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GGE > Genetics 8 - Clotting Disorders and Pharmacogenetics > Flashcards

Genetics 8 - Clotting Disorders and Pharmacogenetics Flashcards

1
Q

learning outcomes

A
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2
Q

overview of coagulation cascade

A

blood clotting to plug damaged BVs

starts with platelets

fibrin - Ia

fibrinogen circulates in blood in high conc

activated to fibrin by thrombin (IIa)

complex cascade (chain rxn) involving 13 factors (mostly protease precursors)

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3
Q

fibrin

A

Ia

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4
Q

thrombin

A

IIa

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5
Q

video

A

https://www.youtube.com/watch?v=FNVvQ788wzk&feature=youtu.be

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6
Q

difference between 2 pathways

A

extrinsic = tissue factor - fast

intrinsic = contact activation - slower

common pathway after factor Xa and Va activate thrombin

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7
Q

time for intrinsic pathway

A

measured by PTT - partial thrombin time

20-35 seconds

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8
Q

time for extrinsic pathway

A

measured by prothrombin time

PT/INR (normal range 0.8-1.2)

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9
Q

overview of coagulation cascade

A
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10
Q

F VIIIa → F VIII

carried out by

deficiency

A

previously activated thrombin

Haemophilia A

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11
Q

F XIa → F IX

carried out by

deficiency

A

thrombin

Haemophilia B

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12
Q

F V → F Va

carried out by

deficiency

A

thrombin

thrombophilia

blood clots in BVs

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13
Q

thrombin and crosslinking of fibrin strands

A

activates F XI (near start of intrinsic pathway) and F XIII which crosslinks the fibrin strands together to form the clot at the end

through amplification loops - +ve and -ve feedback control

a little thrombin goes a long way

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14
Q

haemophilia A

gene

size of gene

mutations may result in

A

gene F8 - factor VIII

X q28

26 exons, > 186 kb DNA

haemophilia A related to mutations in or near F8

mutations may result in:

a null allele - no working product

a hypomorph - product that works a bit

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15
Q

gene F8 types of mutation

classification

A
  1. large rearrangements - insertions, deletions
  2. small mutations (< 50 bp, often SNPs)

mis sense, non sense, splice site variants (mutation changes reading frame)

CLASSIFICATION:

Mild 5-40%

moderate 1-5%

severe <1%

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16
Q

sequence on intron 22 of F8 relevant to Haemophilia A mutation

A

int22h-1

300 kb 5’ (upstream) of F8 gene is a complex structure that includes interspersed repeats in opposite orientation

all 3 int22h sequences identical/very similar, so easy for them to recombine when gene folds

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17
Q

large rearrangements with haemophilia A

A

int22h-2 and int22h-3 are flanked by imperfect palindromic sequences - mirror images of each other

hybridisation and recombination can occur

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18
Q

inversions and deletions - haemophilia A

A

pairing between palindromic sequences (during male meiosis) can invert int22h-2 and int22h-3

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19
Q

what does recombination between copies of int22h result in

A
  1. inversion of F8 exons 1-22
  2. deletion of F8 exons 1-22
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20
Q

summary of haemophilia A

A

chr architecture predisposes to a particular change (major inversion) which accounts for a high proportion of defective alleles and 50% of severe cases

approx 5% of severe cases related to deletions in F8 gene

also other less common mutation

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21
Q

role of factor IX

A
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22
Q

haemophilia B - factor IX

what proportion of haemophilia does it account for

gene associated

carriers

A

12% of haemophilia

locus X q 27.1

wide range of mutations

about 10% of carrier females have < 50% F9 and are at risk for abnormal bleeding

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23
Q

therapy for haemophilia A/B

A

haemorrhage prophylaxis - pads, avoidance of sports like rugby etc

local haemostasis (compression, sutures etc)

clotting factors (pharmacogenetics)

somatic gene therapy

germ-line editing - CRISPR-Cas

24
Q

pharmacogenetics

A

study of impact of single genetic variants on drug metabolism

predicting likely response and risk of adverse events based on mutation at a single locus

25
Q

pharmacogenomics

A

study of drug metabolism in relation to the whole genome of an individual

use of genomics to optimise selection of pharmaceutical agents for individual patients based on better prediction of likely response and risks of adverse effects

26
Q

glucose 6 phosphate dehydrogenase deficiency

what does it infer

type of inheritance

how are symptoms manifested

A

most common genetic disorders

partial malaria resistance in hemi/homozygotes

X-LINKED RECESSIVE - mostly affects males

females affected via skewed XCI

symptoms of haemolysis manifest when body is in oxidative stress caused by:

  • infection
  • medicines, including aspirin, sulfonamides, nitrofurantoin (UTI) and antimalarias
  • foods e.g. fava beans - contain oxidants
27
Q

G6PD deficiency symptoms

A

haemolytic anaemia (chronic)

acute haemolytic crises

anaemia and jaundice (hyperbilirubinemia) in the newborn

kernicterus - irreversible neurological damage

shortness of breath

dark coloured urine

28
Q

G6PD deficiency symptoms - prevention and treatment

A

avoid triggers

bill lights (newborns) - isomerises bilirubin

blood transfusion

29
Q

G6PD - gene map locus

A

Xq28

30
Q

heterogeneity of G6PDD alleles

A

greater heterogeneity

predominant alleles vary between ethnic groups

common in areas with malaria

31
Q

things to remember

A
32
Q

learning outcomes

A
33
Q

coagulation test results indicative of haemophilia A

A
34
Q

pattern of inheritance of haemophilia A

A

X linked recessive

35
Q

symptom common to Haem. A

A

cephalohaematoma

36
Q

phenotypic tests - haemophilia A

A

F8 activity

PTT

PT/INR

37
Q

carrier females and haemophilia A

A

may have disordered coagulation tests or even mild clinical bleeding in tendency (skewed X inactivation) - approx 30%

If good X chr is inactivated more than the bad, female may bleed more

rarely females have severe haemophilia due to skewed X chr inactivation or a disorder of inactivation of X chr

38
Q

Haemophilia A and carrier women

where is F8 expressed

level of activity of a functional F8 allele

A

F8 allele is expressed from whichever X chr is active in a given liver cell

1 functional F8 allele in most women = 50% activity

phenotype = clotting

about 10% of carrier females have < 40% activity - at risk for abnormal bleeding

2 non-functional F8 alleles = no functional gene ⇒ phenotype = bleeding

39
Q

assessing carrier status genetically

A
  1. direct sequencing of F8 (big job but getting less so)
  2. linkage markers within F8
  • dinucleotide repeat in intron 13 and 22 - microsatellites
  • known SNPs in introns 18 and 22
  • need to compare to affected family members
40
Q
A
41
Q
A

Factor IX Leyden

a rare haemophilia B subtype - 3%

anrogen therapy or puberty rise F IX activity from < 1% to 30-60%

associated mutations (>20) from -40 to +20 of F IX

this promoter sequence resembles an androgen response element

42
Q
A

Von Willebrand Disease

most frequent congenital clotting disorder

VWD chr 12p13.3 - large gene - 52 exons 178 Kbp

many alleles ⇒ heterogeneity of subtypes

quantitative or qualitative defects of VW

inheritance can be dominant or recessive

43
Q

gene - VWD

A

VWD chr 12p13.3 - large gene - 52 exons 178 Kbp

44
Q

inheritance pattern of VWD

types of defects

A

many alleles ⇒ heterogeneity of subtypes

quantitative or qualitative defects of VW

inheritance can be dominant or recessive

45
Q

clinical phenotype spectrum

what is often reduced

A

asymptomatic/mild (common) to severe haemorrhaging (rare)

often reduced F VIII levels - metabolised faster without VWF

46
Q

treatment of VWD

A

desmopressin or “factor”

47
Q

thromboembolism

A

formation of thrombus in deep veins - typically leg

pain and swelling of leg

thrombus may become detached from vein (embolus) and travel to pulmonary artery

obstructs blood supply to a segment of lung

obstructs main PA - sudden death

48
Q

role of factor V

A
49
Q

what do people with thromboembolism response poorly to

A

activated protein C (APC) in a coagulation assay

protein C does not inhibit F V as it’s supposed to

50
Q

gene associated with F V Leiden Thrombophilia

how does it affect coagulation cascade

A

1601G>A transition in exon 10 of the F5 gene on Ch1q23

p.Arg506GIn in F V (R506Q) - variant known as F V Leiden - always on

pro-coagulation activity of F V is limited by activated protein C which cleaves at the arginine (R)

F V Leiden - resistant to APC cleavage

excess conversion of prothrombin → thrombin

51
Q

category of mutation - F V Leiden Thrombophilia

A
52
Q

allele frequency of F V Leiden

hetero vs homozygotes

what increases the risk of TE disease

A

allele freq - 5% in Caucasians (founder effect)

heterozygotes 6-7x increase in relative risk of venous thromboembolism

homozygotes 80x increase in relative risk of TE

oral contraceptives increase risk of TE disease - oestrogen can drive clotting factors

53
Q

what is warfarin

risks

A

anticoagulant

vit K antagonist

used to manage patients at risk of thromboembolic disease

too much warfarin can be associated with life threatening haemorrhage

monitor with coagulation test (PT/INR)

adjust dose to maintain within therapeutic window

54
Q
A

blood is clotting faster than expected - risk of thromboembolism

increase warfarin dose

55
Q
A

cytochrome P450 - detox

alleles (CYP2C9*2 and *3) produce a phenotype of poor warfarin metabolism - occurs in 11% and 8% of whites but only 3% and 0.8% of blacks

people with poor metabolism require much lower dose for therapeutic effect

more warfarin circulating in body, higher anticoagulation effect - risk of bleeding

56
Q

things to remember

A

GGE (33 decks)

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