In this CCC we will give an overview of the function of platelets, following by an overview of the anti-platelet drugs to consider and then we will finally take a look at the treatment summaries in which antiplatelet drugs are heavily involved.
🏃 Physiology
Before we discuss the drugs used in antiplatelet therapy, let’s first look at how platelets work:
Platelets contain 2 types of granules:
- Alpha-granules - containing von Willebrand Factor, factor V and fibrinogen.
- Dense granules - contain ATP, ADP, serotonin and Ca2+.
Platelets also have 2 types of surface receptors:
- Agonist receptors - such as receptors for collagen, thrombin, ADP and thromboxanes. They receive stimulation from these molecules when bound.
- Adhesion receptors - promote adhesion of platelets to other platelets or to the vessel wall, or to leukocytes. These include GPIIb-IIIa receptor.
The main role of platelets is haemostasis, for which they have 3 main stages of formation. Let’s take a look at the 3 steps of primary haemostasis (a 4th step can be included, that being fibrinolysis).
1. Adhesion
Vessel injury exposes underlying endothelium and collagen. This exposed collagen binds to vWF that is released from the damaged endothelium. This then binds to the vWF receptors on platelets which promotes adhesion of the platelet.
The collagen also triggers the coagulatory cascade through which soluble fibrinogen is converted into insoluble fibrin which meshes together platelets to form a platelet plug which becomes a stable clot.
2. Activation
Platelet binding to collagen activates the GPIIb-IIIa pathway. This ultimately causes ADP and TXA2 release which then activates other platelets.
When platelets are activated, they undergo a morphological change to increase its surface area and allow it to aggregate more easily.
3. Aggregation
Once the platelets are activated, the GPIIb-IIIa receptor is then expressed, allowing it to bind to vWF or fibrinogen. Fibrinogen helps cross linking of platelets to allow for the platelet plug to be formed.
Drugs
An easy way to think about the difference between antiplatelets and anticoagulants is:
- Antiplatelets prevent thrombus formation (which are made up of mainly platelets) in the arterial blood
- Anticoagulants prevent VTE in the slower-moving venous circuit which are made up of mainly fibrin mesh.
There are 4 main antiplatelet drugs available, and we will discuss each of these in detail:
- Aspirin
- P2Y12 inhibitors such as clopidogrel, prasugrel, ticagrelor
- Dipyridamole
- Glycoprotein IIb-IIIa inhibitors such as abciximab, eptifibatide, tirofiban
Aspirin is an irreversible COX inhibitor that prevents formation of TXA2 within platelets thus inhibiting platelet aggregation.
Indications:
Main indications are:
- Primary prevention of atherothrombotic events in high risk individuals.
- Primary prevention in patients undergoing PCI.
- Secondary prevention in people with ACS, angina, PAD, AF
- Secondary prevention after CVS events such as MI, stent implantation, stroke or TIA.
A quick summary of the when they are used for secondary prevention of CVD and their dosage:
- Angina - 75mg
- AF - dual antiplatelet therapy (DAPT) using aspirin 75mg and clopidogrel 75mg if unwilling or unable to take anticoagulants.
- ACS - 75mg daily + ticagrelor 90mg 2x daily for 12 months.
- + CABG - 75mg + P2Y12 inhibitor.
- PCI
- + ACS - 75mg + P2Y12 inhibitor.
- + stable CAD - 75mg + clopidogrel 75mg.
- PAD - 75mg if clopidogrel is unsuitable.
It can also be used to treat pyrexia mild-moderate pain, acute migraine and also prevention of pre-eclampsia in women at moderate-high risk.
Contraindications:
- Children <16 years old - as it has been associated with Reye’s syndrome.
- Hypersensitivity - to aspirin, salicylates or other NSAIDS.
- Active bleeding - such as in PUD or intracranial haemorrhage.
- Severe cardiac failure
- Severe liver failure
- Severe renal failure
- Haemophilia or other haemorrhagic disorders.
Adverse effects:
- Asthma and bronchospasm
- GI irritation
- Haemorrhage
- Prolonged bleeding
- Skin reactions
Interactions:
It can increase bleeding when when taken with other antiplatelets, anticoagulants and SSRIs.
It can increase toxicity of methotrexate if taken simultaneously. These patients require regular monitoring and adequate safety-netting.
P2Y12 inhibitors inhibit binding of ADP to the P2Y12 receptor and subsequently inhibit the activation of the GPIIb-IIIa pathway.
Indications:
- Preventions of atherothrombotic events in patients with ischaemic disease.
- Stroke
- ACS along with low-dose aspirin
- AF with low-dose aspirin when warfarin is unsuitable.
- PCI along with aspirin
Contraindications
- Active bleeding
- Severe liver impairment
Adverse effects:
Common side effects include: diarrhoea, GI discomfort, haemorrhage, skin reactions.
Interactions:
- Loperamide
- Montelukast
- Pioglitazone
- Repaglinide
- Rifampicin
- Omeprazole - use an alternative PPI.
Prasugrel is also a P2Y12 inhibitor, however, it is licensed for different situations than clopidogrel.
Indications:
- Prevention of atherothrombotic events in people with ACS undergoing PCI (in combination with aspirin)
Contraindications:
- Active bleeding
- History of stroke or TIA
- Severe liver impairment
Adverse effects:
- Anaemia
- Haemorrhage
- Skin reactions
Another P2Y12 inhibitor. However, it is the only one that is reversible.
Indications:
- Prevention of atherothrombotic events in high-risk individuals with ACS or history of MI when used in combination with aspirin.
Contraindications:
- Active bleeding
- History of intracranial haemorrhage
- Severe liver impairment
Adverse effects:
- Constipation
- Diarrhoea
- Dizziness
- Dyspepsia
- Dyspnoea
- Gout and hyperuricaemia
- Haemorrhage
- Hypotension
- Nausea
- Skin reactions
- Vertigo
- Syncope
It is both an antiplatelet but also has vasodilatory properties. It inhibits uptake of adenosine into erythrocytes, platelets and endothelial cells → increasing extracellular concentrations of adenosine. Adenosine is a potent inhibitor of platelet activation and aggregation. It may also work by inhibiting cGMP breakdown.
Indications:
- Adjunct to oral anticoagulation for prophylaxis of thromboembolism associated with prosthetic hearts valves.
- Secondary stroke prevention (although it has been switched for clopidogrel).
Contraindications:
- Cardiac conduction issues
- Arrhythmias
Adverse effects:
- Angina pectoris
- Diarrhoea
- Dizziness
- Headache
- Myalgia
- Nausea
- Skin reactions
- Vomiting
Summary of latest guidance
Condition/scenario | 1st line | 2nd line |
ACS secondary prevention | Aspirin lifelong
+ ticagrelor for 12 months | Clopidogrel lifelong is aspirin is contraindicated |
PCI | Aspirin lifelong
+ prasugrel for 12 months | Clopidogrel lifelong is aspirin is contraindicated |
TIA | Clopidogrel lifelong | Aspirin & dipyridamole lifelong |
Ischaemic stroke | Clopidogrel lifelong | Aspirin & dipyridamole lifelong |
PAD | Clopidogrel lifelong | Aspirin lifelong |