Thrombolysis with Tissue Plasminogen Activator (Tpa) Alone has been A Longstanding Mistake

Current thrombolytic therapy consists of high dose tPA administered iv for 60-90 minutes. This treatment has had only limited success in acute myocardial infarction (AMI) [1-3], and consequently has more recently been replaced by percutaneous coronary intervention (PCI) as the treatment of choice in AMI [4]. Although PCI is time-consuming and delays coronary reperfusion, better clinical outcomes than with tPA were nevertheless obtained [5]. In the treatment of ischemic stroke, a tPA dose reduction was required due to a 20% intracranial hemorrhage (ICH) incidence when the AMI dose was used [6]. Dose reduction diminished the thrombolytic efficacy and resulted in a reperfusion rate of only about 30% [7], and a 7% incidence of symptomatic ICH remained [8]. As in AMI, PCI is now being used increasingly in stroke JTT [9-11]. Historically, the use tPA for thrombolysis was based on the belief that tPA was responsible for intravascular fibrinolysis, whereas the other natural plasminogen activator, urokinase plasminogen activator (uPA), was responsible for extravascular fibrinolysis where its effect is mediated by its uPA receptor, UPAR. Although this belief is rarely questioned, it is belied by a number of findings such as those from gene knockout animal studies. These showed that knocking out the uPA gene, but not the tPA gene, impairs lysis of a venous thrombus. The tPA gene knockout had little effect on thrombus resolution [12]. Similarly, a uPA but not a tPA knockout resulted in spontaneous fibrin formation, and uPA mediated fibrinolysis was not impaired by deletion of the UPAR gene [13], contrary to what had been believed.