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Critical Care
Published in: Critical Care 1/2015

Open Access 01-12-2015 | Research

Association between biomarkers of endothelial injury and hypocoagulability in patients with severe sepsis: a prospective study

Authors: Sisse Rye Ostrowski, Nicolai Haase, Rasmus Beier Müller, Morten Hylander Møller, Frank Christian Pott, Anders Perner, Pär Ingemar Johansson

Published in: Critical Care | Issue 1/2015

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Abstract

Introduction

Patients with severe sepsis often present with concurrent coagulopathy, microcirculatory failure and evidence of vascular endothelial activation and damage. Given the critical role of the endothelium in balancing hemostasis, we investigated single-point associations between whole blood coagulopathy by thrombelastography (TEG) and plasma/serum markers of endothelial activation and damage in patients with severe sepsis.

Methods

A post-hoc multicenter prospective observational study in a subgroup of 184 patients from the Scandinavian Starch for Severe Sepsis/Septic Shock (6S) Trial. Study patients were admitted to two Danish intensive care units. Inclusion criteria were severe sepsis, pre-intervention whole blood TEG measurement and a plasma/serum research sample available from baseline (pre-intervention) for analysis of endothelial-derived biomarkers. Endothelial-derived biomarkers were measured in plasma/serum by enzyme-linked immunosorbent assay (syndecan-1, thrombomodulin, protein C (PC), tissue-type plasminogen activator and plasminogen activator inhibitor-1). Pre-intervention TEG, functional fibrinogen (FF) and laboratory and clinical data, including mortality, were retrieved from the trial database.

Results

Most patients presented with septic shock (86%) and pulmonary (60%) or abdominal (30%) focus of infection. The median (IQR) age was 67 years (59 to 75), and 55% were males. The median SOFA and SAPS II scores were 8 (6 to 10) and 56 (41 to 68), respectively, with 7-, 28- and 90-day mortality rates being 21%, 39% and 53%, respectively. Pre-intervention (before treatment with different fluids), TEG reaction (R)-time, angle and maximum amplitude (MA) and FF MA all correlated with syndecan-1, thrombomodulin and PC levels. By multivariate linear regression analyses, higher syndecan-1 and lower PC were independently associated with TEG and FF hypocoagulability at the same time-point: 100 ng/ml higher syndecan-1 predicted 0.64 minutes higher R-time (SE 0.25), 1.78 mm lower TEG MA (SE 0.87) and 0.84 mm lower FF MA (SE 0.42; all P <0.05), and 10% lower protein C predicted 1.24 mm lower TEG MA (SE 0.31).

Conclusions

In our cohort of patients with severe sepsis, higher circulating levels of biomarkers of mainly endothelial damage were independently associated with hypocoagulability assessed by TEG and FF. Endothelial damage is intimately linked to coagulopathy in severe sepsis.

Trial registration

Clinicaltrials.gov number: NCT00962156. Registered 13 July 2009.
Literature
1.
Schouten M, Wiersinga WJ, Levi M. der PT v. Inflammation, endothelium, and coagulation in sepsis. J Leukoc Biol. 2008;83:536–45.PubMedCrossRef
2.
3.
4.
Faust SN, Levin M, Harrison OB, Goldin RD, Lockhart MS, Kondaveeti S, et al. Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N Engl J Med. 2001;345:408–16.PubMedCrossRef
5.
Ueno H, Hirasawa H, Oda S, Shiga H, Nakanishi K, Matsuda K. Coagulation/fibrinolysis abnormality and vascular endothelial damage in the pathogenesis of thrombocytopenic multiple organ failure. Crit Care Med. 2002;30:2242–8.PubMedCrossRef
6.
Lin SM, Wang YM, Lin HC, Lee KY, Huang CD, Liu CY, et al. Serum thrombomodulin level relates to the clinical course of disseminated intravascular coagulation, multiorgan dysfunction syndrome, and mortality in patients with sepsis. Crit Care Med. 2008;36:683–9.PubMedCrossRef
7.
8.
Gando S, Sawamura A, Hayakawa M. Trauma, shock, and disseminated intravascular coagulation: lessons from the classical literature. Ann Surg. 2011;254:10–9.PubMedCrossRef
9.
Asakura H, Ontachi Y, Mizutani T, Kato M, Saito M, Kumabashiri I, et al. An enhanced fibrinolysis prevents the development of multiple organ failure in disseminated intravascular coagulation in spite of much activation of blood coagulation. Crit Care Med. 2001;29:1164–8.PubMedCrossRef
10.
11.
Johansson PI, Stissing T, Bochsen L, Ostrowski SR. Thrombelastography and tromboelastometry in assessing coagulopathy in trauma. Scand J Trauma Resusc Emerg Med. 2009;17:45.PubMedPubMedCentralCrossRef
12.
Collins PW, Macchiavello LI, Lewis SJ, Macartney NJ, Saayman AG, Luddington R, et al. Global tests of haemostasis in critically ill patients with severe sepsis syndrome compared to controls. Br J Haematol. 2006;135:220–7.PubMedCrossRef
13.
Gonano C, Sitzwohl C, Meitner E, Weinstabl C, Kettner SC. Four-day antithrombin therapy does not seem to attenuate hypercoagulability in patients suffering from sepsis. Crit Care. 2006;10:R160.PubMedPubMedCentralCrossRef
14.
Daudel F, Kessler U, Folly H, Lienert JS, Takala J, Jakob SM. Thromboelastometry for the assessment of coagulation abnormalities in early and established adult sepsis: a prospective cohort study. Crit Care. 2009;13:R42.PubMedPubMedCentralCrossRef
15.
Sivula M, Pettila V, Niemi TT, Varpula M, Kuitunen AH. Thromboelastometry in patients with severe sepsis and disseminated intravascular coagulation. Blood Coagul Fibrinolysis. 2009;20:419–26.PubMedCrossRef
16.
Johansson PI, Stensballe J, Vindelov N, Perner A, Espersen K. Hypocoagulability, as evaluated by thrombelastography, at admission to the ICU is associated with increased 30-day mortality. Blood Coagul Fibrinolysis. 2010;21:168–74.PubMedCrossRef
17.
Sharma P, Saxena R. A novel thromboelastographic score to identify overt disseminated intravascular coagulation resulting in a hypocoagulable state. Am J Clin Pathol. 2010;134:97–102.PubMedCrossRef
18.
Adamzik M, Eggmann M, Frey UH, Gorlinger K, Brocker-Preuss M, Marggraf G, et al. Comparison of thromboelastometry with procalcitonin, interleukin 6, and C-reactive protein as diagnostic tests for severe sepsis in critically ill adults. Crit Care. 2010;14:R178.PubMedPubMedCentralCrossRef
19.
Adamzik M, Langemeier T, Frey UH, Gorlinger K, Saner F, Eggebrecht H, et al. Comparison of thrombelastometry with SAPS II and SOFA scores for the prediction of 30-day survival: a cohort study. Shock. 2011;35:339–42.PubMedCrossRef
20.
Ostrowski SR, Windeløv NA, Ibsen M, Haase N, Perner A, Johansson PI. Consecutive thrombelastography clot strength profiles in patients with severe sepsis and their association with 28-day mortality: a prospective study. J Crit Care. 2013;28:317. e1–11.
21.
Haase N, Ostrowski SR, Johansson PI, Wetterslev J, Lange T, Hyllner M, et al. Thrombelastography in patients with severe sepsis: a prospective cohort study. Intensive Care Med. 2015;41:77–85.PubMedCrossRef
22.
Muller MC, Meijers JC, Vroom MB, Juffermans NP. Utility of thromboelastography and/or thromboelastometry in adults with sepsis: a systematic review. Crit Care. 2014;18:R30.PubMedPubMedCentralCrossRef
23.
Cines DB, Pollak ES, Buck CA, Loscalzo J, Zimmerman GA, McEver RP, et al. Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood. 1998;91:3527–61.PubMed
24.
Monroe DM, Hoffman M. What does it take to make the perfect clot? Arterioscler Thromb Vasc Biol. 2006;26:41–8.PubMedCrossRef
25.
26.
van HV. Endothelium--role in regulation of coagulation and inflammation. Semin Immunopathol. 2012;34:93–106.
27.
Campbell RA, Overmyer KA, Bagnell CR, Wolberg AS. Cellular procoagulant activity dictates clot structure and stability as a function of distance from the cell surface. Arterioscler Thromb Vasc Biol. 2008;28:2247–54.PubMedPubMedCentralCrossRef
28.
Holcomb JB. A novel and potentially unifying mechanism for shock induced early coagulopathy. Ann Surg. 2011;254:201–2.PubMedCrossRef
29.
Brohi K, Cohen MJ, Ganter MT, Matthay MA, Mackersie RC, Pittet JF. Acute traumatic coagulopathy: initiated by hypoperfusion: modulated through the protein C pathway? Ann Surg. 2007;245:812–8.PubMedPubMedCentralCrossRef
30.
Adrie C, Monchi M, Laurent I, Um S, Yan SB, Thuong M, et al. Coagulopathy after successful cardiopulmonary resuscitation following cardiac arrest: implication of the protein C anticoagulant pathway. J Am Coll Cardiol. 2005;46:21–8.PubMedCrossRef
31.
Zambruni A, Thalheimer U, Coppell J, Riddell A, Mancuso A, Leandro G, et al. Endogenous heparin-like activity detected by anti-Xa assay in infected cirrhotic and non-cirrhotic patients. Scand J Gastroenterol. 2004;39:830–6.PubMedCrossRef
32.
Agarwal S, Senzolo M, Melikian C, Burroughs A, Mallett SV. The prevalence of a heparin-like effect shown on the thromboelastograph in patients undergoing liver transplantation. Liver Transpl. 2008;14:855–60.PubMedCrossRef
33.
Nelson A, Berkestedt I, Schmidtchen A, Ljunggren L, Bodelsson M. Increased levels of glycosaminoglycans during septic shock: relation to mortality and the antibacterial actions of plasma. Shock. 2008;30:623–7.PubMedCrossRef
34.
Steppan J, Hofer S, Funke B, Brenner T, Henrich M, Martin E, et al. Sepsis and major abdominal surgery lead to flaking of the endothelial glycocalix. J Surg Res. 2011;165:136–41.PubMedCrossRef
35.
Ostrowski SR, Johansson PI. Endothelial glycocalyx degradation induces endogenous heparinization in patients with severe injury and early traumatic coagulopathy. J Trauma Acute Care Surg. 2012;73:60–6.PubMedCrossRef
36.
Wada T, Gando S, Mizugaki A, Yanagida Y, Jesmin S, Yokota H, et al. Coagulofibrinolytic changes in patients with disseminated intravascular coagulation associated with post-cardiac arrest syndrome–fibrinolytic shutdown and insufficient activation of fibrinolysis lead to organ dysfunction. Thromb Res. 2013;132:e64–9.PubMedCrossRef
37.
Johansson PI, Ostrowski SR. Acute coagulopathy of trauma: balancing progressive catecholamine induced endothelial activation and damage by fluid phase anticoagulation. Med Hypotheses. 2010;75:564–7.PubMedCrossRef
38.
Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, Aneman A, et al. Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. N Engl J Med. 2012;367:124–34.PubMedCrossRef
39.
von EE, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007;370:1453–7.
40.
Johansson PI, Haase N, Perner A, Ostrowski SR. Association between sympathoadrenal activation, fibrinolysis and endothelial damage in septic patients: a prospective study. J Crit Care. 2014;29:327–33.PubMedCrossRef
41.
Sivula M, Tallgren M, Pettila V. Modified score for disseminated intravascular coagulation in the critically ill. Intensive Care Med. 2005;31:1209–14.PubMedCrossRef
42.
Johansson PI, Bochsen L, Andersen S, Viuff D. Investigation of the effect of kaolin and tissue factor-activated citrated whole blood, on clot forming variables, as evaluated by thromboelastography. Transfusion. 2008;48:2377–83.PubMedCrossRef
43.
Rehm M, Bruegger D, Christ F, Conzen P, Thiel M, Jacob M, et al. Shedding of the endothelial glycocalyx in patients undergoing major vascular surgery with global and regional ischemia. Circulation. 2007;116:1896–906.PubMedCrossRef
44.
Blann A, Seigneur M. Soluble markers of endothelial cell function. Clin Hemorheol Microcirc. 1997;17:3–11.PubMed
45.
Blann AD. Endothelial cell activation, injury, damage and dysfunction: separate entities or mutual terms? Blood Coagul Fibrinolysis. 2000;11:623–30.PubMedCrossRef
46.
Ishii H, Uchiyama H, Kazama M. Soluble thrombomodulin antigen in conditioned medium is increased by damage of endothelial cells. Thromb Haemost. 1991;65:618–23.PubMedCrossRef
47.
Lowenstein CJ, Morrell CN, Yamakuchi M. Regulation of Weibel-Palade body exocytosis. Trends Cardiovasc Med. 2005;15:302–8.PubMedCrossRef
48.
Reinhart K, Bayer O, Brunkhorst F, Meisner M. Markers of endothelial damage in organ dysfunction and sepsis. Crit Care Med. 2002;30:S302–12.PubMedCrossRef
49.
Senzolo M, Coppell J, Cholongitas E, Riddell A, Triantos CK, Perry D, et al. The effects of glycosaminoglycans on coagulation: a thromboelastographic study. Blood Coagul Fibrinolysis. 2007;18:227–36.PubMedCrossRef
50.
Reitsma S, Slaaf DW, Vink H, van Zandvoort MA, oude Egbrink MG. The endothelial glycocalyx: composition, functions, and visualization. Pflugers Arch. 2007;454:345–59.PubMedPubMedCentralCrossRef
51.
Becker BF, Chappell D, Bruegger D, Annecke T, Jacob M. Therapeutic strategies targeting the endothelial glycocalyx: acute deficits, but great potential. Cardiovasc Res. 2010;87:300–10.PubMedCrossRef
52.
Salmon AH, Satchell SC. Endothelial glycocalyx dysfunction in disease: albuminuria and altered microvascular permeability. J Pathol. 2012;226:562–74.PubMedCrossRef
53.
Woodcock TE, Woodcock TM. Revised Starling equation and the glycocalyx model of transvascular fluid exchange: an improved paradigm for prescribing intravenous fluid therapy. Br J Anaesth. 2012;108:384–94.PubMedCrossRef
54.
Aird WC. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood. 2003;101:3765–77.PubMedCrossRef
55.
Hirase T, Node K. Endothelial dysfunction as a cellular mechanism for vascular failure. Am J Physiol Heart Circ Physiol. 2012;302:H499–505.PubMedCrossRef
56.
57.
Sakata Y, Curriden S, Lawrence D, Griffin JH, Loskutoff DJ. Activated protein C stimulates the fibrinolytic activity of cultured endothelial cells and decreases antiactivator activity. Proc Natl Acad Sci U S A. 1985;82:1121–5.PubMedPubMedCentralCrossRef
58.
van HV, Bertina RM, van WA, van Tilburg NH, Emeis JJ, Haverkate F. Activated protein C decreases plasminogen activator-inhibitor activity in endothelial cell-conditioned medium. Blood. 1985;65:444–51.
59.
Rezaie AR. Vitronectin functions as a cofactor for rapid inhibition of activated protein C by plasminogen activator inhibitor-1. Implications for the mechanism of profibrinolytic action of activated protein C. J Biol Chem. 2001;276:15567–70.PubMedCrossRef
60.
Johansson PI, Stensballe J, Rasmussen LS, Ostrowski SR. 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.PubMedCrossRef
61.
Ostrowski SR, Sørensen AM, Windeløv NA, Perner A, Welling KL, Wanscher M, et al. High levels of soluble VEGF receptor 1 early after trauma are associated with shock, sympathoadrenal activation, glycocalyx degradation and inflammation. Scand J Trauma Resusc Emerg Med. 2012;20:27.PubMedPubMedCentralCrossRef
62.
Ganter MT, Cohen MJ, Brohi K, Chesebro BB, Staudenmayer KL, Rahn P, et al. Angiopoietin-2, marker and mediator of endothelial activation with prognostic significance early after trauma? Ann Surg. 2008;247:320–6.PubMedCrossRef
63.
Kozar RA, Peng Z, Zhang R, Holcomb JB, Pati S, Park P, et al. Plasma restoration of endothelial glycocalyx in a rodent model of hemorrhagic shock. Anesth Analg. 2011;112:1289–95.PubMedPubMedCentralCrossRef
64.
Haywood-Watson RJ, Holcomb JB, Gonzalez EA, Peng Z, Pati S, Park PW, et al. Modulation of syndecan-1 shedding after hemorrhagic shock and resuscitation. PLoS ONE. 2011;6, e23530.PubMedPubMedCentralCrossRef
65.
Grundmann S, Fink K, Rabadzhieva L, Bourgeois N, Schwab T, Moser M, et al. Perturbation of the endothelial glycocalyx in post cardiac arrest syndrome. Resuscitation. 2012;83:715–20.PubMedCrossRef
66.
Gando S, Nanzaki S, Morimoto Y, Kobayashi S, Kemmotsu O. Out-of-hospital cardiac arrest increases soluble vascular endothelial adhesion molecules and neutrophil elastase associated with endothelial injury. Intensive Care Med. 2000;26:38–44.PubMedCrossRef
67.
68.
69.
Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A. 2013;107:3507–12.CrossRef
70.
Schochl H, Frietsch T, Pavelka M, Jambor C. Hyperfibrinolysis after major trauma: differential diagnosis of lysis patterns and prognostic value of thrombelastometry. J Trauma. 2009;67:125–31.PubMed
71.
Ives C, Inaba K, Branco BC, Okoye O, Schochl H, Talving P, et al. Hyperfibrinolysis elicited via thromboelastography predicts mortality in trauma. J Am Coll Surg. 2012;215:496–02.PubMedCrossRef
72.
Cotton BA, Harvin JA, Kostousouv V, Minei KM, Radwan ZA, Schochl H, et al. Hyperfibrinolysis at admission is an uncommon but highly lethal event associated with shock and prehospital fluid administration. J Trauma Acute Care Surg. 2012;73:365–70.PubMedCrossRef
73.
Kashuk JL, Moore EE, Sawyer M, Le T, Johnson J, Biffl WL, et al. Postinjury coagulopathy management: goal directed resuscitation via POC thrombelastography. Ann Surg. 2010;251:604–14.PubMedCrossRef
74.
Sawamura A, Hayakawa M, Gando S, Kubota N, Sugano M, Wada T, et al. Disseminated intravascular coagulation with a fibrinolytic phenotype at an early phase of trauma predicts mortality. Thromb Res. 2009;124:608–13.PubMedCrossRef
75.
Hayakawa M, Sawamura A, Gando S, Kubota N, Uegaki S, Shimojima H, et al. Disseminated intravascular coagulation at an early phase of trauma is associated with consumption coagulopathy and excessive fibrinolysis both by plasmin and neutrophil elastase. Surgery. 2011;149:221–30.PubMedCrossRef
76.
Schochl H, Cadamuro J, Seidl S, Franz A, Solomon C, Schlimp CJ, et al. Hyperfibrinolysis is common in out-of-hospital cardiac arrest: results from a prospective observational thromboelastometry study. Resuscitation. 2013;84:454–9.PubMedCrossRef
77.
Viersen VA, Greuters S, Korfage AR, Van der Rijst C, Van BV, Nanayakkara PW, et al. Hyperfibrinolysis in out of hospital cardiac arrest is associated with markers of hypoperfusion. Resuscitation. 2012;83:1451–5.PubMedCrossRef
78.
Kim J, Kim K, Lee JH, Jo YH, Kim T, Rhee JE, et al. Prognostic implication of initial coagulopathy in out-of-hospital cardiac arrest. Resuscitation. 2013;84:48–53.PubMedCrossRef
79.
Opal SM. Phylogenetic and functional relationships between coagulation and the innate immune response. Crit Care Med. 2000;28:S77–80.PubMedCrossRef
80.
Delvaeye M, Conway EM. Coagulation and innate immune responses: can we view them separately? Blood. 2009;114:2367–74.PubMedCrossRef
81.
Metadata
Title
Association between biomarkers of endothelial injury and hypocoagulability in patients with severe sepsis: a prospective study
Authors
Sisse Rye Ostrowski
Nicolai Haase
Rasmus Beier Müller
Morten Hylander Møller
Frank Christian Pott
Anders Perner
Pär Ingemar Johansson
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Critical Care / Issue 1/2015
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/s13054-015-0918-5

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