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Sustained antithrombotic activity of hirudin after its plasma clearance:
comparison with heparin
G Agnelli, C Renga, JI Weitz, GG Nenci and J Hirsh
Istituto di Medicina Interna e Medicina Vascolare, Universita di Perugia,
Italy.
Thrombus extension in patients with venous thromboembolism is due to the
accretion of fibrin onto existing thrombi. Extension is promoted by both
circulating and thrombus-bound thrombin, which convert fibrinogen to
fibrin. Heparin is an effective antithrombotic agent, but it requires
continuous administration to achieve persistent inhibition of thrombus
extension. Heparin is highly effective in inhibiting fluid phase thrombin,
but is a relatively ineffective inhibitor of thrombus- bound thrombin.
Hirudin, unlike heparin, inactivates both circulating and fibrin-bound
thrombin and, therefore, has the potential to prevent thrombus extension
even after a short course of treatment. The aim of this study was to
evaluate the time course of the accretion of new fibrin onto preexisting
rabbit jugular vein thrombi after a 3-hour infusion of saline, heparin, and
hirudin. Heparin and recombinant (r)- hirudin (CGP 39399) were infused at
doses that doubled the activated partial thromboplastin time (aPTT). At the
end of the 3-hour infusions in rabbits treated with saline, heparin (0.75
mg/kg), or r-hirudin (1.25 mg/kg), accretion of 125I-fibrinogen was 59 +/-
5 micrograms, 34 +/- 4 micrograms, and 21 +/- 2 micrograms, respectively
(heparin and r- hirudin v saline, P less than .01; r-hirudin v heparin, P
less than .01). Three hours after the end of the infusions, the accreted
125I- fibrinogen in the saline-, heparin-, and hirudin-treated animals was
89 +/- 6 micrograms, 51 +/- 7 micrograms, and 23 +/- 3 micrograms,
respectively; 9 hours after the end of the infusions, the accreted 125I-
fibrinogen was 112 +/- 9 micrograms, 82 +/- 7 micrograms, and 25 +/- 3
micrograms, respectively. aPTT and thrombin clotting time (TCT) returned to
the baseline value 90 minutes after the end of heparin or r- hirudin
infusion. During in vitro experiments, human fibrin clots previously
incubated in human plasma containing r-hirudin did not promote
fibrinopeptide A (FPA) generation when washed and then incubated in human
plasma in the absence of thrombin inhibitors. This persistent inhibition of
FPA production was not observed after incubation in human plasma of human
plasma clots preincubated with heparin. We conclude that heparin is
effective in inhibiting thrombus extension while it is present in the
circulation, but that this effect is rapidly lost after its plasma
clearance. In contrast, the antithrombotic activity of r-hirudin is
sustained beyond its plasma clearance, presumably because of its ability to
inactivate thrombus- bound thrombin. Our findings indicate that r-hirudin
might be an effective antithrombotic agent even when used for short
periods.
Volume 80,
Issue 4,
pp. 960-965,
08/15/1992
Copyright © 1992 by The American Society of Hematology
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