Research Report 2018
A Message from Executive Vice President Gilbert White, II, MD, Chief Scientific Officer
2018 was another strong year for research. Grant and Yan Qing Ma were promoted to Investigator. revenues for the year were $16.1 M, another record Lisa Baumann-Kreuziger, Lynn Malec, and Matt for us and exceeding our 2018 budget by $1 M. Karafin were promoted to Associate Investigator. New NIH R-type grants or competitive renewals Jorge DiPaola of the University of Colorado, David were obtained by Bob Montgomery and by Sandy Lillicrap and Paula James from Queens University in Haberichter. Peter Newman successfully competed Kingston, Canada, James O’Donnell from the Royal for a $6.9 M 7-year R35 Career award from NHLBI. College of Surgeons of Ireland, and Amy Shapiro Karin Hoffmeister received a new $4.8 M K12 award from the Indiana Hemophilia and Thrombosis Center in Glycobiology, one of four in the US together with in Indianapolis were appointed as adjunct Senior Johns Hopkins, Harvard, and UCSD. Gil White is the Investigators at the BRI. PI on a new $1.5 M OT2 consortium grant from NIH that is part of the NIH Precision Medicine Initiative. A Individual accomplishments during the year were new F-type award went to Puja Agrawal in Sid Rao’s numerous. We celebrated Hardy Weiler’s and Pam lab. Altogether, there were 11 new NIH grants in 2018 Christopherson’s 20th year with the organization. that totaled $17.5 M. Nan Zhu received the second Alan Mast chaired the 2018 Hemostasis Gordon R. Douglas Ziegler Innovation Award for her work Conference. Irene Hernandez in Hardy Weiler’s lab related to the pathogenesis of acute myelogenous received Excellence in Action recognition from Versiti. leukemia. Matt Karafin, Josh Field, Peter Newman, Dick Aster received the BizTimes Media Health Care Karin Hoffmeister, and Subra Malarkannan received Heroes Lifetime Achievement Award, recognizing funding for Versiti Moonshot projects. his advancements in transfusion medicine. Karin Hoffmeister chaired the Megakaryocyte and Platelet John Pulikkan joined the faculty as Associate Scientific Committee and the Committee Program Investigator in the stem cell group. John came from the at the annual meeting of the American Society of University of Massachusetts Medical School from the Hematology (ASH). Hervé Falet also serves on the lab of Lucio Castilla, a former scholar of the Leukemia Megakaryocyte and Platelet Scientific Committee. and Lymphoma Society. His research focuses on Peter Newman serves on the Investment and Audit chromatin dynamics and understanding the regulatory Committee of ASH. Alan Mast, Karin Hoffmeister, pathways that are deregulated in hematopoietic stem Magda Chrzanowska, Debra Newman, Roy and progenitor cells in acute myeloid leukemia in order Silverstein and Bob Montgomery continue to serve to better understand the development of leukemia. on NIH review panels. Peter Newman continues His overall goal is to develop novel therapeutic to serve as Associate Editor of Arteriosclerosis, strategies for the treatment of leukemia. Jieqing Zhu Thrombosis, and Vascular Biology (ATVB). Hardy
Research Report 2018 1 Continued: A Message from Executive Vice President Gilbert White, II, MD, Chief Scientific Officer
Weiler and Roy Silverstein serve on the ATVB Editorial University, on November 8th. His talk was titled “T Zheng in Demin Wang’s lab was the 2018 Doolittle Board. Alan Mast is a new Associate Editor of the Cell Exhaustion and PD-a Immunotherapy”. All four Fellow and Saravanan Subramaniam in Hardy Weiler’s Journal of Thrombosis and Haemostasis. Magda lectures were outstanding and examples of cutting lab was the Gallagher Fellow. Waseem Anani in Karin Chrzanowska is on the Editorial Board of Plos One. edge science and translation. Hoffmeister’s lab was named the first Jaqueline and Bonnie Dittel is Associate Editor of Autoimmunity Arlen Fredrick Scholar. New Directors Fellows were and on the Editorial Boards of the Journal of The 1st Annual Great Lakes Translational Glycomics Heather Ashwood in Karin Hoffmeister’s lab and Neuroimmunology and Brain, Behavior, and Immunity. Symposium was held May 31st at the Blood Amy Siebert-McKenzie in Alan Mast’s lab, bringing Subra Malarkannan is Associate Editor of Frontiers in Research Institute (BRI) and was organized by Karin to 6 the number who have been supported through Immunology. Qizhen Shi is on the Editorial Board of Hoffmeister. Featuring speakers from GlycoMimetics, the contributions of Scott and Genevieve Harkness. Molecular Therapy, Methods and Clinical Development. Inc, Washington University in St. Louis, Virginia Chao Yang in Subra Malarkannan’s lab received the Peter Newman is Co-Editor of the 3rd Edition of Commonwealth University, Roswell Park Cancer inaugural J. Evan Sadler Graduate Scholar Award, as Platelets and Gil White is Co-Editor of the 6th Edition of Center, Brigham and Women’s Hospital, and Medical voted by the BRI graduate students and postdoctoral Thrombosis and Hemostasis. Six students completed College of Wisconsin (MCW), it was attended by more fellows. Moua Yang in Roy Silverstein’s lab received the their PhD degrees in 2018: Michael Reimer from Sid than 60 individuals. The 12th Annual Center for Human Mary Rodes Gibson Memorial Award in Hemostasis Rao’s lab, Aye Myat Myat Thinn from Jieqing Zhu’s Immunology Symposium was held October 25th at and Thrombosis for the highest scoring abstract at lab, David Schauder from Weiguo Cui’s lab, Alex Abel the BRI. The symposium, titled “B Cells and Broadly the American Society of Hematology meeting. Five from Subra Malarkannan’s lab, Erin Wesley from Matt Neutralizing Antibodies,” featured renowned speakers new graduate students selected the BRI as their place Riese’s lab, and Moua Yang from Roy Silverstein’s lab. from Harvard University, Scripps Research Institute, to train: Paytsar Topchyan and Christine Nguyen Vanderbilt University, the Feinstein Institute for Medical in Weiguo Cui’s lab, Yaling Wu in Demin Wang’s lab, The 16th Annual Aster Lecture was delivered on Research, and Sanofi Pharmaceuticals. This year’s Savannah Neu in Bonnie Dittel’s lab, and Yuanhua Cai August 15th by Dr. Olja Finn, Distinguished Professor meeting was hosted by Demin Wang and Renren Wen. in Qizhen Shi’s lab. of Immunology and Surgery at the University of Pittsburgh. Her talk was titled “Vaccines in the The Scientific Advisory Board reviewed part of the Sadly, we lost a long-time and beloved colleague Prevention of Non-Viral Cancers”. The 17th Annual Vascular Biology program in October. Overall, there when Joan Gill passed away on May 9, 2018. Joan Mosesson Lecture was delivered on October 4th was high enthusiasm for this group of investigators. In was internationally renowned in the world of bleeding by Dr. Bjorn Dahlback, Senior Professor in the their summary comments, the Board described the disorders and made a number of lasting contributions Department of Laboratory Medicine at Lund University need for continued succession planning, space for through her work with von Willebrand disease and in Malmo, Sweden. His talk was on “Novel Insights continued expansion, attention to retention, and the hemophilia. One of the first women in the field, Joan into the Regulation of Blood Coagulation by FV success of the mentoring program. They also reported served as an example to countless young women in Isoforms, TFPI alpha and Protein S”. The 2nd Annual some faculty anxiety regarding a perceived emphasis hematology and was the face of bleeding disorders Jacqueline Fredrick Lecture, selected and hosted by on cell therapies and uncertainty regarding changes in care in the State of Wisconsin. the graduate students and postdoctoral fellows at the leadership. BRI, was given on September 20th by Melanie Cobb, At years’ end, there were 38 trainees in the BRI. All of Browning Chair in Medical Science in the Department our T32 Training Grant positions were filled in 2018: of Pharmacology at the UT Southwestern Medical Tyce Kearl in Subra Malarkannan’s lab, Alyssa Moroi Center. The talk was titled “Catching a Few Good in Peter Newman’s lab followed by Lauren Pommert in WNKs”. The 2nd Annual R. Douglas Ziegler Innovation Sid Rao’s lab, Nate Schloemer in Subra Malarkannan’s Lecture was by Dr. Rafi Ahmed, Director of the highly lab followed by Amy Siebert-McKenzie in Alan Mast’s Gilbert C. White, II, MD innovative Harrington Discovery Institute at Emory lab, and Jesse Sundlov in Peter Newman’s lab. Yongwei Chief Scientific Officer
2 Research By The Numbers – 2018
10 $122.4 5 New NIH Million New Diagnostic Grants New Applications Tests Developed
$16.1 33 Million 1 Start-Up Company Investigators Research Formed Revenues
$614+ 2 13 Thousand Patents Filed Core Labs Average Funding per Investigator
Research Report 2018 3 Transfusion Medicine
Transfusion Medicine research has a long history at Versiti, reflecting its basic mission to provide a safe and effective supply of blood products for patients who require transfusion.
Effective transfusion therapy requires knowledge of the biology and physiology of blood, satisfactory methods for collecting and storing blood cells with maximum preservation of function, and an understanding of the many diseases in which transfusion of blood components can be beneficial.
Research conducted by the Transfusion Medicine group addresses each of these areas. Investigators in the Transfusion Medicine Program study basic biology and clinical implications of a range of transfusion-related issues. CEO Emeritus and Senior Investigator, Blood Research Institute Richard H. Aster, MD Professor, Department of Medicine, Medical College of Wisconsin (MCW) MD, University of Michigan 1957 Hematology, Harvard University 1965 Faculty, Harvard 1964-1970 Started at Versiti: 1971
cell destruction and improved understanding of the Funding molecular basis for these conditions. RO1-HL-13629-47 National Heart Lung and Blood Awards, Honors and Service Institute. Renewed June 1, 2017 • Founder: GTI Diagnostics (subsidiary of VBRIF) Publications • Karl Landsteiner Award, American Association of Blood 1. Curtis BR, Hsu YS, Podoltsev N, Lacy J, Curtis S, Banks (AABB) Samuel MS, Zutavern K, DeSimone RA, Bougie DW, • Henry Stratton Medal for translational research, Aster RH. Patients treated with oxaliplatin are at risk for American Society of Hematology thrombocytopenia caused by multiple drug-dependent antibodies. Blood. 2018 Mar 29;131(13):1486-1489. • Distinguished Service Award, Medical College of PMID: 29439950 Wisconsin (MCW) 2. Dhakal B, Kreuziger LB, Rein L, Kleman A, Fraser • Reviewer for the journals Blood, New England Journal R, Aster RH, Hari P, Padmanabhan A. Disease of Medicine, Lancet, Nature, Science Translational burden, complication rates, and health-care costs Medicine and Transfusion of heparin-induced thrombocytopenia in the USA: • Grant reviewer (Transfusion Medicine), Center for a population-based study. Lancet Haematol. 2018 Scientific Review, National Institutes of Health May;5(5):e220-e231. PMID: 29703336
Research Interests Immune destruction of red blood cells, white blood cells, and platelets is a major cause of morbidity and mortality in patients. Dr. Aster’s work is aimed at understanding the causes of blood cell destruction by autoantibodies, drug-induced antibodies, and antibodies triggered by blood transfusion or exposure to fetal blood cells during pregnancy. Recent studies in his laboratory have shown that metabolites generated in the body following exposure to various drugs can induce antibodies that cause platelet destruction and bleeding and provide new insights into the cause of “idiosyncratic” drug-sensitivity reactions. Findings made in these and related studies are defining new methods for antibody detection to improve diagnosis and treatment in patients with antibody-induced blood
Research Report 2018 5 Director, Platelet & Neutrophil Immunology Lab, Versiti Brian Curtis, PhD, Senior Director, Versiti Product Development and Clinical Lab, Versiti Investigator, Blood Research Institute, Versiti Assistant Adjunct Professor, Clinical and Translational Science Institute, Medical College of Wisconsin D(ABMLI), MT(ASCP) PhD, University of Wisconsin-Milwaukee SBB, Investigator Started at Versiti: 1991
antibodies that destroy her child’s platelets. Recent work PMID: 29439950 in the Curtis lab has allowed for improved diagnosis of 2. Thinn AMM, Wang Z, Zhou D, Zhao Y, Curtis BR, Zhu J. FNAIT. Autonomous conformational regulation of β3 integrin and the conformation-dependent property of HPA-1a Awards, Honors and Service alloantibodies. Proc Natl Acad Sci U S A. 2018 Sep • Member, Editorial Board, Transfusion 2017 25;115(39):E9105-E9114. PMID: 30209215 • Member, ISBT Granulocyte Antigen Nomenclature 3. Rachel Petermann, Tamam Bakchoul, Brian Curtis, Working Party, 1997 Francois Mullier, Shigeki Miyata, Donald M. Arnold. Investigations for Fetal and Neonatal Alloimmune • Member, AABB Molecular Testing Standards Thrombocytopenia (FNAIT): Recommendations from Committee, 2012 the Platelet Immunology Scientific Subcommittee. J • Member, ISBT International Granulocyte Thromb Haemost 2018; Dec;16(12):2526-2529. doi: Immunobiology Workshop Steering Committee, 2014 10.1111/jth.14294. • Co-Chair, ISTH Platelet Immunology SSC, 2015 1 3 • Member, AABB Selection of Abstracts Program Unit Transfer Lysate
• Member, ASH Scientific Committee on Transfusion 2 Medicine, 2016 Lyse Incubate then wash • Member, Platelet Advisory Board, Ionis beads Pharmaceuticals, 2016 Incubate then wash platelets PE-anti-human IgG Research Interests • Co-chair, ISBT Platelet Immunobiology Working Party, Antibody Subcommittee on Quality, 2018 2 Glycoprotein Antibodies specific for antigens carried on blood Incubate Monoclonal antibody platelets and white blood cells (neutrophils) cause with Bead anti-IgG, 5 Wash beads thrombocytopenia and neutropenia (low neutrophil Funding count) in various immune disorders and can be difficult “Development of a New and Improved Diagnostic Assay Negative result Positive result to identify. Work in Dr. Curtis’ laboratory has led to for Antibody Detection in Patients with Suspected improved methods for detecting such antibodies and to Heparin-Induced Thrombocytopenia (HIT)”. Strategic y new understanding of the blood disorders in which they ensi t
Investment Fund, Versiti (Co-PI). t are involved. Dr. Curtis serves as Director of the Platelet n and Neutrophil Immunology Reference Laboratory of e I Versiti and applies his research findings to improve Publications en c es c the effectiveness with which this laboratory enhances 1. Curtis BR, Hsu YS, Podoltsev N, Lacy J, Curtis S, medical care for patients referred for diagnostic testing. Samuel MS, Zutavern K, DeSimone RA, Bougie DW, luo r
One particular area of expertise for the lab is in diagnosis Aster RH. Patients treated with oxaliplatin are at risk for ead F B of Fetal and Neonatal Alloimmune Thrombocytopenia thrombocytopenia caused by multiple drug-dependent
(FNAIT), a disorder in which a pregnant mother can make antibodies. Blood. 2018 Mar 29;131(13):1486-1489. PE-anti-human IgG – Fluorescence Intensity 6 Versiti Blood Research Institute
Senior Investigator, Versiti Blood Research Institute, Versiti Gregory Denomme, PhD Senior Director of Immunohematology and Innovation, Versiti PhD, Microbiology and Immunology, University of Western Ontario, 1993 Started at Versiti: 2009
Awards, Honors and Service 4. Levitt RN, Gourri E, Gassner C, Banez-Sese G, Salam A, Denomme GA, Yang E. Molecular characterization and • Working Party member, Red Blood Cell multidisciplinary management of Gerbich hemolytic Immunogenetics and Blood Group Terminology disease of the newborn. Pediatr Blood Cancer. 2018 • International Society for Blood Transfusion Jun;65(6):e27014. PMID: 29469208 • Editorial Board Member, International Journal of 5. Yazer MH, Anani WQ, Denomme GA, Karafin MS, Clinical Transfusion Medicine Sayers M, Shaz BH; Biomedical Excellence for Safer Transfusion (BEST) Collaborative. Trends in antigen- • Editorial Board Member, Transfusion negative red blood cell distributions by racial or ethnic groups in the United States. Transfusion. 2018 Funding Jan;58(1):145-150. PMID: 29023750 Designer blood cells: CRISPR/cas9 alteration of red blood cell and platelet antigens. G. Denomme (Principal Investigator) B. Curtis, P. Newman (Senior Investigator). Versiti Strategic Funding 2019.
Publications Antibody mediated lysis of PNH red blood cell clone 1. Storry JR, Clausen FB, Castilho L, Chen Q, Daniels
G, Denomme G, et al. International Society of Blood Inhibits deposition of Transfusion Working Party on Red Cell Immunogenetics DAF complement C3b on red blood cell surface and Blood Group Terminology: Report of the Dubai, Research Interests Copenhagen and Toronto meetings. Vox Sang Inhibits formation of Dr. Denomme is Senior Director of Versiti’s 2019;114:95-102 MIRL membrane attack Immunohematology and Transfusion Service Laboratory, complex 2. Compernolle V, Chou ST, Tanael S, Savage W, Howard a division of Versiti Clinical Laboratories. He is an J, Josephson CD, Odame I, Hogan C, Denomme G, immunology and immunohematology-trained scientist Shehata N; International Collaboration for Transfusion with interests in the immune response to red cell Medicine Guidelines. Red blood cell specifications for antigens, the expression of blood groups, and bench- patients with hemoglobinopathies: a systematic review to-bedside studies in immunohematology. His work and guideline. Transfusion. 2018 Jun;58(6):1555-1566. integrates immunogenetics with transfusion medicine to Review. PMID: 29697146 explore the genetic basis of blood group expression and the functional polymorphisms underlying the pathology 3. Flegel WA, Chen Q, Castilho L, Keller MA, Klapper of immune-mediated red cell hemolysis. EB, Lane WJ, Pirenne F, Stack G, St-Louis M, Tormey CA, Waxman DA, Weinstock C, Wendel S, Denomme GA. Molecular immunohaematology round table discussions at the AABB Annual Meeting, Orlando 2016. Blood Transfus. 2018 Feb 14:1-12. PMID: 29517973
Research Report 2018 7 Investigator, Blood Research Institute, Versiti Hervé Falet, PhD Assistant Professor, Medical College of Wisconsin PhD, Paris Descartes University, 1997 Postdoctoral fellowship, Brigham and Women’s Hospital and Harvard Medical School, 2001 Started at Versiti: 2016
of mortality, mostly due to bleeding. regulates hepatic thrombopoietin production via JAK2- Blood platelets are produced in the bone marrow by STAT3 signaling. Nat Med. 2015;21(1):47-54. PMID: megakaryocytes in a unique process that requires 25485912 extensive intracellular membrane rearrangements. These 2. Bender M, Giannini S, Grozovsky R, Jönsson T, include the formation of the demarcation membrane Christensen H, Pluthero FG, Ko A, Mullally A, Kahr system, the surface-connected membrane extension WHA, Hoffmeister KM, Falet H. Dynamin 2-dependent that invaginates into the cell body and further develops to endocytosis is required for normal megakaryocyte provide membranes for future platelets. development in mice. Blood. 2015;125(6):1014-1024. PMID: 25468568 At the Blood Research Institute, Dr. Falet investigates the roles of novel membrane binding and deforming 3. Begonja AJ, Pluthero FG, Suphamungmee W, Giannini proteins in the formation and organization of the S, Christensen H, Leung R, Lo R, Nakamura F, Lehman megakaryocyte demarcation membrane system. He W, Plomann M, Hoffmeister KM, Kahr WHA, Hartwig anticipates that his studies will yield basic information JH, Falet H. FlnA binding to PACSIN2 F-BAR domain related to megakaryocyte and platelet biology, and lead regulates membrane tubulation in megakaryocytes and to the development of new approaches to reestablish platelets. Blood. 2015;126(1):80-88. PMID: 25838348 thrombopoiesis in the setting of thrombocytopenia (low platelet count). Awards, Honors and Service • Bridge Grant Award, American Society of Hematology Research Interests 2015-2016 Dr. Hervé Falet received his master’s and doctoral • Outstanding Graduate School Educator Award, degree from Paris Descartes University and completed Graduate School of Biomedical Sciences, Medical his postdoctoral fellowship at Brigham and Women’s College of Wisconsin 2018 Hospital and Harvard Medical School. He joined the Blood • Member, Scientific Committee on Megakaryocytes and Research Institute faculty in 2016. His primary research Platelets, American Society of Hematology 2019-2022 interests are associated with blood platelet production (thrombopoiesis) and function. Funding Platelets circulate in blood at a concentration of 150,000- 450,000/µl that is maintained by a fine balance between National Institutes of Health R01 HL126743 “Endocytosis production and clearance. At sites of vascular injury, in Platelet and Megakaryocyte Biology” platelets respond to external stimuli by rapidly changing “Platelet Fireworks”, showing Dnm2-null platelets on shape and recruiting other platelets. Deficient platelet Publications a fibrinogen surface after GPVI activation. production, due to genetic causes, secondary to cancer 1. Grozovsky R, Begonja AJ, Liu K, Visner G, Hartwig JH, Winner, 2019 Platelets cover competition. therapy, or from unknown etiology, poses significant risks Falet H, Hoffmeister KM. The Ashwell-Morell receptor
8 Versiti Blood Research Institute Senior Medical Director, Versiti Joshua Field, MD, MS Investigator, Blood Research Institute Professor of Medicine, Medical College of Wisconsin Medical Director, Adult Sickle Cell Disease Clinic, Froedtert Hospital MD, Carver College of Medicine, University of Iowa, Iowa City, IA 2001 Started at Versiti: 2010
Awards, Honors and Service 2. Yu JC, Lin G, Field JJ, Linden J. Induction of antiinflammatory purinergic signaling in activated • Member, American Society of Hematology Guidelines human iNKT cells. JCI Insight. 2018 Sep 6;3(17). PMID: on Sickle Cell Disease Committee 2017 30185656 • Chair, Acute Pain Taxonomy Project for American Pain 3. AAAPT Diagnostic Criteria for Acute Sickle Cell Society/American Association for Pain Management Disease Pain. Field JJ, Ballas SK, Campbell CM, Crosby 2017 LE, Dampier C, Darbari DS, McClish DK, Smith WR, • Thomas A. Smallwood Award, Froedtert Hospital, WI “In Zempsky WT. J Pain. 2018 Dec 19. recognition of Patient Care Excellence 2017 • American Society of Hematology: Committee on Quality, Washington, DC, 2016-present • Ad hoc reviewer: K01 Diversity Review, NHLBI, Bethesda, MD, 2018 Funding “A Phase 1 Open-Label, Dose-Escalation/Dose-Expansion fMRI Safety and Tolerability Study of INCB059872 in Subjects Cingulate Cortex with Sickle Cell Disease” Incyte Corporation 11/01/2017 – Medial 10/31/2019 Frontal Gyrus Precuneus Research Interests “C1701-202 A Randomized, Placebo-controlled, Phase 2 Study to Evaluate the Safety and Pharmacodynamics Dr. Field is concerned with clinical aspects and of Once-daily Oral IW-1701 in Patients with Stable Amygdala optimization of treatment for adults with sickle cell Sickle Cell Disease” Ironwood Pharmaceuticals, Inc. disease (SCD). He was the principal investigator on 06/01-2018-present. a multi-center trial to evaluate effectiveness of the PAG adenosine2A receptor agonist regadenoson, an inhibitor Pain Centers of inflammation that may be useful for treatment of blood Publications vessel occlusion in SCD, as well as a trial to evaluate the 1. Lanzkron S, Little J, Field J, Shows JR, Wang H, Seufert cysteinyl leukotriene receptor antagonist, montelukast. R. Brooks J, Varadhan R, Haywood C Jr, Saheed M, Dr. Field also examined a novel imaging modality, Huang CY, Griffin B, Frymark S, Piehet A, Robertson D, Peripheral contrast-enhanced ultrasound, for the measurement of Proudford M, Kincaid A, Green C, Burgess L, Wallace Nerves microvascular blood flow in patients with SCD. Currently, PAIN Spinal Cord M, Segal J. Increased Acute Care Utilization in a Dr. Field is pursuing a study to taper opioids in patients Prospective Cohort of Adults with Sickle Cell Disease. INJURY/ with SCD and measure effects on functional MRI imaging INFLAMMATION Blood Adv 2018 Sep 25;2(18):2412-2417. PMID: Opioids of the brain. 30254105 Vascular Occlusion
Research Report 2018 9 Marqus Valentine Marqus Valentine has beaten sickle cell disease – and the odds. Many sickle cell disease patients do not live into adulthood. Marqus has made it into his 30s thanks to the generosity of blood donors, who have helped him receive more than 500 life-saving donations during his life. He’s grateful to blood donors and is now giving back to help other sickle cell patients in need.
“SC got scary for me when I was in high school because I could understand that I might not come out of the hospital.” Senior Medical Director, Versiti Jerome Gottschall, MD Senior Investigator, Blood Research Institute, Versiti Professor of Pathology, Department of Pathology, Medical College of Wisconsin MD, Ohio State University College of Medicine, 1974 Started at Versiti: 1979
blood products in distinct clinical settings. Dr. Gottschall EL; National Heart, Lung, and Blood Institute (NHLBI) also is concerned with the clinical aspects of immune Recipient Epidemiology and Donor Evaluation Study-III hemolytic anemia and in the status of iron levels in repeat (REDS-III). Contemporary Risk Factors and Outcomes blood donors. In 2015, Dr. Gottschall participated as of Transfusion-Associated Circulatory Overload. Crit co-author on two important articles, published in Lancet Care Med. 2018 Apr;46(4):577-585. PMID: 29300236 Haematology and Transfusion, about the importance 4. Van Buren NL, Gorlin JB, Reed RC, Gottschall JL, Nelson of red cell genotyping for transfusion medicine. An avid SC. Ceftriaxone-induced drug reaction mimicking athlete throughout his entire life, Dr. Gottschall says acute splenic sequestration crisis in a child with sports have taught him three critical life skills that he uses hemoglobin SC disease. Transfusion. Apr;58(4):879- in his medical work and throughout his life: discipline; 883 PMID: 29473172 persistence; and setting goals. 5. Wei S, Gonzalez Rodriguez E, Chang R, Holcomb JB, Awards, Honors and Service Kao LS, Wade CE; PROPPR Study Group…Gottschall, JL. Elevated Syndecan-1 after Trauma and Risk • Member, College of American Pathologists of Sepsis: A Secondary Analysis of Patients from • Member, American Association of Blood Banks the Pragmatic, Randomized Optimal Platelet and (AABB) Plasma Ratios (PROPPR) Trial. J Am Coll Surg. 2018 Dec;227(6):587-595. PMID: 30243993 • Member, American Society of Hematology Publications 1. Gehrie EA, Roubinian NH, Chowdhury D, Brambilla Research Interests DJ, Murphy EL, Gottschall JL, Wu Y, Ness PM, Strauss Dr. Gottschall is a Co-Principal Investigator on the RG, Hendrickson JE; NHLBI Recipient Epidemiology- Recipient Epidemiology and Donor Evaluation Study- Donor Evaluation Study (REDS-III). A multicentre III (REDS III) sponsored by the National Heart Lung study investigating vital sign changes occurring in and Blood Institute in which Versiti is one of several complicated and uncomplicated transfusions. Vox participating organizations. REDS III includes studies Sang. 2018 Feb;113(2):160-169. PMID: 29277907 on blood safety, blood availability, HIV transmission and 2. Glisch C, Jawa Z, Brener A, Carpenter E, Gottschall other transfusion-related studies. REDS III will utilize J, Treml A, Karafin MS. Evaluation of a two-sample large donor, component and recipient databases to process for prevention of ABO mistransfusions in a high help answer important transfusion-related questions. volume academic hospital. BMJ Open Qual. 2018 Jul Among subjects to be studied are alloimmunization 15;7(3):e000270. PMID: 30057954 (immunization against transfused blood cells), impact of blood donation on donor iron levels, benefits of red 3. Roubinian NH, Hendrickson JE, Triulzi DJ, Gottschall cell transfusion in the elderly, and transfusion of various JL, Michalkiewicz M, Chowdhury D, Kor DJ, Looney MR, Matthay MA, Kleinman SH, Brambilla D, Murphy
Research Report 2018 11 Medical Director, Medical Sciences Institute, Versiti Matthew Karafin, MD Associate Investigator, Blood Research Institute, Versiti Associate Professor of Pathology, Medical College of Wisconsin MD, Carver College of Medicine, University of Iowa, Iowa City, IA, 2007 Transfusion Medicine Fellowship, Johns Hopkins Hospital, 2011 Anatomical and Clinical Pathology Residency, Johns Hopkins Hospital, 2012 MS, Medical College of Wisconsin, Milwaukee, WI, 2015 Started at Versiti: 2012
• Member, College of American Pathologists (CAP) Donor Evaluation Study-III (REDS-III). Risk factors • Member American Society of Hematology (ASH) for red blood cell alloimmunization in the Recipient Epidemiology and Donor Evaluation Study (REDS-III) • Member, American Society for Clinical Pathology database. Br J Haematol. 2018 Jun;181(5):672-681. (ASCP) PMID: 9675950 • Member, Alpha Omega Alpha (AOA) Funding HHSN268201100003I (Mast) 03/15/2011 – 03/14/2020 NIH/NHLBI $511,520 “Recipient Epidemiology and Donor Evaluation Study III (REDS III)” (Co-I) 1K23HL136787-01A1 (Karafin) 12/15/2017 – 12/15/2022 NIH/NHLBI $165,000 “The Effects of Older Red Cell Units in Adults with Sickle Cell Disease”(PI) Publications 1. Karafin MS, Fu X, D’Alessandro A, Thomas T, Hod EA, Zimring JC, Field JJ, Francis RO. The clinical impact of glucose-6-phosphate dehydrogenase deficiency in patients with sickle cell disease. Curr Opin Hematol. Research Interests 2018 Nov;25(6):494-499. PMID: 30239377 Dr. Karafin’s research interests include the use of red cell 2. Karafin MS, Singh M, Ceesay M, Koduri S, Zhang L, transfusion for patients with sickle cell disease, etiology Simpson P, Field JJ. Dyspareunia is associated with and prevention of red cell alloimmunization, benefits chronic pain in premenopausal women with sickle and risks of red cell storage for patients with sickle cell cell disease. Hematology. 2018 Jan 29:1-6. PMID: disease, benefits and risks of red cell transfusions in the 29376481 elderly, and the etiology and prevention of transfusion 3. Karafin MS, Singavi A, Hussain J, Wandersee N, Heinrich reactions. T, Hurley RW, Zhang L, Simpson P, Field JJ. Predictive factors of daily opioid use and quality of life in adults Awards, Honors and Service with sickle cell disease. Hematology. 2018 May 31:1-8. PMID: 29848208 • Member, American Society for Apheresis (ASFA) 4. Karafin MS, Westlake M, Hauser RG, Tormey CA, • Member, American Association of Blood Banks Norris PJ, Roubinian NH, Wu Y, Triulzi DJ, Kleinman S, (AABB): Chair, Molecular Testing Accreditation Hendrickson JE; NHLBI Recipient Epidemiology and Program Unit Committee
12 Versiti Blood Research Institute Associate Investigator, Blood Research Institute Anand Padmanabhan, Medical Director, Therapeutic Services, Versiti Associate Professor of Pathology, Medical College of Wisconsin MD, Thanjavur Medical College, Thanjavur, TN, India, 2000 MD, PhD, PhD, Brown University, 2006 Started at Versiti: 2010
Awards, Honors and Service 2. Dhakal B, Baumann-Kreuziger L, Rein L, Kleman A, Fraser R, Hari P and Padmanabhan A*. Disease • American Society for Apheresis Lecturer Award, 2018 burden, complication rates, and health-care costs • Editor, Journal of Clinical Apheresis (JCA), of heparin-induced thrombocytopenia in the USA: 08/2015-present a population-based study. Lancet Haematol. 2018 May;5(5):e220-e231 • Chair, JCA Writing Committee on the Use of Apheresis in Human Disease, (2016-present) 3. Pandya K, Davis G, Johnson E and Padmanabhan A. Serotonin Release Assay (SRA)-Negative HIT, a newly • Member, American Association of Blood Banks (AABB) recognized entity: Implications for diagnosis and • Member, American Society for Apheresis (ASFA) management. Thrombosis Research, 2018 Dec;172:169- • Member, American Society of Hematology (ASH) 171. 4. Irani M, Siegal E, Jella A, Aster RH and Padmanabhan Publications: A. Use of Intravenous Immunoglobulin G to Treat Spontaneous Heparin-induced Thrombocytopenia. 1. Jones CG, Pechauer SM, Curtis BR, Bougie DW, Aster Transfusion. Epub ahead of print, Transfusion, Dec 2018 RH and Padmanabhan A*. IgG in Normal Plasma Inhibits HIT Antibody-mediated Platelet Activation: Implications for Plasma Exchange in HIT. Blood 2018 Figure: Model showing how we think HIT antibodies Feb 8;131(6):703-706.* Corresponding Author actually cause platelet activation in HIT (from Padmanabhan et al, Blood 2015) Research Interests Heparin is widely used to prevent and treat thrombosis, but some patients given this otherwise useful anticoagulant become immunized and produce antibodies that cause thrombocytopenia (heparin- induced thrombocytopenia, HIT). Many affected individuals experience thrombosis, which can be life threatening. Dr. Padmanabhan is engaged in studies to define the properties of heparin-induced antibodies that are most likely to cause thrombosis. Findings made are expected to advance the understanding of HIT and to improve laboratory diagnosis and treatment of this dangerous disorder.
Research Report 2018 13 Glycomics Center
The Glycomics Center, led by faculty member Dr. Karin Hoffmeister, opened its doors in 2016 for the Blood Research Institute. Analogous to Genomics and Proteomics, Glycomics focuses on defining the structures and functions of complex carbohydrates (sugars), as found in glycoproteins, glycolipids, and glycosaminoglycans.
Complex carbohydrates are important in many physiological processes and alterations in glycosylation are associated with vast numbers of blood related and unrelated diseases and disorders. The specific focus of the Center is to harness genomic with glycomic approaches with an emphasis on exploring transcriptional and epigenetic regulatory mechanisms of carbohydrate synthesis in health and disease. The data will help to understand and predict molecular mechanisms of carbohydrate expression and recognition by proteins important in human biology and disease. The Center will bring together scientists at BloodCenter of Wisconsin and other institutions to understand the role that sugars play in biology. Senior Investigator, Blood Research Institute, Versiti Karin Hoffmeister, MD Professor of Biochemistry, Medical College of Wisconsin Director of Translational Glycomics Center Lecturer on Medicine, Harvard Medical School, Brigham and Women’s Hospital Associate Professor of Pediatrics, Boston Children’s Hospital MD, Technical University of Aachen, Aachen, Germany, 1993 Doctor of Medicine, Doctoral Research Program, Technical University of Aachen, 1995 Started at Versiti: 2016
functions. Dr. Hoffmeister’s studies expand toward defining glycosyltransferases cell-specific transcriptional regulatory mechanisms during hematopoiesis to combine phenotypic surface carbohydrate expression with genomic and epigenetic data in hematopoietic cells. Awards, Honors and Service • Member, Hemostasis and Thrombosis Study Section • Member, Transfusion Medicine Study Section, special panel • Member, American Society of Hematology • Chair Megakaryocytes and Platelet Scientific Committee Funding RO1 HL089224-10 “Carbohydrate Mediated Platelet Clearance” PO1 HL 107146-06 “Biosynthesis and Function of Research Interests Lactosaminyl Glycans in Hematopoiesis” Dr. Hoffmeister investigates how glycans regulate U54 HL119145-04 “Novel Approaches for Platelet Storage hematopoiesis and end-effector blood cells, including B-Bic Drive” platelets. The general theme of Dr. Hoffmeister’s research K12 HL141954-01 “Glycans in Blood Hematopoiesis and is to better understand the role of carbohydrates in Disease” hematopoietic stem cells, megakaryocytes and platelet function, survival, and interaction with other blood Publications cells. Carbohydrate biosynthesis in nucleated cells is a highly regulated process involving several hundred 1. Hoffmeister KM. TPO-logy accepted. Blood. 2018 Aug glycosyltransferases. Correct glycan biosynthesis 9;132(6):555-557. PMID: 30093383 depends on the correct architecture and topology of the endoplasmic reticulum (ER) and Golgi apparatus. During maturation, differentiation and inflammation programmed remodeling of cell surface glycans takes place by the regulated expression of specific glycosyltransferases to regulate different biological Thrombosis, Hemostasis & Vascular Biology
The Thrombosis, Hemostasis and Vascular Biology Program is concerned with cellular and molecular mechanisms of normal blood clotting, pathological thrombosis, and events impacting the integrity of the blood vessels that transport blood throughout our body.
Studies conducted in the laboratories of the BRI range from basic scientific investigations of blood coagulation and platelet function, to the pathophysiology, treatment, and diagnosis of bleeding and clotting disorders. Executive Vice President, Medical Sciences Institute and Chief Medical Officer, Versiti Thomas C Abshire, MD Senior Investigator, Blood Research Institute Professor of Pediatrics, Medicine and the CTSI, Medical College of Wisconsin MD, Tulane University School of Medicine, 1979 Pediatrics, David Grant USAF Medical Center, Travis AFB, CA 1979-82 Pediatric Hematology, University of Colorado Health Science Center, 1985-88 Started at Versiti: 2009
Awards, Honors, and Service disease in the United States: perspective from the Zimmerman program. Ann Blood. 2018 Jan;3. pii: 7. • Member, American Society of Hematology PMID: 30135959 • Past President, Hemostasis and Thrombosis Research 2. Holm E, Carlsson KS, Lövdahl S, Lail AE, Abshire Society (HTRS) TC, Berntorp E. Bleeding-related hospitalization in • Best Doctors in America 2009-2018 patients with von Willebrand disease and the impact of prophylaxis: Results from national registers in Sweden • CTSI of SE WI Board of Directors compared with normal controls and participants in the von Willebrand Disease Prophylaxis Network. Funding Haemophilia 2018 Jul;24(4):628-633. PMID: 29626372 5R01HL112614-05 Montgomery/Abshire (Multiple PIs) 3. Malec L, Abshire T, Jobe S, White G. rFIXFc for 12/14/2013 – 11/30/2018 NIH/NHLBI “Comparative Immune Tolerance Induction in a Severe Hemophilia Effectiveness in the Diagnosis of VWD” B Patient with an Inhibitor and Prior History of ITI Related Nephrotic Syndrome. Haemophilia. 2018 Publications Jul;24(4):e294-e296. PMID: 30024646 1. Flood VH, Abshire TC, Christopherson PA, Friedman KD, Cox Gill J, Montgomery RR, Haberichter SL; Zimmerman Program Investigators. Von Willebrand
Platelet essel nteraction Research Interests One of Dr. Abshire’s major research interests involves Ad esion A re ation ibrin lot conducting clinical trials in patients with bleeding and thrombotic disorders with the aim of defining disease Unactivated Platelets characteristics and evaluating new approaches to Activated GPIIbIIIa Fibrinogen Fibrin treatment. A recent focus is the evaluation of mild Platelets bleeding conditions in both children and adults, particularly those affected by von Willebrand Disease (VWD). With Robert Montgomery, MD, Dr. Abshire and GPIb a team of investigators from 12 centers across North VWF America have just finished the fifth year of a study funded by the NIH entitled “Comparative Effectiveness in the Endothelial Collagen Acti ated Platelets Diagnosis of VWD” which is focusing on new diagnoses of Cells 1. Alpha granules 2. Dense granules VWD and how to better define this bleeding disorder from -VWF -ATP, ADP a clinical, laboratory and molecular basis. -FV, FXI -Ca++ -Fibrinogen
Research Report 2018 17 Associate Medical Director/Associate Investigator, Blood Research Institute, Versiti Lisa Baumann Kreuziger, Assistant Professor, Dept. of Medicine, Division of Hematology/Oncology, Medical College of Wisconsin MD, University of Wisconsin School of Medicine and Public Health, 2006 MD, MS Started at Versiti: 2013
patients will develop thrombotic complications including 2. Baumann Kreuziger L, Slaughter MS, Sundareswaran stroke or LVAD failure. Dr. Baumann-Kreuziger was K, Mast AE. Clinical Relevance of Histopathologic awarded a pilot grant from the Clinical and Translational Analysis of HeartMate II Thrombi. ASAIO J. 2018 Nov/ Sciences Institute to evaluate potential mechanisms of Dec;64(6):754-759. PMID: 29461277 thrombosis in patients with left ventricular assist devices. 3. Moyer GC, Bannow BS, Thornburg C, Rosovsky R, Wang TF, Woller S, Thornhill D, Kreuziger LB. A Survey Awards, Honors and Service of Oral Anticoagulant Preferences in the Treatment • Top Patient Experience Recognition, Froedtert Hospital of Challenging Patient Populations. Clin Appl Thromb 2018 Hemost. 2018 Oct 2:1076029618804080. PMID: 30278766. Leuk Lymphoma. 2018 Jun;59(6):1348- • Medical Student Teaching Pin, 2018 1355. PMID: 28905668 • American Society of Hematology Thrombophilia 4. Baumann Kreuziger LM, Massicotte MP. Adult and Guideline panel 2018 pediatric mechanical circulation: a guide for the hematologist. Hematology Am Soc Hematol Educ Funding Program. 2018 Nov 30;2018(1):507-515. PMID: “Evaluating thrombi composition and persistent 30504351 coagulation activation in the pathophysiology of left ventricular assist device (LVAD) thrombosis” NIH $80,000 (PI) 7/2015 – 6/2019 “Direct Oral Anticoagulants (DOACs) versus LMWH Research Interests +/- warfarin for VTE in cancer: A Randomized Venous thromboembolism occurs in more than a half Effectiveness Trial (CANVAS)” Alliance Foundation million Americans every year. Anticoagulation after (PI) 05/27/2017 – present venous thrombosis can prevent recurrence but is associated with a risk of bleeding. Dr. Baumann-Kreuziger “Post-Thrombotic Syndrome and Predictors of aims to define the best treatment course for cancer Recurrence in Catheter-Related Thrombosis” patients with thrombosis associated with catheters and determine if a biomarker can be used to predict Publications recurrence. Identification of a biomarker would allow 1. Baumann Kreuziger L, Karkouti K, Tweddell J, anticoagulation to be individualized based on each Massicotte MP. Antithrombotic Therapy Management patient’s risk profile. Patients with heart failure who of Adult and Pediatric Cardiac Surgery Patients. J require implanted left ventricular assist devices (LVADs) Thromb Haemost. 2018 Nov;16(11):2133-2146. Review. are another group that is at high risk for bleeding and PMID: 30153372 thrombotic complications. Despite use of anticoagulant and antiplatelet medications, approximately 10% of LVAD
18 Versiti Blood Research Institute Investigator, Blood Research Institute Magdalena Associate Professor in Pharmacology and Toxicology, Medical College of Wisconsin Research Member, Medical College of Wisconsin Cancer Center Medical College of Wisconsin Cardiovascular Center Chrzanowska, PhD, PhD, University of North Carolina at Chapel Hill, 1996 MSc, Jagiellonian University, Krakow, Poland, 1991 FAHA Started at Versiti: 2005
the blood vessel wall in atherosclerotic disease. In 2016, Center: Atherosclerosis, Thrombosis and Vascular Dr. Chrzanowska succeeded in obtaining the renewal of Biology Signature Program 2011- present grant support from the National Institutes of Health for • Member, Medical College of Wisconsin Cancer Center, her work. Cancer Cell Biology Research Program - 2011 - Present The complications of cardiovascular disease remain • NIH Vascular Cell and Molecular Biology Study Section major killers of the American population. The – 2015-2019 maintenance of normal cardiovascular function is critically dependent on vascular endothelium – cells that line blood vessels. Dr. Chrzanowska’s research Funding is focused on understanding molecular mechanisms NIH/NHLB R01 - HL111582-05 Chrzanowska-Wodnicka, underlying critical endothelial cell functions, such as M, (PI) 4/16/12 - 6/30/20 “Rap1 in endothelial preventing blood leakage, selective transfer of cells and homeostasis” substances to and from the blood stream, regulation of blood pressure, and restorative and pathogenic new blood Publications vessel growth. 1. Lakshmikanthan S, Sobczak M, Li Calzi S, Shaw L, Dr. Chrzanowska’s recent research revealed new Grant MB, Chrzanowska-Wodnicka M. Rap1B promotes mechanisms through which endothelial cells respond VEGF-induced endothelial permeability and is required to the flow of blood and how defects in these responses for dynamic regulation of endothelial barrier. J Cell Sci. contribute to atherosclerosis in an in vivo disease model. 2018 Jan 10;131(1). PMID: 29222111 These are the first necessary steps in developing new strategies to restore endothelial function to prevent Research Interests the progression of atherosclerosis. Furthermore, these Endothelial cells (EC) cover the inner surface of blood studies provided novel insights into mechanisms vessels and perform many critical functions, such as through which endothelial cells maintain barrier under preventing leakage of blood cells and plasma from the normal conditions. Importantly, Dr. Chrzanowska’s circulation, preventing inappropriate blood clotting, studies identified potential novel therapeutic targets for regulating selective transfer of cells and substances into pathological vascular hyper-permeability associated with and out of blood vessels, and maintaining the correct early diabetes. blood pressure. Importantly, EC can adapt their functions to their Awards, Honors and Service environment, by sensing blood flow and the presence of • American Heart Association, ATVB Council – 2019 AHA inflammatory signals. Scientific Sessions Programming Committee 2018 Dr. Chrzanowska studies how a protein, designated Rap1, • Affiliate Member, Clinical and Translational Science regulates the response of EC to changes in blood flow and Institute of SE Wisconsin 2011-present inflammation. Her work helps understand the processes • Member, Medical College of Wisconsin Cardiovascular causing hypertension and the narrowing and hardening of
Research Report 2018 19 Associate Professor of Pediatric Hematology, Medical College of Wisconsin Veronica H. Flood, MD Associate Investigator, Blood Research Institute, Versiti MD, Tufts University School of Medicine, 1999 Started at Versiti: 2016
vessel injury, the VWF-collagen interaction is an important • Co-Chair, Von Willebrand Disease Management component of hemostasis. She also is interested in the Guideline Panel, ASH/ISTH/NHF/WFH genetics of von Willebrand disease (VWD). Through • Outstanding Medical Student Teacher, Medical College collaboration with Dr. Robert Montgomery and the of Wisconsin, 2017-2018 Zimmerman Program for the Molecular and Clinical Biology of VWD, Dr. Flood has worked on characterizing genetic changes in VWD, with particular attention to Funding variants that affect platelet and collagen binding. Dr. R01 HL126810 “Mechanism of Type 4 Collagen Flood has been funded by the National Heart Lung and Interactions with Von Willebrand Factor” (PI) Blood Institute since 2010, initially through a K08 award R01 HL112614 “Comparative Effectiveness in the and subsequently transitioned to independent funding Diagnosis of VWD” (Co-I) through an R01 grant. Awards, Honors and Service Publications 1. Flood, V.H., Johnsen, J.M., Kochelek, C., Slobodianuk, • Standing member, NIH Study Section, National Heart, T.L., Christopherson, P.A., Haberichter, S.L., Udani, R., Lung, and Blood Institute, Mentored Patient-Oriented Bellissimo, D.B., Friedman, K.D., Montgomery, R.R. Research review panel Common VWF Sequence Variants Associated with • Vice-Chair, Mentored Research Award Committee Higher VWF and FVIII Are Less Frequent in Subjects ,Hemostasis and Thrombosis Research Society Diagnosed with Type 1 VWD. Res Pract Thromb Haemost 2(2):390-398, 2018. Research Interests 2. *Alaqzam, T., Stanley, A.C., Simpson, P.M., Flood, V.H., Menon, S. Treatment Modalities in Adolescents Who Dr. Flood is a pediatric hematologist and researcher Present With Heavy Menstrual Bleeding. J Pediatr at the Medical College of Wisconsin in Milwaukee. She Adolesc Gynecol 31(5);451-458, 2018. received her medical degree from Tufts University School of Medicine, and went on to complete a residency in 3. *Keesler, D.A., Flood, V.H. Current Issues in Diagnosis pediatrics at Phoenix Children’s Hospital and a fellowship and Treatment of von Willebrand Disease. Research in pediatric hematology/oncology at Oregon Health and and Practice in Thrombosis and Haemostasis, 2(1):34- Science University. 41, 2018. She began her research career as an undergraduate 4. Flood, V.H., Abshire, T.C., Christopherson, P.A., studying primate genetics in the Department of Friedman, K.D., Gill, J.C., Montgomery, R.R., Anthropology at Harvard University. Her academic career Haberichter, S.L., the Zimmerman Program in hemostasis research includes work on the biology of Investigators. Von Willebrand Disease in the United von Willebrand factor (VWF). Dr. Flood is interested in how States: Perspective from the Zimmerman Program. VWF interacts with two of its main partners, platelet GPlb Ann Blood 2018;3:7. and collagen. Since collagen is exposed at sites of blood * First author a trainee.
20 Versiti Blood Research Institute Medical Director Hemostasis Reference Lab, Diagnostic Labs, Versiti Kenneth Friedman, MD Associate Investigator Blood Research Institute, Versiti Assistant Medical Director Comprehensive Center for Bleeding Disorders Associate Professor of Internal Medicine and Pathology, Medical College of Wisconsin MD, SUNY Upstate Medical University, Syracuse, NY 1980 Started at Versiti: 1997
markers. Dr. Friedman’s other area of interest relates 4. St Ledger K, Feussner A, Kalina U, Horn C, Metzner HJ, to utilization of plasma and genetic markers to better Bensen-Kennedy D, Blackman N, Veldman A, Stowers understand the mechanisms underlying the bleeding that A, Friedman KD. International comparative field occurs in patients with defects of von Willebrand factor. study evaluating the assay performance of AFSTYLA in plasma samples at clinical hemostasis laboratories. Awards, Honors and Service J Thromb Haemost. 2018 Mar;16(3):555-564. PMID: 9274194 • Co-Director, National Marrow Donor Program – Versiti Branch 2017 • Best Doctors in America 2018 • Medical Director of the Apheresis Center for the NMDP site in Milwaukee 2018 • Ad hoc Reviewer, Journal of Thrombosis and Hemostasis, Blood, and Transfusion and Transplantation 2018 Publications 1. Flood VH, Johnsen JM, Kochelek C, Slobodianuk TL, Christopherson PA, Haberichter SL, Udani R, Bellissimo DB, Friedman KD, Montgomery RR. Common VWF Research Interests sequence variants associated with higher VWF and FVIII are less frequent in subjects diagnosed with Thrombotic microangiopathies are a collection of type 1 VWD. Res Pract Thromb Haemost. 2018 Jan diseases characterized by formation of platelet/ 23;2(2):390-398. PMID: 30046743 protein aggregates that obstruct the microcirculation, resulting in multi-organ dysfunction. Microthrombi in 2. Flood VH, Abshire TC, Christopherson PA, Friedman thrombotic thrombocytopenic purpura are rich in von KD, Cox Gill J, Montgomery RR, Haberichter SL; Willebrand factor as a consequence of deficiency of Zimmerman Program Investigators. Von Willebrand the von Willebrand factor control enzyme ADAMTS13. disease in the United States: perspective from the Alternatively in atypical hemolytic uremic syndrome, Zimmerman program. Ann Blood. 2018 Jan;3. pii: 7. the microthrombi are rich in fibrin as a consequence of PMID: 30135959 disordered complement regulation and endothelial cell 3. Friedman KD, Powell JS, Bensen-Kennedy D. injury. The current focus of Dr. Friedman’s research of Response: The coagulation laboratory monitoring of thrombotic microangiopathies is the evaluation of patient AFSTYLA single-chain FVIII concentrate. Haemophilia. plasma and genetic samples in order to identify patterns 2018 May;24(3):e129-e131.PMID: 29603512 of disease, underlying risk factors and prognostic
Research Report 2018 21 Alex & Braxton Woltring
“We were fortunate blood was available to treat our daughter. Now, we can look forward to her future,” says Adelaide’s mom, Katie.
Thanks to BloodCenter’s innovative research, Adelaide is living a normal, healthy life. Adelaide has von Willebrand disease. At age 5, she had multiple spontaneous bleeds and received blood transfusions that helped save her life. (1943-2018) Joan Cox Gill, MD Senior Investigator, Blood Research Institute, Versiti Director, Comprehensive Center for Bleeding Disorders Professor, Pediatrics and Medicine, Medical College of Wisconsin MD, Medical College of Wisconsin 1976 Started at Versiti: 1991
Hemophilia Foundation Regional Committee to (HTCN) Study Investigators. Risk factors associated investigate treatment guidelines in hemophilia and with invasive orthopaedic interventions in males with other bleeding disorders and was leading several haemophilia enrolled in the Universal Data Collection pharmaceutical contract research studies to evaluate program from 2000 to 2010. Haemophilia. 2018 replacement therapy products for patients with Nov;24(6):964-970. PMID: 29957840 hemophilia and von Willebrand disease. Her colleagues at the Blood Research Institute, the Medical College of Wisconsin and the Great Lakes Hemophilia Foundation will miss her wise counsel and her unstinting advocacy for patients with bleeding and clotting disorders. Awards, Honors and Service • Member, Science Committee, CDC Public Health Surveillance for Bleeding Disorders 2017 • Best Doctors in America 2017 • Medical Expert Panel; Federal Division of Vaccine Compensation 2017 Publications 1. Flood VH, Abshire TC, Christopherson PA, Friedman Research Interests KD, Cox Gill J, Montgomery RR, Haberichter SL; The Blood Research Institute and Medical College of Zimmerman Program Investigators. Von Willebrand Wisconsin lost a valued colleague and friend with the disease in the United States: perspective from the passing of Joan Cox Gill in 2018. Dr. Gill devoted her entire Zimmerman program. Ann Blood. 2018 Jan;3. pii: 7. career to clinical research concerning the diagnosis PMID: 30135959 and treatment of bleeding and clotting disorders in 2. Sood SL, Cheng D, Ragni M, Kessler CM, Quon D, both adult and pediatric populations. As of 2018, she Shapiro AD, Key NS, Manco-Johnson MJ, Cuker A, was co-investigator of a study to evaluate the ability of Kempton C, Wang TF, Eyster ME, Kuriakose P, von bleeding questionnaires to predict surgical bleeding Drygalski A, Gill JC, Wheeler A, Kouides P, Escobar MA, in tonsillectomies and molar tooth extractions; co- Leissinger C, Galdzicka S, Corson M, Watson C, Konkle principal investigator of a study to characterize the BA. A cross-sectional analysis of cardiovascular disease pharmacogenetics of the anticoagulant warfarin in in the hemophilia population. Blood Adv. 2018 Jun pediatric patients with thrombosis; and an investigator 12;2(11):1325-1333. PMID: 29895623 and member of the science and advisory committees of the CDC national study of the complications of 3. Tobase P, Lane H, Siddiqi AE, Soucie JM, Ingram-Rich R, hemophilia. She was also chair of the Great Lakes Ward S, Gill JC; Hemophilia Treatment Center Network Research Report 2018 23 Investigator, Blood Research Institute, Versiti Sandra Haberichter, PhD Director of Hemostasis Reference Laboratory, Versiti Associate Professor of Pediatrics, Medical College of Wisconsin PhD, University of Wisconsin-Milwaukee, 1998 Fellowship, Blood Research Institute, Versiti, 1998-2003 Started at Versiti: 1998
defining the molecular basis for accelerated clearance Publications of VWF in patients with this form of VWD. Knowledge gained in these studies is expected to improve laboratory 1. Flood VH, Johnsen JM, Kochelek C, Slobodianuk TL, diagnosis and treatment of this common bleeding Christopherson PA, Haberichter SL, Udani R, Bellissimo disorder. DB, Friedman KD, Montgomery RR. Common VWF sequence variants associated with higher VWF and Awards, Honors and Service FVIII are less frequent in subjects diagnosed with type 1 VWD. Res Pract Thromb Haemost. 2018 Jan • Member, American Society of Hematology 2018 23;2(2):390-398. PMID: 30046743 • Chair, ISTH SSC scientific committee on von Willebrand 3. Jacobi PM, Kanaji S, Jakab D, Gehrand AL, Johnsen JM, Factor 2018 Haberichter SL. Von Willebrand Factor Propeptide to • Member, International Society on Thrombosis and Antigen Ratio Identifies Platelet Activation and Reduced Haemostasis 2018 VWF Survival Phenotype in Mice. J Thromb Haemost. 2018 Feb;113(2):160-169. PMID: 29285851 Funding 4. Kanaji S, Orje JN, Kanaji T, Kamikubo Y, Morodomi Y, Chen Y, Zarpellon A, Eberhardt J, Forli S, Fahs SA, R01 HL136430 “VWF- Mechanisms of Regulation” Sood R, Haberichter SL, Montgomery RR, Ruggeri ZM. Humanized GPIbα-von Willebrand factor interaction in the mouse. Blood Adv. 2018 Oct 9;2(19):2522-2532. PMID: 30287479 Research Interests The plasma protein von Willebrand factor (VWF) plays 33 Increased VWF clearance is prevalent in a critical role in enabling blood platelets to interact with 30 moderately severe type 1 VWD. damaged blood vessels and stop bleeding. Genetically 27 76% 38% 7% determined abnormalities of VWF function and synthesis 24 VWFpp/VWF:Ag < 3 predicts reduced cause von Willebrand Disease (VWD), a source of abnormal bleeding that affects about one percent of the 21 Increased synthesis/secretion phenotype (blue). general population. Dr. Haberichter’s work is aimed at 18 Clearance characterizing various genetic defects that cause VWD 15 (VWFpp/VWF:Ag>3) VWFpp/VWF:Ag > 3 predicts increased plasma and defining how these defects affect the structure and 12 VWF clearance (green). function of the large, highly complex VWF molecule.
VWFpp/VWF:Ag 9 Recent findings have shown that low VWF levels in Reduced 76% of subjects with VWF:Ag ≤ 10 IU/dL and 6 patients with a sub-type of VWD, designated Type 1C, Secretion 38% of subjects with VWF:Ag = 11-20 IU/dL decrease VWF levels by shortening the survival of VWF in 3 have an increased VWF clearance phenotype the circulation and have led to a novel laboratory assay 0 (type 1C). to diagnose this condition. Her current work is aimed at 0 10 20 30 40 50 VWF:Ag (IU/dL) 24 Versiti Blood Research Institute Medical Director, Comprehensive Center for Bleeding Disorders (CCBD) Shawn Jobe, MD, PhD Associate Investigator, Blood Research Institute, Versiti Associate Professor, Department of Pediatrics and Cell Biology, Neurobiology, and Anatomy PhD, Medical College of Wisconsin, 1998 MD, Medical College of Wisconsin, 1999 Started at Versiti: 2013
and prevention of thrombosis in aging-related diseases. Clin North Am. 2018 Jun;65(3):561-578. Review. PMID: Platelet procoagulant activity also is important in the 29803283 prevention of bleeding. In other work, researchers in Dr. 5. Yang M, Kholmukhamedov A, Schulte ML, Cooley BC, Jobe’s lab are investigating how procoagulant platelets Scoggins NO, Wood JP, Cameron SJ, Morrell CN, Jobe might work to prevent bleeding in patients with severe SM, Silverstein RL. Platelet CD36 signaling through hemophilia. ERK5 promotes caspase-dependent procoagulant activity and fibrin deposition in vivo. Blood Adv. 2018 Awards, Honors and Service Nov 13;2(21):2848-2861. PMID: 30381401 • Standing member American Heart Association Thrombosis/Hemostasis Study Section • National Hemophilia Foundation Clinical Fellowship Advisory Board • Member International Society on Thrombosis and Hemostasis Publications 1. Kholmukhamedov A, Janecke R, Choo HJ, Jobe SM. The mitochondrial calcium uniporter regulates procoagulant platelet formation. J Thromb Haemost. Research Interests 2018 Nov;16(11):2315-2321. PMID: 30179298 2. Malec L, Abshire T, Jobe S, White G. rFIXFc for Platelets are required to stop bleeding, but inappropriate Immune Tolerance Induction in a Severe Hemophilia platelet adhesion and activation results in thrombosis. B Patient with an Inhibitor and Prior History of ITI Dr. Jobe’s group is working to understand how platelet Related Nephrotic Syndrome. Haemophilia. 2018 activation is regulated. They have identified a novel Jul;24(4):e294-e296. PMID: 30024646 platelet mitochondrial mechanism that transforms the platelet’s function from proaggregatory to 3. Sakurai Y, Hardy ET, Ahn B, Tran R, Fay ME, Ciciliano procoagulant. Work in Dr. Jobe’s lab currently is focused JC, Mannino RG, Myers DR, Qiu Y, Carden MA, Baldwin on understanding how platelet mitochondrially-mediated WH, Meeks SL, Gilbert GE, Jobe SM, Lam WA. A events are regulated and how they function to regulate microengineered vascularized bleeding model that hemostasis and thrombosis. Changes in mitochondrial integrates the principal components of hemostasis. metabolism are linked closely with many diseases Nat Commun. 2018 Feb 6;9(1):509. PMID: 29410404 associated with aging including diabetes, atherosclerosis 4. Sharma R, Perez Botero J, Jobe SM. Congenital and hypertension. Insights gained from these studies Disorders of Platelet Function and Number. Pediatr are expected to provide novel avenues for the treatment
Research Report 2018 25 Investigator, Blood Research Institute, Versiti Yan-Qing Ma, PhD PhD, Chinese Academy of Sciences, 2004 Started at Versiti: 2011
activation process. An important objective is to identify Publications novel inhibitors of platelet function that can be useful for treatment and prevention of thrombosis. 1. Cao Z, Suo X, Chu Y, Xu Z, Bao Y, Miao C, Deng W, Mao K, Gao J, Xu Z, Ma YQ. Peptides derived from the Awards, Honors and Service integrin β cytoplasmic tails inhibit angiogenesis. Cell Commun Signal. 2018 Jul 3; 16(1):38. PMID: 29970081 • Member, American Heart association 2. Xu Z, Ni B, Cao Z, Zielonka J, Gao J, Chen F, • Member, American Society of Hematology Kalyanaraman B, White GC, Ma YQ. Kindlin-3 negatively • Member, International Society on Thrombosis and regulates the release of neutrophil extracellular traps. Hemostasis J Leukoc Biol. 2018 Sep; 104(3):597-602. PMID: 29656482 Funding R01 HL131654 “Kindlin-3 Signaling in Blood Cells”
Kindlin-3 signaling in platelets and neutrophils
Research Interests Integrins comprise an extensive family of cell membrane proteins that are essential for cell-cell communication and signaling. In blood platelets, the integrin allb/ ß3 undergoes complex intracellular and extracellular structural changes that enable these cells to adhere to damaged blood vessels and to each other to control bleeding. This process must be carefully regulated to enable hemostasis to be achieved without causing a clot to be propagated inappropriately. Dr. Ma’s current work is aimed at understanding intracellular signaling cascades in platelets that control structural changes in integrin allb/ß3 during platelet activation. A particular goal is to define how kindlin-3, a key integrin activator in platelets, coordinates with upstream binding partners and creates a signaling network that regulates the platelet 26 Versiti Blood Research Institute Associate Medical Director of the Center for Comprehensive Bleeding Disorders, Versiti Lynn Malec, MD, MSc MD, UW Madison School of Medicine and Public Health, 2006 MSc, University of Pittsburgh, Institute for Clinical Research Education, 2014 Started at Versiti: 2016
Dr. Malec’s current research interests involve the PINK: An ATHN-LINKED Observational Study into the investigation of inhibitor prevention and eradication in Pink” 2017-2019 (Principal Investigator) $100,000 patients with hemophilia and the impact of prophylactic Children’s Hospital of Wisconsin Hematology/Oncology/ use in this patient population. She currently is Transplant Pilot Project Funding Program “Pilot Study investigating the role that recombinant factor VIII Fc of Whole Genome Sequencing in Brother Cohorts fusion protein (rFVIIIFc) has in immune tolerance with Severe Hemophilia A to identify Candidate Genes induction and is conducting a multi-site observational Implicated in Inhibitor Development 2018-2019 (Principal study to evaluate the efficacy and safety of rFVlllFc for Investigator) $75,000 ITI. Additionally, Dr. Malec was successful in competing for funding amongst a qualified pool of national junior Bioverativ Investigator Initiated Funding Program investigators and received the DREAM Award through “Hemophilia Inhibitor Response to Eloctate” 2016-2020 Hemostasis and Thrombosis Research Society (HTRS) (Principal Investigator) $74,000 to explore the impact of extended half-life products in preventing joint bleeds and joint damage in patients with Publications hemophilia. Dr. Malec is engaged in the care of adult 1. Malec L, Abshire T, Jobe S, White GC. rFIXFc for and pediatric patients with disorders of hemostasis Immune Tolerance Induction in a Severe Hemophilia and thrombosis, as well as other benign hematologic B Patient with an Inhibitor and Prior History of ITI conditions. Related Nephrotic Syndrome. Haemophilia. 2018 Jul;24(4):e294-e296. PMID: 30024646 Awards, Honors and Service 2. Malec LM, Cooper J, Rudolph J, Michaels MG, Ragni MV. • Treasurer, Hemostasis and Thrombosis Research Prophylactic rtPA in the Prevention of Line-associated Research Interests Society, 2018-present Thrombosis and Infection in Short Bowel Syndrome. J • Working Group Member, National Heart, Lung, and Pediatr Gastroenterol Nutr. 2018 Jun;66(6):972-975. Dr. Lynn Malec developed an interest in hemostasis Blood Institute (NHLBI) State of the Science Workshop PMID: 29135819 during her Internal Medicine and Pediatrics residency Factor VIII Inhibitors: Generating a National Blueprint at the University of Pittsburgh. This interest flourished for Future Research, 2018. during her fellowship in Pediatric Hematology/Oncology at Children’s Hospital of Pittsburgh during which time • Learning Action Network Member, Foundation for gained further expertise in the care of, and research Women and Girls with Bleeding Disorders 2014-present involving, patients with congenital bleeding disorders across the age spectrum. During her fellowship, she Funding pursued a Master’s of Science in Clinical Research DREAM Award: Mentored Research Award sponsored by through the University of Pittsburgh Institute for Clinical Hemostasis and Thrombosis Research Society (HTRS) Research Education. This rigorous training furthered and the American Thrombosis Hemostasis Network her interest in clinical research involving patients with (ATHN) “Is Prophylaxis Putting Hemophilic Joints in the bleeding disorders.
Research Report 2018 27 Senior Investigator, Blood Research Institute, Versiti Alan Mast, MD, PhD Medical Director, Medical Services, Versiti Walter A. Schroeder Endowed Chair for Blood Research Associate Professor, Department of Pathology, Medical College of Wisconsin Associate Professor, Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin MD, Duke University, 1991 PhD, Duke University, 1991 Started at Versiti: 2003
indicating that younger donors will benefit from additional • Member, American Society of Hematology Committee safety measures to protect them from iron depletion. for Scientific Affairs, 2018 In his basic research, Dr. Mast studies a protein • Co-Chair, American Society of Hematology Working designated “tissue factor pathway inhibitor (TFPI).” Group on Innovations in Clinical Trials, 2018 This protein plays a critical role in preventing blood • Member, American Society of Hematology Media from clotting inside blood vessels. His basic research Experts Subcommittee, 2018 program has made several important discoveries about the molecular interactions between TFPI and blood coagulation proteins. These have led to new ideas about Funding how bleeding and clotting disorders occur. TFPI alters REDS-III NHLBI bleeding severity in hemophilia. Dr. Mast’s laboratory is TFPI R01 NHLBI working to develop new pharmaceutical agents that block Novo Nordisk Research Grant TFPI as a treatment for hemophilia. Publications Awards, Honors and Service 1. Ellery PER, Hilden I, Sejling K, Loftager M, Martinez • Member, NIH Thrombosis and Hemostasis Study ND, Maroney SA, Mast AE. Correlates of plasma Section, 2018 and platelet tissue factor pathway inhibitor, factor V, and Protein S. Res Pract Thromb Haemost. 2018 Jan;2(1):93-104. PMID: 29354797 2. Maroney SA, Peterson JA, Zwifelhofer W, Martinez Research Interests ND, Yan K, Bercovitz RS, Woods RK, Mast AE. Plasma Proteolytic Cascade Activation during Neonatal Blood donation removes a large amount of iron that is Cardiopulmonary Bypass Surgery. Thromb Haemost. contained in red blood cells. Therefore, many regular 2018 Sep;118(9):1545-1555. PMID: 30086574 blood donors become iron deficient. In his clinical research, Dr. Mast studies the effect of blood donations 3. Peterson JA, Maroney SA, Zwifelhofer W, Wood JP, on iron metabolism and iron deficiency in the donor. Yan K, Bercovitz RS, Woods RK, Mast AE. Heparin- His clinical research program has found that recovery protamine balance after neonatal cardiopulmonary of iron stores following blood donation takes more than bypass surgery. J Thromb Haemost. 2018 six months, emphasizing the need for blood donors to Oct;16(10):1973-1983. PMID: 30016577 take iron pills following each donation. A study found that 4. Tanratana P, Ellery P, Westmark P, Mast AE, Sheehan JP. taking 19 mg iron (the amount of iron in a typical multiple Elevated Plasma Factor IXa Activity in Premenopausal vitamin with iron) for 60 days following each donation is Women on Hormonal Contraception. Arterioscler a simple and effective means for donors to replace iron Thromb Vasc Biol. 2018 Jan;38(1):266-274. PMID: lost during blood donation. A study of teenage blood 29097362 donors found that teenagers are more susceptible to iron deficiency following blood donation than are adults, 28 Versiti Blood Research Institute Senior Investigator, Blood Research Institute, Versiti Robert Montgomery, MD Attending Physician, Children’s Hospital of Wisconsin Professor of the Clinical and Translational Science Institute, Medical College of Wisconsin Professor of Pediatric Hematology & Population Health – Epidemiology, MCW Research Member, Hematologic Malignancy & Transplantation Research Program, MCW MD, University of Pittsburgh Medical School, 1969 Started at Versiti: 1980
approach could be used as an alternative to using FVIII Funding by-passing therapeutics that can sometimes run into more than $1M/yr. No one would have predicted that RO1 HL139847 “Molecular Interactions of FVIII and VWF” gene therapy could work in these individuals. Two other PO1 HL144457 “Zimmerman Program on the Biology of projects are directed at the molecular (DNA) causes of VWD” VWD. RO1 HL112614 “Comparative Effectiveness in the Awards, Honors and Service Diagnosis of VWD” • Executive Secretary, Hemophilia (and Thrombosis) Publications Research Society of North America 1. Flood VH, Abshire TC, Christopherson PA, Friedman • Member, Medical and Scientific Advisory Board KD, Cox Gill J, Montgomery RR, Haberichter SL; National Hemophilia Foundation Zimmerman Program Investigators. Von Willebrand • Chair, Fellowship Review Program, National Hemophilia disease in the United States: perspective from the Foundation Zimmerman program. Ann Blood. 2018 Jan;3. pii: 7. PMID: 30135959 2. Flood VH, Johnsen JM, Kochelek C, Slobodianuk TL, Christopherson PA, Haberichter SL, Udani R, Bellissimo DB, Friedman KD, Montgomery RR. Common VWF sequence variants associated with higher VWF and FVIII are less frequent in subjects diagnosed with Research Interests type 1 VWD. Res Pract Thromb Haemost. 2018 Jan 23;2(2):390-398. PMID: 30046743 Hemophilia and von Willebrand Disease (VWD) are Clot two major hereditary bleeding disorders that Dr. Aggregation 3. Kanaji S, Orje JN, Kanaji T, Kamikubo Y, Morodomi Platelet Montgomery’s laboratory studies. The abnormal protein Y, Chen Y, Zarpellon A, Eberhardt J, Forli S, Fahs SA, in hemophilia is Factor VIII (FVIII) and in VWD is von Sood R, Haberichter SL, Montgomery RR, Ruggeri ZM. αIIbβ3 Ib-IX Willebrand factor (VWF). Although these are regulated by αIIbβ3 Humanized GPIbα-von Willebrand factor interaction in different genes, the two proteins bind together and help 3 the mouse. Blood Adv. 2018 Oct 9;2(19):2522-2532. Adhesion PMID: 30287479 C1 orchestrate the cessation of bleeding. In hemophilia Dr. C1 Montgomery is exploring a unique form of gene therapy 4. Swystun LL, Lai JD, Notley C, Georgescu I, Paine AS, D’D3 in which FVIII is induced to be synthesized and stored in A3 A1 Mewburn J, Nesbitt K, Schledzewski K, Géraud C, platelets where it binds to VWF. This is not its normal site Kzhyshkowska J, Goerdt S, Hopman W, Montgomery to be synthesized, but the platelet targets it to be released RR, James PD, Lillicrap D. The endothelial cell at the site where a blood vessel is damaged. This therapy receptor stabilin-2 regulates VWF-FVIII complex can be effective even if the patient has begun to mount an Initiation half-life and immunogenicity. J Clin Invest. 2018 Aug immune response that normally blocks FVIII (this occurs Collagen 1/3 Collagen 4/6 31;128(9):4057-4073. PMID: 30124466 in 30% of hemophilia patients). Gene therapy using this Research Report 2018 29 Senior Investigator, Blood Research Institute, Versiti Debra Newman, PhD Professor, Department of Pharmacology & Toxicology/Department of Microbiology and Molecular Biology, Medical College of Wisconsin PhD, Biology, Marquette 1989 Started at Versiti: 1989
A major focus of research in Dr. Newman’s laboratory is Publications Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1), which inhibits responses of many circulating blood 1. Bercovitz RS, Shewmake AC, Newman DK, Niebler cells, including platelets and T cells. T cells are immune RA, Scott JP, Stuth E, Simpson PM, Yan K, Woods RK. cells that play an important role in clearing infections Validation of a definition of excessive postoperative and eradicating tumors. Dr. Newman has recently bleeding in infants undergoing cardiac surgery with discovered that PECAM-1 works with another potent T cardiopulmonary bypass. J Thorac Cardiovasc Surg. cell suppressor, Transforming Growth Factor ß (TFGß), 2018 May;155(5):2112-2124. PMID: 29338867 to inhibit T cell anti-tumor responses. Her current work 2. Liao D, Mei H, Hu Y, Newman DK, Newman PJ. CRISPR- is dedicated to developing a better understanding of mediated deletion of the PECAM-1 cytoplasmic domain how PECAM-1 expression is regulated in T cells and of increases receptor lateral mobility and strengthens how PECAM-1 and TGFß work together to inhibit T cell endothelial cell junctional integrity. Life Sci. 2018 Jan responses. This research will help improve T cell-based 15;193:186-193. PMID: 29122551 therapies for treatment of cancer. 3. Newman DK. G6b-B: the “Y’s” and wherefores. Blood. Awards, Honors and Service 2018 Sep 27;132(13):1359-1360. PMID: 30262581 4. Newman DK, Fu G, McOlash L, Schauder D, Newman • Member, Program Project Grant Review Parent PJ, Cui W, Rao S, Johnson BD, Gershan JA, Riese MJ. Committee, National Heart, Lung & Blood Institute, Frontline Science: PECAM-1 (CD31) expression in National Institutes of Health 2017 - present naïve and memory, but not acutely activated, CD8+ T • Ad hoc Manuscript Reviewer: Proceedings of the cells. J Leukoc Biol. 2018 Nov;104(5):883-893. PMID: Research Interests National Academy of Sciences: USA; Science Reports; 30063264 Science Translational Medicine; Science Signaling; 5. Scott JP, Niebler RA, Stuth EAE, Newman DK, Tweddell Platelets are important in early wound healing, where Journal of Experimental Medicine; Blood; Journal JS, Bercovitz RS, Benson DW, Cole R, Simpson PM, Yan they initially stick to damaged blood vessels and then of Cell Biology; Journal of Biological Chemistry; K, Woods RK. Rotational Thromboelastometry Rapidly aggregate with one another to form a platelet plug. American Journal of Physiology: Heart and Circulatory Predicts Thrombocytopenia and Hypofibrinogenemia Excessive bleeding occurs when platelet counts are Physiology; Arteriosclerosis, Thrombosis and Vascular During Neonatal Cardiopulmonary Bypass. low, or when platelets don’t function well. Newborns Biology; Circulation Research; Journal of Thrombosis who undergo heart surgery for congenital heart defects and Hemostasis; Thrombosis and Haemostasis; 6. World J Pediatr Congenit Heart Surg. 2018 Jul;9(4):424- experience very severe bleeding. In Dr. Newman’s lab, Thrombosis Research; Journal of Immunology; 433. PMID: 29945504 they are trying to find out how much decreases in platelet Journal of Cell Science; Human Immunology; BMC 7. Wesley EM, Xin G, McAllister D, Malarkannan S, count and function that occur during heart surgery Immunology; Transfusion; The Anatomical Record; Free Newman DK, Dwinell MB, Cui W, Johnson BD, Riese contribute to severe bleeding in newborn heart surgery Radical Biology and Medicine; Molecular Biology of the MJ. Diacylglycerol kinase ζ (DGKζ) and Casitas patients. This research will help physicians administer the Cell; Cell Adhesion and Migration; PLoS One b-lineage proto-oncogene b-deficient mice have similar right number of platelets at the right time to effectively functional outcomes in T cells but DGKζ-deficient mice control bleeding in this at risk population. Funding have increased T cell activation and tumor clearance. Immunohorizons. 2018 Apr 1;2(4):107-118. PMID: NIH R35- HL139937 (Co-Investigator) 30027154
30 Versiti Blood Research Institute Vice President for Research, Versiti Peter Newman, PhD Associate Director/Senior Investigator, Versiti Blood Research Institute Professor, Department of Pharmacology, Medical College of Wisconsin Professor, Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin PhD, St. Louis University, 1983 Started at Versiti: 1983
technology to generate megakaryocyte progenitor cells, • Chair, NIH Special Emphasis Panel, Consortium Linking megakaryocytes, and platelets from induced pluripotent Oncology with Thrombosis 2018 stem cells to create platelet alloantigen-specific cell lines • Editor, Arteriosclerosis, Thrombosis and Vascular capable of long-term self-renewal, cryopreservation, and Biology (Journal of the American Heart Association) distribution. 2012-present Awards, Honors and Service • Chair, BloodWorks Northwest Scientific Advisory Board 2012-present • R35 Outstanding Investigator Award, NIH National Heart, Lung, and Blood Institute 2018-25 Funding • Distinguished Career Award, International Society of 2018-2025 - NIH Grant R35 HL139937 (Outstanding Thrombosis and Haemostasis 2013 Investigator Award) Publications rid 1. Liao D, Mei H, Hu Y, Newman DK, Newman PJ. CRISPR- mediated deletion of the PECAM-1 cytoplasmic domain increases receptor lateral mobility and strengthens endothelial cell junctional integrity. Life Sci. 2018 Jan 15;193:186-193. PMID: 29122551 2. Newman DK, Fu G, McOlash L, Schauder D, Newman Research Interests PJ, Cui W, Rao S, Johnson BD, Gershan JA, Riese MJ. Frontline Science: PECAM-1 (CD31) expression in Peter Newman’s laboratory divides its attention between s naïve and memory, but not acutely activated, CD8+ T exploring the structure and function of the vascular cell 3 cells. J Leukoc Biol. 2018 Nov;104(5):883-893. PMID: adhesion and signaling receptor, PECAM-1, in platelets 30063264 and endothelial cells, and the generation of antigenically- distinct megakaryocytes and platelets from induced 3. Zhi H, Ahlen MT, Thinn AMM, Weiler H, Curtis BR, pluripotent stem (iPS) cells - both funded by a newly- Skogen B, Zhu J, Newman PJ. High-resolution mapping received, 7-year, $7M Outstanding Investigator Award of the polyclonal immune response to the human from the National Heart, Lung, and Blood Institute of platelet alloantigen HPA-1a (PlA1). Blood Adv. 2018 Nov the National Institutes of Health. Techniques range from eu 13;2(21):3001-3011. PMID: 30413435 Ser 33 CRISPR-mediated gene editing to protein crystallography 469 to the development of animal models of platelet alloimmunity. Projects range from investigating the Gln470 molecular basis of PECAM-1-mediated homophilic binding and the role of carbohydrate residues in this process to exploiting recent advances in CRISPR gene editing Research Report 2018 31 Investigator, Blood Research Institute, Versiti Qizhen Shi, MD, PhD Professor of Pediatric Hematology, Medical College of Wisconsin MD, Fujian Medical University, Fuzhou, China, 1990 PhD, Fujian Medical University, Fuzhou, China, 1998 Molecular Hematology Fellowship, Medical College of Wisconsin 2000 – 2006 Started at Versiti: 2010
aimed at understanding why platelet-derived FVIII can Funding still be effective in hemophilia A even in the presence of inhibitors. In a separate line of research, Dr. Shi’s team R01 HL102035 “Platelet Derived FVIII Gene Therapy of found that that FVIII’s carrier protein, VWF, can modulate Hemophilia A” the antigenicity of FVIII, attenuating FVIII memory NHF Bridge Award “Investigation of VWF as an immune responses in hemophilia A mice. These studies immunomodulator of the immunogenic response towards provide important information about the impact of VWF FVIII”. on FVIII immune responses, which will aid the design Bayer Hemophilia Award “Platelet gene therapy of murine of more effective protocols to prevent FVIII immune hemophilia B with pre-existing anti-FIX immunity”. responses and to induce FVIII immune tolerance in patients with hemophilia A. Biotest Research Grant “The impact of VWF on FVIII immune response in hemophilia A with inhibitors”. Awards, Honors and Service • Reviewer for the Poster Award. The 21st Annual Publications Meeting of American Society of Gene and Cell Therapy 1. Luo X, Chen J, Schroeder JA, Allen KP, Baumgartner (ASGCT), May 2018, Chicago, IL. CK, Malarkannan S, Hu J, Williams CB, Shi Q. Platelet • Moderator, the Oral Session of Blood Coagulation Gene Therapy Promotes Targeted Peripheral Tolerance and Fibrinolytic Factors: The Clotting System in by Clonal Deletion and Induction of Antigen-Specific Inflammation, Immunity, and Cancer. The 60th Regulatory T Cells. Front Immunol. 2018 Sep 6;9:1950. American Society of Hematology (ASH) Annual PMID: 30237796 Research Interests Meeting, December 2018, San Diego, CA. 2. Shi Q. Platelet-Targeted Gene Therapy for Hemophilia. • Editorial board member, Molecular Therapy – Methods Mol Ther Methods Clin Dev. 2018 Feb 7;9:100-108. Development of inhibitory antibodies (inhibitors) against & Clinical Development 2017-present Review. PMID: 29520365 FVIII is a significant problem in the clinical care of patients with hemophilia A. One primary focus of Dr. Shi’s research is to develop a gene therapy approach for the treatment of hemophilia A, including hemophilia A with inhibitors. Dr. Shi’s studies have shown that engineering blood stem cells to have FVIII made and stored in platelets can solve all the problems for hemophilia A. These studies show platelet-targeted gene therapy can efficiently correct the bleeding phenotype in hemophilia A mice even in the presence of neutralizing antibodies. Furthermore, platelet gene therapy can induce profound antigen- specific immune tolerance through peripheral clonal deletion of antigen-specific CD4 T cells and expansion of antigen-specific regulatory T cells. These studies are 32 Versiti Blood Research Institute Senior Investigator, Blood Research Institute, Versiti Roy Silverstein, MD John and Linda Mellowes Professor and Chair, Department of Medicine, Medical College of Wisconsin MD, Emory University School of Medicine 1979 Started at Versiti: 2011
leading to atherosclerosis. The remarkable diversity of SM, Silverstein RL. Platelet CD36 signaling through CD36 functions suggests that further work will have ERK5 promotes caspase-dependent procoagulant implications for treatment and/or prevention of arterial activity and fibrin deposition in vivo. Blood Adv. 2018 disease, thrombosis and cancer. Nov 13;2(21):2848-2861. PMID: 30381401 Awards, Honors and Service • Past-President, Central Society for Clinical and Translational Research 2018 • President-elect, American Society of Hematology 2018 • Chair, AICS study section for NIH 2018 • Editorial Boards: J. Clinical Investigation and J. Experimental Medicine Funding R01 HL142152: “ERK5 and CD36 link oxidative stress to platelet dysfunction and ischemic injury” R01 HL126645: “MRP-14, CD36 and Thrombosis” Advancing a Healthier Wisconsin Endowment Pre Research Interests Program Project Pilot Program: Metabolic Control of Inflammation in Atherosclerosis by Macrophage Research by Dr. Silverstein’s group concerns basic Scavenger Receptors” mechanisms underlying common vascular diseases, especially thrombosis, atherosclerosis and neoplastic Publications angiogenesis, with particular emphasis on the role of a cellular receptor designated CD36 expressed on 1. Chen Y, Silverstein RL. Platelet metabolism meets platelets, endothelial cells, macrophages and other thrombosis. Blood. 2018 Sep 13;132(11):1089-1091. tissues. Recent work has shown that CD36 acts as PMID: 30213838 a negative regulator of new blood vessel formation 2. Silverstein RL. Oxidized Lipid Uptake by Scavenger (angiogenesis), a process critical to tumor growth. Receptor CD36 (Cluster of Differentiation 36) CD36 also enables the recognition by platelets and Modulates Endothelial Surface Properties and May macrophages of danger signals generated in the body Contribute to Atherogenesis. Arterioscler Thromb as the result of inflammation, oxidant stress, diabetes Vasc Biol. 2018 Jan;38(1):4-5. PMID: 29282244 and cancer, and may play a role in the pro-thrombotic state associated with these conditions as well as in 3. Yang M, Kholmukhamedov A, Schulte ML, Cooley BC, accumulation of cholesterol in blood vessel walls, Scoggins NO, Wood JP, Cameron SJ, Morrell CN, Jobe Research Report 2018 33 Senior Investigator, Blood Research Institute, Versiti Hartmut Weiler, PhD Associate Professor, Department of Physiology, Medical College of Wisconsin Director, Transgenic Core Facility, Human Molecular Genetics Center, MCW Dr.rer.nat., Technische Hochschule Darmstadt Germany, 1989 Started at Versiti: 1997