Fathers of Modern Coagulation

AnniversaryIssueContribution

Fathersofmoderncoagulation

Dougald M. Monroe,MaureaneHoffman, Harold R. Roberts 1957–2007)

Division of Hematology/Oncology,Department Medicine,University of North Carolina, Chapel Hill, North Carolinaand DurhamVA Medical y( Center and Duke University,Durham, North Carolina, USA

he best contribution we could make for the 50th anniver- The legend of Figure 2gives the namesofthose whowere pres- sary of Thrombosis and Haemostasis,the former official ent at the meeting. Some members, namely, GwynneMacfarl- Anniversar T journalofthe InternationalSociety on Thrombosis and ane, RosemaryBiggs,Oscar Ratnoff,and Paul Aggeler were ap- th Haemostasis (ISTH), wastorecount the history of some of the parently absent fromthe meeting, buttheir influencewas felt. 50 people whoopenedthe door to major advances in coagulation re- While allofthe membersofthe Committee in Figure 2are shown search.Manyofthese people were among the first to contribute withsmilesontheir faces,the discussions leading to decisions articlestothe Journal whichwas initiallynamed Thrombosiset on nomenclature were often heated and forceful (4). DiathesisHaemorrhagica. Most of the menshown in Figure 2are legendary for their The storybegins in the early1950s shortlyafter the end of the contributionstothe fieldofcoagulation. H. Jensen(#1), who secondWorld War. In the late 1940s throughthe 1950s, scientists worked at the US Army Research Labs, studiedthe proteasesin from several nations made major breakthroughsinour under- coagulation looking at the balancebetween proteolytic action standing of the mechanism of coagulation. This waslargelydue (thrombin generation and fibrinolysis) and anti-proteolytic ac- to the discovery of several newclotting factors. In 1945 the tion. WalterSeegers(#2) had isolatedprothrombin and had dis- major clotting theoryrestedonthat of Morawitz as shown in Fig- covered several other vitamin-K-dependent factorsinhis pro- ure 1(1). Prothrombin wasknown to be converted to thrombin in thrombin preparation whichhecalled“auto” prothrombins be- areaction thatrequired both thromboplastin (nowknowastissue causeheviewedthem as being derived fromprothrombin. His factor)and platelets. In addition, in 1935, Patekand Taylor de- obsession with the autoprothrombin nomenclatureprobably ob- scribed antihaemophilic factor as acomponent of plasma lacking scured much of his original discoveries, since it appears thathe in patients with classic haemophilia (2),and Kenneth Brinkhous actually characterized what latercametobeknown as factor IX, and his colleagues at Iowa showedthat this factor wasnecessary factor X, factor Xa, and activatedprotein C, amongothers. He for the rapidconversion of prothrombin to thrombin.Thrombin alsocalledOwren’sproaccelerin(factor V) “AC(accelerator) wasalso known to convert fibrinogen to fibrin. Also, in 1944, globulin”. Erik Jorpes (#3),from the KarolinskaInstitute in Kenneth Robbins describedfibrin stabilizing factor,now known Sweden, wasinterestedinall the clotting proteins butwas par- as factor XIII (3). After these observations,things beganto ticularlyengagedbythe actions of heparin. Dr.Jorpes also re- change rapidlyasnew factorswere discovered.The trouble was cruitedBirgerand Magareta Blombäckwho worked on both fi- thateach newfactor wasgiven several names and even some of brinogen and factor VIII.Fritz Koller(#4), whodiscovered fac- the olderknown factorshad several names as showninTable 1. tor Xwith Francois Dukert (5), wasone of the first Editorsofthe Lookingatthe different namesfor the same substance,itiseasy Journal. Erwin Deutsch (#5),inaddition to his work on anti- to understand hownomenclature could affect ones interpretation coagulants, wasthe main person whostarted the journal Throm- of results, and because of this an international committee was bosis et Diathesis Haemorrhagica,the journal that later became formedin1954 in an efforttoestablish acommon nomenclature Thrombosis and Haemostasis whichwas the official journalof

for the clotting factors.This committeewas first termed “TheIn- the ISTH for several years.Jean-Paul Soulier (#6) developedthe This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. ternational Committee on Nomenclature of Blood Clotting Fac- so-called PPSB (Prothrombin-Proconvertin-Stuart factor-anti- tors”.The first meeting of this Committeewas heldinBasel and haemophilic factor B) fraction used for treatment of haemo- subsequent meetings were heldinCopenhagen, Boston and philia B. Karl Lenggenhager (#7), in addition to work on hae- Rome. mophilia,performed earlystudiesonboth platelets and anti- Figure 2shows the membersofthe Committee whoattended thrombin. Paul Owren (#8) discovered factor V, whichhecalled the Rome meeting in 1958. It wasatthis meeting that most of the proaccelerin, in 1944 during the Nazi occupation of Norway, but membersagreed to use Romannumerals for the clotting factors. his publication wasdelayed until 1947(6). Louis B. Jaques(#9)

Correspondence to: Received April 12, 2007 Dougald M. Monroe Accepted May11, 2007 UNC Medical School –Hematology/Oncology 932 Mary Ellen Jones,CB#7035 Chapel Hill Prepublished onlineJune 12, 2007 NorthCarolina27599–7035, USA doi:10.1160/TH07–04–0313 Te l.: +19199663311, Fax: +19199667639 E-mail: [email protected] ThrombHaemost 2007; 98: 3–5

3 Monroe et al. Fathers of modern coagulation

from Canada wasanexpertinheparin and helped confirm that headed the group at the University of Leuven. In addition to his heparin, while it hadaweak antithrombotic effect alone, worked work in haemophilia,Dr. Verstraete conducted numerousstudies with anotherplasma protein to exertits primary effect.MarcVer- into different anticoagulants and monitoring of anticoagulants. straete(#10) wasinvolved in clinicaltrials in coagulation and Armand Quick(#11) developedthe prothrombin timetestand also knewthat other,asyet unknown, plasma and serum factors were necessaryfor coagulation to proceednormally. Benjamin

1957–2007) Alexander (#12)was the first to describe SPCA (Serum Pro- thrombinConversion Accelerator,factor VII) deficiency. R. B. y( Hunter (#13)was expertinvitamin Kantagonists; his work sug- gestedthat factorsotherthan prothrombin were alsoreduced with vitamin Kantagonists and that this reduction might playan Figure1:Clotting theoryofP.Morawitz. important roleinthe anticoagulant effect. Irving Wright (#14) wasthe first SecretaryGeneral of the Committeeand as aclini- Anniversar cian wasone of the first to use warfarin and heparin as therapy th Ta ble1:Blood clotting factorsand theirpreviouslyusednames. for thrombosis. Kenneth Brinkhous (#15) and his colleagues at 50 the University of Iowa performed much of the earlywork on fac- Factor Commonname(s) tor VIII; with his ChapelHill colleagues he developedthe partial IFibrinogen thromboplastin timetestin1953 (7).Inaddition, Brinkhous and colleagues developedone of the first purified factor VIII frac- II Prothrombin tions,later produced by BaxterLaboratoriesas“Hemophil”. VLabile Factor Tage Astrup (#16) from Denmarkwas an expertinfibrinolysis Proaccelerin accelerator (AC-) globulin and performed muchofthe earlywork on tissue plasminogen ac- tivator.PietrodeNicola (#17) alsostudiedfactor VII and helped VIISerum Factor to identifyitasaseparateprotein (and activity) from prothrom- Stable Factor Proconvertin bin. SerumProthrombin Conversion Accelerator (SPCA) Althoughnot shown in Figure 2, Alfredo Pavlovskyfrom Ar- Cothromboplastin gentina wasone of the first to recognizethat blood from one phe- Autoprothrombin I notypical haemophiliac could correct the clotting timeofasimi- VIII Hemophilia Afactor larphenotypic patient; buthedid not recognizethat he had ob- AntihemophilicGlobulin (AHG) servedthat blood from apatient with classic haemophilia would Antihemophilic Globulin A correct the clotting timeofapatient with haemophilia B(8).This Antihemophiliac Factor FacteurAntihemophilique A PlasmaThromboplastic Factor PlasmaThromboplastic FactorA Thromboplastic PlasmaComponent Thromboplastinogen Prothrombokinase Platelet Cofactor Plasmakinin Thrombokatalysin IX Hemophilia BFactor AntihemophilicFactor B Christmas Factor PlasmaThromboplastin Component

Autoprothrombin II This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Beta cothromboplastin Pavlovsky Factor XStuart Factor Prower Factor Stuart-Prower Factor Autoprothrombin III XI Hemophilia Cfactor PlasmaThromboplastin Antecedent (PTA) Figure 2: Members of theThe International Committee on No- XII Hageman Factor menclature of Blood Clotting Factors who attendedthe Rome Contact Factor meeting in 1958. #1:H.Jensen, #2: Walter Seegers, #3:ErikJorpes, XIIIFibrin Stabilizing Factor #4:Fritz Koller, #5:Erwin Deutsch,#6: Jean-Paul Soulier,#7: LarlLeng- Laki-Lorand Factor genhager, #8:Paul Owren, #9:Louis B. Jaques, #10: MarcVerstraete, Protransglutamidase #11: Armand Quick,#12: Benjamin Alexander, #13: RobertB.Hunter, RobbinsFactor #14: Irving Wright,#15: Kenneth Brinkhous, #16: Tage Astrup,#17: PietrodeNicola (photo kindlyprovided by theISTH).

4 Monroe et al. Fathers of modern coagulation remained for Paul Aggeler and his colleagues in California and for Biggs and Macfarlane in England (9, 10). Also,Oscar Rat- noff is not shown in this photo, though he haddiscovered Hage- manfactor/factor XII in 1955. Theirphotographsare shownin Figure 3. Not all of the fathers of modern coagulation initiallyagreed

with the Romannumeral nomenclature.Outstanding holdouts 1957–2007) against the nomenclature were WalterSeegersand Oscar Rat- noff, though theycontinued to makemajor contributionstoour y( knowledge of coagulation. The initial InternationalCommittee on Nomenclature of Clotting Factorswas changed in 1959tothe InternationalCom- mittee on Clotting Factorsand later,in1964 the name of the Committee wasagain changed to TheInternational Committee Anniversar on Hemostasis and Thrombosis. Committee activities were en- th larged to deal notonlywith nomenclaturebut also with standards 50 for assays and purification methods and other practicalmatters. Beginningin1959, Committee activities were usually accompa- nied by ascientific session butinternational congresses as we knowthem todaywere notyet started.Inaddition, membership in the Committee was“elective” and sincetherewere an increas- Figure3:Alfredo Pavlovsky, RosemaryBiggs,RobertMacfar- ing number of peopleinthe scientific community whobecame lane,Kenneth Robbins, Paul Aggelerand Oscar Ratnoff (from topleft to bottom right;photos kindlyprovided by theISTH). interested in coagulation, the Committeewas increasingly viewedas“elitist”.Asaresult, in 1969the ISTH wasformed, largelydue to the influenceofDr. Sol Sherry. Forawhile the anism derivefrom these schemes, made possible in part by the Committee remained separate from the Society,although they orderbroughttothe chaos of coagulation factorsby“The Inter- mettogether.In1979, largelydue to the influences of Victor national Committee on Nomenclature of Blood Clotting Fac- Marder,Sol Sherry,Ken Brinkhous and Harold R. Roberts, the tors”.Thus the work of these outstandingpioneers created the ISTH and the InternationalCommittee on Thrombosis and Hae- framework for the subsequent explosion of knowledge about co- mostasis were completelyamalgamated. TheCommittee be- agulation. This framework provided the basis for the devel- came known as the Scientific and Standardization Committee opment of therapies for haemophilia:first purifiedfactorsVIII (SSC) whichisnow the “working arm” of the ISTH thatdeals and IX, thenhighlypurified factors, followedbyrecombinant withstandards and methodsand other practicalmatters of coagu- proteins, leading to the ongoing studies with gene therapythat lation. TheSSC works closelywith regulatorybodies in North hold the promise of acure.This framework alsoprovided the America,Europe,Asia, Australia and South America. The ISTH basis for targeting anti-thrombotic drugs with ongoing studies is nowthe foremost international forum for investigatorsinter- directedtoanti-thromboticagents with minimal risk of bleeding. estedinthrombosis and haemostasis. It wasformed in large Finally, the work of these leadersdemonstrates howinternational measure from the efforts of those shown in Figures2and 3. cooperation and pooling of knowledge,eveninthe face of strong In 1964, Oscar Ratnoffand Earl Davie, at the same timeasR. personalities and occasionaldisagreements, can advance our Gwyn Macfarlane, proposed an organizational scheme for the knowledge and understanding of science. coagulation factors. All modern views of coagulation mech-

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