JACC Vol . 23, No . 2 February 1994 :544-5 544 President's Page : New From Old - Hirudin and CE JeC SYLVAN LEE WEINBERG, MD, FACC President, American College of Cardiology Few would deny that thrombolysis for acute myocardial infarction belongs in the top rank of great therapeutic interventions . There still may be lingering controversy whether one thrombolytic agent is universally superior, but there is consensus on the adjunctive need for antithrombins and that heparin is not the ideal agent . Eugene Braunwald observed recently that anticoagulation is unique in medical pharmacology in that for 50 years it has been limited to warfarin and heparin (1). That is about to change as research progresses on hirudins as an alternative to heparin . Hirudin has significant advantages over heparin . Unlike heparin, it exerts an effect on clui ,bound thrombin . Heparin can be neutralized by activated phitelets while hirudin cannot . Nor does hirudin cause thrombocytopenia. It is a strange incongruity of modern medicine that recombinant hirudin, soon to be available by the most modern of technologies, derives from one of medicine's most ancient therapeutic agents, the leech . The history of leeches and their ancient uses and legends is inexorably intertwined with that of the physician (2) . The origin of the word leech may be from the old English "laece," meaning physician . While we think of blood-letting as an ancient treatment, it was widely used during the 19th and even in the early part of the 20th century (3) . Great 19th-century physicians such as Sydenham, Stokes and Graves followed the practice of using leeches . In 1839 Marshall Hall, a Fellow of the Royal Society, wrote, "Of the remedies of medicine blood-letting ranks preeminently as first ." He advocated bleeding the patient in an upright position until syncope occurred . Bleeding in the recumbent attitude risked taking too much blood . Syncope was, therefore, a kind of clinical failsafe end point in blood-letting . In the 1912 8th edition of his famous text, "Practice of Medicine," William Osler still advocated blood- Address for correspgndence : Sylvan Lee Weinberg, MD . 111 West First Street, Suite 1045, Dayton, Ohio 45402. 01994 by the American College of Cardiology letting as he had in earlier editions : "To bleed at the very onset in robust, healthy individuals in whom the disease sets in with great intensity and high fever is, I believe, a good practice . . . . Late in the course marked dilatation of the right heart is the common indication . The quantity removed must be decided by the effects ; small amounts are often sufficient ." In the long history of blood-letting in medicine, leeches were used for local as well as systemic bleeding . Examples of the use of leeches were hemorrhoidal tumors ; epididymitis, where the leeches were applied over the spermatic cord, and in ocular inflammations, where the leeches were placed over the temporal areas . In the first third of the 19th century, 5 to 6 million leeches were used annually in Parisian hospitals, and as many as 30 million leeches a year were imported to the United States from Germany . At one time the leech was even considered an endangered species. Since the leech is neither a drug nor a device, its modern use has not been constrained by regulatory agencies (4) For medicinal purposes, the most commonly used leech is Hirudo medicinalis, a fresh water creature, 10 cm long, that sucks blood through contractions of its muscular pharnyx with the ability to ingest 10 times its own weight in blood . Hirudin was first described in 1834 as an anticoagulant secreted by the medicinal leech . It's a polypeptide with an affinity for thrombin . Hirudin inhibits the thrombincatalyzed conversion of fibrinogen to fibrin . Leeches also secrete hyaluronidase and a vasodilator in the form of an antihistamine . Leeches are still used today for repair of grafted skin flaps, digital reimplantations, breast reconstruction and, occasionally, to evacuate periorbital hematomas . Markwardt in a paper entitled, "Hirudin and Derivatives as Anticoagulant Agents" (5), further elucidates the action of hirudin and tells how recombinant DNA technology has produced a number of hirudins similar to the natural sub0735-1097/94/$7 .00 JACC vol . 23, No . 2 February 1994:544-5 stance on so large a scale that widespread clinical trials are now possible . Hirudin is an effective antithrombotic agent in antithrombin 111-depleted individuals and exerts no influence on platelet formation and, therefore, can be used in conditions where heparin-induced thrombocytopenia may present a risk. Anyone who has ever dealt with the thrombolytic complications of heparin-induced thrombocytopenia will appreciate the prospect of an alternative to h° °n . A 1992 Lancet editorial, "Hirudins : Return of the Leech," suggests that hir-adins may be a more effective anticoagulant than heparin in arterial thrombosis including thrombosis after angioplasty or thrombolytic therapy and in the prevention of thrombosis during hemodialysis or cardiopulmonary bypass (6). Startling as it may seem, the idea of hirudin in the treatment of coronary thrombosis or intravascular coagulation is not new . In 1943, Howard Lilienthal published an article in the Journal of the Mount Sinai Hospital titled : "Coronary Thrombosis : Proposed Treatment by Hirudin" (7). Lilienthal cited the use of leeches in early thrombophlebitis of the lower extremity with the leech placed over neighboring tissue and not over the vessel. When the animal relaxed its hold and was removed, often rapid recovery followed with loss of pain and swelling and full ambulation in less than a week . Lilienthal attributed this favorable effect to hirudin remaining in the body after the leech was removed . Actually he was seeking a treatment for coronary thrombosis which in 1943, according to data which he presented from the Metropolitan Life Insurance Company, ranked third as a cause of death exceeded only by cancer and other disorders of the heart . Lilienthal referred to a symposium on coronary thrombosis published in the Proceedings of the Staff Meetings of the Mayo Clinic in which the paper on management advised only rest, analgesia and sedation (7) . But this approach to coronary thrombosis did not satisfy Lilienthal . He described other recent (1943) treatments which included blood-letting using leeches . Lilienthal believed that the importance of the leech in the therapy of coronary thrombosis was not to draw blood, but to leave its hirudin in the body of the patient after the leech had been removed . Dr. Lilienthal, in common with many medical innovators before and since, found little interest among his colleagues WEINBERG PRESIDENIS PAGE 545 for his proposed use of leeches in the treatment of coronary thrombosis . Again, nct too surprisingly, surgeons were more receptive than internists and general practitioners to his new ideas . With permission, he quoted a letter that he had received from the great Dr . Alton Ochsner of New Orleans : "I have tried to get my medical friends interested in using leeches in coronary thrombosis and have told them that if I ever develop it I want them to cover me with leeches because I am thoroughly convinced that hirudin is a potent drug and would be of benefit in some cases ." Lilienthal was prophetic in suggesting that hirudin "may turn out to be an advance in the care of this rapidly increasing disease (coronary thrombosis) and that it would be unfortunate to leave this therapeutic experiment to future generations ." He was correct that anticoagulation would indeed be important in the treatment of coronary thrombosis . As it turned out, the therapeutic experiment which Lilienthal had advocated would be left to "future generations ." Now we are the future generations to which he referred and clinical trials are in progress comparing the efficacy of hirudin and heparin . These trials involve prevention of acute closure after angioplasty, recurrent occlusion after myocardial infarction, and the treatment of patients with unstable angina (1) . It remains to be seen how great a role the ancient leech, indirectly through recombinant hirudin, may yet play in the modern treatment of acute coronary thrombotic syndromes, a role anticipated by Lilienthal in a long forgotten paper more than 50 years ago . Refirellices I . Braunwald E . The emerging role of novel antithrombins [audio tape] . ACCEL Jan 1994 ;26 (no . 1). 2. Adams SL. The medicinal leech--a page from the Annelids of internal medicine. Ann Intern Med 1988,109 :399-405, 3 . Randolph BM . The blood letting controversy in the nineteenth century . Ann Med History 1935 ;7:177-82 . 4 . Fenton WF . Leeches to hirulogs and other thrombin-directed antithrombotics . Hematol Oncol Clin North Am 1992 ;6:1121-8 . 5 . Markwardt F . Hirudin and derivatives as anticoagulant agents . Thromb Haemost 1991 ;66:141-52 . 6 . Hirudins : return of the leech [editorial] . Lancet 1992 ;340:579-80 . 7 . Lilienthal H . Coronary thrombosis : proposed treatment by hirodin . J Mt Sinai Hosp 1943 ;10:135-7 . EDUCATION UPDAM 1993--Commom Below is an update of the training programs listed in the October 1993 issue (JA A CCVol. 22, No . 4: 1244-65) . Changes are in bold type . TAMAINMONNG( PRoGRAms iNADuLT CARDioLoGy Total Trainees for 1993-94 STATEICITYIZIP AZ Phoenix FL Miami INSTITUTION/HOSPITAL PROGRAM DIRECTOR 1st YA1. 2nd Yr. 3rd Yr. partev-, 3n TOWND. hv1 y 'no 03 mysew Mwaffm Other Total Pa*rarnhy 1994-95 PmAwsh ThrAh-A 19 Rov 19%95-595 ' Specialty Training Beyond 3rd Yr. AdNmnal Applicabo: the tot 1995-96 Applicatiorts 85062 Good Samaritan Regional Med . Ctr. Carl T. Hayden VA Med . CV ITCArAQUO. K. Desser, M.D . (UT 2119443 3 3 2 0 8 V 3 1101,94 Y N N N 33101 Univ, of Miami School of Medicine' U . of Miant Jackson Memorial Med . Cir. Miami VA Med. Qr. R. Myerburg, M .D. (305) 5&5-65M 5 6 4 4 19 Y 6 12(01/93 Y N N Y N N N R Kber M .D . 6 6 4 0 16 Y 6 2115/94 Y N Y Y N N Y N N N IA Iowa City 52242 Univ . 0 5, Hospitals & QM* (319) 366.2733 KY Lexington Louisville 40536 University Hospital' Lexington VA Med . Ctr. 40292 Univ. of Louisville Affiliated Hospitals M. SmIlh, ALI). (646) 213-5843 S . Wagrer, M.D. (502) 588-1645 5 5 4 0 14 y 5 1101194 Y Y Y Y N Y Y 5 4 4 2 15 Y 4 11KA3 Y N N Y 11 Y )Y 48235 Sinai Hospital of Detroit S. Gtmtheq M.D. (313) *1015516 4 3 2 0 9 y 3 1231/S93 Y N Y Y Y Y Y Salon Hall University St. Joseph's Hospital & Med. Ctr. St. Michael's Med. Ctr. St. Elizabeth's Hospital 07103 IJMDNJ-New Jersey Medical School VA Med . Cit.-E . Orange 111Mh Israel MW. Ctr.-Newark St. Barnabas R. Watson, M.D. (WB)527-041 4 4 4 2 14 Y 4 2114194 Y N N N N N N 13 . HaWar, M .D. (201) 982-4M 8 3 5 0 16 Y 5 1130194 N N N N N N N 11201 B. Vasavada, M.D . (718) 750.1551 3 2 4 0 9 Y 4 3131194 N N N N N N N 45406 Wright State University Good Samaritan Hospital M. Sakhaii, M.D. (513) 278-2612 2 1 3 0 6 V 2 rda N N N N N N N 25755 Marshall Univ. School of Medicine Affiliated Hospitals R . Touchort, M.D . (304) 696.7237 4 4 2 0 10 y 3 1131194 N N N N N N N M11 Detroit NJ S. Orange Newark NY Brooklyn OH Dayton WV Huntington 07207 Long Island College Hospital Woodhull Med. Ctr. Maimonides Med. CI r. WZ *Candidates residing outside North America may apply for clinical, hands-on third-year training 0,9 14 t4 JACC Vol, 23, No. 2 February 1994 :546 .-7 & T EDUCATION UPDATE CORRECTIONS NING PROD MS >(N PE® C IOLOCY Total Trainees for 19 .93-94 PROGRAM DIRECTOR INSTITUTION/HOSPITAL STATE/CITY/ZIP 547 I sl Yr. 2nd Yr . 3rd Yr Other Total Applications Due for 1995-96 Co Denver 80218 The Children's Hospital Univ. of CO-Hith . Sciences Cv. J . Wiggins, Jr., M .D. (303) 861-6820 0 2 1 0 3 51OA4 NewYork 10021 The New York Hospital' Camel Univ. Medical College 0. Friedman, PA.D . (212 )746-3566 2 2 0 0 4 1/31194 MY C. TRAININC PROGRAMS IN C THORACIC SURGERY Total Trainees for 1993- 94 INSTITUTION/HOSPITAL STATE/CITY/ZIP PROGRAM DIRECTOR 1st Yr. 2nd Yr. 3rd Yr . Other Total Applications Due for 1996-97 IL Chicago 60637 Univ. of Chicago Med . CIC Unin d Chicago Hospital Wyler Children's Hospital R . Karp, M .D. P2) 702-2500 1 1 0 0 2 3/01/94 Boston 02115 MgMm arid Women's Hosp.!Childrei Hasp.' L, Cohn, M .D. 3 3 0 0 6 12131193 MA (617) 732-7678 *Candidates residing outside North America may apply for clinical, hands-on third-year training
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