Prevention of microvascular thrombosis by topical application of recombinant tissue factor pathway inhibitor.
Tissue factor pathway inhibitor is a naturally occurring protein inhibitor of factor X and the tissue factor-factor VII complex of the extrinsic pathway of coagulation. The potential of tissue factor pathway inhibitor as a topical antithrombotic agent was evaluated in a rabbit model of thrombosis that combined intimal injury, anastomosis, and a twisted pedicle. In 207 rabbit ears, a near-complete amputation was performed, preserving the central ear artery and vein. The central ear artery was transected, the intima was removed mechanically over a 1-cm length, the artery was anastomosed, and the ear was twisted 360 degrees, wrapping the intact vein around the artery. Before recirculation, the lumen was irrigated on a blinded, randomized basis with either hirudin (100 or 500 units/ml), heparin (50 or 100 units/ml), tissue factor pathway inhibitor (10, 40, 125, or 250 microgram/ml), heparin and tissue factor pathway inhibitor together, or vehicle (control). Upon arterial reflow, the ears were observed for 7 days. Patency rates after 7 days were as follows: hirudin, 30 and 55 percent; heparin, 43 and 50 percent; tissue factor pathway inhibitor, 75 and 90 percent; heparin and tissue factor pathway inhibitor, 75 percent; and vehicle, 6 percent. The higher concentrations of tissue factor pathway inhibitor led to significantly higher patency rates than heparin, hirudin, or control solutions. Electron microscopic evaluation of specimens irrigated with gold- labeled tissue factor pathway inhibitor revealed the inhibitor bound to the injured intimal surface for at least 3 days postoperatively. Coagulation studies showed no change in the clotting profile upon intravascular infusion with tissue factor pathway inhibitor even at the highest dose used topically. We conclude that tissue factor pathway inhibitor is a more effective topical antithrombotic agent than either heparin or hirudin.
Lantieri
L A
LA
Division of Plastic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Mo., USA.
Ozbek
M R
MR
Deune
E G
EG
Ornberg
R L
RL
Brown
D M
DM
Chung
S H
SH
Wun
T C
TC
Cooley
B C
BC
Khouri
R K
RK
D000287:Administration, Topical; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000991:Antithrombins / Q000008:administration & dosage; D001777:Blood Coagulation / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006493:Heparin / Q000008:administration & dosage; D006629:Hirudins / Q000008:administration & dosage; D008074:Lipoproteins / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008833:Microcirculation / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013927:Thrombosis / Q000097:blood / Q000378:metabolism / Q000517:prevention & control*; D014654:Vascular Patency / Q000187:drug effects
D000925:Anticoagulants; D000991:Antithrombins; D006629:Hirudins; D008074:Lipoproteins; D011994:Recombinant Proteins; C051928:lipoprotein-associated coagulation inhibitor; D006493:Heparin