Anticoagulant and antithrombotic properties of platelet protease nexin-1.
Protease nexin-1 (PN-1) is a serpin that inhibits plasminogen activators, plasmin, and thrombin. PN-1 is barely detectable in plasma but is expressed by platelets. Here, we studied platelet PN-1 in resting and activated conditions and its function in thrombosis. Studies on human platelets from healthy donors and from patients with a Gray platelet syndrome demonstrate that PN-1 is present both at the platelet surface and in alpha-granules. The role of PN-1 was investigated in vitro using human platelets incubated with a blocking antibody and using platelets from PN-1-deficient mice. Both approaches indicate that platelet PN-1 is active on thrombin and urokinase-type plasminogen activator. Blockade and deficiency of platelet PN-1 result in accelerated and increased tissue factor-induced thrombin generation as indicated by calibrated automated thrombography. Moreover, platelets from PN-1-deficient mice respond to subthreshold doses of thrombin, as assessed by P-selectin expression and platelet aggregation. Thrombus formation, induced ex vivo by collagen in blood flow conditions and in vivo by FeCl(3)-induced injury, is significantly increased in PN-1-deficient mice, demonstrating the antithrombotic properties of platelet PN-1. Platelet PN-1 is thus a key player in the thrombotic process, whose negative regulatory role has been, up to now, markedly underestimated.
Boulaftali
Yacine
Y
Inserm, U698, Université Paris 7, Paris, France.
Adam
Frédéric
F
Venisse
Laurence
L
Ollivier
Véronique
V
Richard
Benjamin
B
Taieb
Sabrina
S
Monard
Denis
D
Favier
Rémi
R
Alessi
Marie-Christine
MC
Bryckaert
Marijke
M
Arocas
Véronique
V
Jandrot-Perrus
Martine
M
Bouton
Marie-Christine
MC
D000328:Adult; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D000925:Anticoagulants / Q000378:metabolism*; D000991:Antithrombins / Q000378:metabolism*; D001775:Blood Circulation / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D001808:Blood Vessels / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D003094:Collagen / Q000494:pharmacology; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D051379:Mice; D010974:Platelet Aggregation / Q000187:drug effects; D053657:Platelet-Rich Plasma / Q000378:metabolism; D058255:Protease Nexins; D011956:Receptors, Cell Surface / Q000378:metabolism*; D058258:Serpin E2; D013917:Thrombin / Q000037:antagonists & inhibitors; D013925:Thromboplastin / Q000378:metabolism; D013927:Thrombosis / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors
D016564:Amyloid beta-Protein Precursor; D000925:Anticoagulants; D000991:Antithrombins; D006025:Glycosaminoglycans; D058255:Protease Nexins; D011956:Receptors, Cell Surface; C545486:SERPINE2 protein, human; D058258:Serpin E2; D003094:Collagen; D013925:Thromboplastin; D013917:Thrombin; D014568:Urokinase-Type Plasminogen Activator