WASHINGTON UNIVERSITY SCHOOL OF MEDICINE DEPARTMENT OF MEDICINE

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My laboratory studies the pathophysiology of hemorrhage and thrombosis, focusing on the mechanisms that promote and inhibit platelet adhesion. Von Willebrand factor (VWF) is a multimeric protein that mediates platelet adhesion to sites of vascular injury and stabilizes blood coagulation factor VIII; these interactions are essential for hemostasis. Von Willebrand disease (VWD) is caused by deficiency of VWF, and is the most common inherited bleeding disorder. Specific domains of VWF interact with platelet receptor proteins, and binding is regulated allosterically. A single VWF multimer can be enormous, up to 100 micrometers in length, and the largest multimers are the most hemostatically active. We are investigating the mechanism of VWF multimer assembly and the regulation of VWF binding to its receptors on platelets. VWF assembly into large multimers is required to prevent bleeding and, conversely, the proteolytic cleavage of VWF multimers is required to prevent thrombosis. We recently cloned a metalloprotease with a complex multidomain structure, ADAMTS13, which participates in the feedback inhibition of VWF function by cleaving a Tyr-Met bond in the center of the VWF subunit. Interestingly, VWF cleavage by ADAMTS13 is regulated by tensile stress, so that VWF only becomes susceptible when it is stretched at the site of a growing platelet thrombus. We are determining how various domains of ADAMTS13 cooperate to recognize and cleave VWF. Congenital or acquired deficiency of ADAMTS13 causes life-threatening microvascular thrombosis (thrombotic thrombocytopenic purpura), and we are investigating the clinical utility of ADAMTS13 assays in the diagnosis and treatment of thrombotic thrombocyotpenic purpura.

From: Sadler JE A new name in thrombosis, ADAMTS13. Proc Natl Acad Sci U S A 2002 Sep 3;99(18):11552-4

Possible sites of ADAMTS13 action on VWF VWF is released from endothelial cells as unusually large multimers that may diffuse into the circulation (A and B) or adhere to the endothelial cell surface (C). VWF also binds to connective tissue exposed at sites of vascular injury (D). Under conditions of high fluid shear stress, platelets can adhere to VWF in solution (B) or on surfaces (C and D) through the platelet glycoprotein Ib (GPIb) receptor. VWF also may recruit platelets to previously adhering platelets (E). ADAMTS13 cleaves a Tyr-Met bond in the A2 domain of the VWF subunit, severing the multimer. This reaction is slow for VWF in solution (A) but occurs rapidly when platelets adhere to VWF under high fluid shear conditions in suspension (B) or on surfaces (C-E), presumably as a consequence of conformational changes induced by tensile force on the VWF multimer. Failure of this mechanism appears to cause TTP.

Education

1969-1973	AB in Chemistry (summa cum laude), Princeton University, Princeton, NJ
1973-1979	Duke University Medical Center, Durham, NC 1978 - PhD in Biochemistry, Robert L. Hill, advisor 1979 - MD

Post-graduate Training

1979-1981	Duke University Medical Center, Durham, NC 1979 - Research Associate, Department of Biochemistry 1979-1980 - Intern in Medicine 1980-1981 - Junior Assistant Resident in Medicine
1981-1984	University of Washington, Seattle, WA 1981-1984 - Fellow in Hematology, Department of Medicine 1982-1984 - Associate, Department of Pharmacology 1982-1984 - Associate, Howard Hughes Medical Institute at Seattle

Academic Positions

1984-1996	Associate Investigator, Howard Hughes Medical Institute at St. Louis
1984-1989	Assistant Professor of Medicine, Hematology and Oncology Division, The Jewish Hospital of St. Louis
1989-1993	Associate Professor of Medicine, Hematology and Oncology Division, The Jewish Hospital of St. Louis
1985-1993	Assistant Professor of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO
1993-present	Professor of Medicine, Hematology Division, Washington University School of Medicine, St. Louis, MO
1993-present	Professor of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO
1996-present	Investigator, Howard Hughes Medical Institute at St. Louis

University & Hospital Appointments

1984-1990	Assistant Attending, The Jewish Hospital of St. Louis
1990-1996	Associate Attending, The Jewish Hospital of St. Louis
1987-1996	Assistant Physician, Barnes Hospital, St. Louis, Missouri
1996-present	Active Staff Member, Barnes-Jewish Hospital, St. Louis, Missouri
1990-1991	Molecular Biology Steering Committee, Division of Biology and Biomedical Sciences
1989-1991	Metabolic Regulation Preliminary Examination Committee, Division of Biology and Biomedical Sciences 1991 - Chairman
1991	Ad Hoc Committee to Examine the Biomedical Research Computing Facility Services
1989-1993	MA/MD Program Committee, Division of Biology and Biomedical Sciences
1992-1999	Molecular Cell Biology Steering Committee, Division of Biology and Biomedical Sciences
1992-1995	Transfusion Review Committee, The Jewish Hospital of St. Louis
1996-present	Transfusion Review Committee, Barnes-Jewish Hospital
2003-2006	Academic Freedom and Tenure Hearing Committee

Editorial Responsibilities

1988-1992	Editorial Board, Blood
1989-1993	Editorial Board, The Journal of Biological Chemistry
1993-2002	Associate Editor, Blood
1993-present	Editorial Advisory Board, Biochemistry
1998-present	Board of Consulting Editors, Journal of Clinical Investigation
1999-2002	Advisory Board, Thrombosis and Haemostasis
2003-2006	Advisory Board, Journal of Thrombosis and Haemostasis
2003-2007	Editorial Advisory Board, ASBMB Today
2005-2007	Faculty of 1000 Medicine Project
2006-2007	Editorial Board, Arteriosclerosis Thrombosis and Vascular Biology
2007-2013	Editorial Board, Journal of Thrombosis and Haemostasis
2008-present	Editorial Board, Blood

Professional Societies & Organizations

1978-present	Sigma Xi
1981-present	American Association for the Advancement of Science
1985-present	American Society for Biochemistry and Molecular Biology
1985-present	American Society of Hematology 1989-1992 - Scientific Subcommittee on Hemostasis 1994-1996 - Scientific Subcommittee on Hemostasis 1994 - Program Committee 1995 - Co-Chair, Scientific Program Committee 1996 - Program Committee 1997 - Chair, Scientific Program Committee 1998-2002 - Councillor, Executive Committee 2003-2006 - Treasurer 2008-2009 - Co-Chair, Committee on Investment and Audit 2008 - Co-Chair, Scientific Program Committee
1986-present	The Protein Society
1987-present	American Federation for Medical Research
1987-present	International Society on Thrombosis and Haemostasis 1988-2006 - Subcommittee on von Willebrand Factor, Scientific and Standardization Committee    1988-1989 - Co-Chairman    1992-1994 - Co-Chairman    1994-1997 - Chairman    2003-2006 - Chair, Working Party on von Willebrand Disease Classification 1992-1998 - Scientific and Standardization Committee Class of 1998 1996-1997 - Member-at-large, Executive Committee, Scientific and Standardization Committee 1996-2002 - Executive Council Class of 2002 1998-present - Senior Advisory Council, Scientific and Standardization Committee 1998-2003 - Chairman, Standing Committee on Publications 2007 - Scientific Programme Committee, XXI ISTH Congress, Geneva
1987-present	American Heart Association 1987-1997 - Member, Council on Thrombosis 1997-present - Fellow, Council on Arteriosclerosis, Thrombosis, and Vascular Biology 1988-1990 - Executive Committee, Council on Thrombosis 1998-2000 - Executive Committee, Council on Arteriosclerosis, Thrombosis, and Vascular Biology 1998-1999 - Vice Chairman, Program Committee (Thrombosis Section), Council on Arteriosclerosis, Thrombosis, and Vascular Biology 1999-2000 - Chairman, Program Committee (Thrombosis Section), Council on Arteriosclerosis, Thrombosis, and Vascular Biology
1988-present	American Society for Clinical Investigation
1993-present	Association of American Physicians
1993-1997	NIH Hematology Study Section 1 1995-1997 - Chairman
1995-present	Molecular Medicine Society
1996	Vice-Chair, Gordon Conference on Hemostasis
1998	Chair, Gordon Conference on Hemostasis
2004-present	NIH NHLBI von Willebrand Disease Working Group
2006-present	NCRR Protocol Review Committee for the Rare Diseases Clinical Research Network
2006	NIH NHLBI Strategic Planning Level 1 Working Group on Diagnosis and Treatment of Thrombotic Disorders

Board Certification

1982	Diplomate, American Board of Internal Medicine

Honors & Awards

1973	Everett S. Wallis Prize in Organic Chemistry, Princeton University
1973	Robert Thornton McCay Prize (Physical Chemistry), Princeton University
1973	Phi Beta Kappa
1976	Alpha Omega Alpha
1988	American Society for Clinical Investigation
1993	Association of American Physicians
1995	Investigator Recognition Award, Seventh Biennial Awards for Contributions to Hemostasis, ISTH, Jerusalem, Israel
1997	Investigator Recognition Award, Eighth Biennial Awards for Contributions to Hemostasis, ISTH, Florence, Italy
1998	William Dameshek Prize, American Society of Hematology
1998	Fellow, American Association for the Advancement of Science, Medical Sciences (N)
2001	Distinguished Career Award, Tenth Biennial Awards for Contributions to Hemostasis, ISTH, Paris, France
2001	Fellow, American Heart Association

Updated: March 20, 2008