Dual role of collagen in factor XII-dependent thrombus formation.
In vivo mouse models have indicated that the intrinsic coagulation pathway, initiated by factor XII, contributes to thrombus formation in response to major vascular damage. Here, we show that fibrillar type I collagen provoked a dose-dependent shortening of the clotting time of human plasma via activation of factor XII. This activation was mediated by factor XII binding to collagen. Factor XII activation also contributed to the stimulating effect of collagen on thrombin generation in plasma, and increased the effect of platelets via glycoprotein VI activation. Furthermore, in flow-dependent thrombus formation under coagulant conditions, collagen promoted the appearance of phosphatidylserine-exposing platelets and the formation of fibrin. Defective glycoprotein VI signaling (with platelets deficient in LAT or phospholipase Cgamma2) delayed and suppressed phosphatidylserine exposure and thrombus formation. Markedly, these processes were also suppressed by absence of factor XII or XI, whereas blocking of tissue factor/factor VIIa was of little effect. Together, these results point to a dual role of collagen in thrombus formation: stimulation of glycoprotein VI signaling via LAT and PLCgamma2 to form procoagulant platelets; and activation of factor XII to stimulate thrombin generation and potentiate the formation of platelet-fibrin thrombi.
van der Meijden
Paola E J
PE
Department of Biochemistry, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, The Netherlands.
Munnix
Imke C A
IC
Auger
Jocelyn M
JM
Govers-Riemslag
José W P
JW
Cosemans
Judith M E M
JM
Kuijpers
Marijke J E
MJ
Spronk
Henri M
HM
Watson
Steve P
SP
Renné
Thomas
T
Heemskerk
Johan W M
JW
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism / Q000502:physiology; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects / Q000235:genetics; D001780:Blood Coagulation Tests; D003094:Collagen / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D005174:Factor XII / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051966:Phospholipase C gamma / Q000378:metabolism / Q000502:physiology; D010750:Phosphoproteins / Q000378:metabolism / Q000502:physiology; D011485:Protein Binding; D013917:Thrombin / Q000378:metabolism; D013927:Thrombosis / Q000209:etiology*
D048868:Adaptor Proteins, Signal Transducing; C491734:Lat protein, mouse; D008565:Membrane Proteins; D010750:Phosphoproteins; D005174:Factor XII; D003094:Collagen; D051966:Phospholipase C gamma; D013917:Thrombin