6
HISTORY A Tale of Two Anticoagulants: Warfarin and Heparin Charles E. Copeland, MD, and Cheryl K. Six, DO Department of Surgery, UPMC Mercy Hospital, Pittsburgh, Pennsylvania This article relays the story of 3 men, Karl Paul Link, who is the discoverer of warfarin, and William Henry Howell and Jay McLean, who are the discoverers of heparin. (J Surg 66: 176-181. © 2009 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.) KARL PAUL LINK (1901–1978) Karl Paul Link was born in La Porte, Indiana, the 8th of 10 children to Frederika (Mohr) and George Link, who was a Missouri Synod Lutheran Minister. He received a bachelor’s and a master’s degree at the University of Wisconsin and a doctorate while working with William Tottingham, who was a noted plant biochemist from Johns Hopkins University. Link received a 2-year postdoctoral fellowship at a time when fellow- ships were apparently difficult to obtain. He worked with Sir James Irvine, a distinguished carbohydrate chemist at St An- drews, Scotland; Fritz Pregl, a microchemist in Graz, Austria; and Paul Karrer, an organic chemist in Zurich, Switzerland. He returned to join the faculty at the University of Wisconsin and in 1930 and at the age of 29 became a professor of agricultural chemistry. By 1946, Link had an established reputation as a preeminent carbohydrate chemist and was elected to the Na- tional Academy of Sciences. The Academy presented him with the Kovalenko Award in 1967; this research award was estab- lished in 1952, and it is only given every 3 years. Link received several other prestigious awards, which include the Cameron Award in 1952 from the University of Edinburgh, the John Scott Medal in 1959 from the City of Philadelphia, the Lasker Award in 1955 from the American Public Health Association, and a second Lasker Award in 1960 from the American Heart Association. 1,2 In December 1932, Link was invited by Ross A. Gortner to the University of Minnesota to consider a position there. Gort- ner supplied him with Lee Roderick’s paper on “Sweet Clover Disease of Cattle” as a proposed project should he accept a position. 3 Seven years before Roderick’s paper, in 1924, Frank Schofield described a new disease in cattle caused by damaged sweet clover (Melilotus alba or Melilotus officinalis). Schofield showed that Aspergillus mold was the cause of sweet clover spoil- age but not the cause of a prolonged clotting time and bleeding in cattle. 4 Roderick in 1931 clearly demonstrated that the prolongation of the clotting time was a result of a marked reduction in prothrombin. 5 Both veterinarian authors rec- ommended that farmers not feed damaged sweet clover to cattle and that the bleeding could be corrected with normal bovine blood transfusion. 4,5 Two months after his visit to the University of Minnesota in February 1933, Ed Carlson, who was a farmer from Deer Lakes 305.7 km away, arrived as described by Link, “In a howling blizzard and the mercury hovering near zero,” with a dead heifer, a milk can containing nonclotted blood, and about 100 lbs of spoiled sweet clover.” Link could only offer the advice recommended by Schofield and Roderick to stop feeding the cattle spoiled sweet clover and transfuse sick cattle with normal bovine blood. 1,3-5 For the next 6 years, Link and his graduate assistants worked on identifying the hemorrhagic agent present in spoiled sweet clover. On June 28, 1939, Harold A. Campbell viewed on a microscopic slide crystalline dicoumarin, and within 2 hours, he collected 6.0 mg. 1-3 Mark A. Strahmann took over the project and in 4 months was able to crystalize 1.8 g of the anticoagulant. 1-3 Three subsequent publications, which in- clude “The Isolation and Crystallization of the Hemorrhagic Agent” and “Identification and Synthesis of the Hemorrhagic Agent” in 1941 as well as “Anticoagulant Activity and Struc- ture in the 4-Hydroxycoumarin Group” in 1944, were a series of classic papers reprinted to celebrate the centenary of the Journal of Biological Chemistry in 2005. 2,6-8 Link learned that spoilage of sweet clover resulted in oxidation of coumarin to 4-hydroxycoumarin, and the addition of form- aldehyde, which is a product of additional decay, produced dicoumarin. 3,9 On April 9, 1940, Professor Link wrote to C. L. Christensen, Dean of the College of Agriculture, on the research progress of his graduate assistants Harold A. Campbell, Mark A. Stahman, Ralph S. Overman, and Charles F. Huebner; he gave them credit for the work leading to the discovery of dicoumarin (di- Correspondence: Inquiries to Charles E. Copeland, MD, Department of Surgery, UPMC Mercy Hospital, 1400 Locust St, Pittsburgh, PA 15219; fax: (412) 232-2096; e-mail: [email protected] Journal of Surgical Education • © 2009 Association of Program Directors in Surgery 1931-7204/09/$30.00 Published by Elsevier Inc. All rights reserved. doi:10.1016/j.jsurg.2009.03.035 176

A Tale of Two Anticoagulants Warfarin and Heparin

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Page 1: A Tale of Two Anticoagulants Warfarin and Heparin

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ISTORY

Tale of Two Anticoagulants:arfarin and Heparin

harles E. Copeland, MD, and Cheryl K. Six, DO

epartment of Surgery, UPMC Mercy Hospital, Pittsburgh, Pennsylvania

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his article relays the story of 3 men, Karl Paul Link, who is theiscoverer of warfarin, and William Henry Howell and JaycLean, who are the discoverers of heparin. (J Surg 66:

76-181. © 2009 Association of Program Directors in Surgery.ublished by Elsevier Inc. All rights reserved.)

ARL PAUL LINK (1901–1978)

arl Paul Link was born in La Porte, Indiana, the 8th of 10hildren to Frederika (Mohr) and George Link, who was a

issouri Synod Lutheran Minister. He received a bachelor’snd a master’s degree at the University of Wisconsin and aoctorate while working with William Tottingham, who was aoted plant biochemist from Johns Hopkins University. Linkeceived a 2-year postdoctoral fellowship at a time when fellow-hips were apparently difficult to obtain. He worked with Sirames Irvine, a distinguished carbohydrate chemist at St An-rews, Scotland; Fritz Pregl, a microchemist in Graz, Austria;nd Paul Karrer, an organic chemist in Zurich, Switzerland. Heeturned to join the faculty at the University of Wisconsin andn 1930 and at the age of 29 became a professor of agriculturalhemistry. By 1946, Link had an established reputation as areeminent carbohydrate chemist and was elected to the Na-ional Academy of Sciences. The Academy presented him withhe Kovalenko Award in 1967; this research award was estab-ished in 1952, and it is only given every 3 years. Link receivedeveral other prestigious awards, which include the Cameronward in 1952 from the University of Edinburgh, the Johncott Medal in 1959 from the City of Philadelphia, the Laskerward in 1955 from the American Public Health Association,nd a second Lasker Award in 1960 from the American Heartssociation.1,2

In December 1932, Link was invited by Ross A. Gortner tohe University of Minnesota to consider a position there. Gort-er supplied him with Lee Roderick’s paper on “Sweet Cloverisease of Cattle” as a proposed project should he accept a

osition.3 Seven years before Roderick’s paper, in 1924, Frank

orrespondence: Inquiries to Charles E. Copeland, MD, Department of Surgery, UPMC

cercy Hospital, 1400 Locust St, Pittsburgh, PA 15219; fax: (412) 232-2096; e-mail:

[email protected]

Journal of Surgical Education • © 2009 Association of ProgramPublished by Elsevier Inc. All rig

76

chofield described a new disease in cattle caused by damagedweet clover (Melilotus alba or Melilotus officinalis). Schofieldhowed that Aspergillus mold was the cause of sweet clover spoil-ge but not the cause of a prolonged clotting time and bleedingn cattle.4 Roderick in 1931 clearly demonstrated that therolongation of the clotting time was a result of a markededuction in prothrombin.5 Both veterinarian authors rec-mmended that farmers not feed damaged sweet clover toattle and that the bleeding could be corrected with normalovine blood transfusion.4,5

Two months after his visit to the University of Minnesota inebruary 1933, Ed Carlson, who was a farmer from Deer Lakes05.7 km away, arrived as described by Link, “In a howlinglizzard and the mercury hovering near zero,” with a deadeifer, a milk can containing nonclotted blood, and about 100

bs of spoiled sweet clover.” Link could only offer the adviceecommended by Schofield and Roderick to stop feeding theattle spoiled sweet clover and transfuse sick cattle with normalovine blood.1,3-5

For the next 6 years, Link and his graduate assistants workedn identifying the hemorrhagic agent present in spoiled sweetlover. On June 28, 1939, Harold A. Campbell viewed on aicroscopic slide crystalline dicoumarin, and within 2 hours,

e collected 6.0 mg.1-3 Mark A. Strahmann took over theroject and in 4 months was able to crystalize 1.8 g of thenticoagulant.1-3 Three subsequent publications, which in-lude “The Isolation and Crystallization of the Hemorrhagicgent” and “Identification and Synthesis of the Hemorrhagicgent” in 1941 as well as “Anticoagulant Activity and Struc-

ure in the 4-Hydroxycoumarin Group” in 1944, were aeries of classic papers reprinted to celebrate the centenary ofhe Journal of Biological Chemistry in 2005.2,6-8 Linkearned that spoilage of sweet clover resulted in oxidation ofoumarin to 4-hydroxycoumarin, and the addition of form-ldehyde, which is a product of additional decay, producedicoumarin.3,9

On April 9, 1940, Professor Link wrote to C. L. Christensen,ean of the College of Agriculture, on the research progress of

is graduate assistants Harold A. Campbell, Mark A. Stahman,alph S. Overman, and Charles F. Huebner; he gave them

redit for the work leading to the discovery of dicoumarin (di-

Directors in Surgery 1931-7204/09/$30.00hts reserved. doi:10.1016/j.jsurg.2009.03.035

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umarol) and referred to them as “a worthy quartet of stationorkers.”1 In his 1943 Harvey Lecture on “The Anticoagulant

rom Sweet Clover Hay,” Link again acknowledged his gradu-te assistants and their contributions to the discovery of dicou-arin. He referred to Campbell as “a universal laboratory joint:

e can do almost anything” and related that Stahmann haddeveloped a relentless zeal.”9 Link referred to himself as thespokesman—the reporter—for those who made the discover-es.”3 He later characterized Huebner as “sensitive, brilliant andeft.”3

In 1941–1942, Karl Paul Link lectured at the Wisconsineneral Hospital and at the Mayo Clinic on the anticoagulantroperties of dicumarol and on vitamin K. Vitamin K was dis-overed by Henrik Dam in 1935 in Denmark and was synthe-ized by Edward Doisy in 1939 in St Louis, Missouri; for thisork, they jointly received the Nobel Prize in Physiology oredicine in 1943. Link recognized the similarity between the

iochemical structure of dicumarol and vitamin K and con-ucted experiments to demonstrate that vitamin K reversed theypothrombic state of dicumarol.3,9,10 Within a few days of the941 publication on the synthesis of dicumarol, a request cameo Link from the Mayo Clinic for the anticoagulant, and in 3onths, physicians there published a report on the prolonga-

ion of coagulation and prothrombin times in 6 humans.9,11

Link was hospitalized in September 1945 for 2 months inisconsin General Hospital and then transferred to Lakeview

anatorium for 6 months because of reactivated tuberculosis,hich he had acquired as a fellowship student in Switzerland.1,3

uring the 6 months in the sanatorium, he studied laboratoryecords and read about the history of rodent control.3 In 1942,ink conducted field trials on dicumarol and found that itsctivity was not high enough to make it practical for rodentontrol.3 Link assigned Mark Stahmann and Lester Scheel theesponsibility of reappraising 4-hydroxycoumarin analogsumbers 40 through 65, and they found that analog number 42as more potent than dicumarol.1,3 As with dicumarol, theyatented number 42, and in 1948, Link named the productarfarin by combining the first letters of the Wisconsin Alumniesearch Foundation and promoted it as a rodenticide.1,3,12

In 1950, Link recommended the use of warfarin in clinicaledicine.3 The transition of a substance promoted to extermi-

ate rats was generally met with clinical reluctance. Two events,owever, 1 in 1952 and the other in 1955, added impetus to thedoption of warfarin for clinical use. The first was a report in theournal of the American Medical Association, by Lieutenant Royolmes and Captain Julian Love, United States Navy, on an

nductee who had taken 567 mg of warfarin in 6 days in auicide attempt; the patient was treated with 2 blood transfu-ions and 2 injections of vitamin K and recovered without aomplication.12 The second was a presentation at the Americanollege of Angiology that was published in the November 12

ssue of the Journal of the American Medical Association by Colo-el Byron Pollock, who was stationed at Fitzsimons Army Hos-ital, Denver, Colorado, on the clinical experience of 100 pa-

ients with myocardial infarction or deep venous thrombosis

Fo

ournal of Surgical Education • Volume 66/Number 3 • May/June 20

reated with warfarin.13 President Dwight D. Eisenhower wasreated for a heart attack at Fitzsimons that year (ie, September–ovember 1955). Link received a card from a Wisconsiniteorking at the Fitzsimons Hospital who related that the presi-ent was being treated with “one of your drugs and it is noticumarol.” Link knew of Colonel Pollock’s experience witharfarin and surmised that “the most important man in theorld today was being anticoagulated with warfarin.”3

Robert H. Burris, who was a student, then a colleague, andnally the department chairman of Karl Paul Link, wrote inink’s biographic memoir that Link was a talented and giftedeacher, that he taught with a flair, and that he was the bestecturer of the group.1 Burris also noted that Karl Paul Link wasn accomplished biochemical researcher and mentor, that hestablished a student legal defense fund, and that he was notedn campus for nontraditional dress, large bow ties, flannelhirts, shorts, work shoes, knickers, and sometimes a cape1,2

Fig. 1).The University of Wisconsin established a posthumous Karl

aul Link Fellowship for any student “whose area of study isoncerned with the application of scientific research in the evo-ution and encouragement of a peaceful and just internationalrder.”1

IGURE 1. Karl Paul Link. Photograph taken by Edwin Stein and courtesyf the Wisconsin State Journal, Madison, Wisconsin.

09 177

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ILLIAM HENRY HOWELL (1860–1945)

rom 1899 to 1911, William Howell also served as the dean ofhe Johns Hopkins Medical School.16 In 1909, 2 years beforeis retirement as dean, Howell expressed the conviction duringn address on education at the Harvard Medical School, “thathe heads of major clinics, should be made, as the preclinicalhairmen already were, full-time university professors.” Thischievement was accomplished 2 years later at the Johns Hop-ins Medical School (Fig. 2).15

In 1918, William Howell and Emmet Holt published a pa-er on heparin and proantithrombin. In that paper, Howelloined the name “heparin” as an anticoagulant obtained fromhe liver.14,18 Howell acknowledged Jay McLean’s publicationn 1916 in which McLean briefly described a hepatophosphatidnticoagulant.18,19 Howell had asked McLean if he would likeo have his name added as an author to the Howell–Holt paper,nd McLean declined, feeling that he had participated so littlen that work that he was not entitled to the offer.17 In Howell’s917 Harvey Lecture on “The Coagulation of Blood,” he againcknowledged Jay McLean’s contribution to the discovery of annticoagulant on 4 occasions during the presentation.20

tIGURE 2. William Henry Howell (1860–1945). Photograph courtesyf the Alan Mason Chesney Medical Archives, Johns Hopkins University.

78 Journal o

Howell continued his work on purifying heparin, and 10ears later in 1928 he published in the Bulletin of the Johnsopkins Hospital an article titled “The Purification of Heparin

nd Its Chemical and Physiological Reactions.” In that paper,owell had clearly established that heparin was not a phos-

hatide but a sulfur-containing complex carbohydrate.21

On February 1, 1941, 250 friends and admirers gathered fordinner in the Welch Library to celebrate the 60th anniversaryf William Henry Howell’s graduation from the Johns Hop-ins University. Dr. Edward A. Park served as the toastmas-er.22 Dr. Park was a professor of pediatrics at Johns Hopkinsrom 1927 until his retirement in 1946. He received the firstohn Howland Award from the American Pediatric Society,hich is the most prestigious award given by the society.23

hree keynote speakers addressed the audience. First, Dr. Jo-eph Erlanger spoke, who was 1 of Howell’s foremost pupils,hen Dr. William MacCallum, and finally Dr. Simon Flexner.dditionally, 11 letters and telegrams were read. Erlanger em-hasized Howell’s human attributes noting that he was “gra-ious, sympathetic, approachable, helpful, thoughtful, and thate had an “instinctive comprehension of his fellow men and hiso less certain affection for them.”22

In Howell’s response to the occasion, he related that “whatuccess I have had in teaching, I find it difficult to appraise. Inuch matters one cannot well gather precise data . . . . I haveiven thousands of lectures to students but I do not really knowo what extent I have influenced their actions or their ideals.”e told of a trustee who visited his department and posed a

irect question “What discoveries have you made Dr. How-ll? . . . I found it very embarrassing. I could not think of anyeally important discovery that I could claim as my own.” Heoncluded his remarks by saying, “this good fortune has comeo me, and I thank you out of a full heart.”22

William Henry Howell died in 1945, and Joseph Erlangerrote his obituary emphasizing that he was “an accomplished

nd meticulous investigator,” “an inspiring teacher,” “an ablend considerate administrator,” and that he had “a calm, simplehilosophy of life and the ability to live in the light of thathilosophy.”16

AY MCLEAN (1890–1957)

ay McLean was born in San Francisco in 1890. His father,ohn T. McLean, who was a surgeon, died in 1894 when Jayas 4 years old. Several years later, his mother remarried. The

arthquake and fire in 1906 destroyed his family’s home and histepfather’s business. McLean attended the University of Cali-ornia, Berkeley for 2 years and then took 15 months off toork in a Mojave gold mine at 25¢ an hour.24,25 He devoted

pare time to a variety of part-time jobs. McLean worked in theollege infirmary doing blood counts and urinalyses; he alsoorked at the museum of invertebrate zoology and campusookstores. McLean scrubbed ferry boat decks and served as aailroad mail clerk from Oakland to Denver. McLean related

hat he worked at various odd jobs since age 12.25 His final year

f Surgical Education • Volume 66/Number 3 • May/June 2009

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t Berkeley commenced in 1913, which was concurrently therst year as a medical student, and he received a Bachelor ofcience degree in 1914.24 McLean applied to the Johns Hop-ins Medical School and was rejected. He worked for 15onths in the oil fields and paid off a senior year loan to theniversity of California25 (Fig. 3).McLean moved to Baltimore even though rejected for the

econd-year classes at Johns Hopkins; he decided that he couldork there as well as in California and complete an organic

hemistry course requirement at Johns Hopkins University.hortly after he arrived in Baltimore, he learned of an unex-ected vacancy in the second year and that he would be admit-ed to that class. He paid his medical school fees for the year andalled on Dr. William Henry Howell, who was chairman of theepartment of Physiology.25 He informed Dr. Howell of his

esire to prepare for an academic career in surgery and that heanted a problem that he could reasonably hope to finish andublish in 1 academic year entirely by himself. He was given theroblem of determining what portion of the crude extract ofephalin from the brain was an accelerator of clotting.25 Hebserved that an ether-soluable, alcohol-insoluable extract ofephalin, would accelerate the coagulation of blood and thathen saved batches of cephalin had lost their thromboplastic

hIGURE 3. Jay McLean (1890–1957). Photograph courtesy of Alanason Chesney Medical Archives, Johns Hopkins University.

ournal of Surgical Education • Volume 66/Number 3 • May/June 20

ction, they possessed a strong anticoagulant activity.24,25

cLean related the story that “into a small beaker full of catslood, I stirred all of the proven batch of heparphosphatide andlaced this on Dr. Howell’s laboratory table and asked him toell me when it clotted. It never did.”25 In 1916, Jay McLeanublished his work “The Thromboplastic Action of Cephalin”n the American Journal of Physiology.26 He had realized his hopeo publish in 1 academic year by himself. In his publication, heoted that “the heparphosphatid on the other hand when pu-ified by many precipitations in alcohol at 60 degrees has nohromboplastic action and in fact shows a marked power tonhibit coagulation. The anticoagulating action of this phos-hatid is being studied and will be reported upon later.”26 Ap-arently, Howell often permitted research assistants to publishapers without his name on the work.27,28

Howell offered McLean the opportunity to have his namedded to the 1918 Howell and Holt publication in the Ameri-an Journal of Physiology on “Heparin and Pro-antithrombin”;owever, McLean declined feeling that he “had participated touch a small extent in this later work that I did not feel I wasntitled to the privilege offered.”17 McLean in later years mostertainly regretted that decision.

After graduation in 1919, McLean began a surgical residencyith William Stewart Halsted, and in 1924, he served as a

ull-time assistant attending surgeon with Alan O. Whipple,ho was Professor of Surgery at Columbia University and Chieff Surgery at the Presbyterian Hospital. The next year, 1925,cLean left Columbia and entered the private practice of sur-

ery in New York City.28

In July 1939, McLean moved from New York to Columbus,hio, and joined a short-lived practice with Edward Reinhart. His

ractice consisted of radiology, oncology, and electrocoagulation atrant Hospital.28,29 In 1943, McLean was certified by the Amer-

can Board of Radiology.24McLean had become aware in the940s that most physicians in the academic medical communityecognized William Henry Howell as the discoverer of heparin.28

hile in Columbus, McLean began a campaign to receive appro-riate credit for the discovery of heparin.17

On November 14, 1940, McLean wrote to Charles H. Bestn Toronto, Canada, describing his work on heparin. Six

onths later, he wrote to Best again giving him permission tose the information in his prior letter for presentation in Best’sarvey Lecture on “Heparin and Thrombosis.” Best replied

hat the lecture’s time constraints would not permit the addi-ion of a history of the discovery of heparin.28 During his lec-ure, however, Best did acknowledge McLean’s presence in theudience and referred to McLean’s 1916 work.30 In a 1959ublication on the preparation of heparin and its use in the firstlinical cases, Best referred to Jay McLean as the discoverer ofeparin 3 times.31 On June 22, 1945, several months afterilliam Henry Howell’s death on February 6, McLean was

nterviewed on national radio by celebrity Milton Cross onThe Doctors Talk it Over.” McLean was introduced as theiscoverer of heparin and discussed the evidence for the use of

eparin in acute coronary thrombosis.28,29

09 179

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In 1947, McLean moved to Washington, DC, to become theirector of the Bureau of Cancer Control. Two years later, in

949 he moved to Savannah, Georgia, as director of radiationherapy and consultant in malignant disease at the Savannahumor Clinic until his death in November 1957.27,29 In 1959,years after Jay’s death, an unfinished manuscript on “theiscovery of Heparin” authored by Jay McLean was published.cLean opened by stating “The discovery of heparin came as a

esult of my determination to accomplish something by mywn ability.”25

In 1985, Conrad Lam published an article titled “Thetrange Story of Jay McLean, the Discoverer of Heparin,” Lamelated that “the only honor Jay ever received came six yearsfter his death . . . . I wish fate had been kinder to my friend Jayhen he was alive.”29 The honor was in the form of a 2 ft � 4

t brass plaque presented to the Johns Hopkins Medical Schooly the Conference on Bleeding in the Surgical Patient from theew York Academy of Science. Erik Jorpes, who was a Swedish

iochemist involved in the early development of heparin, pro-osed the original inscription on the plaque to read “JaycLean, while a first year medical student working in William. Howell’s laboratory at the Johns Hopkins Medical School in

916, discovered heparin.” The inscription was unacceptable tohomas B. Turner, dean of the medical school, and he wrote to. I. Weisblat of Upjohn and strongly suggested that the in-

cription should in some way recognize Dr Howell’s role in theiscovery of heparin.17,28 The final inscription reads, “JaycLean, 1880–1957. In recognition of his major contribution

o the discovery of heparin in 1916 as a second-year medialtudent in collaboration with Professor William H. Howell,his plaque is presented to the Johns Hopkins Medical School athe Conference on Bleeding in the Surgical Patient held by theew York Academy of Science, May 3, 1963.”17,27,28 A mon-

tary award of $6000 was given to Jay McLean’s widow.27,32

Karl Paul Link and William Henry Howell were brilliantesearchers and outstanding mentors. Link openly acknowl-dged the work of his graduate students, and generally the dis-overy of warfarin is considered a product of the Wisconsinlumni Research Foundation. William Henry Howell permit-

ed McLean, as he had done with other students, to publish aesearch project under his name only. Jay’s publication sealedis wish to accomplish something “entirely by himself.”cLean’s observation led Howell to change course and to focus

n an anticoagulant and later name the anticoagulant heparin.t is appropriate that they share in the recognition for thatiscovery. McLean, however, never attained the goal of becom-

ng an “academic surgeon,” and in fact, during the last 14 yearsf his life, he practiced radiologic oncology.

EFERENCES

1. Burris RH. Karl Paul Link. In: Biographical Memoirs ofKarl Paul Link, vol. 64. Washington, DC: National Acad-

emy of Sciences; 1994:176-195.

80 Journal o

2. Kresge N, Simoni RD, Hill RL. Hemorrhagic sweet cloverdisease, Dicumarol and warfarin: the work of Karl PaulLink. J Biol Chem. 2005;280:e5.

3. Link KP. The discovery of Dicumarol and its sequels.Circulation. 1959;19:97-107.

4. Schofield FW. Damaged sweet clover: the cause of a newdisease in cattle simulating haemorrhic septicemia andblackleg. J Am Vet Med Assoc. 1924;64:553-575.

5. Roderick LM. A problem in the coagulation of blood:“sweet clover disease of cattle”; North Dakota AgriculturalExperimental Station. Am J Physiol. 1931;96:413-425.

6. Campbell HA, Link KP. Studies on the hemorrhagicsweet clover disease iv. The isolation and crystallization ofthe hemorrhagic agent. J Biol Chem. 1941;132:21-33.

7. Stahmann MA, Huebner CF, Link KP. Studies on thehemorrhagic sweet clover disease v. identification and syn-thesis of the hemorrhagic agent. J Biol Chem. 1941;138:513-527.

8. Overman RS, Stahmann MA, Huebner CF, et al. Studiesof the hemorrhagic sweet clover disease xiii. Anticoagulantactivity and structure in the 4-hydroxycoumarin group.J Biol Chem. 1944;153:5-24.

9. Link KP. The anticoagulant from spoiled sweet cloverhay. Harvey Lect. 1943;34:162-216.

0. Last JA. The missing link: the story of Karl Paul Link.Profiles in toxicology. Toxicol Sci. 2002;66:2-4.

1. Butt HR, Allen EV, Bollman JL. A preparation from spoiledsweet clover [3, 31-methylene-bis-(4-hydroxycoumarin)]which prolongs coagulation and prothrombin time of blood:preliminary report of experimental and clinical studies. ProcStaff Meet Mayo Clin. 1941;16:388-395.

2. Holmes RW, Love J. Suicide attempt with warfarin, abishydroxycoumarin-like rodenticide. JAMA. 1952;148:935-937.

3. Pollock BE. Clinical experience with warfarin (coumadin)sodium, a new anticoagulant. JAMA. 1955;159:1094-1097.

4. Fye WB. Heparin: the contributions of William HenryHowell. Circulation. 1984;69:1198-1203.

5. Harvey AM. Fountainhead of American physiology: HNewell Martin and his pupil William Henry Howell.Johns Hopkins Med J. 1975;136:38-46.

6. Erlanger J. Obituary: William Henry Howell (1860-1945). Science. 1945;101:575-576.

7. Baird RJ. Presidential address: “Give us the tools . . .” the

story of heparin—As told by sketches from the lives of

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William Henry Howell, Jay McLean, Charles Best, andGordon Murray. J Vasc Surg. 1990;11:4-18.

8. Howell WH, Holt E. Two new factors in bloodcoagulation—Heparin and pro-antithrombin. Am JPhysiol. 1918;47:328-341.

9. Marcum JA, Howell WH, McLean J. The experimentalcontext for the discovery of heparin. Perspect Biol Med.1990;33:214-230.

0. Howell WH. The coagulation of blood. Harvey Lect.1917;12:273-324.

1. Howell WH. The purification of heparin and its chemicaland physiological reactions. Bull Johns Hopkins Hosp.1928;42:199-206.

2. Park EA. The celebration of the sixtieth anniversary of DrWilliam H Howell’s graduation from the Johns HopkinsUniversity. Bull Johns Hopkins Hosp. 1941;68:291-308.

3. Strain JE. Biographical sketches of the first editorialboard of those who edited pediatrics. Pediatrics. 1998;

102(suppl):191-193.

ournal of Surgical Education • Volume 66/Number 3 • May/June 20

4. [No authors listed]. Jay McLean (1890-1957), discovererof heparin. JAMA. 1967;201:144.

5. McLean J. The discovery of heparin. Circulation. 1959;19:75-78.

6. McLean J. The thromboplastic action of cephalin. Am JPhysiol. 1916;41:250-257.

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