Thrombolysis by human tissue plasminogen activator and urokinase in rabbits with experimental pulmonary embolus

Thromboembolism is a frequent and often lethal complication of many medical diseases and surgical procedures. Streptokinase, a bacterial non-enzymatic protein, and urokinase, an enzyme obtained from human urine, are both potent activators of the human fibrinolytic system, and have been extensively investigated as a means of medical treatment of this condition. Although it is well established that these agents can clear obstructed vessels in roughly 50% of cases, the fact that they induce relatively extensive systemic fibrinogen breakdown and a serious haemorrhagic diathesis has prevented their general application for thrombolysis. The physiological plasminogen activator in blood (blood activator), which is probably released from the vascular wall (vascular activator) and is identical or at least very similar to the activator extracted from human organs (tissue activator), differs from urokinase (for references see ref. 1). This activator has a markedly higher fibrinolytic to fibrinogenolytic ratio than urokinase in vitro1 and might therefore constitute a better thrombolytic agent. We have developed a purification method for tissue plasminogen activator from a human melanoma cell line which enables us to produce milligramme quantities on a laboratory bench scale2 and we have now compared its thrombolytic effect with that of urokinase in an experimental animal model. We have found that tissue plasminogen activator causes thrombolysis at lower doses than urokinase, without extensive plasminogen activation in the circulating blood and without haemostatic breakdown.