My lab focuses on understanding the mechanisms of Hemostasis, Inflammation, and Thrombosis following Trauma and hemorrhagic shock with a translational focus in these areas as well as Transfusion medicine and Surgical outcomes (HIT3S Lab). Uncontrolled hemorrhage is the leading cause of preventable death in trauma, which accounts for nearly 10% of annual mortality worldwide. Over 25% of severely injured patients will present with impaired coagulation which increases morbidity and mortality. Although it is well known that trauma results in a profound inflammatory response driven by innate immune activation, the mechanisms of this acute coagulopathy of trauma are poorly understood. Our lab has recently discovered a potential link between sterile inflammation and impaired coagulation through expression of the innate immune receptor, toll-like receptor 4 (TLR4) and the endogenous danger signal, high mobility group box 1 (HMGB1), on platelets. We now seek to understand the regulation of innate immune signaling on platelets and are testing multiple drug targets to attenuate platelet dysfunction and prevent thrombotic complications following trauma. We have multiple ongoing studies investigating the mechanisms of venous thromboembolic events (VTE) as well as microvascular thrombosis. The lab is presently pursuing the role of platelet derived microparticles and exosomes in trauma and VTE.
We also have a dedicated interest in the development of a synthetic platelet for hemostasis after injury in collaboration with Anirban SenGupta, PhD, as well as the design of novel, platelet directed drug delivery systems. The lab collaborates closely with local and international platelet and coagulation experts. We are also co-lead investigators for the University of Pittsburgh effort in the NIH/DOD funded Trans-Agency Consortium for the study of Trauma Induced Coagulopathy (TACTIC) along with Dr. Brian Zuckerbraun. This multi-disciplinary collaboration combines international experts in platelet biology, coagulopathy, cellular imaging, and innate immune signaling to create a team well suited to this complex problem. The laboratory is supported by the National Institute for General Medical Sciences (NIGMS), the National Heart Lung and Blood Institute (NHLBI), BARDA, and the Vascular Medicine Institute at the University of Pittsburgh, as well as private industry.
Clinical research by the group focuses on surgical outcomes in trauma, transfusion medicine, and emergency general surgery. Examples on ongoing projects include the investigation of outcomes in non-trauma massive transfusion; determination of the significance of thrombocytopenia in the ICU, as well as the design of a scoring system to predict massive transfusion protocol activation in the setting of non-trauma massive hemorrhage. The lab actively participates in 2 Department of Defense (DoD) randomized clinical trials in trauma and transfusion as well as translational analysis of outcomes in TACTIC. Finally, we have an industry sponsored prospective observational trial to investigate the role of thromboelastography in the management of patients on novel direct oral anticoagulants (DOACs).
CLINICAL RESEARCH GROUP
- Sara Myers, MD
- Jurgis Alviks, MD
- Eric Etchill, MD
- Jessica cheung
- Zach Lingus
- Conor Donnelly
Vogel S, Bodenstein R, Chen Q., Feil S, Feil R, Rehinlaender J, Schaffer TE, Bohn E, Frick JS, Borst O, Munzer P, Walker B, Markel J, Csanyi G, Pagano PJ, Loughran P, Jessup ME, Watkins SC, Bullock GC, Sperry JL, Zuckerbraun BS, Billiar TR, Lotze MT, Gawaz M, Neal MD. Platelet-derived HMGB1 is a critical mediator of thrombosis. J Clin Invest. 2015 Dec;125(12):4638-54.
Shukla M, Sekhon UD, Betapudi V, Li W, Hickman DA, Pawlowski CL, Dyer MR, Neal MD, McCrae KR, Sen Gupta A. In vitro characterization of SynthoPlate (synthetic platelet) technology and its in vivo evaluation in severely thrombocytopenic mice. J Thromb Haemost. 2017 Feb;15(2):375-387
Ding N, Chen G, Hoffman R, Loughran PA, Sodhi CP, Hackam DJ, Billiar TR, Neal MD. TLR4 Regulates Platelet Activation and Contributes to Coagulation Abnormality and Organ Injury in Hemorrhagic Shock and Resuscitation. Circulation: Cardiovasc Gen. 2014 Oct:7(5):615-24.
Zettel KR, Dyer M, Raval JS, Wu X, Klune JR, Gutierrez A, Triulzi DJ, Billiar TR, Neal MD. Aged Human Stored Red Blood Cell Supernatant Inhibits Macrophage Phagocytosis in an HMGB1 Dependent Manner After Trauma in a Murine Model. Shock. 2017 Feb;47(2):217-224.
Clinical assessment of trauma-induced coagulopathy and its contribution to postinjury mortality: A TACTIC proposal. Neal MD, Moore HB, Moore EE, Freeman K, Cohen MJ, Sperry JL, Zuckerbraun BS, Park MS; TACTIC Investigators. J Trauma Acute Care Surg. 2015 Sep;79(3):490-2. doi: 10.1097/TA.0000000000000793. No abstract available. PMID:26307885
Neal MD, Jia H, Eyer B, Good M, Guerriero C, Sodhi CP, Afrazi A, Prindle T, Ma C, Branca M, Ozolek J, Brodsky J, Wipf P, Hackam DJ. Discovery and Validation of a New Class of Small Molecule TLR4 Inhibitors. PLoS One. 2013 Jun 12;8(6):e65779.
Neal MD, Sodhi CP, Dyer M, Craig BT, Good M, Jia H, Yazji I, Afrazi A, Richardson WM, Beer-Stolz D, Prindle T, Grant Z, Branca MF, Ozolek J, Hackam DJ. A Critical Role for Toll-like Receptor-4 Induction of Autophagy in the Regulation of Enterocyte Migration and the Pathogenesis of Necrotizing Enterocolitis. J Immunol. 2013 Apr 1;190(7):3541-51.
Neal MD, Sodhi CP, Dyer M, Egan C, Good M, Afrazi A, Yazji I, Ma C, Branca M, Grant Z, Prindle T, Hackam DJ. Toll-like Receptor 4 is Expressed on Intestinal Stem Cells and Regulates Their Proliferation and Apoptosis through the p53 Upregulated Modulator of Apoptosis. J Biol Chem. 2012 Oct 26;287(44):37296-308.
Neal MD, Leaphart C, Billiar TR, Levy R, Prince J, Schreiber A, Ford HR, Hackam DJ. Toll like receptor 4 (TLR4) mediates the phagocytosis of gram negative bacteria by intestinal epithelial cells. J Immunol. 2006 Mar 1;176(5):3070-3079. Cover
Neal MD, Moore HB, Moore EE, Freeman K, Cohen MJ, Sperry JL, Zuckerbraun BS, Park MS and TACTIC Investigators. Clinical Assessment of Trauma Induced Coagulopathy and Its Contribution to Post-Injury Mortality: A TACTIC Proposal. Journal of Trauma and Acute Care Surgery (2015). In press.
Neal MD, Brown JB, Moore EE, Cuschieri J, Maier RV, Minei JP, Billiar TR, Peitzman AB, Cohen MJ, Sperry JL. Prehospital Use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) is Associated with a Reduced Incidence of Trauma-Induced Coagulopathy. Ann Surg. 2014 Jan 13 [Epub ahead of print]
Neal MD, Peitzman AP, Forsythe RM, Marshall GT, Rosengart MR, Alarcon LH, Billiar TR, Sperry JL. Crystalloid To Packed Red Blood Cell Transfusion Ratio In The Massively Transfused Patient: When A Little Goes Along Way. J Trauma Acute Care Surg. 2012 Apr;72(4):892-898.
Neal MD, Alverdy JC, Hall DE, Simmons RL, Zuckerbraun BS. Diverting loop ileostomy and colonic lavage: an alternative to total abdominal colectomy for the treatment of severe, complicated Clostridium difficile associated disease. Ann Surg. 2011 Sep;254(3):423-7; discussion 427-9.
Sodhi CP, Neal MD, Sho S, Good M, Siggers R, Russo AM, Branca M, Ma C, Prindle T, Hackam DJ. A Critical Role for Intestinal Epithelial TLR4 in Goblet Cell Differentiation and the Pathogenesis of Murine Necrotizing Enterocolitis. Gastroenterology. 2012 Sep;143(3):708-718.e5. Cover