Physiology

In the presence of vascular injury, exposed basement membrane and collagen GP Ia on Plts binds to collagen, and VWF links collagen to GP Ib. Remaining endothelial cells secrete PGI₂ in an attempt to inhibit thrombosis (as they typically do). Following these binding events, plts degranulate and release ADP, 5-HT, and TXA₂ which activates other plts, and the 5-HT and TXA₂ also induce vasoconstriction to decrease blood flow to the area in an attempt to decrease hemorrhage and close the injury. Circulating thrombin can also activate plts via PAR-1 receptors. Following large-scale plt activation, which includes inducing conformation changes in the GP IIb/IIIa receptor, plts bind to fibrinogen via the GP IIb/IIIa, cross-linking the plts, and then the plts contract to irreversibly fuse the plt plug. Fibrin (from the coagulation cascade) then stabilizes and anchors the plt plug.

Drug Classes

COX-1 Inhibitors

MOA

ASA is the prototypical COX-1 inhibitor, which acts by irreversibly inhibiting COX-1 in the plts, inhibiting the formation of TXA₂ , which then helps to decrease plt activation. COX-1 specific inhibition does not significantly impact PGI₂ (prostacyclin) production in the vascular endothelia, which is one of the predominant anti-aggregation signaling molecules in plasma.

SEs

• Upper GI bleeding
• ASA overdose (commonly w/ > 150 mg/kg, and > 500 mg/kg can be fatal)
  • N / V / D / Fever / Coma / SIG Acidosis and Resp. Alkalosis

ADP Receptor Inhibitors

MOA

Both P2Y1 (Gq coupled) and P2Y12 (Gi coupled) must be activated to activate plts. Activation leads to GP IIb/IIIa conformation change.

Drugs

• All target P2Y12 directly except Cilostazol
• Clopidogrel (Plavix)
  • Prodrug
  • Irreversible binding
• Prasugrel (Effient)
  • Prodrug
  • Irreversible binding
• Ticlopidine (Ticlid)
  • Prodrug
  • Irreversible binding
  • May induce TTP
• Cangrelor (Kengreal)
  • Reversible binding
• Ticagrelor (Brilinta)
  • Reversible, allosteric antagonist
• Cilostazole
  • Inhibition of PDEIII intracellularly, mimicking the effects of P2Y12 blockade (blocking the inactivation of cAMP causing increased intracellular cAMP)
  • Often given in combination with dipyridamole, which inhibits adenosine reuptake and inhibits adenosine breakdown, both of which increase cAMP

GP IIb/IIIa Inhibitors

MOA

Binds GP IIb/IIIa receptor in place of fibrinogen, which therefore prevents plt cross-linking

Drugs

• Abciximab (ReoPro)
  • Ig against human GP IIb/IIIa
• Eptifibitide (Integrilin)
  • Reversible inhibitor
• Tirofiban (Aggrastat)
  • Reversible inhibitor

Protease Activated Receptor Inhibitors

MOA

Activated thrombin activates plts through the PAR receptor, and vorapaxar induces clevage of PAR-1

Drugs

• Vorapaxar (Zontivity)