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CDL301 > Thrombosis + platelet pharmacology > Flashcards

Thrombosis + platelet pharmacology Flashcards

1
Q

What is the difference between haemostasis and thrombosis?

A 
Haemostasis= appropriate coagulation 
thrombosis= inappropriate coagulation
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2
Q

Primary haemostasis- factors involved and treatments

A 
factors- platelet VWF
treatments
1. platelet transfusion 
2. desmopressin 
3. VWF concentrate
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3
Q

Secondary haemostasis- factors and treatments

A

factors- clotting factors

treatment- specific to clotting factor

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4
Q

Thrombosis can be either

A

Arterial or venous

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5
Q

Arterial thrombosis

A

Factors- high pressure platelets

treatments- antiplatelet drugs

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6
Q

Venous thrombosis

A

factors- low pressure clotting factos

treatments- anti-coagulants

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7
Q

Different components of blood

A
  • platelets
  • fresh from frozen plasma- factors 1, 7 9 ,VWF, 9,10,11,12
  • red cells
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8
Q

Why couldn’t you just give plasma if someone was bleeding?

A

Contains lots of clotting factors
However
not dilute
could get infection

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9
Q

Coagulation cascade

A

Vessel injury- local vasoconstriction
then either:
1. platelet adhesion- platelet aggregation
2. activation of coagulation cascade- fibrin formation

Haemostatic plug
fibrinolytic activity and repair vessel damage

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10
Q

Primary haemostasis mechanism

A
  1. expose collagen
  2. platelet stick to collagen by VWF factor and activate other factors
  3. open confirguation and binds to platelets to form plaque by sticking on top of each other
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11
Q

Platelet disorder bleeding- why?

A
  1. reduced number- inherited or acquired- thrombocytopenia

2. abnormal or reduced function of platelets- could be due to anti-platelet drugs

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12
Q

What is a treatment for platelet disorder?

A

platelet transfusion

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13
Q

What is Von Willebrand disease?

A

Commonest inherited bleeding disorder
1% population have reduced VWF levels
autosomal dominant- 3 main types
milder bleeding disorder than haemophilia

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14
Q

Sites of bleeding in von Willebrand disease?

A

bruising, cuts, gums, epistaxis, menorrhagia

post operative, post trauma

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15
Q

treatment for von Willebrand disease?

A

desmopressin- protein release vmf into the circulation

intermediate purity- VMF and powder mix with water for injection 1:1 (VMF: factor 8)

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16
Q

Secondary coagulation cascade

A

TF/VILa to either X or IXa (back to X by VIII)
from X to Xa
Xa to il
il to ILa which changes fibrinogen to fibrin (mesh will work/ stop things from working)

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17
Q

What inhibits IXa, Xa and iLa?

A

unfractionated heparin

low mol WT heparin

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18
Q

Analogy for stopping bleeding

A 
Hole in vessel= pipe you have to plug 
either 
1. band aid to plug 
- platelets
-more you have the closer together the more it stops bleeding 
2. spray with super glue= 2nd
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19
Q

What are coagulation factor disorders?

A

haemophilia A- factor 8 defiecency
haemophilia B- factor 9 deficiency
others- autosomal recessive, deficiency in fibrinogen, FII FV FVII FX FXI FXII

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20
Q

Sites of bleeding for haemophilia A/B?

A

joints, muscles , post trauma , post operative

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21
Q

Severity of haemophilia

A

severe <1%
moderate 1-5%
mild >5%

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22
Q

Haemophilia

A

don’t have bleeding mucosal so just get bleeding from the joints from operations
bleed from joints- lots of damage to knee- painful- joint replaced
- haemoarthosis/ muscle atrophy
- muscle haematoma- IM injection in haemophilia

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23
Q

Clotting factors

A
  • All plasma derived
  • some recombinant- cell line have gene- 8,9,13
    rare so other companies wouldn’t invest
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24
Q

Treating with clotting factors

A

give to plasma to replace all- dilute form

can give specific if you know what is missing

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25
Q

What is thrombosis?

A
  • blood in blood vessels should be fluid

- inappropriate blood coagulation within a vessel

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26
Q

What are the 2 types of thrombosis

A
  1. arterial= high pressure, platelet rich

2. venous = low pressure, fibrin rich

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27
Q

Clinical thrombosis implications

A
  1. myocardial infarction, thrombotic stoke

2. leg deep vein thrombosis (DVT) or pulmonary embolism (PE)

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28
Q

Treatment for thrombosis

A
  1. antiplatelet drugs- aspirin, clopidogrel, prasugrel, ticagretor, cangregor
  2. anti-coagulation drugs-
    Intravenous= unfractionated heparin
    subcutaneous= low molecular weight heparin
    Oral= warfarin, dabigatixin, rivaoxoban, apixoban
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29
Q

Oral anticoagulant

A

Vit K anticoagulants
96% warfarin
4% acenoncoumarol

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30
Q

Direct oral anti-coagulants

A

dabigatran
apixoban
rivaoxaban
edoxoban

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31
Q

What is heparin?

A

Protein in blood antithrombin and its role is to inhibit different parts of the coagulation cascade
activates antithrombin
given continuously by infusion

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32
Q

Heparin mechanism?

A

binds to antithrombin and increases its activity

indirect thrombin inhibitor

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33
Q

How do you monitor heparin?

A

APPT test

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34
Q

What is low molecular weight heparin?

A 
Smaller molecular made from heparin 
less variation in dose 
weight adjusted dosing 
given subcutaneously, given once a day 
renally excreted
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35
Q

Disadvantages of low molecular weight heparin?

A

Pain to use- continuous infusion

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36
Q

The pharmacology of warfarin?

A

given by mouth completely and rapidly absorbed
99% plasma protein bound
inhibit II, VII, IX, X production
- peak effect 3-4 days after and still present in 4-5 days after

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37
Q

Side effects of warfarin>?.

A

bleeding

embryopathy

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38
Q

Monitoring Warfarin

A

Measure INR- international normalised ratio
dose is based on INR
target for first DVT/PE- 2-3.0
frequency of monitoring depends on stability of patients INR

39
Q

Dose of warfarin

A

no single dose for one person
avg 5mg/day
Genetically controlled
all body makes clotting factor

40
Q

Oxidised vitamin K to reduced Vit K

A

Vit K reductase
which is inhibited by warfarin
functional

41
Q

What turns warfarin from active to inactive metabolite

A

CYP2C9- breaks down warfarin

42
Q

Reduced Vit K to oxidised Vitamin K

A

hypofunctional to functional carboxylated

by gamma-glutamyl carboxynase GCX

43
Q

Vit K + enzyme =

A

makes functional carboxylated

Vit K is recycled so not deficient and warfarin inhibits this recycling of Vit K- becomes deficient (anticoagulant )

44
Q

Why do different people have different doses?

A

People breakdown warfarin at different speeds= different polymorphisms
so people very receptive by VKOR
1. how receptive
2. how quickly you breakdown

45
Q

What replaces heparin and warfarin? and why?

A

the direct oral anticoagulant
Why- oral, no monitoring, standard dosing, short half life, no alcohol/ food interactions
problems= expensive

46
Q

What inhibits Xa

A

Rivaroxaban- 2-3hours work,67% effect, 95% protein binding
Apixaban- 3-4 hours work, 25% effect, 87% protein binding
Edoxaban- 1-3 hours, 35% work, 50% binding
not licensed yet but undergoing trials

47
Q

inhibition of Ila

A

Dabigatran- 2-3 hours work, 80% effect, 35% protein binding

licensed

48
Q

What are all the new drugs positive for

A 
AF
DVT
PE 
none for general thromboprophylaxis 
all but edoxaban pos for orthopaedic thromboprophylaxis
49
Q

Compare advantages of DOAC to warfarin

A

Advantages

  • rapid onset
  • fixed oral dosing
  • low interaction with food/ alcohol
  • no need for blood monitoring

Disadvantages

  • renal elimation
  • no specific antibodies for Xa inhibitor
  • licensed for only specific introduction
  • recent
50
Q

Key phases of drug development

A 
identify drug target 
design and optimise drug 
preclinical trial- proof it works in vivo- efficacy, toxicity 
Phase 1 - first in man
Phase 2- small scale 
Phase 3- large scale= safe and efficacy
51
Q

How atheromas are formed and problem with them

A

normal- fatty streak- fibrous plaque- atherosclerotic plaque- plaque rupture/fissure and thrombosis
leads to:
Stoke, MI, critical leg ischaemia, CVD

52
Q

What does organised atherothrombosis look like?

A

extensive atherosclerotic plaque
organised thrombosis
vascular channel with thrombus potential blood flow through new vascular channels

53
Q

Platelet shape change with activation

A

smooth discoid- spiculated and pseudopodia
increase SA
increases the possibility of cell-cell interactions

54
Q

Glycoproteins Ila/ilb receptor- Where are they and what are they for?

A

On the surface of the platelet- 50,000- 100,000 copies on resting platelet
Help with platelet aggregation- increases with increase in number of receptor, affinity of receptor for fibronegin increase

55
Q

What does fibrinogen do?

A

Links receptors binding the platelets together

known as integrin AilaB3

56
Q

Glycoprotein Ila/Ilb antagonists

A

Intravenous only
drugs- abciximob, tirofiban, epitifibatide
block the Ila/b receptor

57
Q

Risk and benefits of Glycoprotein Ila/Ilb antagonists

A

Risk- increase risk of major bleeding

benefit- reduces ischaemic events

58
Q

Therapeutic window for Glycoprotein Ila/Ilb antagonists

A

not effective at low dose
too much and bleeding will kill
explains why clinical development of oral antagonists failed

59
Q

What is aspirin?

A

Effective antiplatelet drug with limited inhibitory effects

60
Q

Cylooxygenase 1 and 2 pathway

A

Membrane phospholipid to arachidonic acid then either to Cyclooxygenase 1 or 2
1- Gi mucosal integrity, platelet aggregation and renal function
2- mitogenesis and growth, regulation of female production, bone formation, renal function

61
Q

What is the effect of aspirin on platelets?

A
  • Aspirin blocks COX1 by irreversibly acetylating the enzyme
  • effects lost the lifetime of the platelet
  • Prevents conversion of arachidonic acid to prostaglandins H, blocks the pathway that leads to platelet thromboxane A release
  • thromboxane A activates platelet via a surface receptor
62
Q

What is aspirin resistance

A

Continued secretion of thromboxane A2 by platelets in response to appropriate agonist stimulation (such as A collagen) despite therapy with aspirin at a standard dose
*high platelet reactivity despite aspirin therapy does not necessarily equate to this

63
Q

True aspirin resistance

A

Rare
- fontanna et al 2006- 96 healthy volunteers, aspirin 100mg/day for 7 days
1 subject= complete suppression witnessed after loading course of 300mg

64
Q

What induced platelet aggregation in 190 IHD patients?

A

Arachnoid acid

65
Q

Impairment of effects of aspirin due to reversible COX1 inhibition by ibuprofen

A
  • Thromboxane B2 % inhibition was halved after 24 hours when ibuprofen was given before aspirin
  • when rofecoxib was given before aspirin there was no change in % inhibition for 12/24 hours after comparing aspirin
66
Q

What does this paper show- “ expert position paper on the role of platelet function testing in patients undergoing percutaneous coronary intervention”

A

Current evidence doesn’t support the prognostic screening for aspirin in response after PCI
Aspirin show be given at low doses and platelet function testing to adjust dosing is not recommended

67
Q

Conclusions about aspirin

A

reduces risk of MI, Stoke and CV
excellent efficacy at inhibiting platelet thromboxane A2 release
patient compliance is key

68
Q

What else could be used as a potential drug target

A

platelet purinergic receptor (P2)

69
Q

What does targeting P2Y1, P2Y12 and P2X do~?

A 
P2Y1= inhibition of platelet aggregation shape change 
P2Y12= amplification of platelet activation/ aggregation, amplification of granule release and procoagulant activity 
P2Xi= shape change, amplification of platelet activation
70
Q

P2Y12 role in platelet activation

A

Unlike the other P receptors

it activates Platelet aggregation

71
Q

Mean thrombus area in P2Y12 mice

A

laser injury of cremasteric arteriole with fluroesence imaging followed by IV DIOC injection
+/+= area is consistent
-/-= area decreases over time

72
Q

Activation/ inactivation of clopidogrel

A

Clopidogrel-(cyp)- 2-Oxo-clopidogrel - R-130964
clopidogrel by esterase to SR26334
2-oxo-Clopidogrel by esterase to inactive

73
Q

CURE study outcomes

A

clopidogrel plus aspirin vs aspirin alone In ACS patients

Clop- decreased% of CV/MI/Stroke but everything else else was not significantly different

74
Q

What is associated with impaired clopidogrel response

A

Diabetes mellitus

75
Q

What increased clopidogrel active metabolite production

A

Rifampicin

76
Q

Clopidogrel and rifampician effect on P2Y12 receptor blockade

A

has no effect

77
Q

Loss of function allele in CYP2C19 is associated with what?

A

Stent thrombosis in clopidogrel treated patients
relationship between verify now p2y12 PRV and stent thrombosis within 30 days
- definite or probable

78
Q

Factors affecting response to clopidogrel

A 
dose 
age 
eight 
disease states 
drug - drug interaction 
CYP2C19 loss of function or gain of function
79
Q

Prasugrel

A

A more effective thienopyridine prodrug than clopidogrel

prasugrel by esterase- R-95913 by CYP - R-138727

80
Q

Healthy volunteer study with clopidogrel and prasugrel crossover

A

Measured active metabolite by LC/MS
Clopidogrel stops over time
prasugrel plasma conc decreases over time

81
Q

The triton- time 38 study design

A

Acute coronary syndrome and planned percutaneous coronary intervention
double blind
clopidogrel= 300mg/day
prasugrel= 60mg/day

82
Q

Endpoints got titron study

A

1ST- cv death/MI/ stroke
2nd- CV/ MI/ stroke/ Isch/stent thrombosis
safety endpoint- TIMI major bleeds, life threatening bleeds

83
Q

Results from Titron

A

Clopidogrel reduced for all- timi bleed, life threatening, non fatal and fatal

84
Q

What is ticagrelor

A

the first oral reversibly binding platelet P2Y12 antagonist belonging to the class CPTP

85
Q

Pre clinical studies for ticagrelor

A

effect of tricagrelor on thrombus formation
laser injury model- mean thrombus area
- decrease thrombus in -/- mice same as treated

86
Q

Phase 2 study ticagrelor

A

Moderate to high risk patients with ACS
2 groups- ACS with clopidogrel and ticagrelor
12 month max exposure

87
Q

results of ticagrelor

A

ticagrelor had a lower incidence of MI and stroke over time

88
Q

Benefits of using ticagrelor compared to clopidogrel?

A

Cost effectiveness

89
Q

PEAGUSUS-TIMI 54 study design

A

Stable patients >50 years old with history of MI
1-3 years prior>1 additional atherothrombotic risk factor
randomised, double blind
3 different 3 different ticagrelor- 90mg, 60mg, placebo

90
Q

Results

A

41% and 31% TIMI bleeding- 90mg and 60mg

91
Q

Recommendations from the clinical trial

A
  • P2Y12 inhibitor in addition to aspirin- 12 months unless contradictions
  • ticagrelor 180mg twice daily- patients with moderate to high ischeamic events
  • prasugrel- 10mg daily- patients with PCI
  • clopidogrel- 300-600mg loading (cannot receive with the 2 ^)
92
Q

Short and long term treatment

A

short term- P2Y12 inhibitor for a short duration of 3-6 months after DES implantation may be considered in patients deemed high bleeding
long term- P2Y12 inhibitor + aspiring = after careful assessment of ischaemic and bleeding risks

93
Q

General recommendations

A

proton pump inhibitor

combo with DAPT for people with increased risk of of GI bleeds

94
Q

Conclusions

A

Aspiring= effective but weak antiplatelet drug targeting platelet COX1
Platelet P2Y12 receptor= key role in platelet formation, these plus aspirin are the mainstay treatment
clopidogrel= decrease risk of clinical event with arterial thrombosis , variety of response due to efficacy
prasugrel= more effective than thienopyride
ticagrelor= oral P2Y12 antagonist, reduces MI and Stroke

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