Bruce Sachais

faculty photo
Associate Professor of Pathology and Laboratory Medicine at the Hospital of the University of Pennsylvania
Assistant Program Director MTR Program, University of Pennsylvania
Chair, IRB #1, University of Pennsylvania
Department: Pathology and Laboratory Medicine

Contact information
605A Stellar Chance
422 Curie Boulevard
University of Pennsylvania
Philadelphia, PA 19104
Office: 215 898-0568
Fax: 215 573-0252
Graduate Group Affiliations
Education:
B.A. (Chemistry)
Lehigh University , 1988.
Ph.D. (Neuroscience)
Washington University, 1996.
M.D.
Washington University, 1996.
Certif. (Patient Oriented Research)
University of Pennsylvania, 2005.
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Description of Research Expertise

Research Interests
Platelets, Platelet Factor 4, Atherosclerosis, Protein interactions, Murine models, Transcriptional regulation.

Key words: Platelets, Platelet Factor 4, Atherosclerosis, Protein interactions, Murine models, Tanscriptional regulation.

Description of Research
My laboratory is primarily interested in the biology and structure of platelet factor 4 (PF4). PF4 is a cationic protein found in the alpha-granules of platelets and is released upon platelet activation. It binds avidly to glycosaminoglycans on the surface of endothelial cells and is known to inhibit anti-thrombin III, resulting in increased clotting.

We are interested in the role of PF4 in several diseases, specifically atherosclerosis and heparin induced thrombocytopenia (HIT). We have found that PF4 is localized in atherosclerotic lesions and that the presence of PF4 correlated with pathological and clinical disease progression. Further, we have found that in vitro PF4 inhibits endocytosis of the LDL receptor, resulting in decreased LDL degradation and retention of LDL on the cell surface.

A main focus of the lab currently is examining the diagnosis, treatment and molecular mechanisms of HIT. This rare but serious complication of heparin therapy is known to involve the recognition of PF4:heparin complexes by pathogenic auto-antibodies. It is also known that altering the ratio of heparin to PF4 alters the recognition of the complexes. Our working hypothesis is that the structure of the complexes formed at different heparin:PF4 ratios differs and that the structural changes are important for the expression of disease. We are investigating these structural changes and how these changes effect pathogenesis of HIT. Both in vitro and in vivo systems are being employed.

We have recently identified and described small molecule PF4 antagonists which may form the basis for novel treatments of HIT. These molecules also serve as tools to improve our understanding of the mechanisms of HIT. We are also working on improving the diagnosis of HIT but modifying existing assays and developing new assays.

Description of Itmat Expertise

Dr. Sachais's research is primarily interested in atherosclerosis and heparin-induced thrombocytopenia. His work focuses on the pathobiology of platelet factor 4 (PF4). He is also involved in clinical and translational research related to transfusion and apheresis medicine, with a focus on hemostasis.

Selected Publications

Cho, M.J., Lo, A.S.Y., Mao, X., Nagler, A.R., Ellebrecht, C.T., Mukherjee, E.M., Hammers, C.M., Choi, E.J., Sharma, P.M., Uduman, M., Li, H., Rux, A.H., Farber, S.A., Rubin, C.B., Kleinstein, S.H., Sachais, B.S., Posner, M.R., Cavacini, L.A., Payne, A.S.: Shared VH1-46 gene usage by pemphigus vulgaris autoantibodies indicates common humoral immune responses among patients. Nature Communications IN PRESS, 2014.

Farooqi, M.S., Lai, Y., Lancaster, E., Schmitt, S.E., Sachais, B.S.: Therapeutic Plasma Exchange and Immunosuppressive Therapy in a Patient with Anti-GAD Antibody-Related Epilepsy: Quantification of the Antibody Response. Journal of Clinical Apheresis In Press, 2014.

Cuker A.,Rux A.H., Hinds J.L., Dela Cruz M., Yarovoi S.V., Brown I.A., Yang W., Konkle B.A., Arepally G.M., Watson S.P., Cines D.B., Sachais, B.S.: Novel diagnostic assays for heparin-induced thrombocytopenia. BLOOD 121: 3727-3732, May (Feb Ahead of print) 2013.

Callan, M.B., Patel, R.T., Rux, A.H., Bandyopadhyay, S., Sireci, A.N., ODonnel, P.A., Ruane, T., Sikora, T., Marryott, K., Sachais, B.S., and Hod, E.A.: Transfusion of 28-day-old leucoreduced or non-leukoreduced stored red blood cells introduces an inflammatory response in healthy dogs. Vox Sanguinis 105(4): 319-27, 2013.

Litvinov, R.I., Yarovoi, S.V., Rauova, L., Barsegov, V., Sachais, B.S., Rux, A.H., Hinds, J.L., Arepally, G.M., Cines, D.B., Weisel, J.W.: Distinct Specificity and Single-molecule Kinetics Characterize the Interaction of Pathogenic and Non-pathogenic Antibodies against Platelet Factor 4-Heparin Complexes with Platelet Factor 4. Journal of Biological Chemistry 288(46): 33060-70, 2013.

Tanhehco, Y.C., Cuker, A., Rudnick, M., and Sachais, B.S.: Investigation of a potential protective mechanism against heparin-induced thrombocytopenia in patients on chronic intermittent hemodialysis. Thrombosis Research 131: 244-248, 2013 Notes: http://dx.doi.org/10.1016/j.thromres.2012.12.010.

Sachais, B.S., Litvinov, R.I., Yarovoi, S.V., Rauova, L., Hinds, J.L., Rux, A.H., Arepally, G.M., Poncz, M., Cuker, A., Weisel, J.W., and Cines, D.B.: Dynamic antibody binding properties in the pathogenesis of HIT. Blood 120: 1137-1142, August 2012 Notes: PMID: 22577175 (Editorial Accompanying).

Sachais, B.S., Rux. A.H, Cines, D.B., Yarovoi, S.V., Garner, L.I., Watson S.P., Hinds, J.L., Rux,J.J.: Rational design and characterization of platelet factor 4 antagonists for the study of heparin-induced thrombocytopenia. Blood 119(25): 5955-5962, June 2012 Notes: Plenary Paper. Inside Blood Accompanying.

Marshall, C.S., Andrzejewski, C., Carey, P.M., Crookston, K.P., Li, K., Lopez-Plaza, I., Sachais, B.S., Schwartz, J., Winters, J.L., Wong E.C.C, and Wu, Y.: Milestones for apheresis education. Journal of Clinical Apheresis Page: Epub Ahead of Print, June 2012.

Yvette C. Tanhehco, Ann H. Rux, and Bruce S. Sachais: Low Density Lipoprotein Apheresis Reduces PF4 on the Surface of Platelets: a Possible Protective Mechanism Against HITT. Transfusion 51: 1022-1029, October 2010 Notes: PMID: 20977482

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Last updated: 09/12/2014
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