Platelet heterogeneity in activation-induced glycoprotein shedding: functional effects

Constance C. F. M. J. Baaten, Frauke Swieringa, Tomasz Misztal, Tom G. Mastenbroek, Marion A. H. Feijge, Paul E. Bock, Marjo M. P. C. Donners, Peter W. Collins, Renhao Li, Paola E. J. van der Meijden, Johan W. M. Heemskerk*

*Corresponding author for this work

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Abstract

The platelet receptors glycoprotein Ib alpha (GPIb alpha) and GPVI are known to be cleaved by members of a disintegrin and metalloprotease (ADAM) family (ADAM10 and ADAM17), but the mechanisms and consequences of this shedding are not well understood. Our results revealed that (1) glycoprotein shedding is confined to distinct platelet populations showing near-complete shedding, (2) the heterogeneity between (non) shed platelets is independent of agonist type but coincides with exposure of phosphatidylserine (PS), and (3) distinct pathways of shedding are induced by elevated Ca2+, low Ca2+ protein kinase C (PKC), or apoptotic activation. Furthermore, we found that receptor shedding reduces binding of von Willebrand factor, enhances binding of coagulation factors, and augments fibrin formation. In response to Ca2+-increasing agents, shedding of GPIba was abolished by ADAM10/17 inhibition but not by blockage of calpain. Stimulation of PKC induced shedding of only GPIba, which was annulled by kinase inhibition. The proapoptotic agent ABT-737 induced shedding, which was caspase dependent. In Scott syndrome platelets that are deficient in Ca2+-dependent PS exposure, shedding occurred normally, indicating that PS exposure is not a prerequisite for ADAM activity. In whole-blood thrombus formation, ADAM-dependent glycoprotein shedding enhanced thrombin generation and fibrin formation. Together, these findings indicate that 2 major activation pathways can evoke ADAM-mediated glycoprotein shedding in distinct platelet populations and that shedding modulates platelet function from less adhesive to more procoagulant.
Original languageEnglish
Pages (from-to)2320-2331
Number of pages12
JournalBlood advances
Volume2
Issue number18
DOIs
Publication statusPublished - 25 Sep 2018

Keywords

  • THROMBUS FORMATION
  • PHOSPHATIDYLSERINE EXPOSURE
  • HEMOSTATIC FUNCTION
  • SCOTT SYNDROME
  • IN-VIVO
  • ADAM17
  • FIBRIN
  • CLEAVAGE
  • METALLOPROTEINASE
  • MECHANISM

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