Coated platelets function in platelet-dependent fibrin formation via integrin αIIbβ3 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

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Coated platelets, formed by collagen and thrombin activation, have been characterized in different ways: i) by the formation of a protein coat of α-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 αIIbb3 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 αIIbb3. Markedly, in thrombi from mice deficient in transglutaminase factor XIII, platelet-driven fibrin formation and Rhod- A14 binding were abolished by blockage of integrin αIIbβ3. Vice versa, star-like fibrin formation from platelets of a patient with deficiency in αIIbβ3 (Glanzmann thrombasthenia) was abolished upon blockage of transglutaminase activity. We conclude that coated platelets, with initial αIIbβ3 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 αIIbβ3.

Original languageEnglish (US)
Pages (from-to)427-436
Number of pages10
JournalHaematologica
Volume101
Issue number4
DOIs
StatePublished - Mar 31 2016

ASJC Scopus subject areas

  • Hematology

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    Mattheij, N. J. A., Swieringa, F., Mastenbroek, T. G., Berny-Lang, M. A., May, F., Baaten, C. C. F. M. J., van der Meijden, P. E. J., Henskens, Y. M. C., Beckers, E. A. M., Suylen, D. P. L., Nolte, M. W., Hackeng, T. M., McCarty, O. J. T., Heemskerk, J. W. M., & Cosemans, J. M. E. M. (2016). Coated platelets function in platelet-dependent fibrin formation via integrin αIIbβ3 and transglutaminase factor XIII. Haematologica, 101(4), 427-436. https://doi.org/10.3324/haematol.2015.131441