Antiplatelet agents

Antiplatelet agents are drugs that inhibit enzymes or receptors required for platelet activation, platelet aggregation, and/or thrombus formation. The most commonly used antiplatelet agent is acetylsalicylic acid (aspirin), which is an irreversible cyclooxygenase inhibitor with dose-dependent antiplatelet, antipyretic, analgesic, and antiinflammatory actions. Low-dose aspirin is used in the management of cardiovascular events (e.g., acute MI) and for primary/secondary prophylaxis of cardiovascular disease. Adverse effects of aspirin include peptic ulcers, hemorrhage, salicylate toxicity, aspirin-exacerbated respiratory disease, and Reye syndrome. P2Y12 receptor antagonists (clopidogrel, prasugrel, ticagrelor) are mainly used in conjunction with aspirin (dual antiplatelet therapy) in the management of acute coronary syndrome and to prevent stent thrombosis in patients after percutaneous coronary intervention (PCI). Although allergic reactions are more common, P2Y12 receptor antagonists cause fewer hemorrhagic/gastrointestinal complications compared to aspirin. Glycoprotein IIb/IIIa inhibitors (abciximab, eptifibatide, and tirofiban) are parenterally administered, rapid-acting antiplatelet agents that are only used in high-risk patients in which PCI is planned. Gp IIb/IIIa inhibitors can cause a sudden drop in platelet counts (acute profound thrombocytopenia), necessitating platelet count monitoring. All antiplatelet agents increase the risk of hemorrhage and are usually contraindicated in patients who have thrombocytopenia or active/recent bleeding (e.g., hemorrhagic stroke, major surgery within the past 30 days).

For the mechanisms of platelet activation, platelet adhesion, platelet aggregation, and clot formation, see “Hemostasis.”

Agents ^[1]

Acetylsalicylic acid (ASA, aspirin)

Mechanism of action ^[2][3]

ASA covalently attaches an acetyl group to COX.

• Irreversible COX-1 inhibition → inhibition of thromboxane (TXA2) synthesis in platelets → inhibition of platelet aggregation (antithrombotic effect)
  • Onset of antiplatelet action: within minutes
  • Duration of antiplatelet action: 7–10 days
• Irreversible COX-1 and COX-2 inhibition → inhibition of prostacyclin and prostaglandin synthesis → antipyretic, anti-inflammatory, and analgesic effect

Effects

• Low dose (below 300 mg/day): inhibition of platelet aggregation
• Intermediate dose (300-2400 mg/day): antipyretic and analgesic effect
• High dose (2400-4000 mg/day): antiinflammatory effect

Indications

• Acute myocardial infarction
• Acute ischemic stroke ^[4]
• Angina (stable and unstable)
• Management of ASCVD
• Primary prevention of ASCVD and colorectal cancer ^[5]
• Symptomatic peripheral arterial disease
• Giant cell arteritis
• Prevention of stent thrombosis after revascularization procedures (e.g., PTCA, CABG, carotid endarterectomy)
• See “Non-opioid analgesics” for indications in pain management and inflammation.

Adverse effects

• Gastrointestinal (most common): aspirin blocks COX-1 → inhibition of conversion arachidonic acid to PGH2 → ↓ formation of PGE2 ; → ↓ secretion of mucus and bicarbonate by epithelium → loss of protective layer on mucosa → gastric acid damages tissue → ↑ risk of ulcers, bleeding, and perforation
  • Dyspepsia
  • Gastric ulceration, hemorrhage, perforation
• Coagulopathy and bleeding: These effects continue until new platelets are formed.
  • ↑ Bleeding time
  • Prothrombin time (PT) and partial thromboplastin time (PTT) are not affected.
• Tinnitus: aspirin affects the vestibulocochlear nerve
• Renal (in the case of long-term use)
  • Acute kidney injury
  • Acute interstitial nephritis
• Salicylate poisoning: See “Salicylate toxicity.
• Allergic reactions
  • Cutaneous reactions
  • Anaphylactoid reactions

Contraindications

• Febrile illness in individuals < 19 years of age
• Acute gout attack ^[6]

Complications

Aspirin-exacerbated respiratory disease (AERD) ^[7][8][9]

• Description
  • Chronic condition characterized by the Samter triad
  • Exacerbated by a pseudoallergic sensitivity reaction to aspirin and other NSAIDs (NSAID intolerance)
• Etiology: imbalance between proinflammatory leukotrienes and antiinflammatory prostaglandins resulting from COX enzyme inhibition
• Clinical features: Samter triad (asthma, chronic/recurrent rhinosinusitis, nasal polyps)
• Diagnostics
  • Clinical diagnosis
  • NSAID/aspirin challenge test
• Treatment
  • Avoid NSAIDs
  • Aspirin desensitization ^[10][11]
  • Leukotriene receptor antagonists (e.g., Montelukast, Zafirlukast)

Reye syndrome ^[12][13]

• Description: a rare type of hepatic encephalopathy that is associated with aspirin use for viral illness in children < 19 years
• Etiology: aspirin use in individuals < 19 years of age with a febrile illness ^[14][15]
• Pathophysiology ^[16]
  • Viruses alter the metabolism of salicylates → accumulation of salicylate metabolites in the liver → mitochondrial injury and reversible inhibition of enzymes required for fatty acid oxidation; → failure of hepatic ATP production → acute hepatic failure → hyperammonemia, metabolic acidosis, and hepatic steatosis → acute encephalopathy
  • Hyperammonemia → cerebral edema → ↑ ICP
• Clinical features
  • Preceding viral infection (e.g., influenza, varicella or viral gastroenteritis): The first symptoms of Reye syndrome usually begin 3–5 days after a viral illness.
  • Acute encephalopathy
    • Severe vomiting
    • Altered mental status; (ranging from lethargy to delirium and coma)
    • Neurological symptoms (e.g., seizures, fixed pupils)
  • Liver failure
    • Fatty degeneration
    • Hepatomegaly
• Diagnostics: clinical diagnosis; further testing to rule out other causes (diagnosis of exclusion)
  • Laboratory studies
    • ↑ AST and ALT
    • Hyperammonemia
    • Hypoglycemia
    • Metabolic acidosis
    • Prolonged INR
  • Cranial CT/MRI: may show cerebral edema and scattered lesions
  • Lumbar puncture and CSF analysis: WBC < 8/μL
  • Liver biopsy: microvesicular hepatic steatosis
• Treatment: supportive
  • Decrease intracranial pressure (e.g., via osmotic diuresis; elevation of the head)
  • Correction of hypoglycemia
  • Cardiopulmonary support if necessary
• Prevention
  • Aspirin should be avoided in individuals < 19 years of age, especially those with fever.
  • Exception: children with Kawasaki disease
• Prognosis
  • Outcomes vary from complete recovery to permanent neurological deficits.
  • Mortality rate: ∼ 20% ^[12]

The lifespan of a platelet is 7–10 days. If aspirin is held prior to surgery, it should be discontinued one week in advance.

Emergency correction of the antiplatelet effect of aspirin can only be achieved by administering platelet concentrates.

To memorize the symptoms of Reye syndrome, remember that “It’s never Rainy (Reye) in CHILE”: Coma, Hepatomegaly/Hypoglycemia, history of viral Infection, Liver failure, Encephalopathy.

Agents ^[17][18]

• Clopidogrel
  • Pro-drug
  • Activation is dependent on hepatic cytochrome P enzymes.
  • Not effective in individuals with genetic polymorphisms of CYP enzymes or drug-induced inhibition of CYP enzymes (e.g., cimetidine, amiodarone, omeprazole, etc.)
• Prasugrel
  • Pro-drug
  • Faster acting and more potent than clopidogrel
• Ticagrelor
  • Not a pro-drug
  • Orally administered direct antagonist of P2Y12 platelet receptor
  • Faster acting and more potent than clopidogrel
• Ticlopidine: irreversible P2Y12 receptor antagonist
• Cangrelor: IV administered P2Y12 receptor antagonist

Mechanism of action

• Inhibition of P2Y12 receptor on platelets (ADP receptor) → ↓ expression of Gp IIb/IIIa receptors on platelets → inhibition of platelet aggregation
  • ADP usually binds to P2Y12 receptors, leading to activation of Gp IIb/IIIa receptors and subsequent platelet aggregation.
  • Irreversible inhibition: clopidogrel, prasugrel, ticlopidine
  • Reversible inhibition: ticagrelor

Indications

• Dual antiplatelet therapy (in combination with acetylsalicylic acid)
  • STEMI
  • Unstable angina/NSTEMI
  • Secondary prevention of cardiac events in patients post PCI and/or stenting
  • Before PCI
• Alternative to aspirin in cases of intolerance: to prevent recurrence of thromboembolic events, including ischemic stroke, MI, and symptomatic peripheral arterial disease

Adverse effects

• Allergic reactions (rash, pruritus, anaphylaxis)
• Hemorrhage
• Gastrointestinal upset
• Possibly TTP
• Ticlopidine: neutropenia/agranulocytosis

Agents

• Abciximab (Fab region fragments of monoclonal antibodies against glycoprotein IIb/IIIa receptors)
• Eptifibatide
• Tirofiban ^[19]

Mechanism of action ^[20]

• Gp IIb/IIIa inhibitors bind to and block glycoprotein IIb/IIIa receptors (fibrinogen receptor) on the surface of activated platelets → prevention of platelets binding to fibrinogen; → inhibition of platelet aggregation and thrombus formation

Indication ^[21]

• Prevention of thrombotic complications in high-risk patients with unstable angina/NSTEMI planned for PCI within 24 hours

Adverse effects

• Acute profound thrombocytopenia
• Hemorrhage

To remember that ABCiximab targets glycoproteins IIb/IIIa, think ABC rhymes with 123!

Abciximab and tirofiban are contraindicated in patients with thrombocytes < 100,000/mm³!

Eptifibatide and tirofiban are fibrinogen receptor blockers.

• Allergy
• Active/recent bleeding within the past 30 days (e.g., gastric ulcers, intracranial bleeding)
• Major surgery/severe trauma within the past 30 days
• Severe hypertension
• Aortic dissection
• Thrombocytopenia

We list the most important contraindications. The selection is not exhaustive.