Fibrinolytic Agents

Although mechanisms vary, each fibrinolytic agent eventually activates plasminogen to plasmin, which then dissolves the fibrin component of thrombi. Fibrinolytics currently approved in the United States include streptokinase (SK); anisoylated plasminogen-streptokinase activator complex (APSAC), or anistreplase; recombinant tissue plasminogen activator (tPA), or alteplase; reteplase; and urokinase.

STREPTOKINASE AND ANISTREPLASE SK, derived from b-hemolytic streptococci, binds to and activates plasminogen, producing plasmin, which in turn catalyzes fibrin lysis and thrombus dissolution. Circulating fibrinogen also undergoes plasmin-induced lysis, producing a state of "systemic fibrinolysis." SK is administered as a slow infusion (usually 1.0 to 1.5 million U intravenously over 60 min) and has a serum half-life of about 23 min, but in most patients systemic effects persist for up to 24 h. Because of the prolonged fibrinolytic state and increased risk of hemorrhage, anticoagulation with heparin is usually delayed following treatment with SK. SK is the least expensive fibrinolytic; typical wholesale costs approximate $300 per dose. Anistreplase, a modified active plasminogen-streptokinase complex, has an effect similar to that of SK, but its chief advantage is that it can be administered as a slow bolus (usually 30 mg intravenously over 5 min) and has a serum half-life of about 90 min. Anistreplase is costly ($1700 per dose) and has produced no improvement in outcome when compared to SK. Both SK and anistreplase are antigenic. In the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial, allergic reactions occurred in about 6 percent of patients treated with SK and subcutaneous heparin.21 Antibodies to SK develop approximately 5 days after treatment and persist for 6 months; retreatment with SK or anistreplase is not advised during this interval. In addition, SK or anistreplase should not be administered within 12 months of a streptococcal infection.

TISSUE PLASMINOGEN ACTIVATOR AND RETEPLASE tPA is a naturally occurring enzyme in vascular endothelial cells that directly cleaves a specific peptide bond in plasminogen, converting it to active plasmin, with subsequent fibrinolysis. tPA has binding sites for fibrin, which would suggest specificity for activity in the thrombus and less systemic fibrinolysis. Despite the in vitro clot specificity of tPA, its clinical side-effect profile is comparable to that of other fibrinolytics. The serum half-life of tPA is less than 5 min, and it produces a shorter fibrinolytic state that does SK. Heparin is commonly administered shortly after the completion of tPA infusion. Unlike SK and anistreplase, tPA is not antigenic. In the GUSTO trial utilizing front-loaded tPA and intravenous heparin, the rate of allergic reactions was under 2 percent.21 Currently, tPA is commonly used for AMI, for which it is administered in a front-loaded format: 15-mg bolus, then 0.75 mg/kg over 30 min (maximum 50 mg), and then 0.50 mg/kg over 60 min (maximum 35 mg; Iable...216:1). Reteplase, a derivative of tPA, is dosed as a double bolus (10-U bolus followed by a second dose at 30 minutes).22 Both tPA and reteplase are expensive, approximately $3000 per treatment.

UROKINASE Urokinase has become nearly obsolete in acute management of thromboembolic disease, except for dissolution of indwelling-catheter-associated fibrin sheath and thrombosis, for which it is given as a local infusion starting at 500 U/kg/h (without a bolus) delivered directly into the catheter or into the affected vessel. 23 Systemic and other bleeding complications are infrequent with low-dose local therapy.

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