease course
- consist of larger, more abnormal-looking cells with a high rate of mitosis

Low-grade lymphomas:
- slow and gradual cell growth
- may remain localized to certain lymph nodes or tissues for extended periods
- consist of smaller, more mature-looking cells with a lower rate of mitosis
–> these cells may appear more similar to normal lymphocytes but still display abnormal characteristics

Clinical Immunology & Haematology (5 decks)

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