Thrombosis, Hemostasis and Vascular Biology

Platelets are important in early wound healing, where they initially stick to damaged blood vessels and then aggregate with one another to form a platelet plug. Excessive bleeding occurs when platelet counts are low or when platelets don’t function well. Dr. Newman’s research has recently focused on the contributions of platelet abnormalities to excessive bleeding in the fetal and neonatal periods when excessive bleeding can have life-long developmental consequences. Newborns who undergo surgery for congenital heart defects experience very severe bleeding. Dr. Newman’s lab recently demonstrated that decreases in platelet count and function occur normally during heart surgery but can be corrected with platelet transfusion so that they will not complicate bleeding in newborn heart surgery patients. This research justifies administration of the right number of platelets at the right time to effectively control bleeding in this at-risk population.  Deletion of segment 11.2 on the q arm of one copy of chromosome 22 gives rise to 22q11.2 Deletion Syndrome (22q11.2DS), which is commonly found in patients with congenital heart defects.  One the many genes that are deleted in 22q11.2DS is GPIBB, which encodes a component of an important platelet receptor (GPIb-IX-V). Dr. Newman’s lab demonstrated that loss of one copy of GPIBB is not associated with increased bleeding.  This finding indicates that patients with 22q11.2DS who must undergo surgery for congenital heart defects are not at increased risk for severe bleeding because of loss of one copy of GPIBB. Dr. Newman’s lab also studies Fetal/Neonatal Alloimmune Thrombocytopenia (FNAIT), which is a disorder that arises when a mother’s immune system recognizes her baby’s platelets as foreign and clears them from the baby’s circulation. Dr. Newman is currently working in collaboration with several investigators at Versiti to investigate who is at highest risk for development of FNAIT, what causes the most severe forms of the disease, when and where during pregnancy the maternal immune response to her baby’s platelets develops, and why the mechanisms that normally ensure maternal tolerance of fetal differences fail in FNAIT. This research is needed to predict who will deliver babies with severe FNAIT so that they can be treated to prevent the most severe forms of the disease and to prevent immunization of mothers who are exposed to fetal differences that can elicit a damaging maternal immune response.

A major focus of research in Dr. Newman’s laboratory is Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1), which inhibits responses of many circulating blood cells, including platelets and T cells. T cells are immune cells that play an important role in clearing infections and eradicating tumors. Dr. Newman has discovered that PECAM-1 works with another potent T cell suppressor, Transforming Growth Factor ß (TFGß), to inhibit T cell anti-tumor responses. Her current work is dedicated to developing a better understanding of how PECAM-1 expression is regulated in T cells and of how PECAM-1 and TGFß work together to inhibit T cell responses. This research will help improve T cell-based therapies for treatment of cancer and autoimmune disease.

NIH, R35-HL139937 (Co-Investigator), ‘Basic Investigation & Translational Applications Concerning the Cell & Molecular Biology of Blood & Vascular Cells (2018-2024)

Guoping Fu
Research Associate II

Marjorie Kipp
Research Technologist

• Patil, S., D.K. Newman and P.J. Newman. 2001. PECAM-1 serves as an inhibitory receptor that modulates platelet responses to collagen. Blood 97:1727-32.
• Newman, D.K., C. Hamilton, M.J. Armstrong and P.J. Newman. 2001. Inhibition of antigen-receptor signaling by platelet endothelial cell adhesion molecule-1 (CD31) requires an intact ITIM, SHP-2, and p56lck. Blood 97:2351-7.
• Newman, D.K., S. Hoffman, T. Zhao, S. Kotamraju, B. Wakim, B. Kalyanaraman, and P.J. Newman. 2002. Nitration of ITIM tyrosines abrogates phosphorylation and ability to bind SHP-2. Biochemical and Biophysical Research Communications 296:1171-9.
• Gao, C., W. Sun, M. Christofidou-Solomidou, M. Sawada, D.K. Newman, C. Bergom, S.M. Albelda, S. Matsuyama and P.J. Newman. 2003. PECAM-1 functions as a specific and potent inhibitor of mitochondrial apoptosis. Blood 102:169-79.
• Newman, P.J. and D.K. Newman. 2003. Signal transduction pathways mediated by PECAM-1: New roles for an old molecule in platelet and vascular biology. Arteriosclerosis, Thrombosis and Vascular Biology 23:953-64.
• Rathore, V., M.A. Stapleton, C.A. Hillery, R.R. Montgomery, T.C. Nichols, E.P. Merricks, D.K. Newman and P.J. Newman. 2003. PECAM-1 negatively regulates GPIb/V/IX signaling in murine platelets. Blood 102:3658-64.
• Maas, M., R. Wang, C. Paddock, P.J. Newman and D.K. Newman. 2003. Reactive oxygen species induce reversible PECAM-1 tyrosine phosphorylation and SHP-2 binding. American Journal of Physiology: Heart and Circulatory Physiology 285: H2336–H2344.
• Boylan, B., H. Chen, V. Rathore, C. Paddock, M. Salacz, K.D. Friedman, B.R. Curtis, M. Stapleton, D.K. Newman, M.L. Kahn and P.J. Newman. 2004. Anti-GPVI-associated ITP: An acquired platelet disorder caused by autoantibody-mediated clearance of the GPVI/FCRγ-chain complex from the human platelet surface. Blood 104:1350-5.
• Rathore, V., D. Wang, D.K. Newman and P.J. Newman. 2004. Phospholipase Cγ2 contributes to stable thrombus formation on VWF. FEBS Letters 573:26-30.
• Maas, M., M. Stapleton, C. Bergom, D.L. Mattson, D.K. Newman and P.J. Newman. 2005. Endothelial cell PECAM-1 confers protection against endotoxic shock. American Journal of Physiology: Heart and Circulatory Physiology 288:H159-64.
• Falati, S., S. Patil, P.L. Gross, M. Stapleton, G. Merrill-Skoloff, N.E. Barrett, K.L. Pixton, H. Weiler, B. Cooley, D.K. Newman, P.J. Newman, B.C Furie, B. Furie, and J.M. Gibbins. 2006. Platelet PECAM-1 inhibits thrombus formation in vivo. Blood 107:535-541.
• Liu, Y., A.B. Bubolz, Y. Shi, P.J. Newman, D.K. Newman, and D.D. Gutterman. 2006. Peroxynitrite reduces the endothelium derived hyperpolarizing factor component of coronary flow-mediated dilation in PECAM-1-knock out mice. American Journal of Physiology: Heart and Circulatory Physiology 290:R57-65.
• Rathore, V.B., P.J. Newman and D.K. Newman. 2007. Paxillin family members function as Csk binding proteins that regulate Lyn activity in human and murine platelets. Biochemical Journal 403:275-81.
• Machida, K., C.M. Thompson, K. Dierck, K. Jablonowski, S. Karkkainen, B. Liu, H. Zhang, P.D. Nash, D.K. Newman, P. Nollau, T. Pawson, G.H. Renkema, K. Saksela, M. Schiller, D.-G. Shin and B.J. Mayer. 2007. High-throughput phosphotyrosine profiling using SH2 domains. Molecular Cell26:899-915.
• Goel, R., B. Boylan, L. Gruman, P.J. Newman, P. North and D.K. Newman. 2007. The proinflammatory phenotype of PECAM-1-deficient mice results in atherogenic diet-induced steatohepatitis. American Journal of Physiology: Gastrointestinal and Liver Physiology 293:G1205-14.
• Bergom, C., C. Paddock, C. Gao, T. Holyst, D.K. Newman, and P.J. Newman. 2007. An alternatively spliced isoform of PECAM-1 is expressed at high levels in human and murine tissues, and suggests a novel role for the C-terminus of PECAM-1 in cytoprotective signaling. 2008. .J Cell Sci. 121:1235-42.
• Goel, R., B. Schrank, S. Arora, B. Boylan, B. Fleming, H. Miura, P.J. Newman, R.C. Molthen, and D.K. Newman. 2008. PECAM-1 deficiency affects atherosclerosis in LDL receptor-deficient mice in a site-specific manner. Arterioscler. Thromb. Vasc. Biol. 28:1996-2002.
• Boylan, B., C. Gao, V. Rathore, J.C. Gill, D.K. Newman and P.J. Newman. 2008. Identification of FcγRIIa as the ITAM-bearing receptor mediating αIIbβ3 outside-in integrin signaling in human platelets. Blood 112:2780-2786.
• Gao, C., B. Boylan, D. Bougie, J.C. Gill, J. Birenbaum, D.K. Newman, R.H. Aster and P.J. Newman. 2009. Eptifibatide-induced thrombocytopenia and thrombosis in humans require FcγRIIa and the integrin β3 cytoplasmic domain. J. Clin. Invest. 113:504-11.
• Newman, D.K. 2009. The Y's that bind: Negative regulators of Src family kinase activity in platelets. J. Thromb. Haemost. 7 (Suppl 1) 195-9.
• Newman, D.K. 2009. PI3Kβ goes to the head of its class. Blood 114:2011-2.
• Privratsky, J.R., B.E. Tourdot, D.K. Newman and P.J. Newman. 2010. The anti-inflammatory actions of PECAM-1 do not involve regulation of endothelial cell NF-κB. J. Immunol. 184:3157-63.
• Bayat, B., S. Werth, U.J.H. Sachs, D.K. Newman, P.J. Newman, and S. Santoso. 2010. Neutrophil transmigration mediated by the neutrophil-specific antigen CD177 is influenced by the endothelial S536N dimorphism of PECAM-1. J. Immunol. 184:3889-93.
• Fornasa, G., E. Groyer, M. Clement, J. Dimitrov, C. Compain, A.-T. Gaston, A. Varthaman, J. Khallou-Laschet, D. K. Newman, S. Graff-Dubois, A. Nicoletti, and G. Caligiuri. 2010. TCR stimulation drives cleavage and shedding of the ITIM-receptor CD31. J. Immunol. 184:5485-92.
• Crockett, J., D.K. Newman, and P.J. Newman. PECAM-1 is a negative regulatory of laminin-induced platelet activation. J. Thromb. Haemost. 8:1584-93.
• Privratsky, J.R., D. K. Newman, and P.J. Newman. PECAM-1: Conflicts of interest in inflammation. Life Sciences 87:69-82.
• Keane, C., H. Peterson, Reynolds, K., D.K. Newman, D. Cox, H.F. Jenkinson, P.J. Newman and S.W. Kerrigan. 2010. Contribution of outside-in αIIbβ3-mediated activation of human platelets by the colonizing bacterium, Streptococcus gordonii, to the thrombotic complications of infective endocarditis. Arterioscler. Thromb. Vasc. Biol. 30:2408-15.
• Moraes, L.A., L.M. Holbrook, C.I. Jones, N.E. Barrett, M. Spyridon, T. Sage, D.K. Newman, and J.M. Gibbins. 2010. PECAM-1 regulates platelet function through the modulation of the GAB1-SHP-2-PI3-kinase signalling complex. J. Thromb. Haemost. 8:2530-41.
• McCormick, M.E., R. Goel, D. Fulton, S. Oess, D. Newman, and E. Tzima. 2011. Platelet-Endothelial Cell Adhesion Molecule-1 regulates endothelial NO synthase activity and localization through signal transducers and activators of transcription 3 dependent NOSTRIN expression. Arterioscler. Thromb. Vasc. Biol. 31:643-9.
• Ming, Z., Y. Hu, J. Xiang, Polewski, P.J. Newman, and D.K. Newman. 2011. Lyn and PECAM-1: Interdependent inhibitors of platelet responsiveness. Blood 117:3903-6.
• Privratsky, J.R., C.M. Paddock, O. Florey, D.K. Newman, W.A. Muller, and P.J. Newman. 2011. Relative contribution of PECAM-1 adhesion and signaling to the maintenance of vascular integrity. J. Cell. Sci. 124:1477-85.
• Gao, C., B. Boylan, J. Fang, D.A. Wilcox, D.K. Newman, and P.J. Newman. 2011. Heparin promotes platelet responsiveness by potentiating αIIbβ3-mediated outside-in signaling. Blood 117:4946-52.
• Paddock, C., B.L. Lytle, F.C. Peterson, T. Holyst, P.J. Newman, B.F. Volkman, and D.K. Newman. 2011. Residues within a lipid-associated segment of the PECAM-1 cytoplasmic domain are susceptible to inducible, sequential phosphorylation. Blood 117:6012-23.
• Privratsky, J.R., S.B. Tilkens, D.K. Newman, and P.J. Newman.  2012.  PECAM-1 dampens cytokine levels during LPS-induced endotoxemia by regulating leukocyte trafficking.  Life Sciences 90:177-84.
• Ma, P., A. Cierniewska, R. Signarvic, M. Cieslak, H. Kong, A.J. Sinnamon, R.R. Neubig, D.K. Newman, T.J. Stalker, and L.F. Brass.  2012.  A newly-identified complex of spinophilin and the tyrosine phosphate, SHP-1, modulates platelet activation by regulating the binding of RGS proteins to spinophilin.  Blood 119:1935-45.
• Dunne, E., C.M. Spring, A. Rehemann, W. Jin, M.C. Berndt, D.K. Newman, P.J. Newman, H. Ni, and D. Kenny.  2012.  Cadherin 6 has a functional role in platelet aggregation and thrombus formation.  Arerioscler. Thromb. Vasc. Biol. 32:1724-31.
• Zhi, H., L. Rauova, V. Hayes, C. Gao, B. Boylan, D.K. Newman, S.E. McKenzie, B.C. Cooley, M. Poncz, and P.J. Newman.  2013.  Cooperative integrin/ITAM signaling in platelets enhances thrombus formation in vitro and in vivo.  Blood 121:1858-67.
• Zheng, Y., M. Yu, A. Podd, L. Yuan, D.K.Newman, R. Wen, G. Apperally, and D. Wang.  2013. Critical role for marginal zone B cells in PF4/heparin antibody production.  Blood 121:3484-92.
• Tourdot, B.E., M. Brenner, K. Keough, T. Holyst, P.J. Newman, and D.K. Newman.  2013.  Immunoreceptor tyrosine-based inhibitory motif (ITIM)-mediated inhibitory signaling is regulated by sequential phosphorylation mediated by distinct nonreceptor tyrosine kinases: A case study involving PECAM-1.  Biochemistry 184:3157-63.
• Zheng, Y., A.W. Wang, M. Yu, A. Padmanabhan, B.E. Tourdot, D.K. Newman, G.C. White, R.H. Aster, R. Wen, and D. Wang.  2014.  Role of B cell tolerance in regulating production of antibodies causing heparin-induced thrombocytopenia.  Blood 123:931-4.
• Clement, M., G. Fornasa, S. Loyau, M. Morvan, P. Larghi, D. Le Roux, K. Guedj, F. Andreata, J. Khallou-Laschet, G. Bismuth, G. Chiocchia, C. Hivroz, D.K. Newman, A. Nicoletti, and G. Caligiuri. 2015. Upholding the T cell immune-regulatory function of CD31 inhibits the formation of T/B immunological synapses in vitro and attenuates the development of experimental autoimmune arthritis in vivo. Journal of Autoimmunity 56:23-33.
• Zheng, Y., T. Adams, H. Zhi, M. Yu, R. Wen, P.J. Newman, D. Wang and D.K. Newman. 2015. Restoration of responsiveness of PLCγ2-deficient platelets by enforced expression of PLCγ1. PLoS One 10(3):e0119739 (PMCID: PMC4368822).
• Zhi, H., N. Wu, J. Dai, P. Liu, H. Hu, J. Zhu, D.K. Newman, C. Gao and P.J. Newman. 2015. Platelet activation and thrombus formation over IgG immune complexes requires integrin αIIbβ3 and Lyn kinase. PLoS One 10(8):e0135738 (PMCID: PMC4546160).
• Newman, D.K.  2015.  CLEC-2: The Inside Story. Blood 125:3972-4.
• Brenner, M.K., S. Clarke, D.K. Mahnke, R.S. Bercovitz, A. Tomita-Mitchell, M.E. Mitchell and D.K. Newman.  2016.  Effect of 22q11.2 deletion on bleeding and transfusion utilization in children with congenital heart disease undergoing cardiac surgery.  Pediatric Research 79(2):318-24.
• Newman, D.K., G. Fu, T. Adams, W. Cui, V. Arumugam, T. Bluemn, and M.J. Riese. 2016.  The adhesion molecule PECAM-1 enhances the TGFb-mediated inhibition of T cell function.  Science Signaling 9(418):ra27 (PMCID: PMC5087802).
• Bercovitz, R.S., M.K. Brenner, and D.K. Newman.  2016.  A whole blood model of thrombocytopenia that controls platelet count and hematocrit.  Annals of Hematology 95(11):1887-94.
• Lertkiatmongkol, P, C Paddock, DK Newman, J Zhu, MJ Thomas, and PJ Newman. 2016.  The role of sialylated glycans in human PECAM-1-mediated trans-homophilic interactions and endothelial cell barrier function.  Journal of Biological Chemistry 291(50):26216-25 (PMCID: PMC5207088).
• Fu, G., M. Yu, Y. Chen, Y. Zheng, W. Zhu, D. Newman, D. Wang, and R. Wen.  2017.  Phospholipase Cγ1 (PLCγ1) is essential for pre-TCR signal transduction and pre-T cell development. European Journal of Immunology 47(1):74-83.
• Liao, D., H. Mei, Y. Hu, D.K. Newman and P.J. Newman.  2018.  CRISPR-mediated deletion of the PECAM-1 cytoplasmic domain increases receptor lateral mobility and strengthens endothelial cell junctional integrity.  Life Sciences 193:186-93.
• Bercovitz, R.S., A.C. Shewmake, D.K. Newman, R.A. Niebler, J.P. Scott, E.A. Stuth,  P. Simpson, K. Yan, and R.K. Woods. 2018.  A universal definition of excessive postoperative bleeding in infants undergoing cardiac surgery with cardiopulmonary bypass.  The Journal of Thoracic and Cardiovascular Surgery 155(5):2112-24.
• Scott, J.P., R.A. Niebler, E.A.E. Stuth, D.K. Newman, J.S. Tweddell, R.S. Bercovitz, D.W. Benson, R. Cole , P.M. Simpson, K.Yan, and R.K. Woods.  2018.  Rotational Thromboelastometry Rapidly Predicts Thrombocytopenia and Hypofibrinogenemia during Neonatal Cardiopulmonary Bypass.  World Journal for Pediatric and Congenital Heart Surgery 9(4):424-33.
• Wesley, E., G. Xin, D. McAllister, S. Malarkannan, D.K. Newman, M.B. Dwinell, W. Cui, B.D. Johnson, and M.J. Riese.  2018.  Diacylglycerol kinase ζ (DGKζ) and Casitas b-lineage proto-oncogene b-deficient mice have similar functional outcomes in T cells but DGKζ-deficient mice have increased T cell activation and tumor clearance.  Immunohorizons 2(4):107-18 (PMCID: PMC6048965).
• Newman, D.K., G. Fu, L. McOlash, D. Schauder, P.J. Newman, W. Cui, S. Rao, B.D. Johnson, J.A. Gershan, and M.J. Riese.  PECAM-1 (CD31) expression in naïve and memory, but not acutely activated, CD8+ T cells. Journal of Leukocyte Biology 104(5):883-93
• Newman, D.K.  2018.  G6b-B:  The “Y’s” and Wherefores.  Blood (In Press).
• Zwifelhofer, N.M., R.S. Bercovitz, L.A. Weik, A. Moroi, S. LaRose, P.J. Newman and D.K. Newman.  2019.  Hemizygosity for the gene encoding glycoprotein Ib beta (GPIBβ) is not responsible for macrothrombocytopenia and bleeding in patients with 22q11.2 deletion syndrome.  Journal of Thrombosis and Haemostasis 17(2):295-305 (PMCID: PMC6410711 – Available 02-01-2020).
• Moroi, A., N. Johnson, M.J. Riese, D.K. Newman and P.J. Newman.  2019.  Diacylglycerol kinase ζ is a negative regulator of GPVI-mediated platelet activation.  Blood Advances 3(7):1154-66 (PMCID: PMC6457232).
• Zwifelhofer, N., R. Bercovitz, R. Cole, K. Yan, P. Simpson, A. Moroi., P.J. Newman, R. Niebler, J. Scott, E. Stuth, R. Woods, D. Benson, and D.K. Newman. 2020. Platelet function changes during neonatal cardiopulmonary bypass surgery: Mechanistic basis and lack of correlation with excessive bleeding. Thrombosis and Haemostasis 120(1): 94-106 (PMCID: PMC7003188).
• Zhi, H., T. Kanaji, G. Fu, D.K. Newman and P.J. Newman.  Generation of PECAM-1 (CD31) conditional knockout mice. Genesis: The Journal of Genetics and Development 58:e23346, 2020 (PMCID: PMC7021573).
• Zhi H, Ahlen MT, Skogen B, Newman DK, Newman PJ. Preclinical evaluation of immunotherapeutic regimens for fetal/neonatal alloimmune thrombocytopenia. Blood Adv. 2021 Sep 28;5(18):3552-62. doi: 10.1182/bloodadvances.2021004371.