Mary Jo Heeb, PhD

Professor Emeritus
Department of Molecular Medicine
California Campus

Research Focus

Regulation of Blood Coagulation

We study several anticoagulant proteins with the view that understanding mechanisms by which these proteins regulate blood coagulation may lead to new therapies or preventative measures for thrombotic disease. Protein S is a nonenzymatic vitamin K-dependent protein that acts as a cofactor for activated protein C in the proteolytic inactivation of procoagulant factors Va and VIIIa. We showed that protein S also has direct anticoagulant activity by virtue of binding and inhibition of factors Xa and Va. This activity is demonstrable in plasma and is modulated by several mechanisms that we seek to elucidate, including incorporation of intramolecular zinc into protein S.

We found that knock-out mice that were total deficient in protein S died in utero and were characterized by severe coagulopathy and leaky blood vessels. Mice that were heterozygous protein S-deficient were viable but were underrepresented in the litters. Their plasma was deficient in both activated protein C cofactor activity of protein S and direct protein S anticoagulant activity. In a baboon thrombosis model, protein S was antithrombotic in the absence of activated protein C, demonstrating possible therapeutic potential in treating or preventing thrombosis in humans in the future.

Protein Z is another vitamin K-dependent nonenzymatic protein that serves as a cofactor to a recently discovered serpin, protein Z-dependent protease inhibitor (ZPI). We showed that low protein Z levels are associated with stroke. ZPI is an unusual serpin that inhibits procoagulant factor Xa in a manner dependent on phospholipids, protein Z and calcium ions but not requiring formation of a covalent factor Xa-ZPI complex. We found that ZPI also efficiently and rapidly inhibits procoagulant factor IXa independently of phospholipids and protein Z.

A separate focus involves development of plasma assays for forms of prostate specific antigen and human glandular kallikrein that could aid in distinguishing prostate cancer from benign prostate disease, or that could aid in prognosis of prostate cancer. The aims are to reduce the number of prostate biopsies required (2/3 are negative) and to identify which cases of prostate cancer have a poor prognosis and require aggressive treatment.


Ph.D. (Biochemistry), Georgetown University, 1983
M.S. (Microbiology), University of Florida, 1968
B.S. (Chemistry), University of Florida, 1966

Professional Experience

2014-2017 Professor Emeritus, Molecular and Experimental Medicine (MEM), Scripps Research
1999-2014 Associate Professor of Molecular Medicine, Molecular and Experimental Medicine (MEM), Scripps Research
1993-1999 Assistant Professor, Scripps Research
1988-1992 Research Science Associate, Scripps Research
1983-1988 Postdoctoral Fellow, Scripps Research
1981-1982 Research Group Leader, Hazelton Laboratories (Vienna)
1975-1978 Research Group Leader, Hazelton Laboratories (Vienna)
1973-1975 Instructor, Chemistry, The University of North Carolina at Chapel Hill
1971-1972 Algebra Teacher, Hoggard High School
1969-1971 Research Assistant, University of Miami
1963-1965 Technician, University of Florida

Awards & Professional Activities

American Heart Association Established Investigator Who’s Who listings Member, American Society of Hematology, American Society for Biochemistry and Molecular Biology, International Society for Thrombosis and Haemostasis Reviewer for Blood, Journal of Thrombosis and Haemostasis, Thrombosis and Haemostasis,and other journals.

Selected References

All Publications

Burstyn-Cohen, T., Heeb, M.J., Lemke, G., Lack of protein S in mice causes embryonic lethal coagulopathy and vascular dysgenesis. J. Clin. Invest. 119:2942, 2009.

Heeb, M.J., Prashun, D., Griffin, J.H., Bouma, B.N. Plasma protein S contains zinc essential for efficient activated protein C-independent anticoagulant activity and binding to factor Xa, but not for efficient binding to tissue factor pathway inhibitor. FASEB J., 23:2244-2253, 2009.

Fernández, J.A.*, Heeb, M.J.*, Xu, X., Singh, L., Zlokovic, B.V., Griffin, J.H. Species-specific anticoagulant and mitogenic activities of murine protein S. Hematologica, 94:1721-1731, 2009. * These authors contributed equally.

Heeb, M.J., Ruan, L., Cabral, K., Tonnu, L. Downregulation of factor IXa in the factor Xase complex by protein Z-dependent protease inhibitor. J. Biol. Chem., 280:33819-33925, 2005.


Scientific Report 2008