Platelets and Anti-platelet Therapy Flashcards
What molecule is important in platelet activation?
Calcium!
Intracellular calcium is the activator of platelets
How does the endothelium inhibit platelet activity?
It produces NO and PGI2 which act via 2 pathways to reduce intracellular cGMP and reduce calcium intracellularly
What is the intrinsic platelet inhibition mechanism?
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)
What are the 2 types of platelet inactivation?
Intrinsic and extrinsic
intrinsic is platelet mediated
extrinsic is endothelium mediated
Give an overview of platelet activation
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
Describe the process of atherosclerosis formation
It is a complex lipid-drive inflammatory immune process
Platelets recruit leukocytes, they express pro-inflammatory receptors and bind ldl to release chemokines
What is the mechanism of action of aspirin and where does it target?
Aspirin irreversibly acetylates Ser259 of COX1
Describe the kinetics of Aspirin
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
When is aspiring 300mg given?
Following suspicion of ACS given aspiring
when confirmed follow with another anti-platelet
Primary prevention has been argued, what is the evidence on this?
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
Which study supports the view that there is reduced risk of cancer with aspirin use?
Aspirin for the Prevention of Cancer Incidence and Mortality: Systematic Evidence Reviews for the U.S. Preventive Services Task Force. Ann Intern Med 2016
What could be the reasoning behind knocking COX2 having a worse outcome?
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
What are known ADP receptor blockers?
Thienopyridinies - clopi/prasugrel/ticlopidine
Ticagrelor
What are the kinetics of clopidogrel?
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
How is the response to clopidogrel?
30-30% don’t have proper platelet suppression
There are some polymorphisms involving ADP
Compliance as well
How does Prasugrel compare?
higher bioavailability
faster onset and less variability
What about ticagrelor?
IV so very fast onset
reduction in MI and mortality but increased risks of intracranial haemorrhage
Explain the mechanism of action of dipyridamole
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
Why does an increase in extracellular adenosine inhibit thrombotic risk?
Leads to vasodilation
the adenosine binds to A2A receptors on the platelet membrane which increases cAMP via adenylate cyclase to decrease platelet reactivity
What is abciximan?
It is an Glp2b3a blocker and is licensed for ACS and PCI
What are PAR1 antagonists?
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
