John Sheehan

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.

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