Recombinant lipoprotein-associated coagulation inhibitor inhibits tissue thromboplastin-induced intravascular coagulation in the rabbit.
Lipoprotein-associated coagulation inhibitor produces feed-back inhibition of tissue factor (tissue thromboplastin)-induced coagulation in the presence of factor Xa Recombinant lipoprotein-associated coagulation inhibitor (rLACI) was tested for its ability to modify thromboplastin-induced intravascular coagulation in a rabbit model that allows monitoring of iodine-125 fibrin accumulation/disappearance in the lung and sampling of blood for the measurement of coagulation parameters. Infusion of thromboplastin into the rabbit caused a rapid increase of radioactivity over the lungs, possibly due to the accumulation of 125I fibrin in the lungs, followed by a rapid decline of radioactivity, suggestive of removal of fibrin from the lungs. Thromboplastin also caused a rapid decrease of systemic fibrinogen that was accompanied by a lengthening of the activated partial thromboplastin time and prothrombin time. The effect of coinfusion of rLACI with thromboplastin or bolus injection of rLACI before thromboplastin infusion was studied. At a high dose of rLACI (800 micrograms/kg body weight), the thromboplastin-induced radioactivity increase in the lungs and the systemic fibrinogen decrease were completely suppressed. The activated partial thromboplastin time and prothrombin time of the plasma samples lengthened, possibly due to the presence of thromboplastin in circulation. The thromboplastin-induced radioactivity increase over the lungs was not completely suppressed by lower doses of rLACI (135 to 270 micrograms/kg body weight), but these doses of rLACI prevented systemic fibrinogen decrease. At a bolus dose of 23 micrograms/kg body weight, rLACI provided 50% protection of the fibrinogen consumption (fibrinogen decreased to 82% compared with 65% in rabbits treated with thromboplastin alone). These results show that rLACI is effective in the inhibition of thromboplastin-induced coagulation in vivo.
Monsanto Corporate Research, Chesterfield, MO 63198.
K C
KC
Day
L C
LC
Hoffman
M O
MO
Palmier
K K
KK
Kretzmer
M D
MD
Huang
E Y
EY
Pyla
E
E
Spokas
G J
GJ
Broze
T G
TG
Warren
T C
TC
Wun
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D001778:Blood Coagulation Disorders / Q000139:chemically induced / Q000517:prevention & control*; D005167:Factor VII / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D008074:Lipoproteins / Q000627:therapeutic use*; D010314:Partial Thromboplastin Time; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011517:Prothrombin Time; D011817:Rabbits; D011994:Recombinant Proteins / Q000627:therapeutic use; D013925:Thromboplastin / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000627:therapeutic use
D008074:Lipoproteins; D011480:Protease Inhibitors; D011994:Recombinant Proteins; C051928:lipoprotein-associated coagulation inhibitor; D005167:Factor VII; D005340:Fibrinogen; D013925:Thromboplastin