PRELUDES AND PROGRESS

Heparin: the contributions of William HenryHowellW. BRUCE FYE, M.D.

PAUL WEISS, one of America's leading biomedicalscientists for the past half century has claimed, "Sci-entific knowledge is a unitary entity, continuous andcoherent all the way down from the fortuitous discov-ery of novel facts and the emergence of ideas or in-sights, up to the most utilitarian exploitation of theirlessons for the good of man in medicine. " ' The evolu-tion of our understanding of the coagulation of theblood, the discovery of heparin, and its subsequentexpanding role in the practice of cardiology and car-

diovascular surgery amply substantiate Weiss' claim.William H. Howell (1860-1945) was interested in

the physiology of blood coagulation throughout hislong career.'-5 He was born in Baltimore in 1860 andbecame interested in science while a high school stu-dent at Baltimore City College, where he was appoint-ed laboratory assistant to Powhatan Clarke, M.D., theprofessor of natural science. Howell would later recall,"I enjoyed the work immensely. The Professor gave

me every possible encouragement in carrying on pri-vate experiments."3 Howell continued, "Stimulatedby this task of scientific knowledge, I made up my

mind to study medicine. . . I was greatly interested inthe newly-founded Johns Hopkins University and de-cided to take its chemical-biological course as a prep-

aration for a career in medicine."3 When he was 18Howell wrote to John Shaw Billings requesting infor-mation about the newly initiated premedical course atJohns Hopkins. Billings had played a major role inplanning the medical aspects of the Johns HopkinsUniversity and the Johns Hopkins Hospital, andHowell may have attended some of Billings' lectureson medical education delivered at Johns Hopkins be-ginning in the fall of 1877.6 Billings encouraged

Dr. Fye is the Chairman of the Department of Cardiology at theMarshfield Clinic in Marshfield, Wisconsin, a Clinical Assistant Pro-fessor of Medicine at the University of Wisconsin in Madison and at theMedical College of Wisconsin in Milwaukee, and a member of severalsocieties, including the American Osler Society and the American Asso-ciation for the History of Medicine. He has had a long-standing interestin the literature and history of medicine, the history of cardiology, andthe development and implementation of advances in diagnostics andtherapeutics, leading to numerous publications in these areas.

Address for correspondence: W. Bruce Fye, M.D., Department ofCardiology, Marshfield Clinic, 1000 North Oak Ave., Marshfield, WI54449.

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Howell to apply directly to Daniel Gilman, the presi-dent of the university, and advised him "to attend thepreliminary course for those intending to study medi-cine which has been inaugurated at the University."*At this point in his career Howell anticipated practicingmedicine and in his formal application for admission tothe university claimed, "my purpose, in wishing toenter the University, is to obtain that preliminary sci-entific training which I believe to be essential to one

desiring to become a capable and well informed physi-cian. Especially am I anxious to take advantage of theopportunities offered for the experimental study ofphysiology and chemistry.'"tUpon entering the John Hopkins University in 1879

Howell became a pupil of H. Newell Martin, who hadbeen appointed professor of biology upon the openingof the university in 1876. Martin, born in Ireland in1848, had been a student of and assistant to ThomasHenry Huxley and Michael Foster, the leading physi-ologists of Great Britain. Martin had been very suc-

cessful in initiating a program of advanced teachingand research in biology at Johns Hopkins, and withintwo years of its foundation Martin's laboratory was

favorably commented on in the Boston Medical andSurgical Journal, where it was noted that "advancedstudents and persons engaged in biological researchare provided with rooms apart from the general labora-tory, where they can carry on their work without inter-ruption. "7 The officers and first faculty of the JohnsHopkins University had a commitment to original re-

search that was unparalleled in American institutionsof higher learning at the time. Their pride is revealed inthe early official circulars of the university, whereMartin's laboratory is described as "very completelyfitted up and so far at least as regards physiology willpresent facilities for work unequalled, it is believed, inthis country, and excelled by but few laboratoriesabroad. ":t

*John Shaw Billings to William Howell, Feb. 6, 1879. Howell pa-pers, The Alan Mason Chesney Archives, The Johns Hopkins MedicalInstitutions. Hereafter Chesney Archives.

tHowell WH: Excerpts from his original application (to the JohnsHopkins University), Feb. 17, 1879. Chesney Archives.

*Partial arrangements for instruction, 1876-77. Johns Hopkins Uni-versity, Official Circulars, No. 4. Baltimore, August 1876, p 6.

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After receiving his B.A. degree in 1881, Howellformally enrolled as a graduate student in biology inMartin's department at Johns Hopkins. This providedHowell with a unique opportunity to undertake originalresearch in a well-endowed institution staffed with en-thusiastic young scientists. Martin appreciated the rolehis department might play in advancing Americanhigher education. In an 1876 address he noted to hispupils and co-workers, "It behooves you as well as meto recognize what a heavy responsibility lies upon us.Upon the work that we do and the spirit in which we doit, upon the character we give our laboratory at its start,much of its future success or failure depends. If we allwork honestly and thoroughly, it will win esteem andreputation; if we are careless and half-hearted, it willbecome of low repute.. 8To receive a Ph.D. from the university, each grad-

uate student was eXpected to prepare a thesis based onoriginal research. Martin suggested that Howell inves-tigate the difference in coagulability between arterialand venous blood. Although it is impossible to knowwith certainty the reason for Martin's sUggestion, sev-eral contributing factors may be proposed. The mecha-nism of the clotting of blood had interested scientifical-ly oriented physicians for centuries.9 10 Martin's teach-er, Michael Foster, had published an extensive reviewof theories of blood coagulation in 1864." WhileHowell was still an undergraduate, Martin had initiat-ed a series of studies on the mammalian heart and haddeveloped an isolated cardiac preparation to facilitatehis investigations. 12 It had been known for more thanhalf a century that defibrinated blood would not clot,and Martin used this in his experimental preparations.

Howell began to investigate the clotting of arterialand venous blood and later recalled

After working at it for a month or two without any assistance Icame to the conclusion that there was nothing in the problem,and made a formal call upon Martin.. to ask his permission tosubstitute another problem that had been suggested by my read-ing. He agreed, and I worked at my experiments very happilyfor the rest of the year, with only an occasional short visit fromhim to enquire how things were going. But when I took thefinished dissertation to him he expressed himself as pleased withthe result, and thereafter admitted me to a sort of inner circle.*

Howell's thesis, "The Origin of the Fibrin Formed inthe Coagulation of the Blood," was published in De-cember 1884.'3

In the 1880s Martin's department of biology com-

prised a remarkably enthusiastic group of young bio-medical scientists, who would later be identified as

*Howell WH: Autobiographical notes. Manuscript ca. 1933. Ches-ney Archives.

leaders in their specialized fields. They included Wil-liam K. Brooks, morphologist; William T. Sedgwick,embryologist; Henry Sewall, physiologist; and Ed-mund B. Wilson, embryologist. Howell recalled,"The experiences of those years stand out in my mem-ory as the golden period of my life. We were all tre-mendously enthusiastic, for we knew that we weredoing something worthwhile and something that wasnot being done anywhere else in the world, and thespirit that prevailed in the laboratory approached moreclosely the ideal of scientific work than in any environ-ment that I have since experienced.'*

Howell abandoned his original intention of becom-ing a practicing physician and decided to devote him-self to a career in physiology. In this era very fewopportunities for full-time careers in teaching and re-search in the biomedical sciences existed in America.Howell claimed that it was the receipt of a scholarshipand subsequently a fellowship at Johns Hopkins thatwas responsible for his decision to pursue a scientificcareer rather than to eniter medical practice. By the ageof 25 he had published six major papers from Martin'slaboratory and was recognized as a promising experi-mental physiologist. Henry Sewall left the departmentto become professor of physiology at the University ofMichigan in 1882, and William Sedgwick departed in1883 to accept an appointment as assistant professor ofbiology at the Massachusetts Institute of Technology.With these departures Howell's role in Martin's de-partment expanded. Upon the receipt of his doctoratein 1884 Howell became chief assistant in Martin'sdepartment with the title of assistant professor of biol-ogy. To preserve more time for his own research Mar-tin shifted much of the elementary instruction toHowell.

After the publication of his thesis on fibrin, Howellpublished six papers between 1884 and 1890 relatingto the physiology and morphology of blood and itscomponents. In 1888 Howell was promoted to associ-ate professor and assumed responsibility for all theundergraduate courses in physiology. The followingyear Henry Sewall resigned from the chair of physiol-ogy at Michigan because of ill health and suggestedthat his former associate Howell be elected his succes-sor.'4 In a letter to the pregident of the University ofMichigan, Howell claimedThe chief drawback to the pleasant.position 1 hold at present isthat the onerous duty of instructing thirty or.more men in practi-cal laboratory work- together with my lectures and executiveduties leave me little or no time for original research. I under-

*Howell WH: Autobiographical notes. Manuscript ca. 1933. Ches-ney Archives.

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stand that the Ann Arbor position offers opportunities for workof this kind and I therefore feel very anxious to obtain it, as I amprepared for and more than desirous of utilizing every chance toengage in good physiological work.*

During his brief tenure at the University of MichiganHowell was awarded a medical degree and extendedhis studies on the morphology of blood cells, publish-ing the first description of the incomplete extrusion ofthe nucleus of the red blood corpuscle, which mostcommonly occurs after splenectomy (Howell-Jollybody).'5

Excessive teaching demands at the University ofMichigan left relatively little time for original researchand caused Howell to become quickly frustrated withhis appointment there. Responding to a job offer fromHenry P. Bowditch, professor of physiology at Har-vard, Howell noted

It is not altogether easy for me to decide at once for though inmany ways such a position as you describe would be moreagreeable to me than the one I hold at present, yet in somerespects the reverse is true. The laboratory here is well providedwith apparatus and the regents are generous in making appropri-ations for new instruments. The position is one of great freedomas far as the kind and the extent of the work is concerned butheretofore the amount of teaching in the medical and literarydepartments has been so heavy that but little leisure time is leftfor research - though they have promised me relief in thisregard.

He continued

My ambition as a physiologist is to investigate. If your schedulefor the four years' course is sufficiently developed to permit youto say anything more definite as to ihe time I should have to giveto instruction and the probable time I should have for research itwould help tne materially in coming to a conclusion. I recognizethat in a position such as you suggest the subordinate shoulddo much of the drudgery of the teaching, but I feel it necessaryfor a healthy growth to have some leisure time also for inves-tigation. t

Turning to the issue of salary in a letter written threeweeks later Howell claimed, "If the conditions of theposition are such that you could offer me a larger salaryI should feel as though I could accept the positioncheerfully at once.... Certainly a man can not do hisbest work for his College if he feels that he mustalways be looking for chances to augment his incomefrom sources other than his regular salary."'Thus several themes that recur in present-day nego-

tiations regarding academic positions were manifest inthe discussions of William Howell regarding his ap-

*William Howell to James B. Angell, July 10, 1889. Michigan His-torical Collections, Bentley Historical Library, University of Michigan.

tWilliam Howell to Henry P. Bowditch, March 5, 1892. Bowditchpapers, Francis A. Countway Library of Medicine, Harvard University.

*William Howell to Henry P. Bowditch, March 28, 1892. CountwayLibrary.

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pointments nearly a century ago. He remained at Har-vard only one year and returned to Baltimore in 1893as professor of physiology in the newly opened JohnsHopkins Medical School. This appointment was madepossible by the resignation due to ill health of Martin ata critical period in the development of the universityand its medical school. Howell's stature as a physiolo-gist was enhanced by the appearance in 1896 of AnAmerican Text-Book of Physiology, 16 which he editedand which contained contributions by America's lead-ing physiologists. Beginning in 1892 Howell continu-ously served as a member of the council of the recentlyfounded American Physiological Society, until he waselected president of the organization in 1905.

Despite a lapse of more than a decade in productiveresearch relating to anticoagulation, Howell main-tained his interest in the subject. Writing in 1896 heclaimed, "The clotting of blood is such a prominentphenomenon that it has attracted attention at all times,and as a result numerous theories to account for it havebeen advanced. . . It happens that at the present timea great deal of attention is being paid to this subject byexperimenters, and it is possible that at any momentnew facts may be discovered which will alter presentideas of the nature of the process. 17 Writing of bloodcoagulation in his own textbok of physiology in 1905,Howell observed that "the theories that have beenproposed in recent years are numerous and conflict-ing.`"18 Comparing Howell's comments in 1896 on"why blood does not clot within the blood-vessels"with the same section in his 1905 textbook, an impor-tant concept appears, the role of antithrombin. Al-though Howell was skeptical at this point about theexistence of a natural circulating anticoagulant, he ac-cepted the views of others regarding the existence innature of substances that retarded the coagulation ofblood. Among the substances he mentions are snakevenom and a substance called "hirudin," the activeprinciple first extracted from the medicinal leech (Hir-udo medicinalis) in 1905.By 1910 Howell's research was devoted almost ex-

clusively to blood coagulation. In the course of thenext decade he published more than a dozen papersdealing with this subject. Howell's interest in hema-tology and particularly the coagulation of blood wasshared by several of his colleagues at Johns Hopkins. 19

William Osler, the dominant figure at the John Hop-kins medical institutions during his tenure there (1889to 1905), had made classic observations on plateletsearly in his career and maintained his interest in thehistologic and clinical aspects of hematology. Hop-kins' first professor of pathology, William H. Welch,

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had published important studies on thrombosis andembolism. John Jacob Abel, who was a graduate stu-

dent in Martin's biology department in 1883 whenHowell was a fellow, was elected professor of pharma-cology at the Johns Hopkins Medical School upon itsopening in 1893. In the course of Abel's classic experi-

ments which led to the development of "plasmaphaer-esis," a term he coined, the pharmacologist demon-strated that hirudin could be used to prevent thecoagulation of the blood of a dog without adverseeffects. This further stimulated interest in the subject ofanticoagulation at Johns Hopkins.20 21 W. W. Dukedeveloped his techniques for determining the bleedingtime and coagulation time while he was at Johns Hop-kins.22 In his article published in 1910 Duke acknowl-edged Howell's participation in his experiments.Medical students and graduate students at Johns Hop-kins were also involved in original research on bloodcoagulation, in part because of Howell's influence.23A recurring theme in Howell's writings at this time

was the issue of why blood did not clot in vivo. Re-sponding to a theory by Pierre Nolf, Howell recom-

mended in 1910, "Instead . . . of explaining the fluid-ity of the normal plasma by assuming the existence of aspecial substance and giving it the definite name ofantithrombin, it would be a wiser thing for future workto content ourselves with the more general expressionthat in the normal plasma restraining or inhibitory in-fluences are at work which prevent the interaction ofthe fibrin factors, although these may all be present insolution. '23

Howell continued to pursue the concept of physio-logic inhibitors of coagulation, demonstrating in 1911that such a substance is a constituent of normal mam-

malian blood.24 He reported an extensive series of ex-

periments designed to investigate the interactions ofantithrombin and thromboplastin, a clot-promoting tis-sue extract. In his experiments Howell used hirudin as

his antithrombin substance and reported in 1912 that a

substance similar to hirudin was contained in bloodplasma. Furthermore, he demonstrated the transitoryeffect of hirudin on blood coagulation, reporting

If one injects into the circulation a large excess of antithrombin,hirudin for instance, the blood may show a delayed coagulationfor a short time, but soon the excess of antithrombin is destroyedor removed and the normal balance is restored. One may imag-ine in fact that some thrombin is being formed continually in theblood, but that it acts as a hormone to stimulate the liver toproduce a corresponding excess of antithrombin, or possibly theprothrombin itself may have a similar action.25

Howell presented his concept of the mechanism ofcoagulation of the blood at the annual meeting of theNational Academy of Sciences in 1914, where he once

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again emphasized the role of antithrombin in maintain-ing the normal fluidity of the circulating blood.26

Although certain aspects of Howell's conceptualiza-tion of blood coagulation and the factors that preventspontaneous coagulation in vivo have been proved in-correct, his persistence in investigating those phenom-ena led to an important discovery. Heparin was isolat-ed in Howell's laboratory in 1916 by Jay McLean, amedical student from California.27 McLean's cousinwas Herbert McLean Evans, who had returned to Cali-fornia the previous year after receiving his medicaldegree and serving on the staff in the anatomy depart-ment at Johns Hopkins. While a high school senior inSan Francisco, McLean had read Abraham Flexner'sreport on medical education, in which Johns Hopkinswas proclaimed the leading American medical school.Before entering the Johns Hopkins School of Medi-cine, McLean spent one year in the medical depart-ment of the University of California in San Francisco,where he studied physiology under S. S. Maxwell.Maxwell had been a graduate student in H. NewellMartin's Department of Biology at Johns Hopkinsfrom 1888 to 1890. Moreover, McLean had usedHowell's textbook of physiology in the Californiacourse, so he had several reasons to be familiar withthe basic medical science programs at Johns Hopkins.Conceivably emulating his cousin Evans, McLean de-cided to emphasize the basic medical sciences in hiseducation and applied to William Howell for a researchproject in physiology.27 Howell suggested to McLeanthat he study the nature of the thromboplastic sub-stance to identify the active principle of this extract. Itis not surprising that Howell suggested the theme ofblood coagulation to the young student. L. E. Holt,Jr., a freshman medical student the following year,asked Howell to suggest a research project; Howellreplied, "Well, Mr. Holt, you know we're mostlyinterested in blood clotting around here; would youlike to work on that?"4McLean became quite sensitive regarding his own

role in the discovery of heparin. Writing to the Canadi-an physiologist Charles Best in 1940, McLean com-plained that Howell had received disproportionatecredit for the discovery, which McLean claimed washis own.28 It would appear to be true that McLeanidentified a potentially fertile area in the broad subjectof blood coagulation and proceeded with relativelylittle supervision from Howell to identify a specificanticoagulant substance which Howell would name

heparin, reflecting its derivation from liver tissue. De-spite a request from Howell that he delay publicationof his findings until the extract could be more fully

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characterized, McLean reported his experiments in1916. Acknowledging in the introduction of his paperthat the work was undertaken at Howell's suggestion,McLean proceeded to demonstrate that a phospha-tid isolated from the liver "has no thromboplastic ac-tion and in fact shows a marked power to inhibit thecoagulation. "'29

In his Harvey lecture delivered in 1917 Howell ac-knowledged the work of McLean, naming the sub-stance he had discovered "antiprothrombin. "30 In thislecture Howell described experiments in which thenew substance was injected intravenously into dogswithout apparent adverse effects, although the "bloodwithdrawn from the animal a few minutes after theinjection does not coagulate. The effect of the anti-prothrombin wears off gradually, but the coagulationtime may be greatly prolonged forhours after the injec-tion." In experiments in vitro Howell demonstratedthe dose-response relationship of the substance and itseffects on blood clotting. He concluded by noting theapparent lack of injurious effects resulting from theinjection of this substance into the living animal andproclaimed, "We may hope therefore that [it] will finda suitable application in experimental work and possi-bly in the therapeutic treatment of disorders of coagu-lation. " In 1918 Howell published a paper with Holt inwhich he proposed the term "heparin" for the anti-prothrombin substance McLean had isolated two yearsearlier and described its preparation.3"

During the 1920s, Howell together with variousgraduate students and colleagues at Johns Hopkins fur-ther investigated the structure and mechanism of actionof heparin. Experimentation with heparin was facilitat-ed by its commercial availability beginning in 1922through the Baltimore firm of Hynson, Westcott &Dunning. In 1928 Howell reported using heparin inhuman subjects. He wrote

The strong anticoagulant action of heparin, the absence of inju-rious reactions when it is injected intravenously, and the factthat its solutions are very stable and can be readily stabilized byboiling suggested that the purified product might be useful in thetransfusion of blood in human beings. . Its applicability forsuch purposes was tested upon several patients in the medicalwards of the Johns Hopkins Hospital.... Ten transfusionswere made upon six patients....32

Although two of the ten patients developed febrilereactions with chills after the transfusions, Howellconcluded that purified heparin was a safe anticoagu-lant for blood transfusions. In 1930 at the age of 70Howell published a report of repeated intravascularinjections of heparin in a dog. In this brief paperHowell noted, "Single injections of the purified hep-

1202

arin in man or in the dog seem to be entirely withoutinjurious effects, and it has been suggested that theheparin might be used to advantage in cases of venousthrombosis in man. Owing, however, to the transitoryeffect of the heparin when given in vivo it would seemto be necessary, if so used, to repeat the injections atcertain intervals."33Human experiments with heparin were continued in

the 1930s by Best and his colleagues at Toronto,Jorpes and his group in Stockholm, and others. In 1937Crafoord published his important paper demonstratingthe efficacy of heparin in the prevention of postoper-ative thrombosis.34 Howell's studies and the extensionof this pioneering research by others led to the intro-duction of heparin into clinical practice just prior toWorld War 11.28, 35 The value of heparin in the treat-ment of thrombophlebitis and other forms of vascularocclusive disease was rapidly recognized. The devel-opment of modem cardiovascular surgery would havebeen impossible without heparin.36 37 Recently, thetherapeutic applications of heparin have increased withthe renewed interest in thrombolytic therapy for acutecoronary thrombosis and the recognition in vivo ofintracardiac thrombi complicating acute myocardialinfarction and congestive cardiomyopathy, made pos-sible by the development of two-dimensional echocar-diography.38,39

Howell would live to see the results of his basicscience discoveries applied to clinical medicine. Hisfinal review of the broad field of anticoagulation ap-peared in 1941 when he was 81 years old. In this paperHowell discussed the discovery of vitamin K, with itsimportant implications for coagulation physiology andtreatment of hemorrhagic disorders. He mentioned theearly clinical use of heparin in cases of thrombosis andembolism, acknowledging the efforts of Best, Jorpes,and others. Howell concluded, "From many sources,therefore, reports are being made which indicate thatheparin may find a useful application in medicine afterfurther experience has developed the conditions underwhich it can be used most effectively."40 He fullyrecognized that many theoretical issues remained unre-solved, commenting, "On the physiologic side work isstill in progress to determine the origin, chemicalstructure and mode of action of heparin."40

Several factors facilitated Howell's contributions toour understanding of the physiology of blood coagula-tion. He lived at a time when physical and chemicalmethods were being increasingly applied to biologicaland medical problems. After receiving his inspirationfrom Martin and changing institutions three times infour years, Howell spent nearly half a century at Johns

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Hopkins. There he was provided with an intellectuallystimulating atmosphere with adequate support staff

and apparatus for a sustained sophisticated researcheffort. His colleagues shared an interest in the scientif-ic and clinical aspects of the coagulation of the blood.Perhaps most importantly, Howell consistently studiedthe physiology of coagulation for nearly half a century,enhancing his chances for making a significant contri-bution to our understanding of this subject. Writing in1915 he claimed, "Investigators by nature are men

who cannot refrain from following out their ideas.They are driven constantly to such work by interest or

by irritation. Either stimulus is sufficient. I fancy thatamong our greatest investigators it is the irritative im-pulse that predominates."5 Whatever the blend of in-terest and irritation that inspired Howell to doggedlypursue the theme of the physiology of blood coagula-tion throughout his long career, his contributions were

of major theoretical and practical importance. Neverobsessed with the desire to obtain practical results,Howell nevertheless lived to see the introduction ofheparin into clinical practice.

As one of the original members and historian of theAmerican Physiological Society, Howell was in hislater years in a unique position to assess the develop-ment of science in this country. Assessing the develop-ments in American physiology during the previousquarter century Howell remarked in 1931, "In every

part ofphysiology during this short period changes .

have been taking place. When we look back and com-

pare our knowledge then and now we can be wellsatisfied with the progress that has been made, and can

anticipate that the continued application of our presentmethods of research will bring us richer returns in theyears to come. '41

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1945. Nat Acad Sci Biog Memoirs 26: 153, 19503. The celebration of the sixtieth anniversary of Dr. William H.

Howell's graduation from the Johns Hopkins University. BullJohns Hopkins Hosp 68: 291, 1941

4. An anniversary tribute to the memory of the late William HenryHowell. Bull Johns Hopkins Hosp 109: 1, 1961

5. Harvey AM: Fountainhead of American physiology: H. NewellMartin and his pupil, William Henry Howell. Johns Hopkins Med J136: 38, 1975

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Biol Lab Johns Hopkins Univ 2: 119, 188113. Howell WH: The origin of the fibrin formed in the coagulation of

blood. Stud Biol Lab Johns Hopkins Univ 3: 63, 188414. Davenport HW: Physiology, 1850-1923, the view from Michigan.

Physiologist 25 (suppl): 1, 198215. Howell WH: The life history of the formed elements of the blood,

especially the red blood corpuscles. J Morphol 4: 57, 189016. Howell WH: An American text-book of physiology. Philadelphia,

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21. Abel JJ, Rowntree LG, Turner BB: On the removal of diffusiblesubstances from the circulating blood of living animals by dialysis.J Pharmacol Exp Ther 5: 275, 1914

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cases. Circulation 19: 79, 195929. McLean J: The thromboplastic action of cephalin. Am J Physiol

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heparin and pro-antithrombin. Am J Physiol 47: 328, 191832. Howell WH: The purification of heparin and its chemical and

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vascular injections of heparin. Bull Johns Hopkins Hosp 46: 365,1930

34. Crafoord C: Preliminary report on post-operative treatment withheparin as a preventive of thrombosis. Acta Chir Scand 79: 407,1937

35. Jorpes JE: Heparin its chemistry, physiology and application inmedicine. London, 1939, Oxford University Press

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38. Passamani ER, editor: Limitation of infarct size with thrombolyticagents. Circulation 68 (suppl I): I-1, 1983

39. Stratton JR, Lighty GW Jr, Pearlman AS, Ritchie JL: Detection ofleft ventricular thrombus by two-dimensional echocardiography:sensitivity, specificity, and causes of uncertainty. Circulation 66:156, 1982

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W B FyeHeparin: the contributions of William Henry Howell.

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1984 American Heart Association, Inc. All rights reserved.

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