Antiplatelet agents are medications that inhibit platelet aggregation, a critical step in the formation of the initial platelet plug.
Antiplatelets are used in the treatment and/or prevention of arterial thrombosis. Common indications include:
- Acute coronary syndrome (ACS)
- 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:
- ADP inhibitors/P2Y12 receptor antagonists
- Phosphodiesterase inhibitors/adenosine uptake inhibitors
- Glycoprotein (GP) IIb/IIIa inhibitors
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
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.
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)
- Potent platelet activators:
- 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
- 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
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
|Mechanism of Action|
|Specific contraindications||Children < 16 years of age (risk of Reye’s syndrome if child develops a viral infection)|
Overdose of Aspirin
- 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
- 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
- Basic metabolic panel:
- 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)
ADP Inhibitors/P2Y12 Receptor Inhibitors
|Mechanism of Action|
|Specific contraindications||Prasugrel: history of an ischemic stroke or TIA|
TTP: thrombotic thrombocytopenic purpura
|Medication||Clopidogrel (Plavix®)||Prasugrel (Effient®)||Ticagrelor|
|Distribution||Highly protein-bound (98%)|
|Metabolism|| Metabolized in the liver via:||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|
Phosphodiesterase (PDE)/Adenosine Uptake Inhibitors
|Mechanism of Action|| Dual mechanisms of action:|
|Distribution||Protein binding: 95%|
|Specific indications||Intermittent claudication|
|Specific contraindications||Heart failure|
|Complications||May induce tachycardia, tachyarrhythmias, and/or hypotension|
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.
|Agents||Eptifibatide (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|
|Specific contraindications||Severe thrombocytopenia|
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.
- Thachil J. (2016). Antiplatelet therapy—a summary for the general physicians. Clinical Medicine Journal 16:152–160. https://doi.org/10.7861/clinmedicine.16-2-152
- Longo, D., et al. (2012). In Jameson JL, et al. (Ed.), Harrison’s Principles of Internal Medicine, 18th ed., vol, 2, pp. 2207–2215.
- Boyer, E.W., Weibrecht, K.W. (2020). Salicylate (aspirin) poisoning in adults. UpToDate. Retrieved May 12, 2021, from https://www.uptodate.com/contents/salicylate-aspirin-poisoning-in-adults
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