The effect of the fibrinolytic enzyme FIIa from Agkistrodon acutus venom on acute pulmonary thromboembolism

Abstract

Aim: To evaluate the effects of the fibrinolytic enzyme FII(a) from Agkistrodon acutus venom on acute pulmonary thromboembolism (APT) in animal models.

Methods: Both rabbit and dog APT models were used. For the rabbit APT model, the thrombi weight before and after administration was measured. Central venous pressure (CVP) and mean arterial pressure (MAP) were measured before and 15, 30, 60, and 120 min after the injection of the blood clot. Partial thromboplastin time (APTT), prothrombin time (PT), platelet count, and fibrinogen concentration were measured using auto analyzers. Plasminogen activity was measured based on chromogenic substrates. In the dog APT model, pulmonary blood flow was recorded using pulmonary angiography.

Results: Intravenous administration of FIIa (0.1-5.0 mg/kg) improved the APT-induced hemodynamic derangements and reduced thrombi weight. The angiography evidence also showed that the pulmonary emboli had almost disappeared after FII(a) infusion. FII(a) (0.1, 0.5, or 1.0 mg/kg) did not impair the coagulation pathways, although very high doses of FII(a) (5.0 mg/kg) could stimulate the production of plasminogen and result in impairment of the pathways.

Conclusion: FII(a) could effectively protect against APT via degradation of thrombi with less activation of plasminogen, and may provide a novel fibrinolytic enzyme for targeting the main pathological processes of the disease.

Figure 1

Effects of embolization and thrombolytic agents on mean arterial pressure (MAP, A) and central venous pressure (CVP, B). The data demonstrate that (1) embolization leads to an increase in CVP and a decrease in MAP and (2) FII_a and urokinase consistently ameliorate the hemodynamic derangements.

Figure 2

Effect of FII_a on thrombi weight in rabbits (n=10 in each group). Dose-dependent reduction in thrombus weight by FII_a infusion. Data were expressed as mean±SEM. ^bP<0.05, compared with embo-control.

Figure 3

Digital subtraction angiography in APT. Arrows indicate thrombi in the right pulmonary artery. (A) Before pulmonary thromboembolism; (B) Two hours after pulmonary thromboembolism. The right pulmonary artery shows a complete obstruction. (C) FII_a treatment for 30 min. A reduction in obstruction was detected in the lower lobar pulmonary artery branches. (D) FII_a treatment for 60 min. The pulmonary emboli almost completely disappeared.