Platelet Modifying Agents (FETT)

Blood products and modifiers.

ASPIRIN

CLOPIDOGREL

Acetylsalicylic acid (ASA, aspirin)

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

• 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

• Acute myocardial infarction

• Acute ischemic stroke [4]

• Angina (stable and unstable)

• Secondary prevention of CVD

• Primary prevention of CVD 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.

• 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

• Febrile illness in individuals < 19 years of age

• Acute gout attack

Aspirin-exacerbated respiratory disease (AERD)

Reye syndrome

• 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)

• 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]

P2Y12 receptor antagonist

• 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.)

• 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

• 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

• Allergic reactions (rash, pruritus, anaphylaxis)

• Hemorrhage

• Gastrointestinal upset

• Possibly TTP

• Ticlopidine: neutropenia/agranulocytosis

• 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