Top

Critical Care

Published in:

Open Access 01-04-2012 | Research

Using angiogenic factors and their soluble receptors to predict organ dysfunction in patients with disseminated intravascular coagulation associated with severe trauma

Authors: Takeshi Wada, Subrina Jesmin, Satoshi Gando, Sayeeda N Sultana, Sohel Zaedi, Hiroyuki Yokota

Published in: Critical Care | Issue 2/2012

Abstract

Introduction

Disseminated intravascular coagulation (DIC) is characterized by the concomitant activation of coagulofibrinolytic disorders and systemic inflammation associated with endothelial dysfunction-induced microvascular permeability. Angiogenic factors, including vascular endothelial growth factor (VEGF), angiopoietin (Ang), and their receptors, play crucial roles in angiogenesis and microvascular permeability. The aim of the study was to assess the relationship between angiogenic factors, their soluble receptors and organ dysfunction associated with DIC after severe trauma.

Materials and methods

A total of 57 patients with severe trauma were divided into two subgroups; 30 DIC patients and 27 non-DIC patients. The DIC was diagnosed based on the Japanese Association for Acute Medicine (JAAM) DIC and the International Society on Thrombosis and Haemostasis (ISTH) overt DIC criteria. The serum levels of angiogenic factors were measured at the time of admission (Day 1), Day 3 and Day 5. This study compared levels of these angiogenic factors between the two DIC groups, and evaluated their predictive value for organ dysfunction.

Results

DIC patients, especially those with ISTH DIC, showed higher Sequential Organ Failure Assessment (SOFA) scores and lactate levels. There were lower levels of VEGF, Ang1 and the soluble Tie2 in the ISTH DIC patients than the non-DIC patients. The levels of soluble VEGF receptor-1 (sVEGFR1), Ang2 and the Ang2/Ang1 ratio in the ISTH DIC patients were higher than in non-DIC patients. The relationship between the presence of massive transfusion and angiogenic factors indicated the same results. The levels of sVEGFR1, Ang2 and the Ang2/Ang1 ratio correlated with the SOFA scores. In particular, sVEGFR1 and Ang2 were independent predictors of an increase in the SOFA score. The lactate levels independently predicted increases in the levels of sVEGFR1 and Ang2. The decrease in the platelet counts also independently predicted the increase in Ang2 levels in DIC patients.

Conclusions

Angiogenic factors and their soluble receptors, particularly sVEGFR1 and Ang2, are considered to play pivotal roles in the development of organ dysfunction in DIC associated with severe trauma. DIC-induced tissue hypoxia and platelet consumption may play crucial roles in inducing sVEGFR1 and Ang2, and in determining the prognosis of the severity of organ dysfunction.

Available only for authorised users

Gando S, Sawamura A, Hayakawa M: Trauma, shock, and disseminated intravascular coagulation: lessons from the classical literature. Ann Surg 2011, 254: 10-19. 10.1097/SLA.0b013e31821221b1CrossRefPubMed

Hess JR, Brohi K, Dutton RP, Hauser CJ, Holcomb JB, Kluger Y, Mackway-Jones K, Parr MJ, Rizoli SB, Yukioka T, Hoyt DB, Bouillon B: The coagulopathy of trauma: a review of mechanisms. J Trauma 2008, 65: 748-754. 10.1097/TA.0b013e3181877a9cCrossRefPubMed

Gando S: Acute coagulopathy of trauma shock and coagulopathy of trauma: a rebuttal. You are now going down the wrong path. J Trauma 2009, 67: 381-383. 10.1097/TA.0b013e3181a84f63CrossRefPubMed

Sawamura A, Hayakawa M, Gando S, Kubota N, Sugano M, Wada T, Katabami K: Disseminated intravascular coagulation with a fibrinolytic phenotype at an early phase of trauma predicts mortality. Thromb Res 2009, 124: 608-613. 10.1016/j.thromres.2009.06.034CrossRefPubMed

Gando S: Disseminated intravascular coagulation in trauma patients. Semin Thromb Hemost 2001, 27: 585-592. 10.1055/s-2001-18864CrossRefPubMed

Ferrara N: Molecular and biological properties of vascular endothelial growth factor. J Mol Med 1999, 77: 527-543. 10.1007/s001099900019CrossRefPubMed

van Meurs M, Kumpers P, Ligtenberg JJ, Meertens JH, Molema G, Zijlstra JG: Bench-to-bedside review: Angiopoietin signalling in critical illness - a future target? Crit Care 2009, 13: 207. 10.1186/cc7153PubMedCentralCrossRefPubMed

Fiedler U, Augustin HG: Angiopoietins: a link between angiogenesis and inflammation. Trends Immunol 2006, 27: 552-558. 10.1016/j.it.2006.10.004CrossRefPubMed

Ricciuto DR, Dos Santos CC, Hawkes M, Toltl LJ, Conroy AL, Rajwans N, Lafferty EI, Cook DJ, Fox-Robichaud A, Kahnamoui K, Kain KC, Liaw PC, Liles WC: Angiopoietin-1 and angiopoietin-2 as clinically informative prognostic biomarkers of morbidity and mortality in severe sepsis. Crit Care Med 2011, 39: 702-710. 10.1097/CCM.0b013e318206d285CrossRefPubMed

10.

Brindle NP, Saharinen P, Alitalo K: Signaling and functions of angiopoietin-1 in vascular protection. Circ Res 2006, 98: 1014-1023. 10.1161/01.RES.0000218275.54089.12PubMedCentralCrossRefPubMed

11.

Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, Daly TJ, Davis S, Sato TN, Yancopoulos GD: Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 1997, 277: 55-60. 10.1126/science.277.5322.55CrossRefPubMed

12.

Ganter MT, Cohen MJ, Brohi K, Chesebro BB, Staudenmayer KL, Rahn P, Christiaans SC, Bir ND, Pittet JF: Angiopoietin-2, marker and mediator of endothelial activation with prognostic significance early after trauma? Ann Surg 2008, 247: 320-326. 10.1097/SLA.0b013e318162d616CrossRefPubMed

13.

Ong T, McClintock DE, Kallet RH, Ware LB, Matthay MA, Liu KD: Ratio of angiopoietin-2 to angiopoietin-1 as a predictor of mortality in acute lung injury patients. Crit Care Med 2010, 38: 1845-1851. 10.1097/CCM.0b013e3181eaa5bfPubMedCentralCrossRefPubMed

14.

Grad S, Ertel W, Keel M, Infanger M, Vonderschmitt DJ, Maly FE: Strongly enhanced serum levels of vascular endothelial growth factor (VEGF) after polytrauma and burn. Clin Chem Lab Med 1998, 36: 379-383.CrossRefPubMed

15.

Giamarellos-Bourboulis EJ, Kanellakopoulou K, Pelekanou A, Tsaganos T, Kotzampassi K: Kinetics of angiopoietin-2 in serum of multi-trauma patients: correlation with patient severity. Cytokine 2008, 44: 310-313. 10.1016/j.cyto.2008.09.003CrossRefPubMed

16.

Civil ID, Schwab CW: The Abbreviated Injury Scale, 1985 revision: a condensed chart for clinical use. J Trauma 1988, 28: 87-90. 10.1097/00005373-198801000-00012CrossRefPubMed

17.

Roberts I, Shakur H, Afolabi A, Brohi K, Coats T, Dewan Y, Gando S, Guyatt G, Hunt BJ, Morales C, Perel P, Prieto-Merino D, Woolley T: The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet 2011, 377: 1096-1101. 1101 e1091-1092CrossRefPubMed

18.

Hayakawa M, Sawamura A, Gando S, Kubota N, Uegaki S, Shimojima H, Sugano M, Ieko M: 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: 221-230. 10.1016/j.surg.2010.06.010CrossRefPubMed

19.

Gando S, Saitoh D, Ogura H, Mayumi T, Koseki K, Ikeda T, Ishikura H, Iba T, Ueyama M, Eguchi Y, Ohtomo Y, Okamoto K, Kushimoto S, Endo S, Shimazaki S: Natural history of disseminated intravascular coagulation diagnosed based on the newly established diagnostic criteria for critically ill patients: results of a multicenter, prospective survey. Crit Care Med 2008, 36: 145-150. 10.1097/01.CCM.0000295317.97245.2DCrossRefPubMed

20.

Taylor FBJ, Toh CH, Hoots WK, Wada H, Levi M: Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 2001, 86: 1327-1330.PubMed

21.

Sawamura A, Hayakawa M, Gando S, Kubota N, Sugano M, Wada T, Katabami K: Application of the Japanese Association for Acute Medicine disseminated intravascular coagulation diagnostic criteria for patients at an early phase of trauma. Thromb Res 2009, 124: 706-710. 10.1016/j.thromres.2009.06.036CrossRefPubMed

22.

Murakami H, Gando S, Hayakawa M, Sawamura A, Sugano M, Kubota N, Uegaki S, Jesmin S: Disseminated Intravascular Coagulation (DIC) at an early phase of trauma continuously proceeds to DIC at a late phase of trauma. Clin Appl Thromb Hemost 2012, in press.

23.

Ikegami K, Suzuki Y, Yukioka T, Matsuda H, Shimazaki S: Endothelial cell injury, as quantified by the soluble thrombomodulin level, predicts sepsis/multiple organ dysfunction syndrome after blunt trauma. J Trauma 1998, 44: 789-794. discussion 794-785 10.1097/00005373-199805000-00008CrossRefPubMed

24.

Mankhambo LA, Banda DL, Jeffers G, White SA, Balmer P, Nkhoma S, Phiri H, Molyneux EM, Hart CA, Molyneux ME, Heyderman RS, Carrol ED: The role of angiogenic factors in predicting clinical outcome in severe bacterial infection in Malawian children. Crit Care 2010, 14: R91. 10.1186/cc9025PubMedCentralCrossRefPubMed

25.

Karlsson S, Pettila V, Tenhunen J, Lund V, Hovilehto S, Ruokonen E: Vascular endothelial growth factor in severe sepsis and septic shock. Anesth Analg 2008, 106: 1820-1826. 10.1213/ane.0b013e31816a643fCrossRefPubMed

26.

Pickkers P, Sprong T, Eijk L, Hoeven H, Smits P, Deuren M: Vascular endothelial growth factor is increased during the first 48 hours of human septic shock and correlates with vascular permeability. Shock 2005, 24: 508-512. 10.1097/01.shk.0000190827.36406.6eCrossRefPubMed

27.

Shapiro NI, Yano K, Okada H, Fischer C, Howell M, Spokes KC, Ngo L, Angus DC, Aird WC: A prospective, observational study of soluble FLT-1 and vascular endothelial growth factor in sepsis. Shock 2008, 29: 452-457. 10.1097/SHK.0b013e31815072c1CrossRefPubMed

28.

Yang KY, Liu KT, Chen YC, Chen CS, Lee YC, Perng RP, Feng JY: Plasma soluble vascular endothelial growth factor receptor-1 levels predict outcomes of pneumonia-related septic shock patients: a prospective observational study. Crit Care 2011, 15: R11. 10.1186/cc9412PubMedCentralCrossRefPubMed

29.

Webb NJ, Bottomley MJ, Watson CJ, Brenchley PE: Vascular endothelial growth factor (VEGF) is released from platelets during blood clotting: implications for measurement of circulating VEGF levels in clinical disease. Clin Sci (Lond) 1998, 94: 395-404.CrossRef

30.

Verheul HM, Hoekman K, Luykx-de Bakker S, Eekman CA, Folman CC, Broxterman HJ, Pinedo HM: Platelet: transporter of vascular endothelial growth factor. Clin Cancer Res 1997, 3: 2187-2190.PubMed

31.

Mohle R, Green D, Moore MA, Nachman RL, Rafii S: Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets. Proc Natl Acad Sci USA 1997, 94: 663-668. 10.1073/pnas.94.2.663PubMedCentralCrossRefPubMed

32.

Vidal F, Aragones J, Alfranca A, de Landazuri MO: Up-regulation of vascular endothelial growth factor receptor Flt-1 after endothelial denudation: role of transcription factor Egr-1. Blood 2000, 95: 3387-3395.PubMed

33.

Alves BE, Montalvao SA, Aranha FJ, Lorand-Metze I, De Souza CA, Annichino-Bizzacchi JM, De Paula EV: Time-course of sFlt-1 and VEGF-A release in neutropenic patients with sepsis and septic shock: a prospective study. J Transl Med 2011, 9: 23. 10.1186/1479-5876-9-23PubMedCentralCrossRefPubMed

34.

Shibuya M: Structure and dual function of vascular endothelial growth factor receptor-1 (Flt-1). Int J Biochem Cell Biol 2001, 33: 409-420. 10.1016/S1357-2725(01)00026-7CrossRefPubMed

35.

Yano K, Liaw PC, Mullington JM, Shih SC, Okada H, Bodyak N, Kang PM, Toltl L, Belikoff B, Buras J, Simms BT, Mizgerd JP, Carmeliet P, Karumanchi SA, Aird WC: Vascular endothelial growth factor is an important determinant of sepsis morbidity and mortality. J Exp Med 2006, 203: 1447-1458. 10.1084/jem.20060375PubMedCentralCrossRefPubMed

36.

Takahashi H, Shibuya M: The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions. Clin Sci (Lond) 2005, 109: 227-241. 10.1042/CS20040370CrossRef

37.

Orfanos SE, Kotanidou A, Glynos C, Athanasiou C, Tsigkos S, Dimopoulou I, Sotiropoulou C, Zakynthinos S, Armaganidis A, Papapetropoulos A, Roussos C: Angiopoietin-2 is increased in severe sepsis: correlation with inflammatory mediators. Crit Care Med 2007, 35: 199-206. 10.1097/01.CCM.0000251640.77679.D7CrossRefPubMed

38.

Giuliano JS Jr, Lahni PM, Harmon K, Wong HR, Doughty LA, Carcillo JA, Zingarelli B, Sukhatme VP, Parikh SM, Wheeler DS: Admission angiopoietin levels in children with septic shock. Shock 2007, 28: 650-654.PubMedCentralPubMed

39.

van der Heijden M, van Nieuw Amerongen GP, Koolwijk P, van Hinsbergh VW, Groeneveld AB: Angiopoietin-2, permeability oedema, occurrence and severity of ALI/ARDS in septic and non-septic critically ill patients. Thorax 2008, 63: 903-909. 10.1136/thx.2007.087387CrossRefPubMed

40.

Parikh SM, Mammoto T, Schultz A, Yuan HT, Christiani D, Karumanchi SA, Sukhatme VP: Excess circulating angiopoietin-2 may contribute to pulmonary vascular leak in sepsis in humans. PLoS Med 2006, 3: e46. 10.1371/journal.pmed.0030046PubMedCentralCrossRefPubMed

41.

Thurston G, Rudge JS, Ioffe E, Zhou H, Ross L, Croll SD, Glazer N, Holash J, McDonald DM, Yancopoulos GD: Angiopoietin-1 protects the adult vasculature against plasma leakage. Nat Med 2000, 6: 460-463. 10.1038/74725CrossRefPubMed

42.

Reusch P, Barleon B, Weindel K, Martiny-Baron G, Godde A, Siemeister G, Marme D: Identification of a soluble form of the angiopoietin receptor TIE-2 released from endothelial cells and present in human blood. Angiogenesis 2001, 4: 123-131. 10.1023/A:1012226627813CrossRefPubMed

43.

Findley CM, Cudmore MJ, Ahmed A, Kontos CD: VEGF induces Tie2 shedding via a phosphoinositide 3-kinase/Akt dependent pathway to modulate Tie2 signaling. Arterioscler Thromb Vasc Biol 2007, 27: 2619-2626. 10.1161/ATVBAHA.107.150482CrossRefPubMed

44.

van der Heijden M, van Nieuw Amerongen GP, van Hinsbergh VW, Groeneveld AB: The interaction of soluble Tie2 with angiopoietins and pulmonary vascular permeability in septic and nonseptic critically ill patients. Shock 2010, 33: 263-268. 10.1097/SHK.0b013e3181b2f978CrossRefPubMed

45.

Yuan HT, Khankin EV, Karumanchi SA, Parikh SM: Angiopoietin 2 is a partial agonist/antagonist of Tie2 signaling in the endothelium. Mol Cell Biol 2009, 29: 2011-2022. 10.1128/MCB.01472-08PubMedCentralCrossRefPubMed

46.

Gando S: Microvascular thrombosis and multiple organ dysfunction syndrome. Crit Care Med 2010, 38: S35-42.CrossRefPubMed

47.

Pugh CW, Ratcliffe PJ: Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med 2003, 9: 677-684. 10.1038/nm0603-677CrossRefPubMed

48.

Oh H, Takagi H, Suzuma K, Otani A, Matsumura M, Honda Y: Hypoxia and vascular endothelial growth factor selectively up-regulate angiopoietin-2 in bovine microvascular endothelial cells. J Biol Chem 1999, 274: 15732-15739. 10.1074/jbc.274.22.15732CrossRefPubMed

Title: Using angiogenic factors and their soluble receptors to predict organ dysfunction in patients with disseminated intravascular coagulation associated with severe trauma
Authors: Takeshi Wada
Subrina Jesmin
Satoshi Gando
Sayeeda N Sultana
Sohel Zaedi
Hiroyuki Yokota
Publication date: 01-04-2012
Publisher: BioMed Central
Published in: Critical Care / Issue 2/2012
Electronic ISSN: 1364-8535
DOI: https://doi.org/10.1186/cc11309

At a glance: The STEP trials

Springer Medicine

Using angiogenic factors and their soluble receptors to predict organ dysfunction in patients with disseminated intravascular coagulation associated with severe trauma

Abstract

Introduction

Materials and methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Introduction

Materials and methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 2/2012

Replacement of fentanyl infusion by enteral methadone decreases the weaning time from mechanical ventilation: a randomized controlled trial

The rise and fall of β-agonists in the treatment of ARDS

Moderate glucose control results in less negative nitrogen balances in medical intensive care unit patients: a randomized, controlled study

Methicillin-resistant Staphylococcus aureus carriage at ICU admission: to screen (rapidly) or not to screen?

Novel preventive strategies for ventilator-associated pneumonia

Preventable mortality evaluation in the ICU