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: 
Buyue, Y., Misenheimer, T.M., and Sheehan, J.P. (2012) Low Molecular Weight Heparin Inhibits Thrombin Generation via Direct Targeting of Factor IXa: Contribution of the serpin-independent mechanism in human plasma. Journal of Thrombosis and Haemostasis Oct;10(10):2086-98 PMCID: PMC3463736
Buyue, Y., Misenheimer, T.M., and Sheehan, J.P. (2013) Low Molecular Weight Heparin Inhibits Thrombin Generation via Direct Targeting of Factor IXa: A Reply to Rebuttal. Journal of Thrombosis and Haemostasis Mar;11(3):565-6. PMID: 23332108
Geng, Y., Verhamme, I.M., Smith, S.A., Cheng, Q., Sun, M., Sheehan, J.P., Morrissey, J.H., and Gailani, D. (2013) Factor XI Anion-Binding Sites are required for Productive Interactions with Polyphosphate. Journal of Thrombosis and Haemostasis Nov;11(11):2020-8. PMID: 24118982
Westmark, P., Tanratana, P., and Sheehan, J.P. (2015) Selective Disruption of Heparin and Antithrombin-mediated Regulation of Human Factor IX. Journal of Thrombosis and Haemostasis Jun;13(6):1053-63. PMID: 25859812
Schreier, D.A., Forouzan, O., Hacker, T., Sheehan, J., and Chesler, N.C. (2016) Increased Red Blood Cell Stiffness Increases Pulmonary Vascular Resistance And Pulmonary Arterial Pressure. J. Biomech Eng. 138(2):021012. PMID: 26638883
Nazeef, M. and Sheehan, J.P. (2016) New developments in the management of moderate-to-severe hemophilia B. J. Blood Med 7:27-38.
Chanakira, A., Westmark, P.R., Ong, I.M. and Sheehan, J.P. (2017) Protease Activated Receptor-2 Triggers Growth Factor Release and Migration in Ovarian Cancer. Gynecologic Oncology Apr;145(1):167-175. PMID:28148395
Sheehan, J.P. (2017) Commentary: Zebrafish factor 10 and the life aquatic. Blood 130 (5):563-565.
Plautz, W.E., Sekhar Pilli, V.S., Cooley, B., Westmark, P.R., Paul, D., Bergmeier, W., Sheehan, J.P., and Majumder, R. (2017) Protein S Regulates Coagulation by Inhibiting Factor IXa. (Submitted for publication).
Tanratana, P., Ellery, P., Westmark, P.R., Mast, A. and Sheehan, J.P. (2017) Elevated Plasma Factor IXa Activity in Premenopausal Women on Hormonal Contraception. (Submitted for publication).