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In vivo anticoagulant properties of a novel nucleotide-based thrombin
inhibitor and demonstration of regional anticoagulation in extracorporeal
circuits
LC Griffin, GF Tidmarsh, LC Bock, JJ Toole and LL Leung
Gilead Sciences Inc., Foster City, CA 94404.
Using a novel in vitro selection/amplification technique, we have recently
identified a new class of thrombin inhibitors based on single- stranded DNA
oligonucleotides. One oligonucleotide, GGTTGGTGTGGTTGG (thrombin, aptamer),
showed potent anticoagulant activity in vitro. We have initiated
pharmacologic studies in cynomolgus monkeys to study the thrombin aptamer's
in vivo anticoagulant properties. Upon infusion of the thrombin aptamer,
anticoagulation was rapidly achieved, with a plateau reached within 10
minutes. There was a linear dose-response relationship between thrombin
aptamer infusion rate and prolongation of plasma prothrombin time. Ten
minutes after the infusion was stopped, no prolongation of prothrombin time
was observed, indicating that the thrombin aptamer has an extremely short
in vivo half-life, estimated to be 108 +/- 14 seconds. In addition,
inhibition of thrombin-induced platelet aggregation in platelet-rich plasma
was observed ex vivo without an effect on collagen-induced aggregation,
indicating that the inhibition was specific for thrombin and not due to a
nonspecific inhibitory effect on platelets. To exploit the short in vivo
half-life of the thrombin aptamer, its ability to achieve regional
anticoagulation in an extracorporeal hemofiltration circuit in sheep was
tested. Doubling of the prothrombin time in the circuit was observed,
whereas the systemic prothrombin time was minimally prolonged. We conclude
that the thrombin aptamer is a potent anticoagulant in vivo, and
specifically inhibits thrombin-induced platelet aggregation ex vivo. The
rapid onset of action and short half- life in vivo suggest that the
thrombin aptamer may be useful in anticoagulation with extracorporeal
circuits and may have distinct advantages in certain acute clinical
settings.
Volume 81,
Issue 12,
pp. 3271-3276,
06/15/1993
Copyright © 1993 by The American Society of Hematology
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