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