Charles T. Esmon, Ph.D.
Member, National Academy of Sciences
Lloyd Noble Chair in Cardiovascular Biology
Investigator, Howard Hughes Medical Institute
Adjunct Professor, Departments of Biochemistry & Molecular Biology and Pathology, University of Oklahoma Health Sciences Center
In my lab, we study the mechanisms that control the process of blood clotting and the links between the controls of blood clotting and inflammation.
Blood clots are the cause of many serious human diseases, including heart attacks, strokes, pulmonary emboli, and venous thrombosis (phlebitis). They contribute to the mortality and morbidity of septic shock, acute trauma injury, and some of the complications of diabetes.
To understand why abnormal clots occur, we examine the mechanisms by which the normal blood-clotting system is regulated and compare the regulation under normal circumstances to the pathogenic circumstance. To accomplish this, we seek to (1) identify new factors that are involved in regulating the blood-clotting process, (2) understand how the proteins function in the control of the process, (3) understand how the genes are regulated, (4) examine the influence of defects in the function of the proteins on the human disease process, (5) examine the influence of inhibition of the function of the proteins in animal models of human disease, (6) use crystallographic and biophysical techniques to determine the molecular structure of the proteins and complexes, and (7) determine how the regulatory proteins of the coagulation system control inflammation, and vice versa.
Work from our laboratory and from many others has shown that hereditary tendencies toward developing venous thrombosis are most commonly the result of defects in the proteins that participate in the protein C anticoagulant pathway. These proteins are also involved in protection from the deleterious effects of bacterial infection (a process leading to septic shock) of the bloodstream, where the engagement of the protein C anticoagulant pathway is critical to the survival of the patients. Ongoing studies are aimed at elucidating how the pathway protects the individual from septic shock. Earlier we demonstrated that activated protein C (APC) could protect animals, including nonhuman primates, from the lethal effects of Escherichia coli infusion. APC was shown to block coagulation induced by E. coliinfusion, facilitate clot lysis, and limit cytokine elaboration. As such, it was uniquely poised to serve as a candidate for the treatment of severe sepsis in humans, a disease that has a mortality rate of approximately 30-50 percent. A recent phase III trial conducted by Eli Lilly confirmed this hypothesis and demonstrated a decrease of approximately 20 percent in the death rate of severe sepsis patients given APC (this drug is now called Xigris). These clinical results provide impetus to establish the multiple modes of action by which APC accomplishes this function. My laboratory is currently studying the multiple modes of action that make APC effective as a therapy for inflammatory diseases like sepsis. Greater understanding of these mechanisms is likely to generate new diagnostic and therapeutic approaches.
The newest member of the protein C pathway, the endothelial protein C receptor (EPCR), was identified in our laboratory, but the influence of the receptor on the shock process was unknown. Blocking the ability of the receptor to function results in dramatically increased sensitivity to bacterial infusion, resulting in increased blood clotting, increased inflammation, and vascular degeneration. At least part of this function is manifested because of an unexpectedly strong contribution of EPCR to protein C activation. We have now deleted the EPCR gene in mice and have shown that this deletion leads to a hypercoaguable phenotype that is also highly sensitized to death from septic shock. In the deficient mice, inflammation and loss of vascular integrity play dominant roles in their hypersensitivity to inflammatory challenges.
EPCR has an additional unusual property: it can traffic from the plasma membrane and carry APC as cargo. This trafficking appears to alter the expression of a subset of genes. These properties suggested that EPCR plays a critical role in development. This was borne out when deletion of the gene in mice caused an early embryonic lethal phenotype (about embryonic day 8.5). Replacement of wild-type EPCR in mice with specific mutations designed to block single EPCR functions is in progress to elucidate the physiological significance of each of the functions described above.
A complete understanding of how the blood-clotting process is regulated requires an appreciation of the structure of the proteins involved in the process, both alone and in the complexes responsible for their biological activity. Our group solved the crystal structure of EPCR bound to a portion of protein C. The structure confirmed the prediction from the primary sequence that EPCR is structurally very similar to the major histocompatibility complex class I family of molecules. Binding to protein C, however, involves a region of EPCR distinct from the antigen-binding groove found in the class I proteins. A tightly bound lipid (primarily phosphatidylcholine) is, however, present in this groove. Current studies indicate that EPCR deficient mice develop anti-phospholipid antibodies and that these antibodies have significant inhibitory effects on the activated protein C anticoagulant properties. The latter finding probably contributes to the propensity of patients with these antibodies to develop arterial, venous and microvascular blood clots.
When blood vessels are injured, as occurs in angioplasty, the vascular response for the vessel wall is for the cells to proliferate (restenosis). The resultant narrowing of the blood vessel contributes to the requirement to repeat the procedure. In mice, they have found that modulation of the protein C pathway can decrease this vascular thickening dramatically. These results suggest a new approach to treating a common clinical problem.
Together, these studies should improve our understanding of the blood-clotting process in health and disease.
B.S., University of Illinois, 1969
Ph.D., Washington University, St. Louis, MO, 1973
Honors and Awards
1974-1976 National Institutes of Health Postdoctoral Fellowship, University of Wisconsin
1977-1979 John L. Dickinson Memorial Award, American Heart Association
1980-1985 Established Investigator Award, American Heart Association
1983 The Merrick Award for Outstanding Research, OMRF
1983 Distinguished Investigator Award for Contributions to Hemostasis, IXth International Congress on Thrombosis and Haemostasis, Stockholm, Sweden
1985-1995 Merrick Distinguished Scientist, OMRF
1988 M.E.R.I.T. Award, National Heart, Lung and Blood Institute
1988 Investigator, Howard Hughes Medical Institute
1989 Chairman, Gordon Conference on Hemostasis
1990 First Sol Sherry Lecturer in Thrombosis, American Heart Association
1995 E. Donnall Thomas Lecture and Prize, American Society of Hematology
1996 Lloyd Noble Chair in Cardiovascular Research, OMRF
1999 Distinguished Career Award, Biennial Awards for Contributions to Hemostasis, XVII Congress of International Society on Thrombosis and Haemostasis
2001 Edward L. and Thelma Gaylord Prize for Scientific Achievement, OMRF
2002 Inaugural member, Oklahoma Inventors Hall of Fame
2002 Membership, National Academy of Sciences
2004 Member, Advisory Council, National Heart, Lung & Blood Institute, NIH
2005 Participant, 6th Annual Public Interest Organization Meeting
2005 Participant, Board of Extramural Advisors Meeting, NHLBI
2005 Editorial board member, Proceedings of National Academy of Science (USA)
2009 Ruysch Lecture, Discoveries that make a difference, Academic Medical Center, Amsterdam, The Netherlands
2009 Plenary Lecture, European Hematology Association, Berlin, Germany
2009 Honored by Journal of Biological Chemistry, Kresge N, Simoni RD, Hill RL. JBC Classics: Blood clotting and the isolation of factor V: The work of Charles T. Esmon. J Biol Chem 284:e2-e3, 2009.
2010 Elected as Honorary Member, American Society of Clinical Investigation
2010 Recipient, Basic Research Prize, American Heart Association
2011-2014 Member, Scientific Review Board, SMARTT (Science Moving towards Research Translation and Therapy) Program, National Heart, Lung & Blood Institute, NIH
Editorial boards of numerous scientific journals; faculty for courses in coagulation and thrombosis at the University of Oklahoma Health Sciences Center; advisory and review committees for American Heart Association, FASEB, Gordon Conferences, NIH, numerous universities, biotechnology companies, hospitals and professional societies; invited lecturer at conferences and meetings throughout the world.
Joined OMRF Scientific Staff in 1982.
Blood clots may cause heart attacks, strokes, pulmonary emboli and venous thrombosis. They contribute to mortality and morbidity in septic shock, acute trauma injury and complications of diabetes. Our laboratory primarily studies blood clotting and its relationship to inflammation.
We seek to identify factors regulating blood clotting and determine their function. We also investigate clotting protein defects in human disease, clotting protein function in animal models of human disease, structures of clotting proteins and complexes by crystallographic and biophysical techniques, relationships between coagulation and inflammation and regulation of clotting genes.
Proteins of the protein C anticoagulant pathway protect against septic shock, and we investigated activated protein C (APC) protection from lethal effects of Escherichia coli infusion in nonhuman primates. APC blocked E. coli induced coagulation, facilitated clot lysis and limited cytokine elaboration, presenting itself as a candidate for treatment of severe sepsis. A phase III trial conducted by Eli Lilly confirmed that APC effectively treats sepsis and it is now marketed as Xigris. These results provide impetus to establish the numerous mechanisms of APC function. We identified the endothelial protein C receptor (EPCR) and are investigating its function. Blocking receptor function increases sensitivity to bacterial infusion, blood clotting, inflammation and vascular degeneration. We showed that this is partly due to EPCR’s contribution to protein C activation, as hypercoagulation correlating with septic shock lethality occurred in mice lacking the EPCR gene. Mutations to block specific EPCR-functions are in progress.
Structures of clotting proteins and complexes must be solved to fully understand clotting regulation and potential therapies. We solved the crystal structure of EPCR bound to a portion of protein C, showing a requirement for a bound lipid. EPCR deficient mice develop anti-phospholipid antibodies that inhibit activated protein C anticoagulation. We suspect that this contributes to abnormal blood clotting in patients with these antibodies.
Blood vessel injuries, such as in angioplasty, cause cell proliferation and narrowing of vessel diameter and necessitate additional procedures. We found that modulating the protein C pathway in mice decreases vascular damage, suggesting this as a therapy.
McCrindle BW, Li JS, Manlhiot C, Tweddell JS, Giglia TM, Massicotte MP, Monagle P, Krishnamurthy R, Mahaffey KW, Michelson AD, Verdun N, Almond CS, Newburger JW, Brandao LR, Esmon CT, Manco-Johnson MJ, Ichord R, Ortel TL, Chan AK, Portman R, Rose M, Strony J, Kaltman JR. Challenges and priorities for research: a report from the National Heart, Lung, and Blood Institute (NHLBI)/National Institutes of Health (NIH) Working Group on Thrombosis in Pediatric Cardiology and Congenital Heart Disease. Circulation 130:1192-1203, 2014. [Abstract]
Semeraro F, Ammollo CT, Esmon NL, Esmon CT. Histones induce phosphatidylserine exposure and a procoagulant phenotype in human red blood cells. J Thromb Haemost 2014. [Abstract] EPub
Tamayo I, Velasco SE, Puy C, Esmon CT, Dichiara MG, Montes R, Hermida J. sPLA2-V impairs EPCR-dependent protein C activation and accelerates thrombosis in vivo. J Thromb Haemost 2014. [Abstract] EPub
Xu J, Zhang X, Monestier M, Esmon NL, Esmon CT. Extracellular histones are mediators of death through TLR2 and TLR4 in mouse fatal liver injury. J Immunol 187:2626-2631, 2011. [Abstract]
Semeraro F, Ammollo CT, Morrissey JH, Dale GL, Friese P, Esmon NL, Esmon CT. Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4. Blood 118:1952-1961, 2011. [Abstract]
Xu J, Zhang X, Pelayo R, Monestier M, Ammollo CT, Semeraro F, Taylor FB, Esmon NL, Lupu F, Esmon CT. Extracellular histones are major mediators of death in sepsis. Nat Med 15:1318-1321, 2009. [Abstract]
Fukudome K, Esmon CT. Identification, cloning, and regulation of a novel endothelial cell protein C/activated protein C receptor. J Biol Chem 269:26486-26491, 1994. [Abstract]
Esmon CT, Owen WG. Identification of an endothelial cell cofactor for thrombin-catalyzed activation of protein C. Proc Natl Acad Sci U S A 78:2249-2252, 1981. [Abstract]
Esmon CT. The subunit structure of thrombin-activated factor V. Isolation of activated factor V, separation of subunits, and reconstitution of biological activity. J Biol Chem 254:964-973, 1979. [Abstract]
Coagulation Biology Laboratory, MS 51
Oklahoma Medical Research Foundation
825 N.E. 13th Street
Oklahoma City, OK 73104
Phone: (405) 271-6474
Fax: (405) 271-2870
Naomi L. Esmon, Ph.D.
Research Associate Member
Senior Research Assistant
Senior Research Assistant
Senior Research Assistant
Senior Research Assistant
Senior Research Assistant
Senior Research Technician
Administrative Assistant IV
Affiliate – HHMI