Segregation of Platelet Aggregatory and Procoagulant Microdomains in Thrombus Formation: Regulation by Transient Integrin Activation

OBJECTIVE—Platelets play a dual role in thrombosis by forming aggregates and stimulating coagulation. We investigated the commitment of platelets to these separate functions during collagen-induced thrombus formation in vitro and in vivo. METHODS AND RESULTS—High-resolution 2-photon fluorescence mic...

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Published in:	Arteriosclerosis, thrombosis, and vascular biology Vol. 27; no. 11; pp. 2484 - 2490
Main Authors:	Munnix, Imke C.A, Kuijpers, Marijke J.E, Auger, Jocelyn, Thomassen, Christella M.L.G.D, Panizzi, Peter, van Zandvoort, Marc A.M, Rosing, Jan, Bock, Paul E, Watson, Steve P, Heemskerk, Johan W.M
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA American Heart Association, Inc 01-11-2007 Hagerstown, MD Lippincott
Subjects:	Animals Atherosclerosis (general aspects, experimental research) Biological and medical sciences Blood and lymphatic vessels Blood Coagulation - physiology Blood coagulation. Blood cells Blood Platelets - cytology Blood Platelets - physiology Blood vessels and receptors Cardiology. Vascular system Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous Fundamental and applied biological sciences. Psychology Hemorheology Humans Medical sciences Mice Microscopy, Fluorescence Molecular and cellular biology Platelet Platelet Aggregation - physiology Platelet Glycoprotein GPIIb-IIIa Complex - physiology Thrombosis - metabolism Vertebrates: cardiovascular system Vascular disease Aggregation microdomains Platelet Integrin integrin activation Atherosclerosis Cardiovascular disease coagulation platelets
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Summary:	OBJECTIVE—Platelets play a dual role in thrombosis by forming aggregates and stimulating coagulation. We investigated the commitment of platelets to these separate functions during collagen-induced thrombus formation in vitro and in vivo. METHODS AND RESULTS—High-resolution 2-photon fluorescence microscopy revealed that in thrombus formation under flow, fibrin(ogen)-binding platelets assembled into separate aggregates, whereas distinct patches of nonaggregated platelets exposed phosphatidylserine. The latter platelet population had inactivated αIIbβ3 integrins and displayed increased binding of coagulation factors. Coated platelets, expressing serotonin binding sites, were not identified as a separate population. Thrombin generation and coagulation favored the transformation to phosphatidylserine-exposing platelets with inactivated integrins and reduced adhesion. Prolonged tyrosine phosphorylation in vitro resulted in secondary downregulation of active αIIbβ3. CONCLUSIONS—These results lead to a new spatial model of thrombus formation, in which aggregated platelets ensure thrombus stability, whereas distinct patches of nonaggregated platelets effectuate procoagulant activity and generate thrombin and fibrin. Herein, the hemostatic activity of a developing thrombus is determined by the balance in formation of proaggregatory and procoagulant platelets. This balance is influenced by antiplatelet and anticoagulant medication.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1079-5642 1524-4636
DOI:	10.1161/ATVBAHA.107.151100