TY - JOUR
T1 - Coated platelets function in platelet-dependent fibrin formation via integrin alpha(IIb)beta(3) and transglutaminase factor XIII
AU - Mattheij, Nadine J. A.
AU - Swieringa, Frauke
AU - Mastenbroek, Tom G.
AU - Berny-Lang, Michelle A.
AU - May, Frauke
AU - Baaten, Constance C. F. M. J.
AU - van der Meijden, Paola E. J.
AU - Henskens, Yvonne M. C.
AU - Beckers, Erik A. M.
AU - Suylen, Dennis P. L.
AU - Nolte, Marc W.
AU - Hackeng, Tilman M.
AU - McCarty, Owen J. T.
AU - Heemskerk, Johan W. M.
AU - Cosemans, Judith M. E. M.
PY - 2016/4
Y1 - 2016/4
N2 - 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).
AB - 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).
U2 - 10.3324/haematol.2015.131441
DO - 10.3324/haematol.2015.131441
M3 - Article
SN - 0390-6078
VL - 101
SP - 427
EP - 436
JO - Haematologica-the Hematology Journal
JF - Haematologica-the Hematology Journal
IS - 4
ER -