Flow through clots determines the rate and pattern of fibrinolysis

Abstract

Thrombolytic therapy depends on penetration of plasminogen activator into clots which occurs through diffusion and flow. An in vitro system has been developed to characterize the rate and pattern of fibrinolysis in relation to flow through occlusive clots exposed to a pressure gradient. Whole blood clots formed in plastic tubes were perfused with plasma containing 1 microgram/ml tissue plasminogen activator (t-PA) and 0.5 or 1 mmol/l gadolinium-diethylentriamine pentaacetic acid (Gd-DTPA), a paramagnetic substance used as a contrast enhancer for magnetic resonance (MR) imaging. T1-weighted spin echo MR images were obtained during clot perfusion at 3-5 min intervals for 45 min. Characteristic signal intensities allowed identification of non-perfused, perfused but non-lysed, and completely lysed areas of clot. A spatially resolved time course of perfusion and subsequent lysis was constructed for 10 clots. Plasma flowed non-uniformly through clots forming asymmetric channels that left some areas non-perfused. The longitudinal velocity of flow through the dominant channel was 1.6 +/- 0.7 mm/min. The flow rate during the first five minutes was 7.5 +/- 6.5 microliters/min and 15.3 +/- 10 microliters/min between min 26-30 in clots that had not completely recanalized by that time. A sharp increase in flow was noted at the time of recanalization that occurred at 37 +/- 11 min. Clot lysis followed the pattern of perfusion through the dominant channel after a lag time of 13 +/- 4 min, representing the time required for enzymatic processes. The delay time between perfusion and lysis was longer in regions with slower flow indicating that the rate of t-PA delivery influenced the rate of fibrinolysis.(ABSTRACT TRUNCATED AT 250 WORDS)