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BREAKTHROUGHS SUMMARY ARTICLE The Full-length version of this article is also available, published online as http://www.fasebj.org/cgi/content/full/19/6/671e.< /FONT> |
Between 1970 and 2000, life expectancy in the United States increased by six years and nearly two thirds of that increase can be attributed to reductions in mortality due to heart disease and stroke (1)
. Although primary prevention (e.g., improved life style with reduction in smoking, diet, aspirin therapy in high risk individuals, etc.) played an important role in this improvement, the application of newer treatment modalities, such as fibrinolytic drugs, has had a significantly greater effect, at least for coronary artery disease, and perhaps also for cerebrovascular disease. Indeed, thrombolysis itself, which is the therapeutic breakdown of thrombus or blood clots, has led to a 25% relative improvement in mortality compared with placebo in patients with acute myocardial infarction (AMI) (2)
, and a very significant reduction in the rate of death or dependency in patients with acute ischemic stroke from 68.3% to 55.2% (3)
. These benefits of thrombolysis translate into absolute benefits of 26 lives saved per 1,000 patients with AMI treated, and 126 fewer dead or dependent stroke patients for every 1,000 thrombolysis-treated patients within 3 h of symptoms onset.
The story of the development of thrombolytic or, more properly named, fibrinolytic drugs parallels the history of the "reperfusion" theory of treatment for AMI, and subsequently for ischemic strokes. Although very early work in the field had implicated blood clots as the primary culprits in both types of ischemic vascular events, most physicians in the 1940s and 1950s believed that thrombosis was a secondary event to cardiac muscle or brain injury. A sense of urgency to accelerate the removal of occluding blood clots did not drive the field again until Dr. Sol Sherry, working at Washington University in St. Louis with the Drs. Anthony Fletcher and Norma Alkjaersig, applied knowledge of bacterial enzymology to the problem. They demonstrated that blood clots could be dissolved in vivo with streptokinase (SK), a single-chain protein isolated from the broth of Lancefield group C ß-hemolytic streptococci (4)
. Nearly 30 years passed, however, before the combined results of promising (but unconvincing), small earlier trials of SK treatment were subjected to meta-analysis, and shown to reduce significantly the mortality from AMI (5)
. SK was found to induce reperfusion, which resulted in improved ventricular function. This method of revascularization was the beginning of the modern era of combined modality treatment.
The convergence of discoveries in basic and applied research enabled the development of a whole new class of drugs based on the principles learned with SK. Advances in imaging technology and real-time physiologic measurements of cardiac and cerebral function allowed more detailed understanding of the importance of early reperfusion of coronary arteries (and subsequently cerebral vessels) to salvage organ function after vascular occlusion. Advances in biochemistry and molecular biology resulted in the cloning of the gene for tissue plasminogen activator (t-PA), which in contrast to SK, is not immunogenic and has high specificity for fibrin.
Cell culture techniques and recombinant DNA technology facilitated the rapid characterization and subsequent production of quantities of t-PA permitting the application of thrombolysis to large, multi-institutional clinical trials. In recent years thrombolysis has been applied widely, often in situations where other approaches to "reperfusion" (e.g., angioplasty, coronary or cerebrovascular stenting and/or bypass surgery) may not be readily available. The next chapter is already unfolding with the development of many new modified thrombolytics with longer plasma half-lives and newer anticoagulant drugs that can be used to prevent recurrence of thrombosis following effective thrombolysis.
Thus, the story of the development of fibrinolytic drugs is truly the story of modern translational medicine—from bench to bedside and back again, as basic science provides answers to the needs of the patient.
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