Comparative anti-thrombotic activity and haemorrhagic adverse effect of nattokinase and tissue-type plasminogen activator

Anti-thrombotic activity and safety of nattokinase, an enzyme produced by Bacillus subtilis during soybean fermentation, were investigated in comparison with tissue-type plasminogen activator (t-PA). Carotid arterial thrombosis was produced with a FeCl3-soaked paper, followed by intravenous injection of nattokinase or t-PA. Nattokinase and t-PA delayed thrombus formation, near-fully (> 90%) inhibiting at 75 and 8.5 mg/kg, respectively. As adverse effects, t-PA induced petechial haemorrhage at 10 mg/kg in the lungs and thymus, and extensive bleeding at 20 mg/kg. Nattokinase also caused pulmonary haemorrhage from 300 mg/kg. Collectively, the standard safety margins (SSMs) for t-PA and nattokinase were calculated to be 1.2 and 4.0, respectively. Combinational treatment with dexamethasone (2 mg/kg) increased the efficacy and safety of t-PA and nattokinase, widening their SSMs to 2.4 and 8.0, respectively. The results indicate that nattokinase delayed thrombus formation and dissolved thrombi, and that nattokinase could be a good candidate anti-thrombotic agent with relatively-low haemorrhagic risk.