Fibrolase infusion

Figure 2. Thrombolytic effectiveness of natural fibrolase in a subacute iliac venous thrombosis model in the rabbit. Occluding spring coils were introduced retrograde from the jugular vein into both iliac veins. After 48 hours cutdowns on each iliac vein were performed below the coils and a catheter was introduced. Standard heparin infusion was initiated via the ear vein. A control angiogram was taken. Infusion of venom enzyme was then begun and repeat venograms were taken to document the extent of lysis. A, venogram at 0 time B, following 1 hour of fibrolase infusion C, following 2 hours of enzyme infusion.

The present report outlines studies with fibrolase in several different animal thrombosis model systems. Infusion of fibrolase proximal to an occlusive thrombus produces rapid and effective thrombolysis in carotid (22) and renal arterial, and iliac venous thrombosis model systems (23). Recently the recombinant form of fibrolase has been purified from a yeast expression system (24). It appears to be identical in all respects to the natural enzyme and has been used successfully in the carotid arterial thrombosis model system (22). Both natural and recombinant forms of the enzyme have effective thrombolytic activity in the different animal models employed there are no observable side effects nor toxicity, and minimal or no observable hemorrhaging. 

Figure 1. Thrombolysis produced by natural fibrolase in the rabbit acute renal arterial thrombosis model. The arteriograms show A, contrast medium injected through the catheters into both normal renal arteries B, arterial occlusion after introducing thrombus in both renal arteries C, after infusion of fibrolase into the occluded left renal artery there is almost complete clearance of the clot at 30 min. Note the lack of clearance in the non-infused (right) kidney. After 4 hours the right renal artery remained occluded, but was cleared after a 20 min infusion of fibrolase directly into the right renal artery.

Figure 3. Carotid blood flow velocity in treated and control groups. A, carotid blood flow velocity in groups treated either with APSAC alone or APSAC plus 7E3. Thirty min after thrombotic occlusion of the vessel, APSAC was infiised immediately proximal to the thrombus. Five min after restoration of the left carotid artery blood flow velocity, the 7E3 F(ab )2 monocloanl antibody was administered intravenously to only one of the groups receiving APSAC. B, carotid blood flow velocity in both the right and left carotid arteries after occlusive thrombus formation. The right carotid artery served as the control vessel and remained occluded throughout the course of the experimental procedure. Thirty min after occlusion of the left carotid artery, r-fibrolase was infused immediately proximal to the occlusive thrombus. Clot lysis was achieved in each of the five animals in the group. Five min after restoration of blood flow in the left carotid artery, the 7E3 antibody was administered intravenously. Blood flow velocity was maintained in the left carotid artery in four of the five vessels that received the combined treatment.

The present results demonstrate that natural fibrolase exhibits effective in vivo thrombolytic activity in several animal thrombosis model systems. Infusion of the enzyme proximal to an occlusive thrombus induced rapid and specific thrombolysis in rabbit renal arterial and iliac venous thrombosis model systems. No evidence of hemorrhaging or alterations to the hemostatic system were observed in these studies. Additionally, no toxicity was observed and no angiographic, histologic, or functional evidence of side effects were obtained. The enzyme rapidly lysed 48 hr aged thrombi in the venous thrombosis model. This suggests that one of the primary mechanisms of thrombus resistance to PA-based agents. 

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