Antiplatelet Agents

Antiplatelet agents are medications that inhibit platelet aggregation, a critical step in the formation of the initial platelet plug. Abnormal, or inappropriate, platelet aggregation is a key step in the pathophysiology of arterial ischemic events. The primary categories of antiplatelet agents include aspirin, ADP inhibitors, phosphodiesterase/adenosine uptake inhibitors, and glycoprotein IIb/IIIa inhibitors. Common indications for antiplatelet agents include the treatment and prevention of ischemic heart disease and stroke, peripheral artery disease, and other conditions associated with a high risk for arterial thrombosis.

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Antiplatelet agents are medications that inhibit platelet aggregation, a critical step in the formation of the initial platelet plug.

General indications

Antiplatelets are used in the treatment and/or prevention of arterial thrombosis. Common indications include:

  • Acute coronary syndrome (ACS)
  • Angina
  • Percutaneous coronary intervention (PCI) with stenting
  • Mechanical heart valves
  • Atrial fibrillation
  • Acute ischemic stroke
  • Peripheral artery disease
  • Essential thrombocythemia
  • Primary prevention of coronary artery disease


There are several primary classes of antiplatelet agents:

  • Aspirin
  • ADP inhibitors/P2Y12 receptor antagonists
  • Phosphodiesterase inhibitors/adenosine uptake inhibitors
  • Glycoprotein (GP) IIb/IIIa inhibitors
Mechanisms of action of antiplatelet agents

Mechanisms of action of antiplatelet agents
5-HT: 5-hydroxytryptamine
TxA2: thromboxane A2
VWF: von Willebrand factor

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Platelets and Formation of the Platelet Plug

After endothelial injury occurs, exposure of the blood to the subendothelial components triggers formation of the platelet plug. This process is known as primary hemostasis. (Formation of the fibrin clot via the coagulation cascade is secondary hemostasis.) 

Steps in formation of the platelet plug

  • Adhesion
  • Activation
  • Aggregation
  • Secretion
Formation of the temporary hemostatic plug

Formation of the temporary hemostatic plug:
The disrupted endothelial surface exposes VWF to the passing blood. Platelets bind to the VWF via their GpIb receptors and are activated. Platelet activation triggers them to secrete ADP, which stimulates the expression of the GpIIb/IIIa receptors on the platelets. The GpIIb/IIIa receptors bind to fibrinogen, which is able to bind a platelet on each end, causing platelets to aggregate. As more platelets are bound to one another, the platelet plug is generated. As the coagulation cascade is activated, thrombin converts the weaker fibrinogen into the stronger fibrin, creating a much more stable clot.

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Platelet adhesion

Exposure of the blood to subendothelial components at the site of injury causes platelets to adhere to that site.

  • GPIb receptors on platelets bind to exposed von Willebrand factor (VWF) within the subendothelial matrix: The bond is strong enough to withstand the shearing force of flowing blood.
  • Other adhesion interactions occur:
    • Involve collagen, other glycoprotein receptors, and tyrosine kinase receptors
    • Contribute to both adhesion and activation of platelets
  • Adherent platelets are activated.

Platelet activation

Activated platelets enhance further platelet adhesion and aggregation and stimulate secretion of the platelet granules. 

  • Platelet activators:
    • Potent platelet activators:
      • Thrombin: produced in the coagulation cascade
      • Collagen: interact with platelets at the site of injury
    • Weaker platelet activators:
      • ADP: acts in an autocrine fashion → released by platelets to help activate other platelets
      • Thromboxane A2 (sometimes classified as a potent activator)
      • Epinephrine
  • Activated platelets:
    • Undergo a shape change to become an elongated pseudopod → new shape is extremely adherent
    • Activate the GPIIb/IIIa receptor so that the platelets are capable of binding to fibrinogen
    • Release the platelet granules (see Platelet Secretion below) → assist in activation of the coagulation cascade

Platelet aggregation

  • GPIIb/IIIa receptors on activated platelets begin binding to fibrinogen.
  • Fibrinogen is a symmetrical molecule that can bind 2 platelets at the same time (1 on each end of the fibrinogen).
  • Fibrinogen bridges form between platelets
  • Results in platelet aggregation and formation of the primary hemostatic plug

Platelet secretion

Platelets contain granules, each of which releases a number of different substances when platelets are activated. Functions of secreted substances include:

  • Recruit and activate additional platelets
  • Stimulate expression of GPIIb/IIIa on platelets → enhanced aggregation
  • Promotes vasoconstriction
  • Stimulates the vascular repair process via fibroblast/smooth muscle cell recruitment
  • Contributes to initiation of the coagulation cascade


Medication overview

Table: Aspirin
Mechanism of Action
  • Irreversible inhibitor of cyclooxygenases 1 and 2 (COX-1 and COX-2) 
    • COX enzymes produce the precursors to thromboxane A2 (TXA2)
    • TXA2 assists in platelet activation (stimulates expression of the GPIIb/IIIa receptor) and is a vasoconstrictor. 
Physiologic effects
  • COX inhibition → ↓ production of TXA2 → ↓ platelet activation and vasoconstriction
  • Permanently inhibits platelet aggregation for the duration of the platelet’s life → new platelets restore platelet function after 3–7 days 
  • Orally administered
  • Immediate release: rapid absorption
  • Enteric-coated: variable (depends on food and pH in the stomach)
  • Bioavailability: 50%–75% 
  • Time to peak activity: 
    • Immediate release: 1–2 hours (20 minutes when chewed)
    • Enteric-coated: 3–4 hours 
  • VD = 10 L
  • Distributes readily into most body fluids and tissues
  • Protein binding: 
    • High protein binding at typical doses: approximately 90%–94%
    • Protein binding ↓ as salicylate concentration ↑ (e.g., may be only 30% bound in cases of overdose)
  • Hydrolyzed to salicylate (active form) by esterases in the GI mucosa, blood, and synovial fluid
  • Metabolized in the liver to salicyluric acid (less active, more rapidly excreted)
  • Renal
  • Half-life: dose-dependent
    • 3 hours at lower doses (300–600 mg)
    • 5–6 hours at medium doses (approximately 1 g)
    • Up to 10 hours with higher doses
Specific indications
  • ACS
  • Prophylaxis against a subsequent MI
  • Acute ischemic stroke
  • Peripheral arterial ischemia
  • Other typical uses:
    • Pain/inflammation
    • Fever
Specific contraindications Children < 16 years of age (risk of Reye’s syndrome if child develops a viral infection)
Complications/adverse effects
  • Severe bleeding (0.3%)
  • Gastric ulceration
  • Reye’s syndrome 
  • Tinnitus
  • Hyperventilation/respiratory alkalosis
VD: volume of distribution
Overview of prostaglandin and thromboxane synthesis

Overview of prostaglandin and thromboxane synthesis
PG: prostaglandin

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Overdose of Aspirin

Clinical presentation

  • Fever
  • Tinnitus
  • Vertigo
  • Nausea, vomiting, and diarrhea
  • Altered mental status (occurs via direct toxicity, neuroglycopenia, and/or cerebral edema)
  • Hyperventilation (occurs via direct action on the respiratory center to ↑ RR and tidal volume)
  • Acid–base abnormalities: 
    • Respiratory alkalosis
    • Anion-gap metabolic acidosis (lactic acids and ketoacids)
    • These abnormalities represent mixed primary acid–base abnormalities, rather than compensation mechanisms.
  • Pulmonary edema (typically in older adults with chronic salicylate intoxication)
  • Cardiac arrhythmias
  • Hypovolemia
  • Hypoglycemia
  • Hypokalemia


  • Salicylate levels:
    • Therapeutic levels are typically 10–30 mg/dL
    • Toxicity is associated with values > 40 mg/dL 
    • Levels should be measured every 2 hours until:
      • Levels are decreasing on 2 consecutive draws.
      • Levels are < 40 mg/dL.
      • Patient is asymptomatic and has a normal respiratory effort.
  • Other lab values to check:
    • Basic metabolic panel:
      • ↑ Creatinine (renal failure) → patient requires hemodialysis
      • ↓ Potassium → may interfere with urinary alkalinization; should be treated aggressively
      • Assess acid–base status (e.g., HCO3, Cl).
    • Lactate: may be ↑ 
    • Arterial blood gas (ABG): to assess acid–base status


  • Stabilize patients whose condition is unstable by addressing the airway, breathing, and circulation.
  • GI decontamination with activated charcoal
  • Give supplemental glucose to avoid neuroglycopenia.
  • Give potassium to treat hypokalemia.
  • Alkalinization of the plasma and urine with sodium bicarbonate
  • Consider hemodialysis, especially in patients with:
    • Altered mental status
    • Pulmonary edema or respiratory distress
    • Cerebral edema
    • Acute or chronic kidney injury (sufficient to impair salicylate elimination)
    • Fluid overload
    • Severe acidemia (pH < 7.2)
    • Markedly elevated salicylate concentrations (e.g., > 90 mg/dL)

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ADP Inhibitors/P2Y12 Receptor Inhibitors

Table: ADP inhibitors/P2Y12 receptor inhibitors
  • Clopidogrel (Plavix®)
  • Prasugrel (Effient®) 
  • Ticagrelor
  • Cangrelor
  • Ticlopidine (no longer used)
Mechanism of Action
  • Inhibit binding of ADP to P2Y12 receptors on platelets
    • Clopidogrel and prasugrel: irreversible inhibition
    • Ticagrelor: reversible inhibition 
Physiologic effects
  • Activated P2Y12 receptors stimulate the expression of GPIIb/IIIa receptors (which are critical in platelet aggregation)
  • ↓ ADP → ↓ activation of the P2Y12 receptors → ↓ GPIIb/IIIa receptors → ↓ platelet aggregation
Specific indications
  • Prevention of thrombotic strokes and TIAs
  • Acute coronary syndrome
  • Reduce restenosis of stents
  • Clopidogrel: can be used in place of aspirin in cases of aspirin allergy
  • Ticagrelor and cangrelor: often used in the catheterization lab
Specific contraindications Prasugrel: history of an ischemic stroke or TIA
  • TTP, rare
  • Ticlopidine (high toxicity rate is the reason it is no longer used):
    • Severe bleeding (5%)
    • Severe neutropenia (1%)
TIA: transient ischemic attack
TTP: thrombotic thrombocytopenic purpura
Table: Pharmacokinetics of select ADP inhibitors
MedicationClopidogrel (Plavix®)Prasugrel (Effient®)Ticagrelor
  • Rapidly absorbed
  • Dose-dependent onset of action
  • Time to peak: approximately 45 minutes
  • Rapidly absorbed
  • Time to peak: approximately 30 minutes
  • Rapidly absorbed
  • Time to peak: approximately 2 hours
Distribution Highly protein-bound (98%)
  • VD: 44–68 L
  • Highly protein-bound (approximately 98%)
  • VD: 88 L
  • Highly protein-bound (> 99%)
Metabolism Metabolized in the liver via:
  • CYP2C19 oxidation to an active thiol metabolite
  • Hydrolysis to an inactive carboxylic acid derivative
Hydrolyzed in the intestines and serum to an inactive thiolactone intermediate, which is then converted to an active metabolite via CYP3A4 and CYP2B6 oxidation Metabolized by the liver to an active metabolite via CYP3A4
  • Renal (50%) and fecal (46%)
  • Half-life:
    • Parent drug: approximately 6 hours
    • Thiol metabolite: approximately 30 minutes
    • Approximately 2% may have a half-life of up to 11 days
  • Renal (approximately 68%) and fecal (approximately 27%)
  • Half-life: approximately 7 hours
  • Fecal (approximately 58%) and renal (approximately 26%)
  • Half-life: approximately 7‒9 hours

Phosphodiesterase (PDE)/Adenosine Uptake Inhibitors

Table: PDE/adenosine uptake inhibitors
AgentsDipyridamole (Persantine®)Cilostazol
Mechanism of Action Dual mechanisms of action:
  • Inhibit PDE
      • PDE degrades cAMP
      • cAMP inhibits platelet aggregation
      • By inhibiting PDE → cAMP ↑ which → ↓ platelet aggregation
  • Inhibit uptake of adenosine
    • Inhibiting adenosine uptake → ↑ plasma adenosine
    • Adenosine:
      • Activates the A2 receptor on the platelet surface
      • Causes selective vasodilation of the coronary arteries
    • A2 receptor activation stimulates ↑ cAMP levels within the platelet
    • Inhibiting adenosine uptake → ↑ A2 stimulation → ↑ cAMP → ↓ platelet aggregation
Physiologic effects
  • ↑ cAMP → ↓ platelet aggregation
  • Vasodilation
  • Rapid
  • Time to peak concentration: 2–2.5 hours 
  • Orally absorbed
  • Time to peak concentration: 2–3 hours 
  • VD: 2–3 L/kg
  • Protein binding: approximately 95% 
Protein binding: 95%
  • Metabolized in the liver to a glucuronide conjugate
  • Metabolized in the liver, primarily via CYP2C19 and CYP3A4
  • Fecal
  • Half-life: 10–12 hours 
  • Renal (74%)
  • Fecal (20%)
  • Half-life: 11–13 hours 
Specific indications
  • Adjunct to warfarin in patients with heart valve replacements
  • Adjunct to aspirin in patients for secondary prevention of stroke (i.e., after a first stroke, patients get aspirin; if they have a stroke on aspirin, they continue aspirin and add dipyridamole)
Intermittent claudication
Specific contraindications
  • Unstable angina
  • ACS
  • Recent MI
  • Heart block
Heart failure
  • Severe bleeding (1–2%)
  • Worsening angina
May induce tachycardia, tachyarrhythmias, and/or hypotension
Adverse effects
  • Dizziness
  • Vomiting and diarrhea
  • Headache
  • Diarrhea
  • Palpitations
  • Dizziness
PDE: phosphodiesterase

Glycoprotein IIb/IIIa Inhibitors

The 2 primary GPIIb/IIIa inhibitors are eptifibatide (Integrilin®) and tirofiban (Aggrastat®). Abciximab is a monoclonal antibody that is also in this category; however, it is no longer available in the United States.

Table: Glycoprotein IIb/IIIa Inhibitors
AgentsEptifibatide (Integrilin®)Tirofiban (Aggrastat®)
Mechanism of Action Binds to and reversibly inhibits the GPIIb/IIIa receptor 
Physiologic effects Prevents GPIIb/IIIa receptors from binding fibrinogen and thus prevents platelet aggregation
  • Rapid
  • Time to peak: approximately 1 hour
  • Rapid
  • Onset of action seen within 10 minutes
  • Protein binding: approximately 25%
  • VD: 22–42 L
  • Protein binding: 65% (concentration-dependent) 
Metabolism Negligible
  • Renal 
  • Half-life: approximately 2.5 hours
  • Renal (approximately 65%) and fecal (approximately 25%) primarily as unchanged drug
  • Half-life: approximately 2 hours 
Specific indications
  • Used in ACS
  • Prevents restenosis after angioplasty
Specific contraindications Severe thrombocytopenia
  • Bleeding
  • Thrombocytopenia with long-term use (typically only short-term use)

Clinical Relevance

Some of the most common therapeutic uses of antiplatelet agents include:

  • Myocardial infarction: ischemia of the myocardial tissue due to complete obstruction or drastic constriction of coronary artery. This ischemia is usually accompanied by an increase in cardiac enzymes, typical ECG changes, and chest pain. Treatment depends on the timing of presentation and available resources, but most patients initially receive antiplatelet agents, anticoagulation therapy, and medications that decrease oxygen demand of the heart.
  • Thromboembolic ischemic stroke: ischemia of the brain due to thrombotic or embolic obstruction of blood flow. Thrombotic strokes are caused by clots in the large or small vessels of the brain. Embolic strokes are due to clots that break off from somewhere else and ultimately become lodged in the brain; they are often due to cardiac sources. Patients will present with neurologic deficits, and diagnosis is made with CT. Management is complex, but initial treatment often involves the use of antiplatelet agents and anticoagulants.
  • Peripheral artery disease (PAD): obstruction of the arterial lumen resulting in decreased blood flow to the distal limbs. This obstruction can be a result of atherosclerosis or thrombosis. Patients may be asymptomatic, or they may have progressive claudication, skin discoloration, ischemic ulcers, or gangrene. Imaging studies can determine the location and extent of the arterial disease. Treatment varies depending on the severity but can include lifestyle modifications, antiplatelet therapy, phosphodiesterase inhibitors, and revascularization.
  • Atrial fibrillation (AF, or Afib): supraventricular tachyarrhythmia and most common kind of arrhythmia. Atrial fibrillation is caused by rapid, uncontrolled atrial contractions and uncoordinated ventricular responses. Diagnosis is confirmed by an ECG that will show an “irregularly irregular” heartbeat with no distinct P waves and narrow QRS complexes. Atrial fibrillation increases the risk of thromboembolic events, and antiplatelet and/or anticoagulation therapy is often indicated. Treatment is based primarily on ventricular rate and rhythm control.
  • Essential thrombocythemia: type of myeloproliferative neoplasm characterized by excessive production of platelets, resulting in increased thrombotic and hemorrhagic risks. The clinical course of essential thrombocythemia can also be complicated by progression to myelofibrosis and acute myeloid leukemia. The diagnosis is based on laboratory finding of thrombocytosis, bone marrow biopsy, and genetic studies. Treatment aims to reduce platelet count by cytoreductive agents (hydroxyurea) and to decrease thrombosis risk with aspirin and systemic anticoagulation.


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  6. Prasugrel: Drug information (2021). UpToDate. Retrieved May 12, 2021, from
  7. Ticagrelor: Drug information (2021). UpToDate. Retrieved May 12, 2021, from 
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