At the outset, the misunderstanding of fibrinolysis needs to be corrected. Fibrinolysis is not due to tPA alone but rather is due to a combination of tPA and prourokinase (proUK) among which proUK has the dominant fibrinolytic effect.

Unfortunately, fibrinolysis was misunderstood to be due to tPA, which at best is a very weak fibrinolytic, since its sole function is to initiate fibrinolysis; a function analogous to that of the starter in a car. Therefore, tPA requires a second fibrinolytic to continue fibrinolysis after it is initiated, and the second endogenous fibrinolytic is prourokinase (proUK). This has a double fibrinolytic effect, since during fibrinolysis, local plasmin generation activates proUk to UK [2]. Therefore, fully effective fibrinolysis requires the effects of both tPA and proUK/UK, Both tPA and proUK are found in normal blood, and these two endogenous activators have a synergistic fibrinolytic effect in combination.

It is noteworthy and important, that in every one of the trials in which “fibrinolysis” was compared with the efficacy of an interventional procedure, fibrinolysis was induced by tPA alone, which we know is less than half as effective as full fibrinolysis by a sequential combination of tPA and proUK. Therefore, comparing an interventional procedure with fibrinolysis by tPA alone handicaps fibrinolysis, thereby introducing a serious artefact. This invalidates the results of all the comparisons made where fibrinolysis was induced by tPA alone. Therefore, the use of these procedures as the treatment of choice in most cases is probably not justified.

Fully effective fibrinolysis which requires both tPA and proUK has significant advantages over any interventional procedure. Fibrinolysis is significantly faster and easier to use and is not limited by the catheter size. These are important advantages, but even more important is the method by which fibrinolysis is induced. Fibrinolysis has never been defined and therefore has never been standardized.

It was shown that fibrinolysis by tPA alone was seriously flawed, whereas that by a sequential combination of tPA and proUK was more than twice as effective. The interventional procedures that have become the treatment of choice were never compared with fibrinolysis by tPA and proUK. It was only compared with fibrinolysis by tPA alone, which is at best half as effective. view of the advantages of fibrinolysis as treatment, compared with an interventional procedures that have never even been compared with fully active fibrinolysis.

 The fact that these procedures a well reimbursed, adds an ethical dilemma to this therapeutic decision. The only comparison made was against fibrinolysis by tPA alone, which is not a fibrinolytic, as previously explained. Since tPA does not degrade fibrin, it is high time that tPA ceased being called a fibrinolytic. It initiates fibrinolysis but does not degrade fibrin.

Not surprisingly, an interventional procedure was more effective than tPA fibrinolysis, providing a reason for using these procedures. However, these procedures are too slow, often require hospitalization, and can only open an occluded vessel that is larger than the catheter. There is no better treatment better and faster than fibrinolysis, which can be initiated immediately and is not limited by vessel size. However, to take full advantage of fibrinolysis, it has to be well understood. For example, fibrinolysis requires more than tPA, which was responsible for a longstanding mistake, since tPA was believed to dominate fibrinolysis. Instead, fully effective fibrinolysis requires the sequential combination of tPA and proUK. As documented in a successful clinical trial of 101 patients with AMI treated with a combination of tPA and proUK [PATENT tria]. This combination is both highly effective and safe, and is believed to be a copy of the endogenous natural fibrinolytic paradigm.

Since fibrinolysis remains poorly understood, the current treatment of choice for occlusive emergencies like AMI and some ischemic stokes is an interventional procedure, a choice that may be good for the interventionalist but bad for the patient. This is the because the interventional procedures are a slow, clumsy treatments for vascular emergencies that can be easier and faster treated by full fibrinolysis.

Therapeutic fibrinolysis should be based on what as been learned of physiological fibrinolysis. This very simply requires a small, 5 mg bolus of tPA to initiate fibrinolysis. This is followed by a modest infusion of proUK, 40 mg/h for 60-90 minutes. This same dose has been used in 101 patients with AMI (PATENT trial) and 200 patients with ischemic stroke (DUMAS trial).

The misuderstanding of fibrinolysis was mainly due to some confusion about the function of tissue plasminogen activator (tPA), the first endogenous fibrinolytic, known since 1947 and which received clinical approval from the FDA for therapeutic fibrinolysis in 1987. However, despite this history and its classification as a fibrinolytic, tPA does not degrade fibrin, and therefore it is not really fibrinolytic. This conclusion is consistent with the results of gene deletion studies. A tPA gene deletion had surprisingly little effect on the animal’s fibrinolytic activity, whereas deletion of the urokinase plasminogen activator (uPA) gene virtually eliminated fibrinolytic activity [1]. This activator deletion study also showed that the dominant fibrinolytic or plasminogen activator in the body is prourokinase (proUK) [1]. By contrast, the sole fibrinolytic function of tPA is to initiate fibrinolysis, a function analogous to that of the starter in a car. As in this analogy, tPA cannot function on its own and requires the participation of the other endogenous fibrinolytic which was not discovered until 1984 [2]. Even in tPA doses as high as 100 mg administered over 60 minutes, tPA was ineffective but since tPA is the only activator with a fibrin affinity, these high doses led to some tPA binding to hemostatic fibrin causing bleeding. This led to the false idea that fibrinolysis was associated with bleeding side effects. However, this is an artefact left over from these early clinical trials, because no more than a 5mg bolus of tPA is required for fibrinolysis.

 Since tPA is still considered a fibrinolytic, though an unsuccessful one, it has now been replaced by interventional procedures, like PCI and angioplasty. These are less effective than fibrinolysis but are well-compensated as interventional procedures tend to be. Instead, proUK, it is probably not only the fastest reperfusion treatment, it is also the most effective, since it can reperfuse all occluded vessels regardless of size. Although tPA was the only endogenous fibrinolytic for some years, this changed in 1984 with the discovery of the other endogenous plasminogen activator, prourokinase (proUK). tPA and proUK were found to have complementary properties so that fibrinolysis by the combination was more than twice as effective as by tPA alone [1]. Therefore, fibrinolysis by the combination, tPA+proUK, is more than twice as effective, as “fibrinolysis” by tPA, which used to be the standard. It should have replaced the former, but this has not happened illustrating the persistence of well-established habits, since no other reason was found.

Unfortunately, the current treatment of choice for AMI and some strokes is one of the interventional procedures, even though they are slow and not very effective, but they were slightly more effective than tPA “fibrinolysis”. No studies were done comparing a procedure to fibrinolysis by tPA+proUK. Since that latter is more than twice as effective, the current “treatment of choice” has yet to be properly validated. At the same time, the procedures continue to be well-reimbursed.

All else being equal, fibrinolysis has a number of obvious advantages over an interventional procedure. Fibrinolysis is much faster and opens all size vessels. In addition, since only a 5 mg tPA bolus is required followed by a modest infusion of proUK (40 mg/h for 60-90 min) the treatment is free of side effects [2]. By contrast, interventional procedures risk injury to the arterial intima and even an occasional vessel puncture.

The use of these slow procedures for these common emergencies, for which reperfusion that is as rapid as possible can be life-saving, needs re-evaluation. It is high time that “fibrinolysis by tPA be replaced in favor of mini-tPA and proUK. It has been established that this is more than twice as effective and therefore should replace interventional procedures that much too slow and ineffective. Since lives and brain function are at stake it high time these painfully slow procedures be replaced.

Both tPA and proUK are in normal blood and this explains the remarkable potency of endogenous fibrinolysis. For example, in the GUSTO trial of tPA in AMI, in 15% of the yet untreated AMI patients, the infarct artery was patent, meaning the thrombus responsible for the AMI had been rapidly lysed by the endogenous concentrations of tPA and proUK.

Several clot lysis studies also showed that the combination of tPA and proUK induces lysis that is more than twice as effect as that by tPA alone [4]. Further studies of the properties of tPA have shown that tPA is not really a fibrinolytic, it does not degrade fibrin, and only initiates fibrinolysis, a function analogous to that of the stater of a car. This tPA and proUK combination has also served as a model for two successful clinical trials.

The first was the PATENT trial in which 101 AMI patients were treated with a 5 mg tPA bolus followed by an infusion of proUK (40 mg/h) for 90 minutes. The AMI mortality was only 1% and the 24h infarct artery patency rate was 82 % and there were no reocclusions. At the time, the infarct artery patency rate with tPA was 50% and the mortality was 6%. A second trial, DUMAS trial in the Netherlands 200 patients with ischemic stroke was given the same treatment as jn PATENT, except that the proUK infusion was 60 rather than 90 minutes. The study was double-blind and has recently been completed and is scheduled for presentation this fall.

1. Gene deletion studies.
2. Gurewich V, Pannell R, Louie S, Kelley P, Suddith RL, Greenlee R. Effective and fibrin-specific clot lysis by a zymogen precursor form of urokinase (pro-urokinase), A study in vitro and in two animal species. J Clin Invest. 1984; 73: 1731-1739.