Role of Fibrin Affinity of One-chain t-PA on its Sustained Thrombolysis

Abstract

t-PA has been well known to show thrombolytic activity mediated through the activation of plasminogen. The activation is markedly stimulated in the presence of fibrin. Although t-PA tightly binds to fibrin, it has not been clarified how long the activity of the binding t-PA to thrombus is sustained in the physiological condition. Therefore, we examined the correlation between the binding amount of t-PA to thrombus and the duration of the thrombolytic activity induced by only the binding t-PA in vivo.After human plasma clots were immersed in human plasma containing various concentration of t-PA or LUK for 1min, the clots were washed with saline and immersed in the plasma without t-PA or LUK. The clots pretreated with t-PA were lysed for 3 hours continuously and the clot lysis is clearly correlated with the binding amount of t-PA to clot. On the other hand, the clots pretreated with LUK lacking in fibrin affinity were never lysed significantly.When the rabbit with pulmonary embolism was injected with t-PA (300, 000IU/kg i. v.), the circulating t-PA was quickly disappeared and was detected only slight (17±10IU/ml) after 30min. However, the degree of thrombolysis was increased for 120min after the injection of t-PA (17±3.5% at 30min; 31±3.2% at 120min).These results indicate that the binding t-PA not only to plasma clots but also to thrombi is active and the thrombi bound with t-PA continue lysing at least for several hours even in the absence of free form of t-PA in plasma.