Fibrin-specificity of a plasminogen activator affects the efficiency of fibrinolysis and responsiveness to ultrasound: Comparison of nine plasminogenactivators in vitro

In a number of cases, thrombolytic therapy fails to re-open occluded blood vessels, possibly due to the occurrence of thrombi resistant to lysis. We i nvestigated in vitro how the lysis of hardly lysable model thrombi depends on the choice of the plasminogn activator (PA) and is accelerated by ultras onic irradiation. Lysis of compacted crosslinked human plasma clots was mea sured after addition of nine different PAs to the surrounding plasma and th e effect of 3 MHz ultrasound on the speed of lysis was assessed. Fibrin-specific PAs showed bell-shaped dose-response curves of varying widt h and height. PAs with improved fibrin-specificity (staphylokinase, the TNK variant of tissue-type PA [tPA], and the PA from the saliva of the Desmodu s rotundus bat) induced rapid lysis in concentration ranges (80-, 260-, and 3,500-fold ranges, respectively) much wider than that for tPA (a 35-fold r ange). However, in terms of speed of lysis, these three PAs exceeded tPA on ly slightly. Reteplase and single-chain urokinase were comparable to tPA, w hereas two-chain urokinase, anistreplase, and streptokinase were inferior t o tPA. In the case of fibrin-specific PAs, ultrasonic treatment accelerated lysis about 1.5-fold. For streptokinase no acceleration was observed. The effect of ultrasound correlated with the presence of plasminogen in the out er plasma, suggesting that it was mediated by facilitating the transport of plasminogen to the surface of the clot. In conclusion, PAs with improved fibrin-specificity induce rapid lysis of p lasminogen-poor compacted plasma clots in much wider concentration ranges t han tPA; This offers a possibility of using single or double-bolus administ ration regimens for such PAs. However, it is not likely that administration of these PAs will directly cause a dramatic increase in the rate of re-ope ning of the occluded arteries since they are only moderately superior to tP A in terms of maximal speed of lysis. Application of high-frequency ultraso und as an adjunct to thrombolytic therapy may increase the treatment effici ency, particularly in conjunction with fibrin-specific PAs.