Tissue plasminogen activator (t-PA) variants with substitution of leucine for phenylalanine, histidine for arginine, serine for isoleucine and threonine for lysine at amino acid positions (274, 275, 276 and 277) respectively, of wild-type human t-PA are prepared. DNA sequences can be prepared that encode such variants, as well as expression vectors incorporating the DNA sequences, and host cells transformed with the expression vectors. The variants exhibit improved fibrin-specificity and can be used in a pharmaceutical preparation to treat a vascular disease or condition or to prevent fibrin deposition or adhesion formation or reformation in mammals.