Surface-bound
thrombin, which is resistant to inhibition by
heparin/
antithrombin III (/AT), plays a key role in vessel wall disease. In contrast, surface-bound
thrombin is not resistant to inhibition by
heparin cofactor II (HCII) and its acceleration of its inhibitory effect by
dermatan sulfate. However, the potential use of
dermatan sulfate to prevent
thrombus formation in vivo is limited by its low specific activity, which in turn, necessitates excessively high doses when given on a gravimetric basis. Recently, a novel HCII agonist,
Intimatan, has been synthesized by site-specific sulphation of highly purified
dermatan sulfate comprising primarily of L-iduronic acid-4-O-sulphated
N-acetyl-D-galactosamine, yielding a 4, 6-O-disulphate compound on the
galactopyranose ring with a lower molecular weight, higher solubility, and specific activity than its parent,
dermatan sulfate. In this study, we compared the abilities of
Intimatan with its parent compound,
dermatan sulfate, and with
heparin to affect coagulation and to inhibit surface-bound
thrombin both in vitro and in vivo, to determine if
Intimatan demonstrates a better potential than either other compound in preventing
thrombus formation in vivo.
Intimatan prolonged the activated partial thromboplastin time (APTT) more effectively than either
dermatan sulfate or
heparin at comparable
antithrombin concentrations. This activity was attributed to the more selective action of
Intimatan against surface-bound
thrombin in vitro.
Intimatan also inhibited
thrombin bound to an injured vessel wall surface in vivo more effectively than
heparin, i.e., when measured in injured carotid arteries of rabbits injected with
Intimatan or with
heparin at the time of injury. We conclude that
Intimatan effectively inhibits surface-bound
thrombin, thereby exhibiting better
anticoagulant and
antithrombin properties than
heparin and
dermatan sulfate.