Douglas M. Tollefsen, M.D., Ph.D.
- Professor
- Department of Medicine
- Hematology Division
- Department of Pathology & Immunology
- Department of Medicine
- Clinical interests
- General hematology
- Disorders of hemostasis
- Research interests
- Coagulation proteases
- Protease inhibitors
- Anticoagulants
Research
Thrombin is the major protease generated during blood coagulation at sites of vascular injury. It converts fibrinogen to fibrin monomers, which polymerize to form a clot, and cleaves G-protein-coupled receptors on platelets and endothelial cells, causing platelet aggregation, secretion of chemokines, and recruitment of inflammatory cells. Thrombin appears to induce smooth muscle cell proliferation in developing atherosclerotic plaques. Therefore, thrombin participates not only in normal blood clotting, but also in pathologic processes such as thrombosis and atherogenesis.
We are interested in proteins that regulate the activity of thrombin. One of these is heparin cofactor II (HCII), a plasma protein that inhibits thrombin by formation of a covalent 1:1 complex. Dermatan sulfate and heparan sulfate bind to HCII and increase the rate of thrombin inhibition >1000-fold. Biosynthesis of these glycosaminoglycans by cells in the vessel wall may determine the site of action of HCII in vivo. We find that specific oligosaccharide sequences in dermatan sulfate chains are required to stimulate HCII, and we are determining the structures of these oligosaccharides by enzymatic degradation and mass spectrometry. We are also investigating the protease- and oligosaccharide-binding regions of HCII by site-directed mutagenesis of the cDNA. We have generated HCII-deficient mice by homologous recombination in embryonic stem cells and find that these mice develop thrombi more rapidly than do wild-type animals after injury of the carotid arterial endothelium. Using these mice, we have begun to investigate HCII in a variety of other models in which thrombin may play a role.
Distribution of endogenous HCII before and after endothelial injury
Frozen sections of carotid arteries harvested from HCII+/+ mice before (A) or 30 minutes after (B) the onset of injury were stained with a polyclonal goat anti–HCII IgG. No HCII antigen was detected in the injured carotid artery of a control (HCII−/−) mouse (C). Arrow indicates internal elastic lamina; arrowhead, external elastic lamina.
From: He L, Giri TK, Vicente CP, Tollefsen DM
Vascular dermatan sulfate regulates the antithrombotic activity of heparin cofactor II.
Blood 2008 Apr 15;111(8):4118-25
Biographical Sketch
Education
| 1966-1970 | B.A. in Chemistry, Grinnell College, Grinnell, IA |
| 1970-1971 | Stanford University School of Medicine, Palo Alto, CA |
| 1971-1977 | M.D./Ph.D. (Biochemistry), Washington University School of Medicine, St. Louis, MO |
Post-graduate Training
| 1977-1979 | Resident, Department of Internal Medicine, University of Colorado School of Medicine, Denver, CO |
| 1979 | Fellow, Department of Internal Medicine (Hematology-Oncology), Washington University School of Medicine, St. Louis, MO |
Academic Positions
| 1979-1980 | Instructor, Department of Internal Medicine,Washington University, St. Louis, MO |
| 1980-1985 | Assistant Professor, Department of Internal Medicine, Washington University, St. Louis, MO |
| 1983-present | Assistant Professor, Department of Biochemistry & Molecular Biophysics, Washington University, St. Louis, MO |
| 1985-1993 | Associate Professor, Department of Internal Medicine, Washington University, St. Louis, MO |
| 1993-present | Professor, Department of Internal Medicine, Washington University, St. Louis, MO |
| 2005-present | Professor, Department of Pathology & Immunology, Washington University, St. Louis, MO |
Appointments & Committees
| 1983-1988 | Research Peer Review Committee, American Heart Association, Missouri Affiliate |
| 1983-2008 | Medical Scientist Training Program Committee, Washington University School of Medicine |
| 1984 | Secretary-Treasurer, National Blood Club |
| 1985 | NIH Hematology Study Section |
| 1987-1991 | NIH Hematology Study Section |
| 1988-1991 | Secretary, Executive Committee of the Faculty Council, Washington University School of Medicine |
| 1993-1997 | American Society of Hematology, Scientific Subcommittee on Thrombosis |
| 1996 | Program Committee, International Symposium on the Chemistry and Biology of Serpins, Chapel Hill, NC |
| 1996-1998 | Faculty Senate Council, Washington University |
| 1996-1998 | Advisory Committee on Tenure and Academic Freedom, Washington University |
| 1998-2000 | American Heart Association, National Study Committee on Thrombosis |
| 2001 | Board of Scientific Counselors Review Panel, NIH Clinical Center |
| 2002 | American Heart Association, National Study Committee on Thrombosis |
| 2008 | American Heart Association, Lipoproteins, Lipid Metabolism and Nutrition & Thrombosis Peer Review Committee |
| 2008-present | Anticoagulation Subcommittee, Barnes-Jewish Hospital Pharmacy and Therapeutics Committee |
| 2009 | NIH Special Emphasis Panel |
| 2009-2010 | Chairman, Planning Committee, Washington University Medical Scientist Training Program 40th Anniversary Celebration |
| 2011 | Organizer, American Society of Hematology Education Session “Consultative Hematology I: Common Questions in Thrombosis Consults” |
| 2012 | Co-organizer, Highlights of ASH in North America, “Thrombosis and Anticoagulation” |
Editorial Responsibilities
| 1992-1996 | Editorial Board, Journal of Biological Chemistry |
| 1993-1997 | Editorial Board, Blood |
| 2006-present | Peer Reviewer, UpToDate |
| 2008-2009 | Advisory Board, Journal of Thrombosis and Haemostasis |
Professional Societies
| American Society for Biochemistry and Molecular Biology | |
| American Society of Hematology | |
| 1984 | American Society for Clinical Investigation |
| 1988 | Association of American Physicians |
Honors
| 1970 | Phi Beta Kappa |
| 1972-1977 | Medical Scientist Training Program, Washington University |
| 1977 | Alpha Omega Alpha |
| 1982-1987 | NIH Research Career Development Award |
- Updated: February 9, 2012
