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A novel nucleotide-based thrombin inhibitor inhibits clot-bound thrombin
and reduces arterial platelet thrombus formation
WX Li, AV Kaplan, GW Grant, JJ Toole and LL Leung
Division of Hematology, Stanford University School of Medicine, CA.
A novel thrombin inhibitor based on single-stranded (ss) deoxynucleotides
with the sequence GGTTGGTGTGGTTGG (thrombin aptamer) has been recently
discovered. In this study, we tested its efficacy in inhibiting clot-bound
thrombin activity and platelet thrombus formation in an ex vivo whole
artery angioplasty model. The thrombin aptamer showed a specific
dose-dependent inhibition of thrombin-induced platelet aggregation (0.5
U/mL) in human platelet-rich plasma, with an IC50 of approximately 70 to 80
nmol/L. In an in vitro clot-bound thrombin assay system, heparin, used at
clinically relevant concentrations of 0.2 U/mL and 0.4 U/mL, was
ineffective in inhibiting clot-bound thrombin (6.5% and 34.9% inhibition at
0.2 U/mL and 0.4 U/mL, respectively). In contrast, the thrombin aptamer at
an equivalent anticoagulant concentration inhibited clot-bound thrombin
(79.7% inhibition). In an ex vivo whole artery angioplasty model, the
thrombin aptamer markedly suppressed the generation of fibrinopeptide A
(FPA), whereas heparin at 2 U/mL was ineffective. Compared with a scrambled
ssDNA control, the thrombin aptamer reduced platelet deposition by 34.5%
+/- 5% (mean +/- SEM, n = 4, P = .09) at low shear rates (approximately 200
s-1) and 61.3% +/- 11% (mean +/- SEM, n = 4, P = .05) at high shear rates
(approximately 850 s-1). Thrombin aptamers based on ssDNA molecules
represent a new class of thrombin inhibitors with potent anticoagulant and
antithrombotic properties.
Volume 83,
Issue 3,
pp. 677-682,
02/01/1994
Copyright © 1994 by The American Society of Hematology
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