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Scratching the Surface

Endothelial Damage in Traumatic Hemorrhagic Shock
Published:September 24, 2021DOI:https://doi.org/10.1016/j.aan.2021.07.003
      The endothelium and endothelial glycocalyx are components of the vascular system that are intricately involved in blood flow, hemostasis, vascular tone, and organ function.

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      References

        • Johansson P.I.
        • Stensballe J.
        • Ostrowski S.R.
        Shock induced endotheliopathy (SHINE) in acute critical illness - a unifying pathophysiologic mechanism.
        Crit Care. 2017; 21: 25
        • Kozar R.A.
        • Pati S.
        Syndecan-1 restitution by plasma after hemorrhagic shock.
        J Trauma Acute Care Surg. 2015; 78: S83-S86
        • Collins S.R.
        • Blank R.S.
        • Deatherage L.S.
        • et al.
        Special article: the endothelial glycocalyx: emerging concepts in pulmonary edema and acute lung injury.
        Anesth Analg. 2013; 117: 664-674
        • Chignalia A.Z.
        • Yetimakman F.
        • Christiaans S.C.
        • et al.
        The glycocalyx and trauma: a review.
        Shock. 2016; 45: 338-348
        • Juffermans N.P.
        • van den Brom C.E.
        • Kleinveld D.J.B.
        Targeting endothelial dysfunction in acute critical illness to reduce organ failure.
        Anesth Analg. 2020; 131: 1708-1720
        • Astapenko D.
        • Benes J.
        • Pouska J.
        • et al.
        Endothelial glycocalyx in acute care surgery - what anaesthesiologists need to know for clinical practice.
        BMC Anesthesiol. 2019; 19: 238
        • White N.J.
        • Ward K.R.
        • Pati S.
        • et al.
        Hemorrhagic blood failure: oxygen debt, coagulopathy, and endothelial damage.
        J Trauma Acute Care Surg. 2017; 82: S41-S49
        • Angus D.C.
        • van der Poll T.
        Severe sepsis and septic shock.
        N Engl J Med. 2013; 369: 840-851
        • Cannon J.W.
        Hemorrhagic shock.
        N Engl J Med. 2018; 378: 370-379
        • Eastridge B.J.
        • Holcomb J.B.
        • Shackelford S.
        Outcomes of traumatic hemorrhagic shock and the epidemiology of preventable death from injury.
        Transfusion. 2019; 59: 1423-1428
        • Meyer D.E.
        • Cotton B.A.
        • Fox E.E.
        • et al.
        A comparison of resuscitation intensity and critical administration threshold in predicting early mortality among bleeding patients: A multicenter validation in 680 major transfusion patients.
        J Trauma Acute Care Surg. 2018; 85: 691-696
        • Kozar R.A.
        • Peng Z.
        • Zhang R.
        • et al.
        Plasma restoration of endothelial glycocalyx in a rodent model of hemorrhagic shock.
        Anesth Analg. 2011; 112: 1289-1295
        • Wang P.
        • Ba Z.F.
        • Chaudry I.H.
        Endothelial cell dysfunction occurs very early following trauma-hemorrhage and persists despite fluid resuscitation.
        Am J Physiol. 1993; 265: H973-H979
        • Hoffman M.
        • Monroe 3rd, D.M.
        A cell-based model of hemostasis.
        Thromb Haemost. 2001; 85: 958-965
        • MacLeod J.B.
        • Lynn M.
        • McKenney M.G.
        • et al.
        Early coagulopathy predicts mortality in trauma.
        J Trauma. 2003; 55: 39-44
        • Brohi K.
        • Singh J.
        • Heron M.
        • et al.
        Acute traumatic coagulopathy.
        J Trauma. 2003; 54: 1127-1130
        • MacLeod J.B.
        • Winkler A.M.
        • McCoy C.C.
        • et al.
        Early trauma induced coagulopathy (ETIC): prevalence across the injury spectrum.
        Injury. 2014; 45: 910-915
        • Cohen M.J.
        • Call M.
        • Nelson M.
        • et al.
        Critical role of activated protein C in early coagulopathy and later organ failure, infection and death in trauma patients.
        Ann Surg. 2012; 255: 379-385
        • Johansson P.I.
        • Henriksen H.H.
        • Stensballe J.
        • et al.
        Traumatic endotheliopathy: a prospective observational study of 424 severely injured patients.
        Ann Surg. 2017; 265: 597-603
        • Henriksen H.H.
        • McGarrity S.
        • SigurEthardottir R.S.
        • et al.
        Metabolic systems analysis of Shock-Induced Endotheliopathy (SHINE) in trauma: a new research paradigm.
        Ann Surg. 2020; 272: 1140-1148
        • Levi M.
        • van der Poll T.
        • Schultz M.
        Systemic versus localized coagulation activation contributing to organ failure in critically ill patients.
        Semin Immunopathol. 2012; 34: 167-179
        • Zhang X.
        • Sun D.
        • Song J.W.
        • et al.
        Endothelial cell dysfunction and glycocalyx - A vicious circle.
        Matrix Biol. 2018; 71-72: 421-431
        • Rahbar E.
        • Cardenas J.C.
        • Baimukanova G.
        • et al.
        Endothelial glycocalyx shedding and vascular permeability in severely injured trauma patients.
        J Transl Med. 2015; 13: 117
        • Alphonsus C.S.
        • Rodseth R.N.
        The endothelial glycocalyx: a review of the vascular barrier.
        Anaesthesia. 2014; 69: 777-784
        • Zuurbier C.J.
        • Demirci C.
        • Koeman A.
        • et al.
        Short-term hyperglycemia increases endothelial glycocalyx permeability and acutely decreases lineal density of capillaries with flowing red blood cells.
        J Appl Physiol (1985). 2005; 99: 1471-1476
        • Schulz E.
        • Gori T.
        • Munzel T.
        Oxidative stress and endothelial dysfunction in hypertension.
        Hypertens Res. 2011; 34: 665-673
        • Rubio-Gayosso I.
        • Platts S.H.
        • Duling B.R.
        Reactive oxygen species mediate modification of glycocalyx during ischemia-reperfusion injury.
        Am J Physiol Heart Circ Physiol. 2006; 290: H2247-H2256
        • van Zyl N.
        • Milford E.M.
        • Diab S.
        • et al.
        Activation of the protein C pathway and endothelial glycocalyx shedding is associated with coagulopathy in an ovine model of trauma and hemorrhage.
        J Trauma Acute Care Surg. 2016; 81: 674-684
        • Nieuwdorp M.
        • Meuwese M.C.
        • Mooij H.L.
        • et al.
        Tumor necrosis factor-alpha inhibition protects against endotoxin-induced endothelial glycocalyx perturbation.
        Atherosclerosis. 2009; 202: 296-303
        • Johansson P.I.
        • Ostrowski S.R.
        Acute coagulopathy of trauma: balancing progressive catecholamine induced endothelial activation and damage by fluid phase anticoagulation.
        Med Hypotheses. 2010; 75: 564-567
        • Pascual J.L.
        • Ferri L.E.
        • Seely A.J.
        • et al.
        Hypertonic saline resuscitation of hemorrhagic shock diminishes neutrophil rolling and adherence to endothelium and reduces in vivo vascular leakage.
        Ann Surg. 2002; 236: 634-642
        • Pati S.
        • Matijevic N.
        • Doursout M.F.
        • et al.
        Protective effects of fresh frozen plasma on vascular endothelial permeability, coagulation, and resuscitation after hemorrhagic shock are time dependent and diminish between days 0 and 5 after thaw.
        J Trauma. 2010; 69: S55-S63
        • Naumann D.N.
        • Hazeldine J.
        • Midwinter M.J.
        • et al.
        Poor microcirculatory flow dynamics are associated with endothelial cell damage and glycocalyx shedding after traumatic hemorrhagic shock.
        J Trauma Acute Care Surg. 2018; 84: 81-88
        • Wade C.E.
        • Matijevic N.
        • Wang Y.W.
        • et al.
        Absences of endothelial microvesicle changes in the presence of the endotheliopathy of trauma.
        Shock. 2019; 51: 180-184
        • Gonzalez Rodriguez E.
        • Cardenas J.C.
        • Lopez E.
        • et al.
        Early identification of the patient with endotheliopathy of trauma by arrival serum albumin.
        Shock. 2018; 50: 31-37
        • Ostrowski S.R.
        • Johansson P.I.
        Endothelial glycocalyx degradation induces endogenous heparinization in patients with severe injury and early traumatic coagulopathy.
        J Trauma Acute Care Surg. 2012; 73: 60-66
        • Ostrowski S.R.
        • Henriksen H.H.
        • Stensballe J.
        • et al.
        Sympathoadrenal activation and endotheliopathy are drivers of hypocoagulability and hyperfibrinolysis in trauma: A prospective observational study of 404 severely injured patients.
        J Trauma Acute Care Surg. 2017; 82: 293-301
        • Johansson P.I.
        • Stensballe J.
        • Rasmussen L.S.
        • et al.
        A high admission syndecan-1 level, a marker of endothelial glycocalyx degradation, is associated with inflammation, protein C depletion, fibrinolysis, and increased mortality in trauma patients.
        Ann Surg. 2011; 254: 194-200
        • Johansson P.I.
        • Stensballe J.
        • Rasmussen L.S.
        • et al.
        High circulating adrenaline levels at admission predict increased mortality after trauma.
        J Trauma. 2011; 72: 428-436
        • Naumann D.N.
        • Hazeldine J.
        • Davies D.J.
        • et al.
        Endotheliopathy of trauma is an on-scene phenomenon, and is associated with multiple organ dysfunction syndrome: a prospective observational study.
        Shock. 2018; 49: 420-428
        • Woodcock T.E.
        • Woodcock T.M.
        Revised Starling equation and the glycocalyx model of transvascular fluid exchange: an improved paradigm for prescribing intravenous fluid therapy.
        Br J Anaesth. 2012; 108: 384-394
        • Guerci P.
        • Ergin B.
        • Uz Z.
        • et al.
        Glycocalyx degradation is independent of vascular barrier permeability increase in nontraumatic hemorrhagic shock in rats.
        Anesth Analg. 2019; 129: 598-607
        • Hahn R.G.
        • Zdolsek M.
        • Krizhanovskii C.
        • et al.
        Elevated plasma concentrations of syndecan-1 do not correlate with increased capillary leakage of 20% albumin.
        Anesth Analg. 2021; 132: 856-865
        • Desai K.H.
        • Tan C.S.
        • Leek J.T.
        • et al.
        Dissecting inflammatory complications in critically injured patients by within-patient gene expression changes: a longitudinal clinical genomics study.
        Plos Med. 2011; 8: e1001093
        • Relja B.
        • Land W.G.
        Damage-associated molecular patterns in trauma.
        Eur J Trauma Emerg Surg. 2020; 46: 751-775
        • Oppenheim J.J.
        • Yang D.
        Alarmins: chemotactic activators of immune responses.
        Curr Opin Immunol. 2005; 17: 359-365
        • Zhang Q.
        • Raoof M.
        • Chen Y.
        • et al.
        Circulating mitochondrial DAMPs cause inflammatory responses to injury.
        Nature. 2010; 464: 104-107
        • Jawa R.S.
        • Anillo S.
        • Huntoon K.
        • et al.
        Interleukin-6 in surgery, trauma, and critical care part II: clinical implications.
        J Intensive Care Med. 2011; 26: 73-87
        • Gebhard F.
        • Pfetsch H.
        • Steinbach G.
        • et al.
        Is interleukin 6 an early marker of injury severity following major trauma in humans?.
        Arch Surg. 2000; 135: 291-295
        • Degen J.L.
        • Bugge T.H.
        • Goguen J.D.
        Fibrin and fibrinolysis in infection and host defense.
        J Thromb Haemost. 2007; 5: 24-31
        • Brinkmann V.
        • Reichard U.
        • Goosmann C.
        • et al.
        Neutrophil extracellular traps kill bacteria.
        Science. 2004; 303: 1532-1535
        • Christiaans S.C.
        • Wagener B.M.
        • Esmon C.T.
        • et al.
        Protein C and acute inflammation: a clinical and biological perspective.
        Am J Physiol Lung Cell Mol Physiol. 2013; 305: L455-L466
        • Engelmann B.
        • Massberg S.
        Thrombosis as an intravascular effector of innate immunity.
        Nat Rev Immunol. 2013; 13: 34-45
        • Henry C.B.
        • Duling B.R.
        TNF-alpha increases entry of macromolecules into luminal endothelial cell glycocalyx.
        Am J Physiol Heart Circ Physiol. 2000; 279: H2815-H2823
        • Mulivor A.W.
        • Lipowsky H.H.
        Inflammation- and ischemia-induced shedding of venular glycocalyx.
        Am J Physiol Heart Circ Physiol. 2004; 286: H1672-H1680
        • Gangloff C.
        • Mingant F.
        • Theron M.
        • et al.
        New considerations on pathways involved in acute traumatic coagulopathy: the thrombin generation paradox.
        World J Emerg Surg. 2019; 14: 57
        • Davenport R.
        • Brohi K.
        Fibrinogen depletion in trauma: early, easy to estimate and central to trauma-induced coagulopathy.
        Crit Care. 2013; 17: 190
        • Rourke C.
        • Curry N.
        • Khan S.
        • et al.
        Fibrinogen levels during trauma hemorrhage, response to replacement therapy, and association with patient outcomes.
        J Thromb Haemost. 2012; 10: 1342-1351
        • Britten M.W.
        • Lümers L.
        • Tominaga K.
        • et al.
        Glycocalyx components affect platelet function, whole blood coagulation, and fibrinolysis: an in vitro study suggesting a link to trauma-induced coagulopathy.
        BMC Anesthesiol. 2021; 21: 83
        • Verni C.C.
        • Davila A.
        • Balian S.
        • et al.
        Platelet dysfunction during trauma involves diverse signaling pathways and an inhibitory activity in patient-derived plasma.
        J Trauma Acute Care Surg. 2019; 86: 250-259
        • Darlington D.N.
        • Wu X.
        • Keesee J.D.
        • et al.
        Severe trauma and hemorrhage leads to platelet dysfunction and changes in cyclic nucleotides in the rat.
        Shock. 2020; 53: 468-475
        • Johansson P.I.
        • Sørensen A.
        • Perner A.
        • et al.
        Disseminated intravascular coagulation or acute coagulopathy of trauma shock early after trauma? An observational study.
        Crit Care. 2011; 15: R272
        • Maegele M.
        The coagulopathy of trauma.
        Eur J Trauma Emerg Surg. 2014; 40: 113-126
        • Sandoo A.
        • Veldhuijzen Van Zanten J.J.C.S.
        • Metsios G.S.
        • et al.
        The endothelium and its role in regulating vascular tone.
        Open Cardiovasc Med J. 2010; 4: 302-312
        • Jacob T.D.
        • Ochoa J.B.
        • Udekwu A.O.
        • et al.
        Nitric oxide production is inhibited in trauma patients.
        J Trauma. 1993; 35 ([discussion: 596–7]): 590-596
        • Ochoa J.B.
        • Udekwu A.O.
        • Billiar T.R.
        • et al.
        Nitrogen oxide levels in patients after trauma and during sepsis.
        Ann Surg. 1991; 214: 621-626
        • Greven J.
        • Pfeifer R.
        • Zhi Q.
        • et al.
        Update on the role of endothelial cells in trauma.
        Eur J Trauma Emerg Surg. 2018; 44: 667-677
        • Verma S.
        • Wang C.H.
        • Li S.H.
        • et al.
        A self-fulfilling prophecy: C-reactive protein attenuates nitric oxide production and inhibits angiogenesis.
        Circulation. 2002; 106: 913-919
        • Schwedler S.B.
        • Kuhlencordt P.J.
        • Ponnuswamy P.P.
        • et al.
        Native C-reactive protein induces endothelial dysfunction in ApoE-/- mice: implications for iNOS and reactive oxygen species.
        Atherosclerosis. 2007; 195: e76-e84
        • Hein T.W.
        • Singh U.
        • Vasquez-Vivar J.
        • et al.
        Human C-reactive protein induces endothelial dysfunction and uncoupling of eNOS in vivo.
        Atherosclerosis. 2009; 206: 61-68
        • Cabrales P.
        • Tsai A.G.
        • Intaglietta M.
        Exogenous nitric oxide induces protection during hemorrhagic shock.
        Resuscitation. 2009; 80: 707-712
        • Nachuraju P.
        • Friedman A.J.
        • Friedman J.M.
        • et al.
        Exogenous nitric oxide prevents cardiovascular collapse during hemorrhagic shock.
        Resuscitation. 2011; 82: 607-613
        • Landry D.W.
        • Oliver J.A.
        The pathogenesis of vasodilatory shock.
        N Engl J Med. 2001; 345: 588-595
        • Ullian M.E.
        The role of corticosteroids in the regulation of vascular tone.
        Cardiovasc Res. 1999; 41: 55-64
        • Bond R.F.
        • Bond C.H.
        • Peissner L.C.
        • et al.
        Prostaglandin modulation of adrenergic vascular control during hemorrhagic shock.
        Am J Physiol. 1981; 241: H85-H90
        • Ratz P.H.
        • Miner A.S.
        • Huang Y.
        • et al.
        Vascular smooth muscle desensitization in rabbit epigastric and mesenteric arteries during hemorrhagic shock.
        Am J Physiol Heart Circ Physiol. 2016; 311: H157-H167
        • Gu S.X.
        • Tyagi T.
        • Jain K.
        • et al.
        Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation.
        Nat Rev Cardiol. 2021; 18: 194-209
        • Xiang Y.
        • Hwa J.
        Regulation of VWF expression, and secretion in health and disease.
        Curr Opin Hematol. 2016; 23: 288-293
        • Donato A.J.
        • Magerko K.A.
        • Lawson B.R.
        • et al.
        SIRT-1 and vascular endothelial dysfunction with ageing in mice and humans.
        J Physiol. 2011; 589: 4545-4554
        • Neumar R.W.
        • Nolan J.P.
        • Adrie C.
        • et al.
        Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A consensus statement from the International Liaison Committee on Resuscitation (American Heart Association, Australian and New Zealand Council on Resuscitation, European Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Asia, and the Resuscitation Council of Southern Africa); the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; and the Stroke Council.
        Circulation. 2008; 118: 2452-2483
        • Marcu R.
        • Choi Y.J.
        • Xue J.
        • et al.
        Human organ-specific endothelial cell heterogeneity.
        iScience. 2018; 4: 20-35
        • Aslan A.
        • Van Meurs M.
        • Moser J.
        • et al.
        Organ-specific differences in endothelial permeability-regulating molecular responses in mouse and human sepsis.
        Shock. 2017; 48: 69-77
        • Huber-Lang M.
        • Lambris J.D.
        • Ward P.A.
        Innate immune responses to trauma.
        Nat Immunol. 2018; 19: 327-341
        • Hatton G.E.
        • Isbell K.D.
        • Henriksen H.H.
        • et al.
        Endothelial dysfunction is associated with increased incidence, worsened severity, and prolonged duration of acute kidney injury after severe trauma.
        Shock. 2021; 55: 311-315
        • Wu F.
        • Chipman A.
        • Pati S.
        • et al.
        Resuscitative strategies to modulate the endotheliopathy of trauma: from cell to patient.
        Shock. 2020; 53: 575-584
        • Sperry J.L.
        • Guyette F.X.
        • Brown J.B.
        • et al.
        Prehospital plasma during air medical transport in trauma patients at risk for hemorrhagic shock.
        N Engl J Med. 2018; 379: 315-326
        • Moore H.B.
        • Moore E.E.
        • Chapman M.P.
        • et al.
        Plasma-first resuscitation to treat haemorrhagic shock during emergency ground transportation in an urban area: a randomised trial.
        Lancet. 2018; 392: 283-291
        • Reitz K.M.
        • Moore H.B.
        • Guyette F.X.
        • et al.
        Prehospital plasma in injured patients is associated with survival principally in blunt injury: Results from two randomized prehospital plasma trials.
        J Trauma Acute Care Surg. 2020; 88: 33-41
        • Jehan F.
        • Aziz H.
        • OʼKeeffe T.
        • et al.
        The role of four-factor prothrombin complex concentrate in coagulopathy of trauma: A propensity matched analysis.
        J Trauma Acute Care Surg. 2018; 85: 18-24
        • Zeeshan M.
        • Hamidi M.
        • Feinstein A.J.
        • et al.
        Four-factor prothrombin complex concentrate is associated with improved survival in trauma-related hemorrhage: A nationwide propensity-matched analysis.
        J Trauma Acute Care Surg. 2019; 87: 274-281
        • Joseph B.
        • Hadjizacharia P.
        • Aziz H.
        • et al.
        Prothrombin complex concentrate: an effective therapy in reversing the coagulopathy of traumatic brain injury.
        J Trauma Acute Care Surg. 2013; 74: 248-253
        • Pati S.
        • Potter D.R.
        • Baimukanova G.
        • et al.
        Modulating the endotheliopathy of trauma: Factor concentrate versus fresh frozen plasma.
        J Trauma Acute Care Surg. 2016; 80 ([discussion: 584–5]): 576-584
        • Potter D.R.
        • Trivedi A.
        • Lin M.
        • et al.
        The effects of human prothrombin complex concentrate on hemorrhagic shock-induced lung injury in rats: Implications for testing human blood products in rodents.
        J Trauma Acute Care Surg. 2020; 89: 1068-1075
        • Barry M.
        • Trivedi A.
        • Miyazawa B.Y.
        • et al.
        Cryoprecipitate attenuates the endotheliopathy of trauma in mice subjected to hemorrhagic shock and trauma.
        J Trauma Acute Care Surg. 2021; 90: 1022-1031
        • CRASH-2 Trial Collaborators
        • Shakur H.
        • Roberts I.
        • et al.
        Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial.
        Lancet. 2010; 376: 23-32
        • Guyette F.X.
        • Brown J.B.
        • Zenati M.S.
        • et al.
        Tranexamic acid during prehospital transport in patients at risk for hemorrhage after injury: a double-blind, placebo-controlled, randomized clinical trial.
        JAMA Surg. 2020; 156: 11-20
        • Diebel L.N.
        • Martin J.V.
        • Liberati D.M.
        Early tranexamic acid administration ameliorates the endotheliopathy of trauma and shock in an in vitro model.
        J Trauma Acute Care Surg. 2017; 82: 1080-1086
        • Rowell S.E.
        • Meier E.N.
        • McKnight B.
        • et al.
        Effect of out-of-hospital tranexamic acid vs placebo on 6-month functional neurologic outcomes in patients with moderate or severe traumatic brain injury.
        JAMA. 2020; 324: 961-974