Using PAR4 Inhibition as an Anti-Thrombotic Approach: Why, How, and When?

Figure 1. Currently available anti-platelet agents (black text) target five distinct platelet proteins: Cyclooxygenase (aspirin), P2Y12 (clopidogrel, prasugrel, ticlopidine, ticagrelor, cangrelor), αIIbβ3 (abciximab, tirofiban, eptifibitide), phosphodiesterase (dipyridamole, cilostazol, triflusal) or PAR1 (vorapaxar). PAR4 is an emerging target for anti-platelet drugs, with a number of different strategies to inhibit the receptor currently being pursued, as indicated (red italicised text).

Figure 2. Top: Increasing platelet activation, moving from resting platelets (unactivated; gray) through to initial shape change (yellow) and ultimately PS-exposing procoagulant platelets (red). Middle: Increasing extent of thrombosis correlates with increasing platelet activation. When a blood vessel gets injured, platelets adhere to the site of injury through the binding of exposed subendothelial proteins in the vasculature and glycoprotein receptors on the platelet. Adhesion triggers initial platelet activation, shape change and release of molecular contents. Following activation, phosphatidylserine is exposed on the platelet surface, and these platelets become procoagulant, resulting in further thrombin generation and platelet activation. Bottom: Effects of blocking PAR1 (early stage platelet activation; purple) versus PAR4 (late stage platelet activation; red). Initial platelet function is driven by low thrombin concentrations and PAR1 activation. Later platelet responses, including procoagulant platelet function, is driven by PAR4. Reproduced with permission from Reference [31].