Clinical Haematology (1-6) Flashcards

Question

What are the genetics of haematological maligancies?

Answer 1

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

Answer 2

cytogenetics - karyotype analysis of cells in metaphase - translocations, deletions, monosomies molecular studies - PCR: sensitive - FISH: dividing or non-dividing cells

Answer 3

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

Answer 4

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

Answer 5

- 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

Answer 6

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

Answer 7

B cell lymphocytosis in peripheral blood cytopenias - marrow infiltration incidence increases w age increased frequency/severity of infections - low Ig level common

Answer 8

Flow cytometry - CD markers differentiate from other low grade lymphoproliferative disorders Genetics - chromosomal abnormalities - p53 deletion

Answer 9

- 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

Answer 10

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

Answer 11

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)

Answer 12

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

Answer 13

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

Answer 14

- donor dependent - transfusion transmitted infection - limited storage time - blood group matching/compatibility - no blood transfusion service in developing world

Answer 15

Pro: would solve a lot of problems w current blood transfusion Con: high cost for low amount of blood, more from donation

Answer 16

- few lymphocytes - nucleated RBCs - no bona-fide HSCs

Answer 17

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

Answer 18

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

Answer 19

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.

Answer 20

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%%

Answer 21

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

Answer 22

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

Answer 23

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

Answer 24

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

Answer 25

- measured in grams/L - reflects the functional activity of the fibrinogen protein

Answer 26

- 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

Answer 27

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)

Answer 28

anticoagulants: inhibit different sites in the coagulation pathway eg Draculin: blocks active site if IXa in intrinsic tenase complex

Answer 29

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

Answer 30

- 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

Answer 31

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

Answer 32

ABO and Rhesus are the most important in clinical practice - more than 300 different blood group antigens - minority cause clinically significant transfusion reactions

Answer 33

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

Answer 34

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)

Answer 35

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

Answer 36

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

Answer 37

- Acute intravascular haemolysis - complement-mediated destruction of the transfused RBCs and release of inflammatory cytokines --> may be life-threatening: shock, renal failure and DIC

Answer 38

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)

Answer 39

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

Answer 40

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

Answer 41

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

Answer 42

O Rh D negative --> not 100% 'compatible' w everyone but the best chance

Answer 43

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

Answer 44

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

Answer 45

- 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

Answer 46

- 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

Answer 47

iron overload

Answer 48

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

Answer 49

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

Answer 50

- 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

Answer 51

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

Answer 52

acute myeloid leukaemia (AML) - common in old age acute lymphoblastic leukaemia (ALL) - common in children

Answer 53

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

Answer 54

- 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

Answer 55

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

Answer 56

- 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

Answer 57

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

Answer 58

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