Methods for increasing plasmin activity in a patient in need thereof are provided, comprising administering to the patient a therapeutic amount of an agent which binds to α2-antiplasmin at a binding site to increase conversion of cc2-antiplasmin from an inhibitor to a plasmin substrate, thereby increasing plasmin activity in the patient. Also provided are methods for the identification of compounds or molecules that increase plasmin activity, comprising determining whether the compound or molecule binds to a binding site on α2-antiplasmin which increases the conversion of α2-antiplasmin from an inhibitor to a plasmin substrate, wherein the compound or molecule is not an antibody, thereby identifying a compound or molecule which increases plasmin activity. Further provided are pharmaceutical compositions and methods of use thereof for the treatment of myocardial infarction, thrombosis, ischemic stroke, and pulmonary embolism.