ABSTRACT
Alfimeprase is a recombinantly produced, truncated form of fibrolase, a known directly
fibrinolytic zinc metalloprotease that was first isolated from the venom of the southern
copperhead snake (Agkistrodon contortrix contortrix). Both fibrolase and alfimeprase have
direct proteolytic activity against the fibrinogen Aa chain. In contrast, agents such as streptokinase or t-PA are not directly fibrinolytic; instead they promote thrombolysis through
plasminogen activation. In vivo pharmacology studies have shown that thrombolysis with
alfimeprase is up to six times more rapid than with plasminogen activators. Alfimeprase can
be bound and neutralized by serum a2-macroglobulin, a prevalent mammalian protease inhibitor, which is capable of forming a macromolecular complex with alfimeprase. As a result, systemic
bleeding complications have been greatly reduced by the inhibitory effects of a2-macroglobulin. However, when systemic dosages exceed the a2-macroglobulin inhibitory capacity, toxicities appear, including hypotension and impaired hemostatis. The hypotensive effects have subse-
quently been found to be due to the generation of kinins and their effects evoked through the
BK2 receptor. However, these toxicities are not likely to be encountered in clinical testing as
estimates of safe dosages have been calculated from more than 200 patients with peripheral
vascular disease; clinically useful doses are likely to remain within these bounds. This chapter
reviews the biochemical, in vitro, and in vivo characteristics of this novel-acting thrombolytic
agent.
