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.


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 alphaIIb beta3 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 alphaIIb beta3.


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.
Munnix
Imke C A
IC
Department of Biochemistry, Maastricht University, CARIM, Maastricht University, The Netherlands.
Kuijpers
Marijke J E
MJ
Auger
Jocelyn
J
Thomassen
Christella M L G D
CM
Panizzi
Peter
P
van Zandvoort
Marc A M
MA
Rosing
Jan
J
Bock
Paul E
PE
Watson
Steve P
SP
Heemskerk
Johan W M
JW
D000818:Animals; D001777:Blood Coagulation / Q000502:physiology*; D001792:Blood Platelets / Q000166:cytology / Q000502:physiology; D018056:Hemorheology; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence; D010974:Platelet Aggregation / Q000502:physiology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000502:physiology; D013927:Thrombosis / Q000378:metabolism*
D019039:Platelet Glycoprotein GPIIb-IIIa Complex