Alpha-fibrinogenases

Snake venoms contain a number of serine and metalloproteinases, included among these are the fibrinolytic metalloproteinases. When the fibrinolytic enzymes were first isolated from viper venoms it was postulated that there may be a clinical application for these enzymes in the treatment of occlusive thrombi, such as those occurring in the great arteries and veins of cardiac and cerebral circulation as well as peripheral arteries and veins. In the ensuing years a substantial body of literature has been generated on the identification and characterization of the fibrinolytic enzymes from a broad spectrum of snake species. In this report we describe the biological properties and positive clinical features of the class of enzymes known as alpha-fibrinogenases. Fibrolase, a fibrinolytic metalloproteinase originally isolated from Agkistrodon contortrix contortrix venom, is the representative fibrinolytic enzyme used for the description and characterization of the alpha-fibrinogenases in this chapter. The biochemical and physiochemical properties and in vivo activity of the enzyme are described as well as in vitro studies using a platelet avid chimera of fibrolase. The chimera was formed by coupling fibrolase to an Arg-Gly-Asp (RGD) like peptide imparting inhibitory activity on platelet aggregation and thrombus formation, while maintaining full fibrinolytic activity. Fibrolase has also been modified through the adduction of polyethylene glycol to reduce the rate of clearance from the circulation. In this review we also include a description of alfimeprase, a recombinant fibrinolytic enzyme derived from fibrolase, and follow the development of the enzyme as a potential clinical agent in the clearance of occlusive thrombi. Alfimeprase is presently in clinical trials for two indications: the treatment of peripheral arterial occlusions (in which phase II is nearing successful completion), and for use in the clearance of occluded vascular access catheters in direct competition with plasminogen activators.