Platelets and Anti-platelet Therapy

Question 1

What molecule is important in platelet activation?

Answer 1

Calcium!

Intracellular calcium is the activator of platelets

Question 2

How does the endothelium inhibit platelet activity?

Answer 2

It produces NO and PGI2 which act via 2 pathways to reduce intracellular cGMP and reduce calcium intracellularly

Question 3

What is the intrinsic platelet inhibition mechanism?

Answer 3

Occurs in platelets and the cell surface receptors trigger at the same time of activation to help inactivation
The receptors are: PECAM1, CEACAM1, G6B-beta (etracellular) and RXR, PPARbeta/gamma, Semphorin3 (intracellular)

Question 4

What are the 2 types of platelet inactivation?

Answer 4

Intrinsic and extrinsic
intrinsic is platelet mediated
extrinsic is endothelium mediated

Question 5

Give an overview of platelet activation

Answer 5

Vessel damage leads to capture of vwf via the A3 binding site, this causes unravelling of vwf exposing A1 binding sites for platelets
Platelets are captured on the vwf via GP1b, and more also to the collagen directly using the GPVI and integrin alpha2beta1
There is then intracellular signalling activating the platelet through release of granule contents (ADP and thromboxane) and expression of integrins on the platelet surface
More activation then occurs through the granule contents and activated platelets recruit more platelets and aggregate via alpha2bB3 and fibrinogen.
Throbin further activates platelets via PAR receptors and converts fibrinogen to fibrin
Fibrin cross-linking forms a contracted thrombus

Question 6

Describe the process of atherosclerosis formation

Answer 6

It is a complex lipid-drive inflammatory immune process

Platelets recruit leukocytes, they express pro-inflammatory receptors and bind ldl to release chemokines

Question 7

What is the mechanism of action of aspirin and where does it target?

Answer 7

Aspirin irreversibly acetylates Ser259 of COX1

Question 8

Describe the kinetics of Aspirin

Answer 8

Platelet inhibition in less than an hour
It has a cumulative effect with repeated dosing
It lasts for the lifetime of the platelets as platelets are anucleate

Question 9

When is aspiring 300mg given?

Answer 9

Following suspicion of ACS given aspiring

when confirmed follow with another anti-platelet

Question 10

Primary prevention has been argued, what is the evidence on this?

Answer 10

Conflicting views
Absolute risk of vascular incident in a healthy patient is very small and there is increased GI bleeds with long term aspirin use
But risk of bleeding is seen as > the CVD risk
some evidence points to reduced risk of cancer

Question 11

Which study supports the view that there is reduced risk of cancer with aspirin use?

Answer 11

Aspirin for the Prevention of Cancer Incidence and Mortality: Systematic Evidence Reviews for the U.S. Preventive Services Task Force. Ann Intern Med 2016

Question 12

What could be the reasoning behind knocking COX2 having a worse outcome?

Answer 12

Knocking out COX2 leads to an imbalance in the amount of COX1 that is produced, usually more is pushed out leading to increased thromboxane production which is prothrombotic

Question 13

What are known ADP receptor blockers?

Answer 13

Thienopyridinies - clopi/prasugrel/ticlopidine

Ticagrelor

Question 14

What are the kinetics of clopidogrel?

Answer 14

It is a prodrug metabolised by the liver CYP450 enzyme
It is taken orally once daily and irreversibly inactivates P2Y12 receptor
40-50% inhibition of ADP induced platelet aggregation

Question 15

How is the response to clopidogrel?

Answer 15

30-30% don’t have proper platelet suppression
There are some polymorphisms involving ADP
Compliance as well

Question 16

How does Prasugrel compare?

Answer 16

higher bioavailability

faster onset and less variability

Question 17

What about ticagrelor?

Answer 17

IV so very fast onset

reduction in MI and mortality but increased risks of intracranial haemorrhage

Question 18

Explain the mechanism of action of dipyridamole

Answer 18

It is a phosphodiesterase inhibitor which increases platelet cAMP and cGMP which leads to reduced calcium and activation
There is increased adenosine leading to more vasodilation and platelet inhibition

Question 19

Why does an increase in extracellular adenosine inhibit thrombotic risk?

Answer 19

Leads to vasodilation
the adenosine binds to A2A receptors on the platelet membrane which increases cAMP via adenylate cyclase to decrease platelet reactivity

Question 20

What is abciximan?

Answer 20

It is an Glp2b3a blocker and is licensed for ACS and PCI

Question 21

What are PAR1 antagonists?

Answer 21

Thrombin is a potent platelet agonist
2 types of PAR receptor on human platelets
PAR1 - activates at low thrombin con and contributes to platelet rich thrombus - occurs in pathological thrombosis more than physiological haemostasis