Coated platelets function in platelet-dependent fibrin formation via integrin alpha(IIb)beta(3) and transglutaminase factor XIII

Nadine J. A. Mattheij, Frauke Swieringa, Tom G. Mastenbroek, Michelle A. Berny-Lang, Frauke May, Constance C. F. M. J. Baaten, Paola E. J. van der Meijden, Yvonne M. C. Henskens, Erik A. M. Beckers, Dennis P. L. Suylen, Marc W. Nolte, Tilman M. Hackeng, Owen J. T. McCarty, Johan W. M. Heemskerk, Judith M. E. M. Cosemans*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

44 Citations (Web of Science)

Abstract

Coated platelets, formed by collagen and thrombin activation, have been characterized in different ways: i) by the formation of a protein coat of alpha-granular proteins; ii) by exposure of procoagulant phosphatidylserine; or iii) by high fibrinogen binding. Yet, their functional role has remained unclear. Here we used a novel transglutaminase probe, Rhod-A14, to identify a subpopulation of platelets with a cross-linked protein coat, and compared this with other platelet subpopulations using a panel of functional assays. Platelet stimulation with convulxin/thrombin resulted in initial integrin alpha(IIb)beta(3) activation, the appearance of a platelet population with high fibrinogen binding, (independently of active integrins, but dependent on the presence of thrombin) followed by phosphatidylserine exposure and binding of coagulation factors Va and Xa. A subpopulation of phosphatidylserine-exposing platelets bound Rhod-A14 both in suspension and in thrombi generated on a collagen surface. In suspension, high fibrinogen and Rhod-A14 binding were antagonized by combined inhibition of transglutaminase activity and integrin alpha(IIb)beta(3). Markedly, in thrombi from mice deficient in transglutaminase factor XIII, platelet-driven fibrin formation and Rhod-A14 binding were abolished by blockage of integrin alpha(IIb)beta(3). Vice versa, star-like fibrin formation from platelets of a patient with deficiency in alpha(IIb)beta(3) (Glanzmann thrombasthenia) was abolished upon blockage of transglutaminase activity. We conclude that coated platelets, with initial alpha(IIb)beta(3) activation and high fibrinogen binding, form a subpopulation of phosphatidylserine-exposing platelets, and function in platelet-dependent star-like fibrin fiber formation via transglutaminase factor XIII and integrin alpha(IIb)beta(3).
Original languageEnglish
Pages (from-to)427-436
JournalHaematologica-the Hematology Journal
Volume101
Issue number4
DOIs
Publication statusPublished - Apr 2016

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