We studied whether there was a relationship between the
anticoagulant effects of recombinant human soluble
thrombomodulin (rhsTM) and activation of
protein C in a primate model of acute vascular graft
thrombosis in 11 baboons (Papio species). Baboons were pretreated with 0.1, 1 and 5 mg/kg of rhsTM, with or without co-injection of a neutralising
monoclonal antibody to
protein C (HPC4) in the 1 mg/kg rhsTM group. Subsequently, thrombogenic
polyester grafts were deployed for 3 h into chronic exteriorised arteriovenous shunts.
Thrombus growth in the graft, plasma-activated
protein C (APC) levels, coagulation and
thrombosis markers were determined. In untreated baboons, baseline circulating APC levels more than doubled and graft thrombi propagated until reaching equilibrium in about 1 h. Treatment with rhsTM reduced
thrombus propagation rates, prolonged the clotting and bleeding times, decreased
thrombin-antithrombin complex,
beta-thromboglobulin and
fibrinopeptide A levels, and, surprisingly, also decreased systemic APC levels, in a dose-dependent manner. In the presence of HPC4 antibody to inhibit APC generation, the acute antithrombotic activity of rhsTM on graft
thromboses was not attenuated for up to 80 min, but sustained
thrombus accumulation was observed over a 180-min period. These findings suggest that, in contrast to the prevailing hypotheses, the primary antithrombotic activity of rhsTM is independent of
protein C, at least in this primate model. Direct inhibition of
thrombin's prothrombotic activity upon complex formation with rhsTM might explain the molecular mechanism of the observed antithrombotic effect.