Pharmacodynamic Properties of Antiplatelet Agents

Current Knowledge and Future Perspectives

Kallirroi I Kalantzi; Maria E Tsoumani; Ioannis A Goudevenos; Alexandros D Tselepis


Expert Rev Clin Pharmacol. 2012;5(3):319-336. 

In This Article

Novel Antiplatelet Agents

vWF plays a key role in platelet adhesion and aggregation, especially under high shear conditions. vWF binds to GPIbα of the GPIbα–GPIX–GPV receptor complex of the platelet surface.[123] Collagen is also a potent platelet agonist inducing platelet adhesion and aggregation. GPVI is a major receptor of collagen on the platelet surface that mediates the initial platelet contacting with collagen, thus leading to platelet adhesion, aggregation and thrombosis.[124] Consequently, the interaction of platelets with vWF and collagen may represent an attractive prospective target for developing novel antiplatelet agents.

Promising data have been obtained with the use of antibodies targeting vWF itself or its binding receptor GPIbα on platelets. These vWF antagonists can effectively inhibit thrombosis, specifically in the setting of ACS, and result in fewer systemic hemorrhages.

AJW200 is an IgG4 humanized monoclonal antibody that specifically inhibits high shear stress-induced platelet aggregation, while it does not affect platelet aggregation under low shear stress conditions.[125] 82D6A3, a monoclonal antibody of the collagen-binding A-3 domain of vWF, inhibits vWF binding to collagen.[126] ALX-0081 and ALX-0681 are bivalent humanized nanobodies targeting the GPIbα binding domain of vWF that also inhibit platelet adhesion to vWF.[127,128] Aptamers are oligonucleotides with drug-like properties and similar characteristics to monoclonal antibodies. ARC1779 is a second-generation nuclease-resistant aptamer that binds to the activated vWF A1 domain. ARC1779 inhibits vWF-dependent platelet aggregation by preventing the formation of the vWF–GPIbα complex.[129,130] It also reduces platelet adhesion to collagen-coated matrices and platelet thrombus formation.[131] ARC15105 is a chemically advanced aptamer with an assumed higher affinity to vWF. ARC15105 is a more potent but less specific inhibitor of vWF-dependent platelet aggregation than ARC1779.[131]

Antibodies targeting GPIba include h6B4-Fab, GPG-290 and SZ2. h6B4-Fab, a murine monoclonal antibody targeting GPIbα, inhibits platelet adhesion by competing with vWF for binding to GPIba under high shear conditions.[132] GPG-290 is a novel recombinant chimeric protein containing the N-terminal 290 amino acids of GPIbα linked to human IgG1 Fc, which inhibits vWF–GPIbα interaction.[133] SZ2 is a monoclonal antibody against GPIba that prevents platelet adhesion to vWF under high shear stress.[134]

Monoclonal antibodies that inhibit collagen–GPVI interactions have been also developed. They potently inhibit platelet adhesion and aggregation.[135] Furthermore, GPVI has been the target for new antiplatelet agents.[136–138] Anti-GPVI antibodies, such as the monoclonal antibody JAQ1, can significantly prevent thrombosis with a little prolonged bleeding time.[139] Further studies in vitro as well in animal models in vivo are necessary to completely elucidate the pharmacokinetic and pharmacodynamic profile of the above agents before their clinical evaluation.


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