JUNIPER PUBLISHERS-Journal of Cardiology & Cardiovascular Therapy
Fibrinolytic Therapy with TPA Failed because it was based on a Flawed Concept
Authored by Victor Gurewich,
Fibrinolytic therapy has become synonymous
with tPA based on the belief that tPA alone was responsible for natural
fibrinolysis. Although this assumption was belied from the outset by
disappointing clinical results, it persisted, eventually causing fibrinolysis to
be discredited and replaced by an endovascular procedure. Since time to
reperfusion is the critical determinant of outcome, which in acute myocardial
infarction (AMI) means within two hours, a time-consuming hospital procedure is
ill-suited as first line treatment. For this purpose, fibrinolysis is better
suited. The assumption that tPA is responsible for fibrinolysis is contradicted
by published findings. Instead, tPA initiates fibrinolysis which is continued
by urokinase plasminogen activator (uPA) which has the dominant effect. tPA and
uPA gene deletion and clot lysis studies showed the activators to have
complementary functions, requiring both for a full effect at fibrin-specific
doses. They are also synergistic in combination thereby requiring much lower
doses. A clinical proof of concept study in 101AMI patients was published. Each
received a mini IV bolus of tPA followed by a 90 minute infusion of pro-uPA,
the native form of uPA. A near doubling of the 24h TIMI-3 infarct artery
patency rate compared to tPA was obtained. In further contrast to tPA, there
were no reocclusions and the mortality was only 1%. A sequential combination of
both activators, mimicking natural fibrinolysis, holds promise to significantly
improve the efficacy and safety of therapeutic fibrinolysis.
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