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Inhibition of coagulation and thrombin-induced platelet activities by a
synthetic dodecapeptide modeled on the carboxy-terminus of hirudin
JA Jakubowski and JM Maraganore
Department of Hemostasis Research, Boston Veterans Administration Medical
Center, MA.
A synthetic, tyrosine-sulfated, dodecapeptide (BG8865) modeled on residues
53-64 of hirudin was found to elevate the activated partial thromboplastin
time (APTT), prothrombin time (PT), and thrombin time (TT) of human plasma
in a dose-dependent manner. The most sensitive assay was the TT, which was
prolonged 2 and 3 times control values at 2.2 and 4.1 micrograms/mL hirudin
peptide, respectively. The sulfated dodecapeptide exhibited no dependency
on antithrombin III as monitored by the APTT in the presence of sheep
anti-human antithrombin III antibodies, and its activity was not
neutralized by platelet releasates or platelet factor 4. In studies of
thrombin-induced platelet activation, the hirudin peptide was found to
block aggregation, serotonin release and thromboxane A2 generation. At
thrombin concentrations of 0.25 U/mL, the IC50 (concentration resulting in
50% inhibition) for inhibition of platelet aggregation was 0.72
micrograms/mL peptide. Inhibition of TXA2 generation and serotonin release
correlated closely with inhibition of aggregation. Using platelets from
patients with clinically documented heparin-induced thrombocytopenia
anticoagulant doses of heparin were found to induce platelet aggregation
and thromboxane A2 generation. In sharp contrast, anticoagulant-equivalent
doses of hirudin peptide had no effect on patient platelets, as evidenced
by a lack of platelet aggregation and thromboxane A2 generation. These data
provide compelling in vitro evidence that the hirudin peptide has several
potential advantages over heparin, namely effective inhibition of
thrombin-induced platelet activities, co-factor independence, insensitivity
to endogenous heparin- neutralizing factors, and an apparent lack of direct
or immune-mediated platelet stimulating properties.
Volume 75,
Issue 2,
pp. 399-406,
01/15/1990
Copyright © 1990 by The American Society of Hematology
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