Fibrinolytic Therapy Failed Because of a Misunderstanding; Tpa Must be Combined with Upa as in Nature
Correspondence Address :
Dept Medicine, Mt Auburn
Hospital, Cambridge, MA, USA
Received on: February 20, 2018, Accepted on: March 12, 2018, Published on: March 19, 2018
Citation: Victor Gurewich (2018). Fibrinolytic Therapy Failed Because of a Misunderstanding; Tpa Must be Combined With Upa as in Nature
Copyright: 2018 Victor Gurewich. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
In acute myocardial infarction (AMI), reperfusion of the infarct artery within the first two hours is the principal determinant of infarct size and mortality. Only fibrinolytic therapy can meet this reperfusion time requirement. However, tissue plasminogen activator (tPA) has been so ineffective and hazardous that it has been replaced by percutaneous coronary intervention (PCI) as the treatment of choice for AMI, which is a time-consuming treatment. For other indications like ischemic stroke, tPA remains the principal available option.
Published studies of fibrinolysis show that in natural, physiological fibrinolysis, tPA initiates fibrinolysis which is then completed by urokinase-type plasminogen activator (uPA), the native form of which is a proenzyme, prouPA. tPA and prouPA have complementary modes of action and in combination their fibrinolytic effect is synergistic. This activator combination is, therefore, more effective than either activator is alone, and the combination is also much safer since significantly lower doses are required. tPA and uPA gene deletion studies in mice confirmed that both activators were required for efficacy, and that uPA was the dominant activator. Superior efficacy by the combination was also seen in clot lysis studies in human plasma. Finally, a clinical proof of this concept has already been done. In a multicenter AMI trial, 101 patients were treated with a mini-bolus of tPA followed by a prouPA infusion. This resulted in almost a doubling of the 24h infarct artery patency rate compared to that in the best of the tPA trials. There were no re-occlusions and the mortality was only 1%, which compares with a 6.3% mortality with tPA.