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Erschienen in: European Journal of Trauma and Emergency Surgery 5/2021

25.05.2020 | Original Article

Soluble terminal complement activation fragment sC5b-9: a new serum biomarker for traumatic brain injury?

verfasst von: Joshua Parry, Jiho Hwang, Cedric F. Stahel, Corey Henderson, Jason Nadeau, Stephen Stacey, Kathryn Beauchamp, Ernest E. Moore, Philip F. Stahel

Erschienen in: European Journal of Trauma and Emergency Surgery | Ausgabe 5/2021

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Abstract

Purpose

Terminal complement pathway activation after traumatic brain injury (TBI) leads to formation of the membrane attack complex (MAC/C5b-9) which induces neuronal cell death and host-mediated secondary brain injury. Serum levels of soluble MAC (sC5b-9) have not been previously determined in patients with isolated TBI.

Methods

A prospective observational cohort study was performed during a 5-year time-period on adult patients with isolated TBI admitted to an academic level I trauma center in the United States. Controls consisted of patients with femur shaft fractures with or without TBI to mitigate the effect of systemic complement activation by peripheral trauma. Healthy volunteers served as internal controls. The sC5b-9 serum concentrations were measured on the day of admission by enzyme-linked immunosorbent assay (ELISA) and compared between the study cohorts. Univariate analysis was performed to determine independent predictive variables of major complications during hospital admission.

Results

Serum sC5b-9 levels were significantly elevated in patients with isolated TBI (n = 42), compared to patients with isolated femoral shaft fractures (n = 36) or combined TBI and femoral shaft fractures (n = 30; p < 0.05). There was no significant difference in serum sC5b-9 levels between the femur group and the combined injury group, compared to the healthy volunteers (n = 21). Univariate analysis revealed serum sC5b-9 levels as an independent predictor of major postinjury complications after isolated TBI (p < 0.01).

Conclusion

The soluble terminal complement complex sC5b-9 represents a potential novel serum biomarker specific for isolated head injuries, since peripheral trauma did not appear to affect the serum sC5b-9 levels.
Literatur
1.
Zurück zum Zitat Maegele M, Lefering R, Sakowitz O, Kopp MA, Schwab JM, Steudel WI, Unterberg A, Hoffmann R, Uhl E, Marzi I. The incidence and management of moderate to severe head injury. Dtsch Arztebl Int. 2019;116:167–73. Maegele M, Lefering R, Sakowitz O, Kopp MA, Schwab JM, Steudel WI, Unterberg A, Hoffmann R, Uhl E, Marzi I. The incidence and management of moderate to severe head injury. Dtsch Arztebl Int. 2019;116:167–73.
2.
Zurück zum Zitat Lustenberger T, Kern M, Relja B, Wutzler S, Stormann P, Marzi I. The effect of brain injury on the inflammatory response following severe trauma. Immunobiology. 2016;221:427–31.CrossRef Lustenberger T, Kern M, Relja B, Wutzler S, Stormann P, Marzi I. The effect of brain injury on the inflammatory response following severe trauma. Immunobiology. 2016;221:427–31.CrossRef
3.
Zurück zum Zitat Schmidt OI, Infanger M, Heyde CE, Ertel W, Stahel PF. The role of neuroinflammation in traumatic brain injury. Eur J Trauma. 2004;30:135–49.CrossRef Schmidt OI, Infanger M, Heyde CE, Ertel W, Stahel PF. The role of neuroinflammation in traumatic brain injury. Eur J Trauma. 2004;30:135–49.CrossRef
4.
Zurück zum Zitat Stahel PF, Morganti-Kossmann MC, Kossmann T. The role of the complement system in traumatic brain injury. Brain Res Rev. 1998;27:243–56.CrossRef Stahel PF, Morganti-Kossmann MC, Kossmann T. The role of the complement system in traumatic brain injury. Brain Res Rev. 1998;27:243–56.CrossRef
5.
Zurück zum Zitat Hammad A, Westacott L, Zaben M. The role of the complement system in traumatic brain injury: a review. J Neuroinflammation. 2018;15:24.CrossRef Hammad A, Westacott L, Zaben M. The role of the complement system in traumatic brain injury: a review. J Neuroinflammation. 2018;15:24.CrossRef
6.
Zurück zum Zitat Roselli F, Karasu E, Volpe C, Huber-Lang M. Medusa's head: the complement system in traumatic brain and spinal cord injury. J Neurotrauma. 2018;35:226–40.CrossRef Roselli F, Karasu E, Volpe C, Huber-Lang M. Medusa's head: the complement system in traumatic brain and spinal cord injury. J Neurotrauma. 2018;35:226–40.CrossRef
7.
Zurück zum Zitat Kossmann T, Stahel PF, Morganti-Kossmann MC, Jones JL, Barnum SR. Elevated levels of the complement components C3 and factor B in ventricular cerebrospinal fluid of patients with traumatic brain injury. J Neuroimmunol. 1997;73:63–9.CrossRef Kossmann T, Stahel PF, Morganti-Kossmann MC, Jones JL, Barnum SR. Elevated levels of the complement components C3 and factor B in ventricular cerebrospinal fluid of patients with traumatic brain injury. J Neuroimmunol. 1997;73:63–9.CrossRef
8.
Zurück zum Zitat Bellander BM, Singhrao SK, Ohlsson M, Mattsson P, Svennson M. Complement activation in the human brain after traumatic brain injury. J Neurotrauma. 2001;18:1295–311.CrossRef Bellander BM, Singhrao SK, Ohlsson M, Mattsson P, Svennson M. Complement activation in the human brain after traumatic brain injury. J Neurotrauma. 2001;18:1295–311.CrossRef
9.
Zurück zum Zitat Kaczorowksi SL, Schiding JK, Toth CA, Kochanek PM. Effect of soluble complement receptor-1 on neutrophil accumulation after traumatic brain injury in rats. J Cereb Blood Flow Metab. 1995;15:860–4.CrossRef Kaczorowksi SL, Schiding JK, Toth CA, Kochanek PM. Effect of soluble complement receptor-1 on neutrophil accumulation after traumatic brain injury in rats. J Cereb Blood Flow Metab. 1995;15:860–4.CrossRef
10.
Zurück zum Zitat Rancan M, Morganti-Kossmann MC, Barnum SR, Saft S, Schmidt OI, Ertel W, Stahel PF. Central nervous system-targeted complement inhibition mediates neuroprotection after closed head injury in transgenic mice. J Cereb Blood Flow Metab. 2003;23:1070–4.CrossRef Rancan M, Morganti-Kossmann MC, Barnum SR, Saft S, Schmidt OI, Ertel W, Stahel PF. Central nervous system-targeted complement inhibition mediates neuroprotection after closed head injury in transgenic mice. J Cereb Blood Flow Metab. 2003;23:1070–4.CrossRef
11.
Zurück zum Zitat Leinhase I, Schmidt OI, Thurman JM, Hossini AM, Rozanski M, Taha ME, Scheffler A, John T, Smith WR, Holers VM, Stahel PF. Pharmacological complement inhibition at the C3 convertase level promotes neuronal survival, neuroprotective intracerebral gene expression, and neurological outcome after traumatic brain injury. Exp Neurol. 2006;199:454–64.CrossRef Leinhase I, Schmidt OI, Thurman JM, Hossini AM, Rozanski M, Taha ME, Scheffler A, John T, Smith WR, Holers VM, Stahel PF. Pharmacological complement inhibition at the C3 convertase level promotes neuronal survival, neuroprotective intracerebral gene expression, and neurological outcome after traumatic brain injury. Exp Neurol. 2006;199:454–64.CrossRef
12.
Zurück zum Zitat Leinhase I, Holers VM, Thurman JM, Harhausen D, Schmidt OI, Pietzcker M, Taha ME, Rittirsch D, Huber-Lang M, Smith WR, Ward PA, Stahel PF. Reduced neuronal cell death after experimental brain injury in mice lacking a functional alternative pathway of complement activation. BMC Neurosci. 2006;7:55.CrossRef Leinhase I, Holers VM, Thurman JM, Harhausen D, Schmidt OI, Pietzcker M, Taha ME, Rittirsch D, Huber-Lang M, Smith WR, Ward PA, Stahel PF. Reduced neuronal cell death after experimental brain injury in mice lacking a functional alternative pathway of complement activation. BMC Neurosci. 2006;7:55.CrossRef
13.
Zurück zum Zitat Leinhase I, Rozanski M, Harhausen D, Thurman JM, Schmidt OI, Hossini AM, Taha ME, Rittirsch D, Ward PA, Holers VM, Ertel W, Stahel PF. Inhibition of the alternative complement activation pathway in traumatic brain injury by a monoclonal anti-factor B antibody: a randomized placebo-controlled study in mice. J Neuroinflamm. 2007;4:13.CrossRef Leinhase I, Rozanski M, Harhausen D, Thurman JM, Schmidt OI, Hossini AM, Taha ME, Rittirsch D, Ward PA, Holers VM, Ertel W, Stahel PF. Inhibition of the alternative complement activation pathway in traumatic brain injury by a monoclonal anti-factor B antibody: a randomized placebo-controlled study in mice. J Neuroinflamm. 2007;4:13.CrossRef
14.
Zurück zum Zitat Stahel PF, Flierl MA, Morgan BP, Persigehl I, Stoll C, Conrad C, Touban BM, Smith WR, Beauchamp K, Schmidt OI, Ertel W, Leinhase I. Absence of the complement regulatory molecule CD59a leads to exacerbated neuropathology after traumatic brain injury in mice. J Neuroinflamm. 2009;6:2.CrossRef Stahel PF, Flierl MA, Morgan BP, Persigehl I, Stoll C, Conrad C, Touban BM, Smith WR, Beauchamp K, Schmidt OI, Ertel W, Leinhase I. Absence of the complement regulatory molecule CD59a leads to exacerbated neuropathology after traumatic brain injury in mice. J Neuroinflamm. 2009;6:2.CrossRef
15.
Zurück zum Zitat Neher MD, Weckbach S, Flierl MA, Huber-Lang MS, Stahel PF. Molecular mechanisms of inflammation and tissue injury after major trauma - is complement the "bad guy"? J Biomed Sci. 2011;18:90.CrossRef Neher MD, Weckbach S, Flierl MA, Huber-Lang MS, Stahel PF. Molecular mechanisms of inflammation and tissue injury after major trauma - is complement the "bad guy"? J Biomed Sci. 2011;18:90.CrossRef
16.
Zurück zum Zitat Stahel PF, Morganti-Kossmann MC, Perez D, Redaelli C, Gloor B, Trentz O, Kossmann T. Intrathecal levels of complement-derived soluble membrane attack complex (sC5b-9) correlate with blood-brain barrier dysfunction in patients with traumatic brain injury. J Neurotrauma. 2001;18:773–81.CrossRef Stahel PF, Morganti-Kossmann MC, Perez D, Redaelli C, Gloor B, Trentz O, Kossmann T. Intrathecal levels of complement-derived soluble membrane attack complex (sC5b-9) correlate with blood-brain barrier dysfunction in patients with traumatic brain injury. J Neurotrauma. 2001;18:773–81.CrossRef
17.
Zurück zum Zitat Szeplaki G, Szegdei R, Hirschberg K, Gombos T, Varga L, Karadi I, Entz L, Szeplaki Z, Garred P, Prohaszka Z, Fust G. Strong complement activation after acute ischemic stroke is associated with unfavorable outcomes. Atherosclerosis. 2009;204:315–20.CrossRef Szeplaki G, Szegdei R, Hirschberg K, Gombos T, Varga L, Karadi I, Entz L, Szeplaki Z, Garred P, Prohaszka Z, Fust G. Strong complement activation after acute ischemic stroke is associated with unfavorable outcomes. Atherosclerosis. 2009;204:315–20.CrossRef
18.
Zurück zum Zitat Ganter MT, Brohi K, Cohen MJ, Shaffer LA, Walsh MC, Stahl GL, Pittet JF. Role of the alternative pathway in the early complement activation following major trauma. Shock. 2007;28:29–34.CrossRef Ganter MT, Brohi K, Cohen MJ, Shaffer LA, Walsh MC, Stahl GL, Pittet JF. Role of the alternative pathway in the early complement activation following major trauma. Shock. 2007;28:29–34.CrossRef
19.
Zurück zum Zitat Burk AM, Martin M, Flierl MA, Rittirsch D, Helm M, Lampl L, Bruckner U, Stahl GL, Blom AM, Perl M, Gebhard F, Huber-Lang M. Early complementopathy after multiple injuries in humans. Shock. 2012;37:348–54.CrossRef Burk AM, Martin M, Flierl MA, Rittirsch D, Helm M, Lampl L, Bruckner U, Stahl GL, Blom AM, Perl M, Gebhard F, Huber-Lang M. Early complementopathy after multiple injuries in humans. Shock. 2012;37:348–54.CrossRef
20.
Zurück zum Zitat Neher MD, Keene CN, Rich MC, Moore HB, Stahel PF. Serum biomarkers for traumatic brain injury. South Med J. 2014;107:248–55.CrossRef Neher MD, Keene CN, Rich MC, Moore HB, Stahel PF. Serum biomarkers for traumatic brain injury. South Med J. 2014;107:248–55.CrossRef
21.
Zurück zum Zitat Chakraborty S, Karasu E, Huber-Lang M. Complement after trauma: suturing innate and adaptive immunity. Front Immunol. 2018;9:2050.CrossRef Chakraborty S, Karasu E, Huber-Lang M. Complement after trauma: suturing innate and adaptive immunity. Front Immunol. 2018;9:2050.CrossRef
22.
Zurück zum Zitat Stahel PF, Frei K, Eugster HP, Fontana A, Hummel KM, Wetsel RA, Ames RS, Barnum SR. TNF-alpha-mediated expression of the receptor for anaphylatoxin C5a on neurons in experimental Listeria meningoencephalitis. J Immunol. 1997;159:861–9. Stahel PF, Frei K, Eugster HP, Fontana A, Hummel KM, Wetsel RA, Ames RS, Barnum SR. TNF-alpha-mediated expression of the receptor for anaphylatoxin C5a on neurons in experimental Listeria meningoencephalitis. J Immunol. 1997;159:861–9.
23.
Zurück zum Zitat Stahel PF, Frei K, Fontana A, Eugster HP, Ault BH, Barnum SR. Evidence for intrathecal synthesis of alternative pathway complement activation proteins in experimental meningitis. Am J Pathol. 1997;151:897–904. Stahel PF, Frei K, Fontana A, Eugster HP, Ault BH, Barnum SR. Evidence for intrathecal synthesis of alternative pathway complement activation proteins in experimental meningitis. Am J Pathol. 1997;151:897–904.
24.
Zurück zum Zitat Stahel PF, Kossmann T, Morganti-Kossmann MC, Hans VH, Barnum SR. Experimental diffuse axonal injury induces enhanced neuronal C5a receptor mRNA expression in rats. Mol Brain Res. 1997;50:205–12.CrossRef Stahel PF, Kossmann T, Morganti-Kossmann MC, Hans VH, Barnum SR. Experimental diffuse axonal injury induces enhanced neuronal C5a receptor mRNA expression in rats. Mol Brain Res. 1997;50:205–12.CrossRef
25.
Zurück zum Zitat Stahel PF, Kariya K, Shohami E, Barnum SR, Eugster H, Trentz O, Kossmann T, Morganti-Kossmann MC. Intracerebral complement C5a receptor (CD88) expression is regulated by TNF and lymphotoxin-alpha following closed head injury in mice. J Neuroimmunol. 2000;109:164–72.CrossRef Stahel PF, Kariya K, Shohami E, Barnum SR, Eugster H, Trentz O, Kossmann T, Morganti-Kossmann MC. Intracerebral complement C5a receptor (CD88) expression is regulated by TNF and lymphotoxin-alpha following closed head injury in mice. J Neuroimmunol. 2000;109:164–72.CrossRef
26.
Zurück zum Zitat Stahel PF, Barnum SR. The role of the complement system in CNS inflammatory diseases. Expert Rev Clin Immunol. 2006;2:445–56.CrossRef Stahel PF, Barnum SR. The role of the complement system in CNS inflammatory diseases. Expert Rev Clin Immunol. 2006;2:445–56.CrossRef
27.
Zurück zum Zitat Stahel PF, Smith WR, Moore EE. Role of biological modifiers regulating the immune response after trauma. Injury. 2007;38:1409–22.CrossRef Stahel PF, Smith WR, Moore EE. Role of biological modifiers regulating the immune response after trauma. Injury. 2007;38:1409–22.CrossRef
28.
Zurück zum Zitat Weber B, Lackner I, Knecht D, Braun CK, Gebhard F, Huber-Lang M, Hilderbrand F, Horst K, Pape HC, Ignatius A, Schrezenmeier H, Haffner-Luntzer M, Kalbitz M. Systemic and cardiac alterations after long bone fracture. Shock. 2020 (March 19, Epub ahead of print) Weber B, Lackner I, Knecht D, Braun CK, Gebhard F, Huber-Lang M, Hilderbrand F, Horst K, Pape HC, Ignatius A, Schrezenmeier H, Haffner-Luntzer M, Kalbitz M. Systemic and cardiac alterations after long bone fracture. Shock. 2020 (March 19, Epub ahead of print)
29.
Zurück zum Zitat Amara U, Flierl MA, Rittirsch D, Klos A, Chen H, Acker B, Bruckner UB, Nilsson B, Gebhard F, Lambris JD, Huber-Lang M. Molecular intercommunication between the complement and coagulation systems. J Immunol. 2010;185:5628–36.CrossRef Amara U, Flierl MA, Rittirsch D, Klos A, Chen H, Acker B, Bruckner UB, Nilsson B, Gebhard F, Lambris JD, Huber-Lang M. Molecular intercommunication between the complement and coagulation systems. J Immunol. 2010;185:5628–36.CrossRef
30.
Zurück zum Zitat Levi M, Cohn DM, Zeerleder S. Hereditary angioedema: linking complement regulation to the coagulation system. Res Pract Thromb Haemost. 2019;3:38–433.CrossRef Levi M, Cohn DM, Zeerleder S. Hereditary angioedema: linking complement regulation to the coagulation system. Res Pract Thromb Haemost. 2019;3:38–433.CrossRef
31.
Zurück zum Zitat Barrett CD, Moore HB, Kong YW, Chapman MP, Sriram G, Lim D, Moore EE, Yaffe MB. Tranexamic acid mediates proinflammatory and anti-inflammatory signaling via complement C5a regulation in a plasminogen activator-dependent manner. J Trauma Acute Care Surg. 2019;86:101–7.CrossRef Barrett CD, Moore HB, Kong YW, Chapman MP, Sriram G, Lim D, Moore EE, Yaffe MB. Tranexamic acid mediates proinflammatory and anti-inflammatory signaling via complement C5a regulation in a plasminogen activator-dependent manner. J Trauma Acute Care Surg. 2019;86:101–7.CrossRef
32.
Zurück zum Zitat Harhausen D, Khojasteh U, Stahel PF, Morgan BP, Nietfeld W, Dirnagl U, Trendelenburg G. Membrane attack complex inhibitor CD59a protects against focal cerebral ischemia in mice. J Neuroinflammation. 2010;7:15.CrossRef Harhausen D, Khojasteh U, Stahel PF, Morgan BP, Nietfeld W, Dirnagl U, Trendelenburg G. Membrane attack complex inhibitor CD59a protects against focal cerebral ischemia in mice. J Neuroinflammation. 2010;7:15.CrossRef
33.
Zurück zum Zitat Barnum SR. Therapeutic inhibition of complement: well worth the risk. Trends Pharmacol Sci. 2017;38:503–5.CrossRef Barnum SR. Therapeutic inhibition of complement: well worth the risk. Trends Pharmacol Sci. 2017;38:503–5.CrossRef
34.
Zurück zum Zitat Edwards P, Arango M, Balica L, et al. Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury-outcomes at 6 months. Lancet. 2005;365(9475):1957–9.CrossRef Edwards P, Arango M, Balica L, et al. Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury-outcomes at 6 months. Lancet. 2005;365(9475):1957–9.CrossRef
35.
Zurück zum Zitat Beauchamp K, Mutlak H, Smith WR, Shohami E, Stahel PF. Pharmacology of traumatic brain injury: where is the "golden bullet"? Mol Med. 2008;14:731–40.CrossRef Beauchamp K, Mutlak H, Smith WR, Shohami E, Stahel PF. Pharmacology of traumatic brain injury: where is the "golden bullet"? Mol Med. 2008;14:731–40.CrossRef
36.
Zurück zum Zitat Stahel PF. The inherent dangers of high-dose steroids for acute inflammatory conditions. Lancet. 2016;388(10039):102.CrossRef Stahel PF. The inherent dangers of high-dose steroids for acute inflammatory conditions. Lancet. 2016;388(10039):102.CrossRef
37.
Zurück zum Zitat Wong EK, Kavanagh D. Anticomplement C5 therapy with eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Transl Res. 2015;165:306–20.CrossRef Wong EK, Kavanagh D. Anticomplement C5 therapy with eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Transl Res. 2015;165:306–20.CrossRef
38.
Zurück zum Zitat Barnum SR. Complement: a primer for the coming therapeutic revolution. Pharmacol Ther. 2017;172:63–72.CrossRef Barnum SR. Complement: a primer for the coming therapeutic revolution. Pharmacol Ther. 2017;172:63–72.CrossRef
39.
Zurück zum Zitat Flierl MA, Stoneback JW, Beauchamp KM, Hak DJ, Morgan SJ, Smith WR, Stahel PF. Femur shaft fracture fixation in head-injured patients: when is the right time? J Orthop Trauma. 2010;24:107–14.CrossRef Flierl MA, Stoneback JW, Beauchamp KM, Hak DJ, Morgan SJ, Smith WR, Stahel PF. Femur shaft fracture fixation in head-injured patients: when is the right time? J Orthop Trauma. 2010;24:107–14.CrossRef
40.
Zurück zum Zitat Picetti E, Maier RV, Rossi S, Kirkpatrick AW, Biffl WL, Stahel PF, Moore EE, Kluger Y, Baiocchi GL, Ansaloni L, Agnoletti V, Catena F. Preserve encephalus in surgery of trauma: online survey (PESTO). World J Emerg Surg. 2019;14:9.CrossRef Picetti E, Maier RV, Rossi S, Kirkpatrick AW, Biffl WL, Stahel PF, Moore EE, Kluger Y, Baiocchi GL, Ansaloni L, Agnoletti V, Catena F. Preserve encephalus in surgery of trauma: online survey (PESTO). World J Emerg Surg. 2019;14:9.CrossRef
Metadaten
Titel
Soluble terminal complement activation fragment sC5b-9: a new serum biomarker for traumatic brain injury?
verfasst von
Joshua Parry
Jiho Hwang
Cedric F. Stahel
Corey Henderson
Jason Nadeau
Stephen Stacey
Kathryn Beauchamp
Ernest E. Moore
Philip F. Stahel
Publikationsdatum
25.05.2020
Verlag
Springer Berlin Heidelberg
Erschienen in
European Journal of Trauma and Emergency Surgery / Ausgabe 5/2021
Print ISSN: 1863-9933
Elektronische ISSN: 1863-9941
DOI
https://doi.org/10.1007/s00068-020-01407-z

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