Dual role of collagen in factor XII-dependent thrombus formation

TY - JOUR

T1 - Dual role of collagen in factor XII-dependent thrombus formation

AU - van der Meijden, Paola E J

AU - Munnix, Imke C A

AU - Auger, Jocelyn M

AU - Govers-Riemslag, José W P

AU - Cosemans, Judith M E M

AU - Kuijpers, Marijke J E

AU - Spronk, Henri M

AU - Watson, Steve P

AU - Renné, Thomas

AU - Heemskerk, Johan W M

PY - 2009/7/23

Y1 - 2009/7/23

N2 - 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.

AB - 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.

KW - Adaptor Proteins, Signal Transducing

KW - Animals

KW - Blood Coagulation

KW - Blood Coagulation Tests

KW - Collagen

KW - Factor XII

KW - Humans

KW - Membrane Proteins

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Phospholipase C gamma

KW - Phosphoproteins

KW - Protein Binding

KW - Thrombin

KW - Thrombosis

U2 - 10.1182/blood-2008-07-171066

DO - 10.1182/blood-2008-07-171066

M3 - SCORING: Journal article

C2 - 19372258

VL - 114

SP - 881

EP - 890

JO - BLOOD

JF - BLOOD

SN - 0006-4971

IS - 4

ER -