Figure 5 now looks at the whole cascade in a little more detail from the platelet coagulation point of view, in order to understand exactly how the different treatment modalities that can modulate atherothrombosis work to block specific steps along the pathway.

Vascular injury on the arterial side usually involves plaque disruption.  That plaque disruption exposes collagen and von Willebrand factor, and platelets adhere to these proteins and become activated.  The activated platelets synthesize and release thromboxane A₂ (TXA₂) and adenosine diphosphate (ADP), and these act as agonists in the local platelet environment to recruit additional platelets and to activate them.  

TXA₂ synthesis involves cyclooxygenase 1 (COX-1), which is the target of aspirin, of course.  Aspirin irreversibly acetylates COX-1 and blocks this pathway.  TXA₂ synthesis is attenuated, and with reduced TXA₂ synthesis and release, platelet activation and aggregation is reduced.  ADP is stored within the platelet; when platelets are activated, they release ADP; the thienopyridines (ticlopidine, clopidogrel, and prasugrel) work at the level of the ADP receptor (P2Y12) on the platelets and block that receptor.

The thienopyridines produce irreversible inhibition of P2Y12, whereas ticagrelor, a newer ADP receptor antagonist, inhibits this ADP receptor in a reversible fashion.  The net result is not that ADP secretion is reduced but rather that ADP cannot find its target because the ADP receptor on adjacent platelets is blocked, which also attenuates platelet activation and aggregation.  

Once platelets are activated there is a conformational change that occurs in glycoprotein (GP) IIb/IIIa, the most abundant receptor on the platelet surface and the receptor that mediates platelet-to-platelet bridging by binding fibrinogen or von Willebrand factor, thus bridging adjacent platelets together and causing them to aggregate.  We can block this process by using inhibitors of the GP IIb/IIIa receptor; these inhibitors include the antibody abciximab and the small-molecule inhibitors, eptifibatide and tirofiban.  By blocking the GP IIb/IIIa receptor, these inhibitors prevent platelet-to-platelet interaction and prevent the aggregation process.

That is what happens on the platelet side.  It should be remembered that plaque disruption also exposes tissue factor, which initiates the whole coagulation pathway shown in Figure 2.  We can block that pathway with anticoagulation agents, and those anticoagulants can either prevent thrombin generation or they can target thrombin directly and block thrombin activity.  

Thrombin can activate the platelets and recruit additional platelets.  As described previously, thrombin activates platelets through PAR1 and as shown in Figure 5, the PAR1 antagonist vorapaxar blocks that receptor and prevents thrombin activation of platelets.  

So in summary, Figure 5 shows the integration between platelet activation / aggregation and coagulation, and these two processes are orchestrated to result in the formation of a platelet–fibrin clot.  Inhibitors and antithrombotic drugs can target specific steps in platelet activation and recruitment; in platelet aggregation; in the formation of thrombin or inhibition of thrombin activity; or they can block the thrombin receptor on the platelets.  As a result, the drugs shown in Figure 5 can be used, alone or in various combinations, to attenuate atherothrombosis.  Weitz JI. Am J Med 2013; published on-line at http://education.amjmed.com/00000.