In 1983, I first entered into the realm of plasminogen activation, the enzymatic process underpinning fibrinolysis and thrombolysis. Tissue-type plasminogen activator (tPA) has just been cloned and expressed and had great expectations for thrombolysis for patients with myocardial infarction and was eventually approved by the FDA in 1987. There was little to no expectation that tPA would ever be considered as a treatment option for acute ischaemic stroke (AIS). In fact, it was actively discouraged. But eventually it was tested for AIS and approved by the FDA in 1996.
During this period, my research was focused on how tPA was expressed and regulated and I soon found out that almost everything regulated tPA expression, from cytokines, oncogenes, growth factors and others. In the early 1990’s tPA was found to be expressed in the brain while we and others went on to show that tPA could be neurotoxic. That tPA could be neurotoxic coincided with its FDA approval for AIS. tPA thrombolysis was not an easy road and was immensely controversial and became the subject of much litigation. Adding to this was the growing sense among the basic science community that tPA and the fibrinolytic system, did not only focus on fibrin and blood clot removal, but played critical roles in areas well outside of haemostasis. Its physiological role in the brain was becoming clearer, influencing neuronal function, blood-brain barrier permeability and in neurotransmission. Adding further to the mystery was the role of tPA in inflammation, immunity, cell migration, development…and the list goes on.
tPA was the only approved thrombolytic for AIS, but it was poorly efficacious, required an infusion over 1h, and could promote intracerebral haemorrhage. Tenecteplase (TNK), which is over 98% identical to tPA, was developed before tPA was approved for AIS and before the broad biology of tPA was appreciated and was made for one reason only, that being to extend the plasma half-life of tPA to avoid the need for infusions and to administer as a bolus injection. However, large scale clinical trials have reported that TNK is “non-inferior” to tPA, hence we are essentially back to the start, looking for a more efficacious and safer means to remove blood clots.
I will overview the field of thrombolysis from the beginning and to where we are at present and what the future might hold.