Platelet heterogeneity in activation-induced glycoprotein shedding: functional effects

Blood Advances
Constance C F M J BaatenJohan W M Heemskerk

Abstract

The platelet receptors glycoprotein Ibα (GPIbα) 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 GPIbα was abolished by ADAM10/17 inhibition but not by blockage of calpain. Stimulation of PKC induced shedding of only GPIbα, 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 f...Continue Reading

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Citations

Mar 21, 2020·Frontiers in Cardiovascular Medicine·Emily C Reddy, Margaret L Rand
Jul 15, 2020·International Journal of Molecular Sciences·Elena MasselliGiuliana Gobbi
Mar 3, 2020·Frontiers in Immunology·Stefanie MaurerKorbinian N Kropp
Feb 23, 2020·Frontiers in Immunology·Samantha J MontagueElizabeth E Gardiner
Dec 5, 2019·Blood·Frederik DenormeRobert A Campbell
Oct 18, 2020·International Journal of Molecular Sciences·Patrizia AmadioSilvia Stella Barbieri
Jan 6, 2021·Cytometry. Part a : the Journal of the International Society for Analytical Cytology·Benjamin E J SpurgeonAndrew L Frelinger
Jan 26, 2021·Frontiers in Cardiovascular Medicine·Jiayu WuConstance C F M J Baaten
May 6, 2021·Current Protocols·Benjamin E J SpurgeonAndrew L Frelinger
Jul 9, 2021·Frontiers in Cardiovascular Medicine·Gaukhar BaidildinovaPaola E J van der Meijden
Sep 10, 2021·Arteriosclerosis, Thrombosis, and Vascular Biology·Gina PerrellaJohan W M Heemskerk

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