on August 30, 2007
Published online before print August 30, 2007, doi: 10.1161/ATVBAHA.107.151100
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on February 23, 2007
Accepted on July 22, 2007
Segregation of Platelet Aggregatory and Procoagulant Microdomains in Thrombus Formation. Regulation by Transient Integrin Activation
Imke C.A. Munnix ;
From the Departments of Biochemistry and Biophysics (I.C.A.M., J.J.E.K., C.M.L.G.D.T., M.A.M.v.Z., J.R., P.E.B., J.W.M.H.), CARIM, Maastricht University, The Netherlands; the Centre for Cardiovascular Sciences (J.A., S.P.W.), University of Birmingham, United Kingdom; and the Department of Pathology (P.P., P.E.B.), Vanderbilt University School of Medicine, Nashville, Tenn.
* To whom correspondence should be addressed. E-mail: jwm.heemskerk{at}bioch.unimaas.nl.
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 during thrombus formation under flow, fibrin(ogen)-binding platelets assembled into separate aggregates, whereas distinct patches of nonaggregated platelets formed, exposing phosphatidylserine. The latter platelet population had inactivated 
IIb
3 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 IIb3.
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.
Key words: aggregation • coagulation • microdomains • platelets • integrin activation
This article has been cited by other articles:
 |
|
 |
|
  P. E. J. van der Meijden, I. C. A. Munnix, J. M. Auger, J. W. P. Govers-Riemslag, J. M. E. M. Cosemans, M. J. E. Kuijpers, H. M. Spronk, S. P. Watson, T. Renne, and J. W. M. Heemskerk Dual role of collagen in factor XII-dependent thrombus formation Blood, July 23, 2009; 114(4): 881 - 890. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Bergmeier, M. Oh-hora, C.-A. McCarl, R. C. Roden, P. F. Bray, and S. Feske R93W mutation in Orai1 causes impaired calcium influx in platelets Blood, January 15, 2009; 113(3): 675 - 678. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Jobe, K. M. Wilson, L. Leo, A. Raimondi, J. D. Molkentin, S. R. Lentz, and J. Di Paola Critical role for the mitochondrial permeability transition pore and cyclophilin D in platelet activation and thrombosis Blood, February 1, 2008; 111(3): 1257 - 1265. [Abstract] [Full Text] [PDF]
|
|