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BRIEF PROPOSAL AN ORTHOMOLECULAR APPROACH TO THROMBOLYSIS DALE G. DEUTSCH* Thromboembolic diseases contribute to the high morbidity and mortality associated with diseases of the heart and blood vessels which account for more than half of all deaths in the United States. Nevertheless, at the present time no clinical reagent is routinely available to the medical community for dissolving blood clots. Of all the possible approaches to this problem, therapy with human plasmin is the most obvious, and yet the least explored. It appears that many of the obstacles that have prevented the use of plasmin in the past are now resolvable . The field of thrombolytic therapy is mainly occupied with clinical evaluation of current forms of experimental therapy [I]. Two agents being tested are the fibrinolytic activators urokinase and streptokinase. Individual studies as well as controlled clinical trials indicate that these substances have great promise for the lysis of thrombi. However, both pose problems as therapeutic agents. Streptokinase , a protein excreted by /3-hemolytic streptococci, is antigenic. Many patients have an antibody due to previous streptococcal infection and continued treatment is contraindicated because of possible anaphylactic reaction. A major shortcoming with urokinase treatment is the great expense: a course of therapy costs thousands of dollars since only a few milligrams of enzyme can be purified from hundreds of gallons of urine after a multistep procedure. Another experimental approach to thrombolysis is based upon the observation that certain pharmacological agents (nicotinic acid, adrenaline, corticosteroids, etc.) temporarily increase fibrinolytic activity in vivo. This has led to a search for a low molecular weight synthetic agent which dissolves blood clots [2]. To date such an ideal compound has not been reported. From a theoretical viewpoint, opinions differ on whether the use of activator or plasmin is the best approach to thrombolytic therapy. An early hypothesis justifying the use of activator argues that the clot contains sufficient plasminogen to account for its dissolution, after activator has diffused to it and produced plasmin (intrinsic clot lysis theory). Furthermore, it is thought that any plasmin formed in the blood is neutralized by antiplasmin [3]. On the other hand, proponents of the plasmin approach contend that the administered plasmin forms a reversible complex with a plasma inhibitor which is transported via the blood to ?Department of Biochemistry, State University of New York at Stony Brook, Stony Brook, New York 11794. Perspectives in Biology and Medicine ¦ Winter 1977 | 307 the clot. Plasmin, having greater affinity for fibrin than inhibitor, then dissociates from the complex attacking the clot (extrinsic clot lysis theory). In this way, it is postulated, coagulation factors (e.g., fibrinogen, V, VIII) and other proteins, except fibrin, are protected from the proteolytic affects of plasmin thus preventing bleeding due to a coagulation defect [4]. Since these hypotheses have been proposed, dozens of in vitro studies have appeared confirming and refuting them [5-8]. This is not surprising. The fibrinolytic enzyme system is complex and new components are still being discovered: an inhibitor of plasminogen activation [9], which may also inhibit plasmin [10], has recently been characterized . Therefore, the pursuit of thrombolytic therapy cannot be based solely on these theories, although by extension they can provide a guide for new approaches. For example, to overcome the bleeding complications that have been reported with urokinase and streptokinase therapy [11, 12], which may also be a problem with plasmin therapy, it may be beneficial to administer these fibrinolytic agents with a dissociable inhibitor which would protect everything but the clot. Plasmin was suggested and briefly investigated as a thrombolytic agent nearly 2 decades ago [13, 14]. Unfortunately, early commercial "plasmin" preparations were of poorly defined potency and composition, and despite some optimistic findings they were abandoned as therapeutic agents. In view of the technological advances of the last few years, it is now possible (I think for the first time) to make plasmin of well-defined purity and potency on a large scale. The best strategy for the production of plasmin involves a two-step procedure: first, plasminogen is isolated from a human blood fraction by affinity chromatography , and second, plasminogen is converted to plasmin by an enzymatic process employing immobilized plasminogen activator. Specifically, a single-step affinity chromatography...


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