31. Antiplatelet Agents Flashcards
Draw a diagram of a platelet showing all the receptors that are activated during platelet aggregation and adhesion.
Fig. 31.1 Platelet showing main receptors involved in clot formation
1 > Membrane glycoproteins GPIa/IIa, GPVI and GPIV, function as receptors in platelet adhesion to collagen.
2
> GPIIb/IIIa (also known as integrin αIIbβ3)
is a receptor for fibrinogen
and von Willebrand factor.
3
> Adenosine diphosphate (ADP)
binds to P2Y1 (Gq)
and P2Y12 (Gi) receptors.
4
> Thrombin binds to protease-activated
receptors (PARs), PAR-1 and PAR-4.
5
> Thromboxane A2 (TxA2)
is produced from arachidonic acid
through conversion by cyclo-oxygenase-1.
The TxA2 receptor (TP) is also
activated by the prostaglandin
endoperoxides PGG2 and PGH2.
How are platelets involved in clotting?
Platelets are critical in haemostasis
and the development of arterial thrombi.
Damaged endothelium initiates a
multistep interaction
between platelets and the adhesive macromolecules within the extracellular matrix, resulting in platelet activation, adhesion to the endothelium and platelet aggregation.
> Initial contact:
von Willebrand factor (vWF)
binds to GPIbα,
and collagen bind
to collagen receptor GPVI,
activating platelets.
> Platelet adhesion:
bound vWF activates
GPIIb/IIIa membrane glycoproteins,
allowing them to bind fibrinogen,
resulting in a firm adhesion
of platelets to the endothelium.
> Platelet activation:
activated platelets release
TxA2 and ADP,
which results in
recruitment,
activation and
degranulation of surrounding platelets.
Thrombin, a product of the coagulation cascade,
also mediates this process.
All three act via
G-protein-coupled receptors (GPCRs),
causing a conformational change in
GPIIb/IIIa receptors.
> Platelet aggregation:
fibrinogen binds to GPIIb/IIIa receptors,
converts to fibrin and stabilises the
thrombus by cross-linkage of platelets.
Platelet activation,
adhesion and
aggregation
are inhibited by the
endothelium derived
mediator nitric oxide (NO),
also known as endothelium-derived relaxing factor (EDRF), and prostacyclin (PGI2).
These mediators act via GPCRs,
increasing intracellular levels of
cyclic adenosine monophosphate (cAMP)
and cyclic guanosine monophosphate (cGMP)
in platelets, thereby inhibiting them.
How can anti-platelet agents be classified?
> Anti-platelet agents decrease
platelet aggregation and
inhibit thrombus formation.
> They are most effective in the treatment or prevention of arterial clots
that are composed largely of platelets,
where anticoagulants have little effect.
> The main anti-platelet agents in clinical use are:
• Cyclo-oxygenase (COX) inhibitors
• ADP receptor inhibitors
(thienopyridines and non-thienopyridines)
- Dipyridamole
- Parenteral GPIIb/IIIa inhibitors
• Other agents include
thromboxane inhibitors and PAR-1 antagonists.
How can anti-platelet
agents be classified?
1
COX inhibitors
Aspirin
2
ADP receptor inhibitors
Ticlopidine Clopidogrel Cangrelor Ticagrelor Prasugrel
3
Phosphodiesterase inhibitors
Dipyridamole
4
GPIIb/IIIa inhibitors
Abciximab
Tirofiban
Eptifibatide
What are the mechanisms of action of anti-platelet
agents?
Aspirin:
Aspirin:
> Changes the balance between
prostacyclin (which inhibits platelet aggregation)
and thromboxane (which promotes aggregation).
> It irreversibly and non-selectively
acetylates and inhibits
the enzyme COX, and
is 50–100 times more effective against COX-1.
> The conversion of
arachidonic acid (AA) to endoperoxide (EPO)
inhibited with resultant prevention of
synthesis of TxA2
in platelets and prostacyclin (PGI2) in endothelial cells.
> The vascular endothelium recovers
can synthesise more prostacyclin,
but thromboxane synthesis
only recovers after new platelets are formed.
ADP receptor blockers
> Thienopyridines
(e.g. ticlopidine, clopidogrel and prasugrel)
• Act by inhibiting the
ADP-dependent pathway of
platelet activation.
• They are prodrugs whose active metabolites inhibit the P2Y12 subtype of the ADP receptor, preventing binding of adenosine diphosphate (ADP) to its receptor on the platelet surface.
• They are competitive antagonists and their
effects are irreversible.
• Platelet function returns to
normal with the formation of
new platelets in
7–10 days.
>
Ticagrelor
Ticagrelor
• New drug that indirectly inhibits ADP.
• It acts on an independent
ligand-binding site on the P2Y12 receptor,
which results in a conformational change
in the receptor, rendering it inactive.
• This process displays dose-dependent,
reversible non-competitive binding with ADP.
> Cangrelor
> Cangrelor
• New, rapidly acting, reversible ADP blocker that binds selectively and specifically to the P2Y12 receptor on the platelet surface.
• It has a rapid onset and offset of action,
and does not require activation or
conversion by the liver to an active metabolite.
• It is administered by i.v. infusion,
with a plasma half-life of 3–5 minutes,
resulting in full recovery of platelet activity
within 60 minutes.
Dipyridamole
> Inhibits cellular uptake of
adenosine by platelets,
erythrocytes and endothelial cells,
increasing the extracellular
concentration of adenosine,
which increases cAMP levels within the platelets.
> Also inhibits platelet phosphodiesterases (PDEs), which normally break down
cAMP and cGMP to inactive molecules.
> Elevated levels of cAMP and cGMP
inhibit activation and aggregation of
platelets
(by blocking the platelet response to ADP).
> In high doses, it is also a potent vasodilator.
GPIIb/IIIa inhibitors (e.g. abciximab and tirofiban)
> Have the greatest antiplatelet activity
as they inhibit the final common pathway
of platelet aggregation where
fibrinogen binds to the GPIIb/IIIa receptor.
> Platelet inhibition is reversible
with return of normal platelet function by
48 hours with abciximab and by
6–8 hours with tirofiban.
> They are administered parenterally and are primarily used in the management of acute coronary syndromes (ACS) and percutaneous coronary interventions (PCI).
What are the peri-operative considerations for anti-platelet agents (i.e. when to stop for surgery and neuroaxial blocks)?
With increasing use of anti-platelet agents
in an ageing population, much
consideration has been given to
peri-operative management.
Each patient should be stratified
according to individual thrombotic
and surgical bleeding risk and
joint multidisciplinary team involvement in the decision-making process
(surgeon, anaesthetist, cardiologist, haematologist) is recommended.
Aspirin monotherapy:
> Primary prevention or AF:
can be safely discontinued 7–10 days before surgery.
> Secondary prevention with
low risk of bleeding: relative risk
is in favour of
continuation.
> High risk of bleeding
(cardiac, intracranial, prostate and hip surgery):
discontinue 7–10 days before surgery.
Dual anti-platelet therapy (aspirin & ADP inhibitors):
> Low-risk situations:
ADP inhibitors should be discontinued
5–7 days before surgery,
and aspirin should be continued.
> High-cardiovascular risk
(recent MI, PCI, BMS <6 weeks,
DES <12 months, risk of myocardial ischaemia/infarct):
• Delay elective surgery
• Proceed with emergency surgery
despite no discontinuation in DAPT.
May require platelet transfusion in life-threatening bleeding.
• Urgent surgery where bleeding risk is high: may require complete discontinuation of anti-platelet medications. In these situations, bridging therapies, such as heparin or GPIIb/IIIa inhibitors, should be considered
Regional anaesthesia:
> Carries a relative risk of bleeding
in patients on anti-platelet agents.
> Guidelines published by the Association of Anaesthetists of Great Britain and
Ireland in 2013 recommend risk should be minimised by:
• Ensuring that neuraxial and
peripheral nerve blocks
are performed by
experienced clinicians
• Where possible they should be
performed under ultrasound guidance
• Stopping anti-platelet agents
where applicable in a timely manner.
> Procedures carrying the greatest risk of haematoma are epidural with a catheter, one-shot epidural, spinal, paravertebral blocks, deep blocks, and superficial perivascular blocks.
Fascial blocks, superficial blocks and local
infiltration approach normal risk
Table 31.1
Table 31.1 Timeframes for stopping anti-platelet therapy
1
Drug
2
Time after stopping
drug before block
performance
3 Administration of drug while spinal or epidural catheter in place
4 Time to next drug dose after block performance or catheter removal
1 2 3 4
Clopidogrel 7 days Not recommended 6 hours
Prasugrel 7 days Not recommended 6 hours
Ticagrelor 5 days Not recommended 6 hours
Tirofiban 8 hours Not recommended 6 hours
Abciximab 48 hours Not recommended 6 hours
NSAIDs or aspirin No additional
precautions
No additional
precautions
No additional precautions
Dipyridamole No additional
precautions
No additional
precautions
6 hours
