In a patient experiencing a stroke, tPA must be administered in a hospital setting following a computed tomography (CT) scan (to rule out a hemorrhagic stroke), and this must be done within 0-4.5 hours following stroke onset. Even if this strict time window is achieved, high-dose tPA carries a risk of brain hemorrhage.
The main treatment for heart attacks is primary percutaneous coronary intervention (PCI, or balloon angioplasty), an invasive procedure that may cause smaller clots to break off and occlude smaller vessels downstream of the initial blockage, thereby increasing risk of future events.
The standard thrombolytic regimen of high-dose tPA monotherapy contrasts with how tPA functions biologically. In the fibrinolytic (fibrin-dissolving) pathway, tPA induces fibrinolysis together with prourokinase (proUK), the body’s other natural plasminogen activator. During tPA's clinical development, experts did not sufficiently recognize that without proUK, thrombolysis by tPA alone was suboptimal. However, when these two activators were tested in a low-dose sequential regimen, investigators observed a synergistic fibrinolytic effect in vitro; a comparable effect was later confirmed in vivo, in human subjects.