Kininogens are antithrombotic proteins In vivo.
Kininogens have recently been shown to possess antiadhesive, anticoagulant, and profibrinolytic properties and can inhibit platelet activation at low thrombin concentrations. To test whether kininogens have antithrombotic properties in vivo, we devised a model of limited arterial injury confined to removal of the endothelium. Brown-Norway Katholiek strain rats with an absence of low- and high-molecular-weight kininogen due to a single point mutation, A163T, were compared in the thrombosis model to the wild-type animals, which were otherwise genetically identical. Despite an equivalent vascular injury, the mean time (+/-SEM) for a 90% decrease in flow measured by laser Doppler was 38.4+/-17 minutes in the kininogen-deficient rats compared with 194+/-29 minutes in the wild-type animals (P<0.002). The degree of vascular injury was the same. No evidence for disseminated intravascular coagulation (decrease in factor V, antithrombin, or fibrinogen) or excessive fibrinolysis (elevation of fibrinogen degradation products) was found in either group of animals. The results suggest that kininogens have antithrombotic properties at low concentrations of thrombin and that inhibitory peptides derived from kininogen may constitute a new antithrombotic strategy.
Colman
R W
RW
Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pa 19140. colmanr@astro.temple.edu
White
J V
JV
Scovell
S
S
Stadnicki
A
A
Sartor
R B
RB
D000818:Animals; D001011:Aorta / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000502:physiology*; D005260:Female; D005337:Fibrin / Q000378:metabolism; D007704:Kininogens / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017078:Laser-Doppler Flowmetry; D008297:Male; D008970:Molecular Weight; D017354:Point Mutation; D051381:Rats; D011914:Rats, Inbred BN; D012016:Reference Values; D012039:Regional Blood Flow; D013927:Thrombosis / Q000517:prevention & control*; D017539:Tunica Intima / Q000293:injuries / Q000378:metabolism; D014947:Wounds and Injuries / Q000503:physiopathology
D015853:Cysteine Proteinase Inhibitors; D007704:Kininogens; D005337:Fibrin