Rationale for the bolus administration of fibrin-specific thrombolytic agents

The bolus administration of fibrin-specific thrombolytic agents, mainly recombinant tissue-type plasminogen activator (rt-PA), is supported by a number of experimental and clinical pharmacology studies with these agents. Experimental animal studies have shown that the thrombolytic activity of rt-PA is sustained beyond its plasma clearance and that the thrombolytic effect of a rt-PA dose is inversely correlated with the duration of infusion while its haemorrhagic effect is directly correlated with the duration of infusion. Furthermore, experimental bleeding with rt-PA is delayed up to 1 h after the start of its infusion suggesting that bleeding after rt-PA is, at least in part, the result of the generation of a plasma proteolytic state. This is possibly due to the interaction in the circulation of rt-PA with the large fibrin degradation fragments (XL-FDP) produced by the thrombus lysis. Bolus administration of rt-PA is potentially less haemorrhagic than its prolonged infusion because the short half-life of this agent precludes its interaction with circulating XL-FDP. Most of the experimental studies on the bolus administration of fibrin specific plasminogen activators have been performed with rt-PA. Experimental studies have also compared the efficacy and safety of the bolus administration of rt-PA and plasminogen activators with prolonged half-life. Clinical pharmacology studies provide further support for the bolus administration of a fibrin specific plasminogen activator. These studies have shown that the thrombolytic activity of rt-PA is sustained over time and that bolus administration of rt-PA produces less thrombin generation as compared with a continuous infusion. A number of fibrin specific plasminogen activators have been recently administered as a bolus in patients with myocardial infarction, unstable angina and pulmonary embolism. Taken together, these clinical trials showed promising although non-definitive results. Recently planned clinical outcome trials will define the value of the bolus administration of fibrin specific plasminogen activators.