Stroke as an emergency: Semmelweis redivivus?

Abstract

Simply told, the story of tPA or ‘tissue-type plasminogen activator’ begins like this. In 1952, Danish biochemists isolated a fibrinolytic substance from normal animal tissues. It had been detected a few years before and was known to act through activation of plasminogen. In the mid-1970s, groups in New York and Leuven found that several malignant tumours also secrete a plasminogen activator, generally in proportion to their degree of invasive behaviour. The Leuven group obtained a highly productive melanoma cell line from an American patient and eventually purified it. The Belgian group also observed that the human plasminogen activator had a specific affinity for fibrin: in the absence of fibrin it had only a weak-activating effect on plasminogen, through competitive binding and ‘silencing’ of tPA by α2-antiplasmin. This selective action represented a great advantage—at least theoretically—over the non-specific plasminogen activators urokinase and streptokinase that were available at the time. Indeed in the early 1980s, animal experiments in Leuven and St Louis showed that tPA could dissolve thrombi of venous and arterial origin without systemic fibrinolysis. The first humans to be treated with tPA (from the melanoma cell line, in hindsight with low doses) were two patients in Rotterdam with thrombosis of renal and iliofemoral veins in the region of a transplanted kidney (Weimar et al ., 1981); one of them survives to this day. The clinical experiment resulted from a chance conversation at a scientific meeting between a nephrologist from Rotterdam and a biochemist from the Leuven group. After pilot experiments in patients with coronary thrombosis had proved successful, a proper clinical trial was on the agenda but would require far greater quantities of the substance than could be extracted from the tumour cell line. In collaboration with the Leuven group, scientists at the Genentech corporation cloned the complementary DNA for …