2. Introduction
Fibrinolysis is the body’s natural defense that
prevents physiological fibrin, needed for the repair of wear and tear vascular
injuries, from building up and interfering with blood flow. Evidence that this
system is ongoing comes from the invariable presence of the fibrinolytic
degradation product D-dimer in plasma (110-250 ng/ml). This normal
concentration goes up as much as twenty-fold in the presence of
thromboembolism, representing endogenous fibrinolysis.
The idea that tPA alone was responsible for this
efficient system represents a fundamental misunderstanding of this biological
system, which remains to be addressed [1]. Ever
since the FDA approved tPA for the treatment of AMI in 1987, it has been the
activator choice and it has been used alone. As a result, the current
understanding of the clinical benefit of fibrinolysis is based almost
exclusively on tPA monotherapy. At the same time, it was well established that
there are two plasminogen activators, the second one being Urokinase
Plasminogen Activator (uPA), the native form of which is a proenzyme (prouPA) [2]. Both are required for clot lysis in vitro,
and their fibrinolytic properties are complementary and synergistic in
combination. Therefore, the clinical benefits of the full potential of
fibrinolytic therapy remains to be established.
3. Discussion
With few exceptions, the fibrinolytic clinical
experience has been that of tPA or one of its two longer half-life mutant
forms. This experience has been sufficiently disappointing that fibrinolysis
has become discredited, and it has been replaced by Primary Percutaneous
Coronary Intervention (PPCI) as the treatment of choice for AMI. For ischemic
stroke, the tPA bleeding risk is higher and has obliged a one third tPA dose
reduction which further diminished its efficacy. Even with this reduction, a
6-7% risk of intracranial hemorrhage remains [3].
Due to this risk, reperfusion therapy must be delayed until a careful history
and diagnostic studies have eliminated a bleeding risk. Because of these risks
tPA treatment of stroke remains “mired in controversy” making a more effective
and safer fibrinolytic particularly urgently needed for this indication.
Although PPCI is now the treatment of choice for AMI,
it is handicapped by being a hospital procedure that is time-consuming,
technically demanding, and costly. This limits the patient population that can
be served, and PPCI is further limited by the time consumed by the procedure. Reduction
in AMI mortality is greatest when reperfusion is accomplished within 1-2 hours
of the event [4]. When it can be done within 70
minutes, the mortality was 1.2% [5]. Similarly,
in animal models the longer the coronary occlusion, the less salvageable
myocardium remains [6]. This makes any inpatient
treatment particularly challenging. Therefore, it is not only for stroke but
also for AMI that a more effective and safer fibrinolytic is needed.
The endogenous fibrinolytic system, in contrast to
therapy, uses not one activator but two. Fibrinolysis is initiated by tPA when
it is released from the vessel wall at the site of a fibrin clot. The tPA binds
to the clot at its fibrin binding site on the D-domain of fibrin and activates
plasminogen on the same domain fibrin [7,8]. The
unbound tPA is then promptly cleared by its short (5 min) half-life and
inhibited by its potent plasma inhibitor (PAI-1). Therefore, tPA does not
contribute further to fibrinolysis. The rapid elimination of iv tPA serves the
important physiological function of protecting hemostatic fibrin since it has
the same tPA binding site as a clot. Lysis of hemostatic fibrin is the main
cause of bleeding during tPA therapy [1]. Therefore,
the current practice of administering tPA by iv infusion is particularly unphysiological
and risky.
After fibrinolysis is initiated by tPA, additional
plasminogen binding sites are created which are on the E-domain of fibrin [9] and of which there are two [10]. Plasminogen on the first of these undergoes a conformational
change which allows the intrinsic activity of prouPA to activate it [11]. This step is followed by reciprocal activation
of prouPA to its enzymatic form (tcuPA) [12] and
tcuPA then activates the remaining plasminogen completing fibrinolysis.
This dual activator pathway is consistent with the
modes of action of the activators since they are complementary [13] and have a synergistic lytic effect when combined
[14]. This mechanism was also corroborated the
finding that tPA plasminogen activation was specifically promoted by the fibrin
D-domain and that by prouPA is promoted only by the fibrin E-domain [15]. The finding also explains why both tPA and
prouPA are required for lysis at fibrin-specific doses. Since uPA activates two
fibrin-bound plasminogen, one by prouPA and the other by tcuPA, it is
responsible for two-thirds of the fibrinolysis, and tPA one third.
The PATENT trial referred to in the abstract is the
only published study in which the endogenous fibrinolytic paradigm of a
sequential combination of the activators was tested clinically. In 101 AMI patients
a mini bolus (5 mg) of tPA was administered to initiate fibrinolysis. In
keeping with the findings that tPA was only responsible for this step, no
additional tPA was given and it was followed by a prouPA infusion of 90
minutes. The treatment resulted in a complete infarct artery opening rate of
82% and an AMI mortality of 1% [16]. This result
compares with a 45% opening rate and a mortality of 6.3% in the best of the tPA
studies (GUSTO) [17].
Had this fibrinolytic regimen been adopted in 1995
when the PATENT trial was published, almost one million patients who died from
AMI in the US since then could have been saved. In Europe, the number of lives
that could have been saved would be similar.
Unfortunately, not long after this trial the company
that supported the PATENT trial (Farmitalia) was sold to Pharmacia, which
abandoned all cardiovascular drug development. Therefore, the opportunity to do
a second trial with this combination was lost. More recently, a single site
mutant of prouPA has been developed which has the advantage of being five-fold
more stable in plasma at therapeutic concentrations, making it much less likely
to cause bleeding side effects since these are related to non-specific tcuPA
generation. The mutant uPA has all the other properties of native prouPA [18-25] and will be used in a synergistic combination
with tPA.
For ischemic stroke, the need for a more effective and
safer fibrinolytic is particularly urgent since tPA therapy is both
inadequately effective and hazardous. Therefore, a sequential combination of a
mini bolus of 5 mg tPA followed by a mutant proUK infusion (40 mg/h), which is
safe and highly effective is ideally suited for this condition.
4. Conclusion
The function of tPA in fibrinolysis is limited to the
initiation of fibrin degradation which is accomplished by the fibrin-bound
portion of tPA. The traditional administration of tPA by an IV infusion is
based on a misunderstanding of how it functions. It is analogous to trying to
run a car on only its staring motor. Instead, uPA is responsible for continuing
and completing fibrinolysis and the two activators have sequential and
complementary modes of action which gives them a synergistic lytic effect when
combined. Only by using both activators can all the fibrin-bound plasminogen’s
be activated at fibrin-specific, safe doses. This concept was validated
clinically in a study of AMI. According to the results obtained in this study,
had this regimen been adopted in 1995 when it was published, about 50,000
deaths from AMI annually, or close to one million lives, could have been saved.
We don’t have similar figures for stroke, but it is evident that this regimen
of sequential fibrinolysis would have had a major impact on morbidity and
mortality in stroke as well.
5. Acknowledgements
The author was fully responsible for this paper.
6. Conflicts of Interest
The author is the Scientific Director of TSI, the
company developing a uPA mutant for use in therapeutic fibrinolysis.
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