Thrombolytic Therapy: An Orchestra without a Conductor

Manyclinicians mistakenly have the perception that thrombolysis is a novel approach to treatment of thrombo~mbolic disease states. In fact, its history is long and extensive. Several sentinal observations have lead to our modern day understanding of thrombolysis. In 1903, Delezenne and Pozerski [1] observed that chloroform treatment of serum save rise to a proteolytic enzyme capable of dissolving blood clots; in 1949, Tillet and Sherry [2] demonstrated that extravascular clots in humans can be dissolved by local installation of streptokinase; in 1952, Johnson and Tillet [3] dissolved experimentally created rabbit ear thrombi with streptokinase infused intravenously; and in 1952, Agress and colleagues [4,5] demonstrated that fibrin clots in canine coronary arteries could be dissolved by a fibrinolytic substance (trypsin) infused intravenously. Demonstration that intravascular thrombus could be dissolved by systemic administration of thrombolytics set the stage for experimentation and clinical use in the treatment of human thromboembolic disease states, recognized collectively as the major cause of morbidity and mortality in modernday medical practice (Table 1). As the broad range of clinical utility offered by thrombolytic therapy was being recognized, potentiallimitations were noted as well. In particular, the thrombolytic agents were found to lack fibrin specificity. Furthermore, their circulating half-lives, potency, and hemorrhagic potential were considered by many to be unsatisfactory. As a result, the scientific community embarked on an intensive campaign to produce "new and improved" thrombolyrics (Table 2) [6-13]. In addition, varying dosing strategies, including prolonged, bolus, and "front loaded" infusions, were, and continue to be, investigated. Although many scientists and authorities in the field believed that newer generation thrombolytics would address the problems of thrombolytic resistance, reocclusion, and hemorrhage, others believed that adjuvant pharmacological therapy was the answer. In other words, the thrombolytics were acceptable, yet because of heightened platelet and thrombin activity in many thromboembolic disease states, additional agents would be required to achieve a maximal response (Table 3) [14-33]. Growth and development of the field of thrombolysis certainly surpasses that of any other area in medicine. There is a wealth of information concerning individual agent structure, function, and activity. Some of the advantages and disadvantages of alternative dosing strategies are also known. This knowledge, coupled with an already impressive and steadily growing assortment of adjunctive agents, places the medical and scientific communities in a challenging position. Clearly, basic science knowledge has advanced far beyond clinical research. To some, it is almost out of sight. A<:, a result, many clinicians find the area of thrombolytic therapy confusing and continue to ask the questions, "What agent should I use, for wtom, at what dose, over what period of time, with which adjunctive treatment, at what risk, at what cost? " It is time to ask an important question: "Should an already limited pool of resources for clinical research be devoted to developing each new thrombolytic or adjunctive agent that springs forth from the bench? " Clearly, the answer to this question is no; however, research dollars are currently being stretched dan-