23.1 Anti-Platelets

Question 1

a) What are the indications for anti-platelet drugs in clinical practice? (25%)

Answer 1

> > Primary prevention in patients
at risk of thrombotic cardiovascular events.

> > Primary prevention in patients at risk
of thrombotic cerebrovascular events.

> > Secondary prevention
of thrombotic events in patients who have had
myocardial infarction,
any percutaneous coronary intervention including
coronary stent or bypass surgery.

> > Secondary prevention of thrombotic events in patients who have transient ischaemic attacks or thrombotic stroke.

> > Anticoagulation of
e.g. haemofiltration circuits when heparin cannot be
used.

> > Side effect of a drug’s intended use, e.g. antipyretics, analgesics.

Question 2

b) List the agents currently in clinical use and their underlying mechanisms of action. (50%)

Answer 2

Agent Mechanism of action
1. Aspirin
Irreversible nonselective cyclo-oxygenase inhibitor, stopping thromboxane A2 production.

2. Thienopyridines
   (clopidogrel, ticlopidine)
   Irreversible inhibition of P2Y12 ADP receptor.
3. Glycoprotein IIb/IIIa receptor inhibitors
   (tirofiban, abciximab)

Prevents GPIIb/IIa fibrin cross-linking
with other activated platelets or
von Willebrand Factor cross-linking to the subendothelium.

4. Dipyridamole

a. Phosphodiesterase inhibitor.
Increases the presence of cAMP
by reducing its breakdown by
phosphodiesterase,
increasing the tendency of platelets to
remain in the inactive state.

b. Blocks thromboxane A2 receptors.

5. Prostacyclin

Binds to platelet G-protein coupled receptor,
increasing cAMP production by adenylate cyclase,
helping maintain platelets in their inactive state.

Question 3

c) How may active bleeding be managed following administration of one of these agents? (25%)

Answer 3

How do you manage any bleeding?
Make sure you cover the basics before
launching in with platelet transfusions.

> > I would assess and manage the patient simultaneously,
following an ABC
approach, to include administration of oxygen, assessment of adequacy of ventilation with definitive management as indicated, and large-bore cannulation.

> > Discontinue further antiplatelet
administration if risk/benefit assessment
makes this appropriate.

> > Pressure, tourniquet use,
surgical or radiological management of the
source of bleeding.

> > Early consultation with a haematologist for guidance. Activate Major Haemorrhage Protocol if appropriate.

> > Point-of-care and laboratory tests
of full blood count and coagulation to
guide administration of blood,
fresh frozen plasma, cryoprecipitate and
coagulation factor concentrates.

> > May need large volumes of platelet
transfusions as infused platelets will
become inactivated by the presence of the antiplatelet drug.

> > Consideration of tranexamic acid.

Question 4

platelet activation

Answer 4

> > The intact endothelium releases chemicals
such as prostacyclin and nitric oxide,

which keep platelets in their inactive form.

Inactive platelets maintain calcium
efflux via a cAMP-driven pump.

> > Exposed collagen or von Willebrand’s Factor
(due to damage to the endothelium)
or thrombin in the blood
(due to activation of the
coagulation pathways)
activates platelets.

> > The activated platelets release ADP f
rom granules and make
thromboxane A2 via the COX pathway

> > ADP and thromboxane A2
go on to activate other platelets:

ADP reduces cAMP, thus inactivating
the outward pump of calcium,
allowing a conformational change in the platelets, resulting in degranulation,
and thromboxane A2 activates other platelets’
GPIIb/IIa receptors.

> > The glycoprotein IIb/IIIa receptors
on the surfaces of activated platelets
change from resting to active.

> > Activated GPIIb/IIIa receptors will bind fibrinogen at both ends, thus
linking activated platelets together, or bind to von Willebrand Factor
exposed in the damaged endothelium, thus anchoring the platelet plug
in place