Background: Enhanced
thrombin generation has been found in patients with peripheral
arterial obstructive disease (PAOD). The objective of this study is to investigate the effect of
thrombin inhibition in PAOD patients. Methods:
Argatroban (20 mg/day) was infused intravenously over 2 hours for 14-68 days in 27 patients with chronic PAOD of the lower extremities. Plasma
thrombin-antithrombin III complex (TAT) levels and clinical signs were assessed. Results: TAT levels before
argatroban therapy were significantly higher in the PAOD patients than in age- and gender-matched controls. In the PAOD patients, TAT levels increased stepwise in the presence of rest
pain classified as Fontain III and IV. To assess the effect of
thrombin inhibition, we divided the patients into a high-TAT group (pretreatment TAT level >/=5 ng/ml, n = 12) and a low-TAT group (pretreatment TAT level <5 ng/ml, n = 15). In the high-TAT group, TAT levels were suppressed in 8 of 12 patients after the administration of
argatroban, along with improvement of their clinical symptoms and a decrease in the size of ischemic
skin ulcers, indicating that
argatroban clearly inhibited
thrombin generation in vivo. Even in the low-TAT group,
argatroban improved the clinical signs and symptoms, and also reduced the size of ischemic
skin ulcers although TAT levels remained within the low range (<5 ng/ml) in 13 of the 15 patients, indicating that PAOD signs and/or symptoms may be related to small amounts of
thrombin generated locally at the sites of atherothrombotic stenotic lesion. Conclusions: These results suggest that
thrombin generation was enhanced in PAOD and that the amount was related to disease severity.
Thrombin inhibition by
argatroban may break this vicious cycle and lead to clinical improvement in PAOD.