John Sheehan, MD

Associate Professor
Medicine
Address: 
K6/536 CSC
600 Highland Avenue
Madison, WI 53792
Telephone: 
(608) 262-1964
Focus Groups: 
Cancer Biology
Signal Transduction
Education: 
BS, University of Norte Dame
MD, University of Missouri
Medicine, University of Minnesota
Hematology-Oncology, Washington University
Research Summary: 
Molecular regulation of the coagulation serine proteases; novel therapeutic targets for antithrombotic therapy; mechanisms for hormone-induced and cancer-associated thrombosis.
Research Detail: 

My laboratory is focused on understanding the regulation of coagulation serine proteases, particularly with respect to interactions with serpins and glycosaminoglycans. The underlying theme of this work is that understanding regulation of the coagulation response will identify novel targets for antithrombotic therapy and aid in the design of hemostatic proteins with enhanced in vivo therapeutic properties. Modeling of tissue factor-initiated blood coagulation identifies the intrinsic tenase (factor IXa-factor VIIIa) complex as the rate-limiting step for thrombin generation. The factor IXa protease is poorly reactive with substrates and inhibitors in solution, yet undergoes a dramatic 106-fold enhancement in catalytic efficiency upon incorporation into the intrinsic tenase complex. We have demonstrated that the factor IXa protease demonstrates a remarkable ability to persist in biologic milieu such as plasma relative to factor Xa and thrombin, suggesting that it contributes to systemic hypercoagulability.

We are pursuing parallel projects investigating in vivo mechanisms for regulation of factor IX(a) clearance and activity in the mouse and the role of circulating factor IXa activity in the clinical hypercoagulable states associated with hormonal contraception and cancer. The former project employs a panel of recombinant human factor IX(a) proteins with mutations in critical regulatory exosites for the serpin antithrombin, heparin, protein S and extravascular type IV collagen. Mutagenesis of these protease exosites modifies clearance and in vivo activity of recombinant factor IX in hemophilia B mice. Optimal combinations of these mutations are being evaluated to design factor IX molecules with enhanced therapeutic properties for hemophilia B. The translational projects involve analysis of: 1) plasma and GWAS data from blood donors on hormonal contraception and 2) ascites and blood samples from patients presenting with newly diagnosed ovarian cancer. While the increased risk of venous thromboembolism associated with oral contraceptive use has long been recognized, the specific mechanism(s) leading to this acquired hypercoagulable state remain undefined. Likewise, although the clinical association between cancer and thrombosis has been established for over a century, the responsible mechanisms have only begun to be elucidated. Thus, these investigations address the underlying mechanisms for long-standing and important clinical problems.

Selected Publications: 
Anticoagulant Protein S Targets the Factor IXa Heparin-BindingExosite to Prevent Thrombosis.Plautz WE, Sekhar Pilli VS, Cooley BC, Chattopadhyay R, Westmark PR, Getz T, Paul D, Bergmeier W, Sheehan JP, Majumder R.Arterioscler Thromb VascBiol. 2018 Apr;38(4):816-828. doi: 10.1161/ATVBAHA.117.310588. Epub 2018 Feb 1.PMID: 29419409
Elevated Plasma Factor IXa Activity in Premenopausal Women on Hormonal Contraception.Tanratana P, Ellery P, Westmark P, Mast AE, Sheehan JP.Arterioscler Thromb Vasc Biol. 2018 Jan;38(1):266-274. doi: 10.1161/ATVBAHA.117.309919. Epub 2017 Nov 2.PMID: 29097362
Recent trends in the prevalence of type 2 diabetes and the association with abdominal obesity lead to growing health disparities in the USA: An analysisof the NHANES surveys from 1999 to 2014.Caspard H, Jabbour S, Hammar N, Fenici P, Sheehan JJ, Kosiborod M.Diabetes Obes Metab. 2018 Mar;20(3):667-671. doi: 10.1111/dom.13143. Epub 2017 Dec 1.PMID: 29077244
Zebrafish factor 10 and the life aquatic.Sheehan JP.Blood. 2017 Aug 3;130(5):563-565. doi: 10.1182/blood-2017-06-789149. No abstract available.PMID: 28775159
Tissue factor-factor VIIa complex triggers protease activated receptor 2-dependent growth factor release and migration in ovarian cancer.Chanakira A, Westmark PR, Ong IM, Sheehan JP.Gynecol Oncol. 2017 Apr;145(1):167-175. doi: 10.1016/j.ygyno.2017.01.022. Epub 2017 Jan 29.PMID: 28148395
New developments in the management of moderate-to-severe hemophilia B.Nazeef M, Sheehan JP.J Blood Med. 2016 Apr 1;7:27-38. doi: 10.2147/JBM.S81520. eCollection 2016. Review.PMID: 27099538
Increased Red Blood Cell Stiffness Increases Pulmonary Vascular Resistance and Pulmonary Arterial Pressure.Schreier DA, Forouzan O, Hacker TA, Sheehan J, Chesler N.J Biomech Eng. 2016 Feb;138(2):021012. doi: 10.1115/1.4032187.PMID: 26638883
Solutions for a cultivated planet.Foley JA, Ramankutty N, Brauman KA, Cassidy ES, Gerber JS, Johnston M, Mueller ND, O'Connell C, Ray DK, West PC, Balzer C, Bennett EM, Carpenter SR, Hill J, Monfreda C, Polasky S, Rockström J, Sheehan J, Siebert S, Tilman D, Zaks DP.Nature. 2011 Oct 12;478(7369):337-42. doi: 10.1038/nature10452.PMID: 21993620
The regulation of factor IXa by supersulfated low molecular weight heparin.Misenheimer TM, Sheehan JP.Biochemistry. 2010 Nov 23;49(46):9997-10005. doi: 10.1021/bi100906q. Epub 2010 Oct 27.PMID: 20945941
Engineering direct conversion of CO(2) to biofuel.Sheehan J.Nat Biotechnol. 2009 Dec;27(12):1128-9. doi: 10.1038/nbt1209-1128. No abstract available.PMID: 20010592