Potential approaches for therapeutic intervention of thrombosis by fibrinolytic agents

Fibrin-specific thrombolytic agents are being developed based on a better understanding of the molecular mechanisms that regulate in vivo fibrinolysis. These agents may be more effective than those available currently and may induce less systemic fibrinolysis. In this respect, t-PA has been extensively investigated. Another fibrinolytic substance with anticipated fibrin-selectivity is scu-PA. Although scu-PA has been much less extensively investigated than t-PA, sufficient knowledge is available to evaluate its potential as a fibrin-specific thrombolytic agent. Both t-PA and scu-PA are single-chain glycoproteins with a catalytic mechanism common to all serine proteases (active site composed of the charge relay system). Both molecules occur as single-chain forms but are converted easily to two-chain disulfide bonded molecules by digestion with plasmin. Unlike most other serine proteases for which the single-chain molecular form is a zymogen with little or no activity toward its natural substrate, both single-chain t-PA and scu-PA have inherent plasminogen-activating potential. Both t-PA and scu-PA induce fibrin-specific thrombolysis in a plasma environment and in animal models of thrombosis. However, the fibrin specificity of t-PA- and scu-PA-induced thrombolysis is based on different molecular mechanisms. The effectiveness and fibrin specificity of t-PA obtained by recombinant DNA technology recently were established by three randomized multicenter trials in patients with acute myocardial infarction. For scu-PA, clinical results are presently more limited.