The effects of a new tissue plasminogen activator analogue, Fb‐Fb‐CF, on cerebral reperfusion in a rabbit embolic stroke model

Abstract

Early fibrinolytic therapy with full molecular tissue plasminogen activator (t‐PA) has been observed to be both angiographically and clinically effective when employed in animal stroke models. Preliminary clinical trials with t‐PA are in progress. It is possible to refine t‐PA by developing fragments or analogues of the drug. Using recombinant DNA technology in the Escherichia coli system, a t‐PA analogue consisting of the catalytic fragment of t‐PA and a dimer of the B fragment of staphylococcal protein A (Fb‐Fb‐CF) has been produced. Because this analogue has a long serum half‐life of 90 minutes, we employed Fb‐Fb‐CF in a rabbit cerebral embolic stroke model to assess its efficacy as a reperfusion agent. When given as a bolus to 10 animals 15 minutes after embolization, Fb‐Fb‐CF produced angiographic cerebral reperfusion in 48 ± 21 minutes (± SD), while in 8 saline‐treated controls, reperfusion was not observed at 180 minutes in any animal (p < 0.01). In another experiment reperfusion was demonstrated at 66 ± 32 minutes in 11 animals treated with Fb‐Fb‐CF 90 minutes after embolization as compared with 100 ± 25 minutes in 12 saline‐treated controls (p < 0.01). A small macroscopic hemorrhage within an infarct was seen in 1 Fb‐Fb‐CF‐treated animal in the 15‐minute experiment and in none of the controls. In the 90‐minute experiment, macroscopic hemorrhagic infarction was seen in 4 Fb‐Fb‐CF‐treated animals and in 3 controls. Plasma fibrinogen levels measured in the 15‐minute Fb‐Fb‐CF treatment group declined by 16% immediately after the Fb‐Fb‐CF bolus was administered and by 19% after 180 minutes. These data demonstrate that Fb‐Fb‐CF can rapidly reestablish cerebral perfusion with only modest reductions in plasma fibrinogen when given either 15 or 90 minutes after cerebral embolization.