Release of ADP or PAR4 Activation is Required to Sustain Thrombin-induced Platelet Aggregation
(English)Manuscript (preprint) (Other academic)
Thrombin activates human platelets through cleavage of two G-protein-coupled proteaseactivatedreceptors (PARs) denoted PAR1 and PAR4. The aim of this study was to investigatedifferences in PAR1 and PAR4 signaling regarding formation and stability of plateletaggregates. We show that weak PAR1-mediated aggregation is reversible, whereas PAR4-mediated aggregation, weak or strong, is always sustained. PAR1-induced plateletaggregation is decreased and more reversible in the presence of the P2Y12 antagonistcangrelor. However, the effects by cangrelor can be concentration-dependently reversed byconcomitant PAR4 activation in a PI3-kinase-dependent manner. In contrast; in PAR4-APstimulated platelets, aggregation is reduced by cangrelor or inhibition of PI3-kinase byLY294002 but remains irreversible. However, a combined inhibition of PI3-K and P2Y12results in reduced and reversible aggregation. In the light of recently published data on PAR1desensitization, we suggest that the physiological role of the differences between PAR1 andPAR4 activation on aggregate and clot stability could be to fine-tune the response tothrombin. A repeated or continuous very low thrombin generation will desensitize PAR1 andeven if small platelet aggregates are formed they will dissolve, preventing inappropriatethrombus formation. At higher concentrations of thrombin, PAR4 will become activatedabrogating desensitization of PAR1 and enforcing stability of platelet aggregates.
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-71394OAI: oai:DiVA.org:liu-71394DiVA: diva2:448088