Effects of Plasma Tainted with CJD Still Under Scrutiny in U.K

Tuesday, July 14 Boston, Massachusetts ISTH 2009 Daily XXII Congress International Society on Thrombosis and Haemostasis

Dr. Hill cautioned against making inside Effects of Plasma Tainted with too much of these findings. “There are many uncertainties about this data, and Late-breaking results there are questions about the current Latest data released on five trials risk assessment. page 2 CJD Still Under Scrutiny in U.K. “We possibly don’t know the full ex- bout half of the 8,730 people in Among those 792 patients, 1,157 tent of contaminated batches. The pat- History from the the United Kingdom who were have had treatment or exposure epi- terning incubation of time of variant Beginning Aexposed to plasma tainted with sodes with 12.7 million units of the im- CJD following exposure to plasma prod- variant Creutzfeldt-Jacob disease have plicated product. That is about half of uct may well be different even to expo- ISTH was founded 40 years ago not yet been treated. the 23 million that have been issued. sure through cellular product.” page 4 Physicians are trying to assess the risk Sixty-seven percent of this cohort had Finding answers to these questions to the patients who received the tainted received only one batch from an im- may involve better recruitment, post Snake bite treatment plasma from 1987 to 1999. Frank G. H. plicated donor, “but all have received mortem, results of longitudinal studies Research ongoing about when, if to Hill, MB, ChB, FRCPath, FRCPCH, other batches which may add to their involving these patients and the devel- administer fresh frozen plasma at Birmingham Children’s Hospital NHS cumulative risk.” opment of a blood test. page 6 Trust and the U.K. Haemophilia Centre Directors Organization, discussed the ex- Opening tent of exposure and risk stratification dur- Young investigators ing a plenary session Monday morning. Ceremony Four Pier M. Mannucci Awards “Information on the National Haemo- announced Draws Large, page 8 philia Database shows us we have in ex- cess of 23,000 registered patients; 8,730 Festive Crowd of those have been treated,” said Hill. Hundreds of delegates “From annual return data, we can iden- gathered Sunday night tify 4,580 patients who have received to celebrate the opening U.K. plasma products and therefore are of the XXII ISTH at risk of variant CJD and require public Congress. TUESDAY health precautions with certain opera- AT A GLANCE tive procedures. Of those, 792 have been positively notified as having received an Ongoing implicated batch,” Dr. Hill said. Oral Communications, State- of-the-Art Lectures, Abstract Symposia, Nurses’ Sessions 9:45 a.m. – 10:30 a.m. PrPSC Detected in Spleen of Adult Hemophilic Patient in U.K. Plenary Lecture: Contribution nalyses of tissues from 17 Unit, said Monday products. All we can say we know for of Allosteric Disulfide Bonds patients exposed to variant that the patient “like- sure is that there was an infected donor to Regulation of Hemostasis Creutzfeldt-Jakob disease in ly” contracted the in this pool.” (Philip Hogg) A the United Kingdom showed that one disease from an un- Investigators performed prospective 3:00 p.m. – 3:15 p.m. patient with hemophilia had disease-as- identified source. and retrospective analyses on tissues ISTH General Membership sociated prion protein – PrPSC - in his “Because of the collected from biopsies or autopsies, Assembly spleen tissues. large volume of non- searching for the presence of disease-as- It is not yet known whether the pa- implicated products Dr. James W. sociated prion protein. All patients had 3:15 p.m. – 4:00 p.m. tient came in contact with the disease received, it is likely Ironside, FRCPath been treated with U.K.-sourced pooled Presidential Plenary through diet, blood transfusion or this could be the source of the infec- factor concentrates for bleeding disor- Abstracts pooled clotting factor concentrate. Dr. tion,” he said. “On the relative risk, it ders from 1980 and 2001. That pool is James W. Ironside, FRCPath, director is very difficult to discriminate between known to contain tainted plasma from 4:00 p.m. – 4:15 p.m. of the U.K.’s National CJD Surveillance the implicated and non-implicated (Ironside, continued on page 11) ISTH 2009 Congress Awards Presentation Tuesday, July 14, 6:30 PM – 7:30 PM 4:15 p.m. – 5:00 p.m. Industry Sponsored Technical Sessions TIPS OF THE DAY Presidential Plenary Abstracts Add future professional conferences to your calendar after • Network for Continuing • Rovi stopping by the Future Events Kiosk. 6:30 p.m. – 7:30 p.m. Medical Education (Novo Room 104 ABC Technical Sessions Nordisk) Stay connected at the Cyber Café & Message Center in the (Industry Sponsored) Room 107 ABC Exhibition Area.

The ISTH 2009 Daily Congress news will also appear on the ISTH website at www.isth.org. tuesday • July 14, 2009

LATE BREAKING TRIAL ADVANCE-2: Favorable Risk-Benefit Profile With Apixaban pixaban for thromboprophy- lower major and paring efficacy and safety of 2.5 mg bleeding (major and clinically rel- laxis after total knee replace- clinically relevant apixaban twice daily for preventing evant nonmajor). A ment had better efficacy and non-major bleed- VTE vs. the current European stan- The primary outcome occurred safety compared to the current stan- ing rates in patients dard of care, 40 mg subcutaneous in 15.1% of patients in the apixaban dard of care enoxaparin, according to undergoing total enoxaparin once daily, said Michael group vs. 24.4% in the enoxaparin late-breaking results of ADVANCE-2 knee replacement. Lassen, MD, of the University of Co- group (P,.001). Major VTE oc- presented Monday. A D V A N C E - 1 penhagen, Hørsholm, Denmark. curred in 1.1% of apixaban patients ADVANCE-1 results, presented in compared apixa- Michael Primary efficacy outcome was the treated with apixaban vs. 2.2% of December 2008 at the 50th ASH An- ban with the North Lassen, MD composite of DVT by venography, patients treated with enoxaparin, Dr. nual Meeting, showed that apixaban American dosage symptomatic objectively confirmed Lassen said. failed to meet one of two prespeci- of enoxaparin 30 mg twice daily. DVT or pulmonary embolism, or Apixaban also conferred a better fied noninferiority criteria margins ADVANCE-2 was a randomized, death from any cause during treat- safety profile compared with apixaban in reducing rates of VTE but showed double blind, multicenter trial com- ment. Primary safety outcome was (3.5% vs.4.8%; respectively; P=.09).

LATE BREAKING TRIAL dependent radiologists. The primary efficacy endpoint Four-Week Prophylaxis Better Than One Week was the combined incidence of total documented symptomatic and After Abdominal, Pelvic Surgery asymptomatic DVT, nonfatal pulmonary embolism and deaths due to hen compared with a tients undergoing cancer abdominal patients; the efficacy analysis, 488. any cause. Primary safety endpoint one-week prophylaxis, or pelvic surgery. Prior to randomization, all patients was major hemorrhage, according to W four weeks with the low These results were part of the CAN- received 3,500 IU bemiparin starting six Dr. Kakkar. molecular weight heparin bemiparin BESURE trial presented Monday by hours postsurgery for eight days. They Patients assigned bemiparin had significantly reduced the rate of ma- Dr. Vijay V. Kakkar, MD, director were then randomly assigned 3,500 IU a 24.4% relative risk reduction for jor venous thromboembolism with- of the Thrombosis Research Institute, bemiparin once daily or placebo for 20 the primary endpoint and a 82.4% out increased complications in pa- London, as part of the late-breaking more days, Dr. Kakkar said. relative risk reduction for incidence abstracts session. Follow-up was three months. of major VTE (see chart). C A N B E S U R E Twenty-eight days after surgery, bi- Rates of major bleeding were simi- was a multicenter, lateral ascending venography was lar in both groups (0.6% vs. 0.3%, re- randomized, double performed and examined by five in- spectively; P=.572). blind parallel group trial. The study included 703 patients LATE BREAKING TRIAL aged 40 or older who were undergoing surgery on the gastroin- Better Anticoagulant Control testinal or genitouri- nary tract, or female With Warfarin reproductive organs. The safety analysis atients who switched from were randomly assigned to warfa- included data on 625 acenocoumarol to warfarin and 254 to phenprocoumon. P rin spent more time within An equal number of patients initiat- therapeutic ranges than those who ing and switching therapies were in switched to phenprocoumon, ac- both groups. LATE BREAKING TRIAL cording to late-breaking After six months’ follow- results presented Monday. up, the overall mean per- Enoxaparin Effective for VTE Prevention The trial compared warfa- centage of time spent within rin and phenprocoumon therapeutic ranges was in Advanced Pancreatic Cancer in patients who were ei- 74.6% for the warfarin group ther initiating anticoagulant and 65.3% for the phen- ONKO 004 trial results sug- CONKO 004 trial. treatment or switching from procoumon group (95% CI, gest that the low molecular In an intent-to-treat analysis, the vitamin K antagonist 5.8-12.8), she said. C weight heparin enoxaparin enoxaparin reduced the risk of VTE acenocoumarol to a new Yvonne van The difference in mean helped prevent symptomatic ve- by 65% with no increased safety com- therapy. Leeuwen, MSc percentage of time spent nous thromboembolism in patients plications, Dr. Reiss said. Yvonne van Leeuwen, within therapeutic ranges undergoing chemotherapy for ad- From April 2004 to January 2009, MSc, from the department of clini- was more substantial in patients vanced pancreatic cancer. 312 VTE- and chemotherapy-naive cal epidemiology at Leiden Univer- who switched therapies: 78.3% for H.B. Reiss, MD, at the University patients with advanced pancreatic sity Medical Center, said Monday the warfarin group vs. 57.6% in the Medicine in Berlin, presented these cancer were recruited. One hundred that the results indicate that, overall, phenprocoumon group (95% CI, late-breaking results on Monday. sixty patients were assigned chemo- warfarin leads to better anticoagu- 16.3-25.1). The researchers observed Patients with advanced pancre- therapy plus once-daily 1 mg/kg start- lant control than phenprocoumon. no difference in mean percentage of atic cancer are among those with the ing dosage of enoxaparin for the first The researchers recruited 504 time spent within therapeutic ranges highest risk for VTE, Dr. Reiss said. 12 weeks, after which the dosage was patients at Leiden Anticoagulation for patients initiating therapy. To investigate the role of enoxapa- reduced to once-daily 40 mg. The re- Clinic from March 2004 to Sep- Excluding the first six weeks of rin in the prevention of VTE, Reiss maining 152 patients were assigned to tember 2008. follow-up did not change the re- and colleagues began the open, pro- chemotherapy alone (observation). Two hundred and fifty patients sults, according to van Leeuwen. spective, randomized, multicenter (Reiss, continued on page 11)

tuesday • July 14, 2009

under the direction of Dr. Fritz Koller. The Founding of ISTH: 40 Years Ago This joint meeting of the originating committee and the ISTH was to focus Harold R. Roberts, MD Liege in Belgium made a proposal to The consensus was that the com- on the theme “Immunology, Throm- Gilbert C. White, MD the assembled committee, one that he mittee would go offer membership op- bosis and Haemostasis.” he history of the International had previously aired at the 7th Con- portunities to the broader community, Interested readers will find a de- Society on Thrombosis and gress of the European Society of He- including researchers in the field of he- tailed account of the Society’s organi- T Haemostasis can be traced matology, calling for a new entity sup- mostasis and thrombosis. zation between 1960 and 1969 in the back to 1954, with the formation of porting a broader forum for discussion Over the next nine years, commit- article, “The Founding of the Inter- the International Committee on the for hemostasis and thrombosis, as well tee members planned for a new orga- national Society on Thrombosis and Nomenclature of the Blood Clotting as nomenclature: He proposed that nization that would be open to all inter- Haemostasis: How It Came About,” Factors. The initial committee was the committee consider widening its ested scientists and clinicians working by Dr. Sol Sherry (Thrombosis and Hae- composed of investigators who were aims. The committee members began in the many interrelated fields of blood mostasis, 1990; 64(2):188-191). all internationally well known for their discussing the possibilities. clotting, hemorrhage, thrombosis and And the rest, as they say, is history. contributions to modern knowledge of Dr. Wright agreed that Dr. Ros- vascular biology. They planned the You are cordially invited to see the blood coagulation and was funded by kam’s proposal was important and be- structure, function, leadership, and ISTH History display in the North the National Heart, Lung, and Blood lieved that there was no other agency mission of this new society. Lobby of the Convention Center Institute. There were, however, rela- organized at that time that could ac- At the 15th Annual Meeting of the during this XXII ISTH Congress tively few members, and as interest complish such a project. Perhaps the International Committee on Haemo- and 55th Annual Meeting of the Sci- grew, it became necessary to enlarge committee should consider it? stasis and Thrombosis in Bath, Eng- entific and Standardization Commit- the membership to include all investi- Dr. Tage Astrup of Copenhagen land, the new organization finally tee. Among the items on display are gators interested in the basic and clini- observed that such an endeavor would came to a vote. the roster of founding officers and cal aspects of blood coagulation, in- require the reorganization of the com- The committee unanimously ap- council members; the original invi- cluding hemorrhage and thrombosis. mittee and would result in taking into proved establishing a society called tation to join the society; a roster of An international society was en- membership many more individuals the International Society on Thrombosis those who accepted the invitation; visioned as early as 1960. During the from other disciplines. He suggested and Haemostasis. Quickly following and several other bits of information planning for the sixth meeting of the that it might be better to form a new were the adoption of a constitution that have been donated by members, committee in Princeton, New Jersey, organization for this purpose that and unanimous election of the first of- past and present. Dr. Irving Wright wrote to Dr. Ken- would be coordinated with the current ficers, council members and honorary If you have documents or memo- neth Brinkhous that deliberations Committee on the Nomenclature of members. rabilia of the Society or Committee of the committee had become con- the Blood Clotting Factors. The first meeting of the new Inter- that you would like to donate to the strained by the growing number of In a question that foreshadowed the national Society on Thrombosis and permanent archives of the Society, scientists, “innumerable well-quali- eventual mission of the new organiza- Haemostasis was set for the following kindly contact the executive secretary fied delegates,” who wished to be in- tion, Dr. Wright asked Dr. Roskam for year, 1970, in Montreux, Switzerland, at ISTH Headquarters. cluded in the committee’s discussions clarification of his intention: “Dr. Ros- but were turned away because of the kam … are you interested in the ap- committee’s restricted size. proach of the committee towards stim- At this point, attendees were invited, ulating research and interest [of] more Risk for VTE Linked to Ethnicity and only about 70 could be chosen. investigators to work in the field [or] at- ccumulating data suggest VTE three- to fourfold in patients These attendees were individually se- tempting to stimulate more new young that genetic risk factors with the mutation. lected based on their internationally rec- investigators to work in this field?” A linked to ethnicity may The effect of protein S1K196E ognized expertise and their ability and The answer being affirmative for both play a large role in risk for ve- in VTE has also been confirmed willingness to contribute to the meeting. objectives, Dr. Wright reminded the nous thromboembolism for some by two independent Japanese (A complete list of the 1960 attendees is membership that they had avoided en- people, according to Toshiyuki groups. This mutation, referred available from the ISTH archives.) larging the committee to a point where Miyata, PhD, of the National Car- to as protein SK196E or Protein At the committee’s business meet- “we cannot finance it or it becomes too diovascular Center Research Insti- S Tokushima, is present in the ing, Dr. Wright reported to the assem- large to function efficiently,” although, tute, Osaka, Japan. second EGF-like domain of pro- bled members that “the catalytic effect “on the other hand, over the years we In white populations, genetic tein S. of [our] few conferences … has been will bring together many people inter- factors such as Factor V Leiden Three studies, including Dr. explosive. It has stirred the imagina- ested in the big fields of thrombosis and G20210A confer greater risk Miyata’s, have also identified the tion and interest of many people who and coagulation.” for venous thromboembolism frequency of this mutation in Japa- are not members of [this] committee.” The problem before the commit- (VTE). Different genetic mutations nese patients. Overall, 74 heterozy- Committee member Dr. Armand tee was how to accomplish these goals may increase risk for VTE in Japa- gotes have been identified in 4,137 Quick raised the possibility of ex- without compromising effectiveness. nese populations. people. The mutant allele frequen- panding the committee’s purpose and Committee member Dr. Louis “In 2006, we identified protein cy was 0.89%, which means that scope, noting that there were three Jacques said: “Dr. Roskam has raised a S-K196E as a risk factor for VTE in about 10,000 Japanese are hetero- groups that should be considered as point which is our responsibility, aris- the Japanese population that is not zygotic, said Dr. Miyata. constituents: (1) the current committee ing from what we have already done. present in a white population.” In addition, the studies found with a primarily chemical character, If the job we have done [is] too nar- To confirm the role that the pro- that people heterozygous for the that is, those isolating factors, methods row to provide the picture needed by tein plays in VTE, a case control mutant allele had lower plasma for assay and so on; (2) those interpret- [those with] responsibility for patients, study was conducted in 3,500 men protein S activity than wild-type ing results in terms of physiology, that responsibility for teaching students and women aged 30 to 79. Protein patients (71.9% vs. 87.9%, respec- is, hemostasis; and (3) clinicians. who are going to practice medicine, it S-K196E increased the odds of tively; P <.0001). Dr. J. Roskam of the University of means we have not finished our job.”

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TODAY at 9:45 am — 10:30 am: Grand Ballroom Contribution of Allosteric Disulfide Bonds to Regulation of Hemostasis (Philip Hogg)

he inaugural Oscar Ratnoff Memorial Lecture will sue factor, von Willebrand factor and integrin β3, and may be delivered today by Professor Philip J. Hogg be at the heart of how hemostasis is regulated. T from the University of South Wales, Sydney, New Professor Hogg is a National Health and Medical Re- South Wales, Australia. Professor Hogg will present his search Council Senior Principal Research Fellow at the novel research on allosteric disulfide bonds, disulfide University of South Wales, where he is also founder and bonds that control protein function by forming or break- director of its Cancer Research Centre. He was a key fig- ing in a precise way. ure in the establishment of the university’s Lowy Cancer Professor Hogg’s groundbreaking research in disulfide Research Institute and will serve at its co-director when bonds enabled his discovery of a structural motif that it opens in late 2009. characterizes these allosteric disulfide bonds and distin- Professor Hogg is the recipient of numerous awards guishes them from other functional disulfide bonds. Pro- including the Australian Society for Thrombosis and fessor Hogg predicts that about one in 15 of all structurally Haemostasis Speywood Medal, the New South Wales determined disulfides is a potential allosteric bond, imply- Biomedical Sciences Scientist of the Year and most re- ing a significant role for these bonds in controlling protein cently the Premiers Award for Outstanding Cancer Re- function. Allosteric disulfide bonds have been studied sig- searcher of the Year, the highest cancer research honor nificantly in important hemostatic proteins, including tis- in New South Wales.

Oscar Ratnoff (1926-2008) was a distinguished physician-scientist who made seminal contributions to our understanding of blood coagulation mechanisms and bleeding disorders. Over a 60-year career at Johns Hopkins and Case Western Reserve Uni- versities, he conducted original studies that revolutionized and advanced the field. His achievements included the proposal of the waterfall sequence of blood coagulation with Earl Davie, the discovery of Factor XII (Hageman factor) and high molecular weight kininogen (Fitzgerald factor), the development of an immunoassay to differentiate Factor VIII deficiency and von Wil- lebrand disease and early recognition of potential danger of contamination with a putative AIDS agent in Factor VIII concentrates. Ratnoff was an outstanding teacher and clinician who trained many fellows who went on to establish their own distinguished careers. The Ratnoff Lectureship was established following his death in 2008. The initial lecture will be given at this Congress. Best Treatment for Snake Bite Coagulopathy Still in Question he widely accepted treatment “However, it will often take as long patients, and of course the antiven- Because it is not possible to do a for snake bite coagulopathy as 24 hours before you get a blood om doesn’t work unless you give 10 placebo controlled trial in snake bites, T prior to 2008 was antivenom recording that is normal. Physicians times the toxin. the study instead used variations of until reversal of coagulopathy. How- are trying to find out if the antivenom “By knowing the venom concen- timing and doses of antivenom and ever, ongoing research in Australia has worked, but whether clotting has tration in patients, we can do the fresh frozen plasma. The main out- suggests that delaying the use of fresh recovered does not answer that ques- same tests again with a much lower come measure was time until recov- frozen plasma until coagulopathy is tion,” he said. concentration of antivenom. In those ery from venom-induced consump- reversed may be unnecessary. Currently, the Australian Snake- tests, we have shown that one vial [of tion coagulopathy. Geoff Isbister, MD, of the Men- bite Project is conducting prospective antivenom] is more than enough.” They found that administration zies School of Health Research, studies to determine the efficacy of Therefore, the recommendation of fresh frozen plasma within four Charles Darwin University, Austra- antivenom, the proper doses and ad- in Australia since 2007 is to give only hours was the only important deter- lia, said Saturday that much research ministration. Randomized controlled two vials of antivenom. minant of venom-induced consump- has examined toxins and venoms that trials of fresh frozen plasma are also tion coagulopathy. Neither earlier cause coagulant effects. “But, despite in progress. Together these studies Fresh frozen plasma administration of antivenom nor an that, we know very little about toxin should help develop evidence-based A more controversial question has increased dose of antivenom had any and venom effects in patients.” guidelines for the treatment of venom- been when and if to administer fresh effect on venom-induced consump- Not much is known about how induced consumption coagulopathy. frozen plasma. tion coagulopathy. venoms work, according to Dr. Is- “There have been some lab stud- When Dr. Isbister and colleagues Dr. Isbister said that his research bister. Traditionally, multiple doses ies that showed that antivenom began studies of fresh frozen plasma results may be unique to Australian of antivenom were given during the doesn’t work,” Dr. Isbister said. “In it was with the recommended prac- snakes. He challenged other research- first 24 hours after a snake bite until the test tube, researchers have used tice of using no more than two vials ers to examine these findings in snake coagulopathy was reversed. 10,000 times the venom you find in of antivenom. bite cases in other parts of the world. Plenary Lecture tuesday • July 14, 2009

Human Genetics Research Offers Clues About CHD Prevention

or the 20th Shirley Johnson genes that contributed to differences activity and hypocholesterolemia, The findings have not been repli- Memorial Lecture, Helen H. in plasma levels of LDL, in particular and low plasma levels of LDL,” Dr. cated in African American but they F Hobbs, MD, examined the elevated levels of LDL. All Mendelian Hobbs said. have been reproduced in European- potential future impact of genetics forms of severe hypercholesterolemia A study by Dr. Hobbs and col- Americans, she said. research on cardiovascular disease are associated with premature coro- leagues demonstrated that African prevention. nary heart disease, irrespective of the Americans have one of two nonsense Using PCSK9 to prevent CHD “In human genetics, there are two mechanism, she said. mutations that do not secrete PCSK9 Major drug companies are current- major approaches to use genetics to into the blood. Using an ELISA assay, ly pursuing PCSK9 as a therapeutic try to identify genes and sequence Discovery of PCSK9 gene they determined that people who are target to lower plasma levels of LDL variations that contribute to differ- The discovery of PCSK9, a gene heterozygous for nonsense mutations and prevent coronary heart disease, ences in traits; in this case our focus that causes a dominant form of hy- had lower levels of PCSK9 circulating according to Dr. Hobbs. has been on LDL,” Dr. Hobbs said percholesterolemia, led to research in the blood and lower levels of LDL. “The work with PCSK9 in human Monday. This research has “shed new in mice that demonstrated that when Their next study followed patients populations really drives home work insights into LDL metabolism” with PCSK9 was expressed in the liver, with PCSK9 for 15 years. Among that has come from many directions implications for public health. there was no change in LDL receptor the African American patients in the and many different studies really fo- Dr. Hobbs is a Howard Hughes messenger RNA, a dramatic reduc- study, 28% lower LDL levels were cusing on the role of LDL in this dis- investigator and professor of internal tion in LDL receptor protein, and the associated with an 88% reduction in ease,” she said “Also, others have de- medicine and molecular genetics at mice became hypercholesterolemic. coronary artery disease, even though veloped other approaches to reducing the University of Texas Southwestern “It was here that we became inter- over half of the population was hy- PCSK9.” Medical Center in Dallas. Research ested in PCSK9. Our thinking was pertensive, a third smoked, and al- Research with PCSK9 also empha- by Dr. Hobbs and her colleagues is that if a wildtype protein promotes most 20% had diabetes. sizes the need for CHD prevention, providing the framework for future the degradation of the LDL receptors She reported similar results in lowering the threshold of treatment, development of new cholesterol-low- and retards the clearance of a lipo- European-Americans: a 15% lower by intervening earlier in life with diet ering drugs protein, then if you have a mutation LDL level – the equivalent of a very modifications and possibly low doses They began their research by look- in PCSK9, you would expect there low dose of statin – resulted in a 46% of drugs that are now available, Dr. ing at Mendelian disorders to find to be an increase in LDL receptor reduction in coronary artery disease. Hobbs said.

In July 2005, Dr. Leme finished her will finish in 2012. Both his thesis and Pier M. Mannucci Awards PhD thesis, which was focused on the training are at the Departments of In- study of dental biofilm and saliva pro- ternal and Vascular Medicine of the he Pier M. Mannucci Awards China. While pursuing this degree, teome. After that, she started postdoc- Academic Medical Center in Amster- is an annual competition for she focused on the tolerance induction toral training with Dr. Solange Serrano dam under supervision of Professors T the best articles published in of autoreactive T cells in idiopathic at Instituto Butantan, Brazil, where she Marcel Levi and Harry R. Büller. He the Journal of Thrombosis and Haemostasis thrombocytopenic purpura (ITP) and continued the study of biological fluids, hopes to continue his scientific work in that rewards and encourages investiga- finished her study on the underlying particularly snake venoms. Her studies the field of thrombosis and hemostasis tors in the early stages of their careers. mechanisms of CTLA4-Ig in treating are mainly aimed at understanding the with emphasis on clinical studies on Established in honor of Pier Mannucci, ITP. Her supervisor is Professor Ming mechanisms by which snake venom risk factors for venous thrombosis and founding editor of the journal, the prize Hou. After graduation, she started her serine proteinases and metallopro- new anticoagulant therapies. is made available through a generous clinical training in the Department of teinases disrupt hemostasis upon en- Dr. Jonathan Tardos won a Man- contribution by Bayer Healthcare. Hematology, Qilu Hospital, Shandong venoming. She hopes to identify new nucci award for his paper “SR Pro- This year four prizes were awarded University. She hopes to continue molecules that could contribute to our teins ASF/SF2 and SRp55 Participate for papers in the following categories: her scientific work in immunology of understanding of the coagulation and in Tissue Factor Platelets, Fibrinolysis, Clinical and platelets, especially the etiology and fibrinolytic systems. Biosynthesis in Vascular Biology. new therapies of refractory ITP. Dr. Michiel Coppens earned a Human Mono- Dr. Xiaolin Zhang was given a Dr. Adriana F. Paes Leme's paper Mannucci award for his paper “Testing cytic Cells,” which Mannucci award for her paper “Mod- “Bothrops Protease A, a Unique High- for Inherited Thrombophilia Does Not shows that exonic ulation of Immune Response with ly Glycosylated Serine Proteinase, Is Reduce Recurrence of Venous Throm- splicing enhances CTLA4-Ig−Induced Anergic T Cells a Potent, Specific bosis.” Testing for inherited thrombo- interact with bind- in Chronic Idiopathic Thrombocyto- Fibrinogenolytic philia in patients with a first venous ing motifs in the penic Purpura," which focused on the A g e n t ” e a r n e d thrombosis or pulmonary embolism is Jonathan Tardos tissue factor gene. cytotoxic T-lymphocyte−associated an- her a Mannucci controversial. In his Vascular Biology These appear to tigen 4 immunoglobulin (CTLA4-Ig) award. Bothrops nested case-control interact with the −induced GP-spe- protease A (BPA), study, he shows variable tissue factor exon 5, altering cific anergic T cells the most glycosyl- that testing as car- splicing and regulated biosynthesis and their inhibi- ated snake venom ried out in clinical of the gene in monocytes tory function on Adriana F. serine proteinase practice does not Dr. Tardos is currently finishing his GP-reactive T-cell Paes Leme (SVSP), is a non- reduce the risk internal medicine residency at Beth proliferation and Fibrinolysis coagulant, ther- of recurrence of Israel Medical Center, New York, antibody produc- mostable enzyme. Michiel Coppens thrombosis. These with plans to start a cardiovascular tion. Using in vitro She has shown that BPA is a potent Clinical results add another fellowship at SUNY Stony Brook Xiaolin Zhang culture systems, fibrinogenolytic agent in vitro and in argument against University, New York, in July 2010. Platelets she found that the vivo. She has also studied partially testing for inherited thrombophilia. His career goals are to continue his anergized GP-spe- N-deglycosylated BPA (p-N-d-BPA), In February 2008, Dr. Coppens fin- training with an additional fellowship cific T cells have profound effects on which has enhanced activity. This ished his PhD thesis entitled “Thrombo- in electrophysiology cardiology, ulti- both GP-specific T-cell proliferation investigation identifies a new, ther- philia,” from which his paper is derived. mately working at an academic cen- and antibody production. mostable, specific defibrinogenating After his thesis, he started his training ter to continue translational research Dr. Zhang was awarded her doctor- agent that may have application in in internal medicine with a subspecial- identifying risk factors and novel indi- ate in 2007 at Shandong University, preventing thrombus formation. ization in vascular medicine, which he cations for cardiac resynchronization.

10 tuesday • July 14, 2009

Education Should Reach All Professionals in Thrombosis and Hemostasis Around the World he Outreach Forum mem- ISTH improved over the past de- American Thrombosis and He- bers and the ISTH Council cade, the education committee orga- mostasis Society (CLAHT) were a T Education Committee mem- nized 20 educational events through- great success. The half-day dry lab bers met Saturday to discuss current out the world. These events have course as well as the two full-day and future Reach the World pro- included standalone symposia, dry educational course were well re- grams and to identify the needs for and wet laboratory workshops, sym- ceived and well attended by physi- education around the globe. posia linked to regional congresses cians, biochemists and students in This year, for the first time, with and state-of-the-art seminars. related medical fields. help from Drs. Ken Bauer, Bruce Following the successful educa- In 2007, former Chair- and Barbara Furie, a fully integrated tion symposia that were organized man of Council Pro- education meeting took place during at the biennial Thrombosis and He- fessor Ian Peake the SSC sessions of the Congress. mostasis Congresses of Latin Ameri- proposed at the Numerous young and senior can countries since 2001, ISTH was Geneva ISTH investigators or medical doctors decided to organize two educational Congress to who study the science of thrombo- activities in Latin America every substantially in- year. The aim is crease the bud- to enable edu- get for educa- provide indica- cation in the tion and create tions of the pri- Latin American a forum in less orities of educa- countries using privileged coun- tion programs that native language. tries of eminent peo- are needed in the Professor Raul ple who are familiar countries or regions. Altman was with the needs for clinical An analysis of the ques- appointed to and laboratory education in their tionnaire yielded the following in- Raul Altman Orly Katz Frits Rosendaal lead this mis- respective countries or regions. formation: sion, and in this An Outreach Forum was formed l The status of thrombosis and he- sis and hemostasis, live and work role he has been fostering science- that includes 25 dedicated individu- mostasis is more advanced than around the world. However, not related medical education in the ar- als from countries that might benefit was expected. all of them can acquire advanced, eas of problems of thrombosis and from educational activities. The aim l In most countries, hematology up-to-date skills and knowledge. hemostasis, standardization of meth- was to first identify and evaluate the embraces thrombosis and hemo- Some of these professionals do not ods of diagnosis, and introduction of needs for education. stasis. have the financial means to travel appropriate therapy for the preven- A survey was held among the Out- l All countries have national meet- abroad to congresses or attend edu- tion and treatment of thrombotic reach Forum members to evaluate ings with an educational element cational seminars where they could and bleeding disorders. the status of thrombosis and hemo- to which ISTH-sponsored events attain additional education. Since Working from the course evalu- stasis centers, coagulation laborato- can be linked. its inception, the ISTH has tried to ations collected after the educa- ries, formal training of physicians l Most countries have training pro- develop educational activities, but tional meetings, Professor Altman and laboratory scientists, national grams for hematologists and hema- with limited resources. reported that the first ISTH courses meetings and educational activities. tology laboratory technicians, and Because the financial status of organized together with the Latin The Outreach Forum also aimed to more than half have PhD students in thrombosis and hematology. l There is a great need for the three modalities of education we can Select Abstracts Presented Today at offer: theoretical courses, dry laboratory and wet laboratory workshops, mainly for physicians and Presidential Plenary Abstract Session laboratory technicians. ix of the most highly rated abstracts submitted • Feedback Activation of Factor XI by Thrombin l A visiting professor program to the ISTH 2009 Congress will be featured in Is Essential for Hemostasis In Vivo could be a “winner.” S a special Presidential Plenary Abstract Session — Henri Spronk Future programs of Reach the to be held today at 3:15 p.m. in the Grand Ballroom. • Evidence of the First X-Linked Thrombophilia World will include a fellowship pro- These abstracts cover a wide range of topics and were Due to a Novel Mutation in Clotting Factor IX gram to enable young professionals selected both for their quality and for their potential Gene Resulting in Hyperfunctional FIX: Fac- to visit for several weeks an advanced interest among a broad cross-section of delegates. tor IX Arginine 338 Leucine (Factor IX Padua) center in the field. In addition, a vis- Congress President Barbara Furie noted: “Ab- — Paolo Simioni iting professor program will enable stracts are regularly submitted on seminal work im- • Kindlin3 in Integrin Activation leading physicians and scientists to portant to our entire field, and we wanted to create a — Tatiana V. Byzova spend several days in centers around forum where we could showcase these abstracts to a • Thrombomodulin Mutations Predispose to the world to give lectures, seminars, large audience.” Atypical Hemolytic-Uremic Syndrome Via short courses and scientific advice. Abstracts to be presented include: Impaired Complement Regulation E-Learning throughout the world is • Genome-Wide Scan in Affected Sibling Pairs — Mieke Delvaeye also planned. (Gift Study) Identifies a Novel Susceptibility Young Investigators Travel Region for Venous Thromboembolism The XXII Congress Awards Presentation will take Awards were established to assist — Marieke de Visser place from 4:00 p.m. to 4:15 p.m. between the third those who come to the meetings • Examination of the Final Stages of Platelet and fourth abstract presentations. and to promote the involvement of Production young Society members at the ISTH — Jonathan N. Thon meetings. ISTH 2009 Daily 11

LATE BREAKING TRIAL therapeutic doses for four weeks, or to a control group. Patients in the Nadroparin Failed to Improve Survival treatment arm were then assigned to six cycles of therapeutic-dose nad- in Patients with Cancer roparin at two-week intervals every six weeks. The primary endpoint reliminary data from the IN- from two prior trials that showed that pancreatic cancer or stage IIIb non- was death from all causes; the sec- PACT trials indicate that nadroparin prolonged survival in pa- small-cell lung cancer. The primary ondary endpoint was time to cancer P treating patients with the low tients with cancer who did not have outcome was death due to all causes progression; and the safety endpoint molecular weight heparin nadropa- venous thromboembolism. and time to cancer progression, Dr. was major bleeding. rin did not improve survival among The multicenter, randomized, Buller said. To date, data indicate that the patients with can- open-label INPACT study included Patients were randomly assigned median survival of nadroparin cer, according 503 patients with hormone-refracto- to subcutaneous nadroparin once patients was 12.5 months vs. 11.9 to Dr. H. Roger ry prostate cancer, locally advanced daily for two weeks followed by half months for patients not assigned Buller, MD, of the drug (P=.48), according to Dr. the department Comparison of Endpoints Buller. The HR adjusted for type of of vascular medi- Survival Nadroparin No nadroparin cancer was 0.92, a nonsignificant, cine, Academic nonclinically relevant difference. Medical Center, Major Bleeding 10 (4.1%) 9 (3.5%) In addition, the survival difference Dr. H. Roger Amsterdam. did not vary over time. Buller, MD R e s e a r c h e r s One major bleed or nonmajor The use of nadroparin was not 22 (9.0%) 21 (8.1%) conducted the IN- clinically relevant bleeding associated with an increased risk of PACT study to confirm the findings bleeding (see table). Reiss Shock with Injury Linked to Coagulopathy (continued from page ) njury, regardless of severity, is not we see the real picture. Patients be- tion, and whatever clots that are made The primary endpoint was enough to cause coagulopathy, come coagulopathic when they are are broken down thought this fibrino- symptomatic VTE at three I Karim Brohi, FRCS, FRCA, both shocked and injured,” he said. “A lytic mechanism,” Dr. Brohi said. months. said during an educational session on patient can be very injured and never “Our current model of trauma-in- The incidence rate for VTE Sunday. Shock is a crucial component get coagulopathic, and he can be very duced coagulopathy, the global pic- was 9.9% in the observation of the condition. shocked and never become clinically ture, is that it starts with a snowball, group, which was reduced to The onset of coagulopathy, he coagulopathic, but the combination a combination of trauma and shock 1.3% in the enoxaparin group noted, is much earlier than previously of the two does something that makes leading to acute traumatic coagulopa- (P,.01). This was an absolute thought and is often fatal. In a retro- patients bleed. It is not clear what is thy. Then the avalanche takes over risk reduction of 8.6% and a rela- spective study of patients who were going on in those patients yet, but it is when we start getting the dilution, hy- tive risk reduction of about 90%. transported by helicopter to London certainly not normal.” pothermia and acidosis.” The incidence of bleeding at Royal Hospital, 24% of patients were Dr. Brohi described acute trau- Mortality from trauma is increas- three months was 3.75% in the coagulopathic upon arrival. Mortality matic coagulopathy as a snowball ing, Dr. Brohi said, and hemorrhage enoxaparin group vs. 2.63% in was four times greater than normal that rolls downhill to become an ava- accounts for about 40% of those the observation group, accord- for those patients. lanche. As patients become coagu- deaths. Death from the bleeding is the ing to Dr. Reiss. Dr. Brohi, a surgeon at London lopathic, they begin to experience most preventable cause of mortality Although the rate of VTE Royal Hospital and professor of trau- several attendant conditions such in the world. and bleeding events increased ma sciences at Barts and The London as decreased fibrinogen utilization, “All is not dilution, although it at 30 weeks compared with School of Medicine and Dentistry, dropping protein C levels and in- certainly does come into play later,” three months, patients as- said there is a linear increase in mor- creased levels of APC. he said. “Early on, the beast is some- signed enoxaparin still had re- tality depending on injury severity “In this systemic anticoagulation thing different. If we’re going to make duced rates of both compared and the patient’s level of shock, but with fibromyositis and increased fi- an impact on these significant death to observation. Data on re- the whole story is more complicated. brinogen utilization, you see this rates associated with trauma hemor- sponse rate, progression-free Neither patients who are only injured perfect storm of coagulopathy where rhage and traumatic coagulopathy, survival and overall survival nor those who are shocked develop a patients don’t use fibrinogen, inhibit understanding the beast is our first will be analyzed after a longer condition he calls “acute traumatic TOP formation through APC activa- process.” follow-up. coagulopathy,” characterized by early coagulopathy associated with both injury and shock. also received very large quantities, disease-associated prion protein in his “When you put the two together, Ironside 400,000 units, of UK Factor XIII not spleen had the MV genotype. (continued from page ) known to be implicated. “This raises questions whether the asymptomatic donors with variant “In addition, the patient had been other two unit types will eventually CJD (Creutzfeldt-Jakob disease). transfused with 14 units of red blood have clinical cases because we know Dr. Ironside and his colleagues dis- cells in the past and undergone mul- that they can suffer from sporadic covered disease-associated prion pro- tiple surgical and endoscopic proce- CJD,” Dr. Ironside said. “This is one 2009 Daily tein in one-quarter of spleen samples dures, all of which are potential risk of the great uncertainties.” ISTH collected from the autopsy of a single factors,” Dr. Ironside said. He added that as many as one in ISTH 2009 Daily is published four times patient with hemophilia. There was There is a genetic susceptibility 10,000 people in the U.K. could be during the XXII Congress International one evidence of variable levels of the associated with variant CJD. All pa- infected without showing signs of Society on Thrombosis and Haemostasis disease-associated prion protein in tients who had the MM genotype the disease. “The other uncertainty is frozen tissue. All other samples in- at position 129 in the prion protein whether the number of patients so far cluding brain and other lymphoid tis- have developed the disease, he said. who have died from the disease repre- sues were negative. In comparison, 38% of the normal sent merely the tip of an iceberg – the Publishers of HemOnc Today The patient had received more population in the West have the MM iceberg beneath the water represent- SLACK Incorporated, 6900 Grove Road, than 8,000 units of variant CJD-impli- genotype, and 50% have the MV gen- ing the number of patients who are Thorofare, NJ 08086; Phone 856-848-1000 cated Factor XIII; however, he had otype. The patient in this study with infected but so far asymptomatic.” 12 tuesday • July 14, 2009

Forum Provides Online Access to Experts and More reated at the beginning of question to the relevant subcommit- tion of Factor XI by Thrombin Is Es- abstract session that you attended, 2009 and unveiled at this tee chair. sential for Hemostasis In Vivo look for the speaker’s name and title C year’s Congress, ISTH is Paolo Simioni: Evidence of the of the lecture. Attendees may post pleased to introduce you to the new- Speakers’ Forum: Open to All First X-Linked Thrombophilia Due to questions to the ISTH Forum via est opportunity to communicate with Congress Attendees a Novel Mutation in Clotting Factor the Congress Internet Cafe or at the fellow Society members and interna- The XXII Congress is the first ISTH IX Gene Resulting in Hyperfunctional Society’s booth (#161) located in the tional experts. Congress to use an online forum to FIX: Factor IX Arginine 338 Leucine Exhibition Area. Questions to the promote interaction between delegates (Factor IX Padua) speakers must be submitted no later What Is ISTH Forum? and featured speakers. A section of the Tatiana V. Byzova: Kindlin3 in In- than July 22, 2009. ISTH Forum is an evolution of The forum (entitled “ISTH 2009”) is open tegrin Activation Reminders on how and where to Haemostasis Forum, an online resource to all attendees for an extended plenary Mieke Delvaeye: Thrombomodu- post questions will be shown during that provided a medium for discussion session question and answer period. lin Mutations Predispose to Atypical participating sessions, and instructions of clinical questions posed by registered We thank the following speakers Hemolytic-Uremic Syndrome Via Im- are located on the ISTH Forum. We members. The original forum was cre- who have agreed to answer questions paired Complement Regulation hope you find the enhanced online ated in 1996 by Dr. Harold R. Roberts on the ISTH Forum for one week after dialogue informative and easy to use. and was supported by an unrestricted the Congress: How to Use ISTH Forum Please experience the ISTH Forum educational grant by Novo Nordisk. At ISTH Forum is located on the for yourself. Post a question, poll the the end of 2008, Novo Nordisk trans- Plenary Speakers Society’s website. Go to http://www. membership, add your expertise to ferred ownership of the forum (and its Helen Hobbs: Protection from isth.org and click on “ISTH Forum” the discussion or simply connect with archive of information) to the Society. Cardiovascular Disease: Getting to the (http://www.isth.org/ISTHForum/ members around the world. We hope The new ISTH Forum, in keeping Heart of the Matter tabid/60/Default.aspx). Go to “ISTH that you have a great week connecting with the spirit of the original Haemo- William Geerts: Thrombopro- 2009” to post Congress-related ques- with your colleagues in Boston; now stasis Forum, will continue to allow phylaxis as a Key Patient Safety Prior- tions. To ask a specific question on go to the ISTH Forum to continue the members to post questions and reply ity: Current Approaches and Future a plenary or presidential plenary conversation! to fellow members on topics ranging Directions from research queries to clinical di- Philip Hogg: Contribution of Allo- agnostic and treatment dilemmas in steric Disulfide Bonds to Regulation of thrombosis and hemostasis. Hemostasis All Congress Party Features The enhanced ISTH Forum also Shaun Jackson: Modern Concepts allows members to conduct polls, of Platelet Activation During Thrombus Something for Everyone announce new registries, organize Development and discuss research collaborations, Evan Sadler: von Willebrand As- he All Congress Party Thursday evening from 6:30 p.m. to 11:00 and post job openings. The ISTH sembly and Secretion p.m. will feature food from Boston’s many neighborhoods, a special Forum can be used to inform mem- Rudolf Jaenisch: Stem Cells, Pluri- T performance by the renowned conductor Keith Lockhart and the bers about future conferences or to potency, and Nuclear Reprogramming Boston Pops Esplanade Orchestra, and activities for guests of all ages. facilitate meetings with colleagues in Guests will stroll among Boston’s “neighborhoods,” with each offering advance of an upcoming conference. Presidential Plenary its own characteristic food and entertainment. Get a hot dog and have a The ISTH Forum can also be used to Abstract Presenters souvenir baseball photo taken at the famous “Green Monster” left field wall support the work of the subcommit- Marieke de Visser: Genome-wide of Fenway Park, home of the Boston Red Sox. Visit the Cheers bar and tees of the Scientific and Standard- Scan in Affected Sibling Pairs (Gift pose for a caricaturist while toasting your colleagues. Authentic Chinese ization Committee during the year. Study) Identifies a Novel Susceptibility lion dancers will entertain the tasters at the Chinatown neighborhood, and If you have a question for the SSC Region for Venous Thromboembolism a vocal and accordion duo will serenade the samplers of a little taste of Italy or simply want to become involved Jonathan N. Thon: Examination of from Boston’s North End. From the waterfront to Beacon Hill, Boston’s in SSC work, the ISTH Forum of- the Final Stages of Platelet Production neighborhoods have something for everyone. fers the perfect opportunity to post a Henri Spronk: Feedback Activa- In a special program for ISTH 2009, the Boston Pops Esplanade Or- chestra will highlight music by composers with ties to Boston, as well as music that is so well known that the audience will be asked to sing along. Afterward, dessert will be served and an All Congress Party DJ will keep the Important Announcement music going. Regular bus service will take guests back to Congress hotels. Advance reservations are required for the All Congress Party, but there is he ISTH XXII General tional nongovernmental organization. still time to purchase tickets if you have not already done so. Please inquire Membership Assembly will Programs and activities of ISTH at the Registration Desk. T take place today, July 14, in and the Scientific and Standardization the Grand Ballroom from 3 p.m. to Committee (SSC) are entirely mem- 3:15 p.m. ber-driven and include: Members will receive reports from • The Journal of Thrombosis and the Society’s leaders: Haemostasis: JTH • Congress Presidents Drs. Bruce • Congresses and SSC annual and Barbara Furie on the organi- meetings zation of the XXII Congress. • SSC scientific subcommittees • ISTH Council Chairman Dr. Frits • ISTH programs, such as the Reach Rosendaal reporting to the mem- the World Initiative with its educa- bership on actions of Council taken tion and outreach components and at this year’s business meeting. the new ISTH Forum • ISTH Executive Director Dr. Gil- ISTH members are encouraged to bert C. White II summarizing the attend this brief meeting and to raise state of the Society over the past questions or make remarks. This year and to date. is the membership’s opportunity Bank of America Pavilion, a Live Nation Amphitheater, just a short walk from the The ISTH is an individual member- to hear from leadership, and this is BCEC, is the site of the All Congress Party to be held Thursday evening from ship association and exists for and by the leadership’s opportunity to hear 6:30 p.m. to 11:00 p.m. the will of all members as an interna- from you.