J. Evan Sadler, M.D., Ph.D.

Evan Sadler
  • Professor
    • Department of Medicine
      • Hematology Division
    • Department of Biochemistry & Molecular Biophysics
    • Howard Hughes Medical Institute
  • Clinical interests
    • Hemostasis
  • Research interests
    • Blood coagulation
    • Serine proteases
    • von Willebrand disease
    • Enteropeptidase

Research

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.

vWF

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.

Biographical Sketch

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

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