Download PDF
Semin Thromb Hemost 2021; 47(05): 589-600
DOI: 10.1055/s-0041-1725096
Review Article

Fibrinolytic Alterations in Sepsis: Biomarkers and Future Treatment Targets

Julie Brogaard Larsen
1   Thrombosis and Haemostasis Research Unit, Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
,
Anne-Mette Hvas
1   Thrombosis and Haemostasis Research Unit, Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
2   Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
› Author Affiliations
› Further Information
    Permissions and Reprints

Abstract

Sepsis is a life-threatening condition which develops as a dysregulated immune response in the face of infection and which is associated with profound hemostatic disturbances and in the most extreme cases disseminated intravascular coagulation (DIC). In addition, the fibrinolytic system is subject to alterations during infection and sepsis, and impaired fibrinolysis is currently considered a key player in sepsis-related microthrombus formation and DIC. However, we still lack reliable biomarkers to assess fibrinolysis in the clinical setting. Furthermore, drugs targeting the fibrinolytic system have potential value in sepsis patients with severe fibrinolytic disturbances, but these are still being tested in the preclinical stage. The present review provides an overview of key fibrinolytic changes in sepsis, reviews the current literature on potential laboratory markers of altered fibrinolysis in adult sepsis patients, and discusses future perspectives for diagnosis and treatment of fibrinolytic disturbances in sepsis patients.

Keywords

sepsis - coagulation - fibrinolysis - plasminogen - plasmin - plasminogen activator - plasminogen activator inhibitor - thrombin-activatable fibrinolysis inhibitor - antifibrinolytic proteins


Publication History

Article published online:
20 April 2021

© 2021. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Rudd KE, Johnson SC, Agesa KM. et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet 2020; 395 (10219): 200-211
    CrossrefPubMedGoogle Scholar
  • 2 Bone RC, Balk RA, Cerra FB. et al; The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992; 101 (06) 1644-1655
    CrossrefPubMedGoogle Scholar
  • 3 Levy MM, Fink MP, Marshall JC. et al; SCCM/ESICM/ACCP/ATS/SIS. 2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference. Crit Care Med 2003; 31 (04) 1250-1256
    CrossrefPubMedGoogle Scholar
  • 4 Singer M, Deutschman CS, Seymour CW. et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016; 315 (08) 801-810
    CrossrefPubMedGoogle Scholar
  • 5 Raith EP, Udy AA, Bailey M. et al; Australian and New Zealand Intensive Care Society (ANZICS) Centre for Outcomes and Resource Evaluation (CORE). Prognostic accuracy of the SOFA score, SIRS criteria, and qSOFA score for in-hospital mortality among adults with suspected infection admitted to the intensive care unit. JAMA 2017; 317 (03) 290-300
    CrossrefPubMedGoogle Scholar
  • 6 Vincent JL, Sakr Y, Sprung CL. et al; Sepsis Occurrence in Acutely Ill Patients Investigators. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med 2006; 34 (02) 344-353
    CrossrefPubMedGoogle Scholar
  • 7 Levi M, van der Poll T. Coagulation and sepsis. Thromb Res 2017; 149: 38-44
    CrossrefPubMedGoogle Scholar
  • 8 Page MJ, Pretorius E. A champion of host defense: a generic large-scale cause for platelet dysfunction and depletion in infection. Semin Thromb Hemost 2020; 46 (03) 302-319
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Liaw PC, Ito T, Iba T, Thachil J, Zeerleder S. DAMP and DIC: the role of extracellular DNA and DNA-binding proteins in the pathogenesis of DIC. Blood Rev 2016; 30 (04) 257-261
    CrossrefPubMedGoogle Scholar
  • 10 Osterud B, Flaegstad T. Increased tissue thromboplastin activity in monocytes of patients with meningococcal infection: related to an unfavourable prognosis. Thromb Haemost 1983; 49 (01) 5-7
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Hoffman M. A cell-based model of coagulation and the role of factor VIIa. Blood Rev 2003; 17 (Suppl. 01) S1-S5
    CrossrefPubMedGoogle Scholar
  • 12 Fijnvandraat K, Derkx B, Peters M. et al. Coagulation activation and tissue necrosis in meningococcal septic shock: severely reduced protein C levels predict a high mortality. Thromb Haemost 1995; 73 (01) 15-20
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Massberg S, Grahl L, von Bruehl ML. et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med 2010; 16 (08) 887-896
    CrossrefPubMedGoogle Scholar
  • 14 Aird WC. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood 2003; 101 (10) 3765-3777
    CrossrefPubMedGoogle Scholar
  • 15 Bernardo A, Ball C, Nolasco L, Moake JF, Dong JF. Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultralarge von Willebrand factor multimers under flow. Blood 2004; 104 (01) 100-106
    CrossrefPubMedGoogle Scholar
  • 16 Boehme MW, Deng Y, Raeth U. et al. Release of thrombomodulin from endothelial cells by concerted action of TNF-alpha and neutrophils: in vivo and in vitro studies. Immunology 1996; 87 (01) 134-140
    PubMedGoogle Scholar
  • 17 Kienast J, Juers M, Wiedermann CJ. et al; KyberSept investigators. Treatment effects of high-dose antithrombin without concomitant heparin in patients with severe sepsis with or without disseminated intravascular coagulation. J Thromb Haemost 2006; 4 (01) 90-97
    CrossrefPubMedGoogle Scholar
  • 18 Dhainaut JF, Yan SB, Joyce DE. et al. Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation. J Thromb Haemost 2004; 2 (11) 1924-1933
    CrossrefPubMedGoogle Scholar
  • 19 Gando S, Saitoh D, Ogura H. et al; Japanese Association for Acute Medicine Sepsis Registry Study Group. A multicenter, prospective validation study of the Japanese Association for Acute Medicine disseminated intravascular coagulation scoring system in patients with severe sepsis. Crit Care 2013; 17 (03) R111
    CrossrefPubMedGoogle Scholar
  • 20 Longstaff C, Kolev K. Basic mechanisms and regulation of fibrinolysis. J Thromb Haemost 2015; 13 (Suppl. 01) S98-S105
    CrossrefPubMedGoogle Scholar
  • 21 Hethershaw EL, Cilia La Corte AL, Duval C. et al. The effect of blood coagulation factor XIII on fibrin clot structure and fibrinolysis. J Thromb Haemost 2014; 12 (02) 197-205
    CrossrefPubMedGoogle Scholar
  • 22 Horrevoets AJ, Pannekoek H, Nesheim ME. A steady-state template model that describes the kinetics of fibrin-stimulated [Glu1]- and [Lys78]plasminogen activation by native tissue-type plasminogen activator and variants that lack either the finger or kringle-2 domain. J Biol Chem 1997; 272 (04) 2183-2191
    CrossrefPubMedGoogle Scholar
  • 23 Thunø M, Macho B, Eugen-Olsen J. suPAR: the molecular crystal ball. Dis Markers 2009; 27 (03) 157-172
    CrossrefPubMedGoogle Scholar
  • 24 Aoki N. Discovery of alpha2-plasmin inhibitor and its congenital deficiency. J Thromb Haemost 2005; 3 (04) 623-631
    CrossrefPubMedGoogle Scholar
  • 25 Binder BR, Christ G, Gruber F. et al. Plasminogen activator inhibitor 1: physiological and pathophysiological roles. News Physiol Sci 2002; 17: 56-61
    PubMedGoogle Scholar
  • 26 Bajzar L, Morser J, Nesheim M. TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex. J Biol Chem 1996; 271 (28) 16603-16608
    CrossrefPubMedGoogle Scholar
  • 27 Bouma BN, Mosnier LO. Thrombin activatable fibrinolysis inhibitor (TAFI)—how does thrombin regulate fibrinolysis?. Ann Med 2006; 38 (06) 378-388
    CrossrefPubMedGoogle Scholar
  • 28 Gabriel DA, Muga K, Boothroyd EM. The effect of fibrin structure on fibrinolysis. J Biol Chem 1992; 267 (34) 24259-24263
    CrossrefPubMedGoogle Scholar
  • 29 Collet JP, Park D, Lesty C. et al. Influence of fibrin network conformation and fibrin fiber diameter on fibrinolysis speed: dynamic and structural approaches by confocal microscopy. Arterioscler Thromb Vasc Biol 2000; 20 (05) 1354-1361
    CrossrefPubMedGoogle Scholar
  • 30 Wolberg AS, Monroe DM, Roberts HR, Hoffman M. Elevated prothrombin results in clots with an altered fiber structure: a possible mechanism of the increased thrombotic risk. Blood 2003; 101 (08) 3008-3013
    CrossrefPubMedGoogle Scholar
  • 31 Ariëns RA. Fibrin(ogen) and thrombotic disease. J Thromb Haemost 2013; 11 (Suppl. 01) 294-305
    CrossrefPubMedGoogle Scholar
  • 32 Lisman T, Arefaine B, Adelmeijer J. et al. Global hemostatic status in patients with acute-on-chronic liver failure and septics without underlying liver disease. J Thrombosis Haemostasis: JTH 2020; DOI: 10.1111/jth.15112.
    CrossrefPubMedGoogle Scholar
  • 33 van Deventer SJ, Büller HR, ten Cate JW, Aarden LA, Hack CE, Sturk A. Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood 1990; 76 (12) 2520-2526
    CrossrefPubMedGoogle Scholar
  • 34 Jansen PM, Boermeester MA, Fischer E. et al. Contribution of interleukin-1 to activation of coagulation and fibrinolysis, neutrophil degranulation, and the release of secretory-type phospholipase A2 in sepsis: studies in nonhuman primates after interleukin-1 alpha administration and during lethal bacteremia. Blood 1995; 86 (03) 1027-1034
    CrossrefPubMedGoogle Scholar
  • 35 Stouthard JM, Levi M, Hack CE. et al. Interleukin-6 stimulates coagulation, not fibrinolysis, in humans. Thromb Haemost 1996; 76 (05) 738-742
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Huebner BR, Moore EE, Moore HB. et al. Thrombin provokes degranulation of platelet α-granules leading to the release of active plasminogen activator inhibitor-1 (PAI-1). Shock 2018; 50 (06) 671-676
    CrossrefPubMedGoogle Scholar
  • 37 Gould TJ, Vu TT, Stafford AR. et al. Cell-free DNA modulates clot structure and impairs fibrinolysis in sepsis. Arterioscler Thromb Vasc Biol 2015; 35 (12) 2544-2553
    CrossrefPubMedGoogle Scholar
  • 38 Larsen JB, Hvas CL, Hvas AM. The lectin pathway in thrombotic conditions—a systematic review. Thromb Haemost 2018; 118 (07) 1141-1166
    Article in Thieme ConnectPubMedGoogle Scholar
  • 39 Howes JM, Richardson VR, Smith KA. et al. Complement C3 is a novel plasma clot component with anti-fibrinolytic properties. Diab Vasc Dis Res 2012; 9 (03) 216-225
    CrossrefPubMedGoogle Scholar
  • 40 Liesenborghs L, Verhamme P, Vanassche T. Staphylococcus aureus, master manipulator of the human hemostatic system. J Thromb Haemost 2018; 16 (03) 441-454
    CrossrefPubMedGoogle Scholar
  • 41 Hou PC, Filbin MR, Wang H. et al; ProCESS Investigators(*). Endothelial permeability and hemostasis in septic shock: results from the ProCESS trial. Chest 2017; 152 (01) 22-31
    CrossrefPubMedGoogle Scholar
  • 42 Martínez MA, Peña JM, Fernández A. et al. Time course and prognostic significance of hemostatic changes in sepsis: relation to tumor necrosis factor-alpha. Crit Care Med 1999; 27 (07) 1303-1308
    CrossrefPubMedGoogle Scholar
  • 43 Mavrommatis AC, Theodoridis T, Economou M. et al. Activation of the fibrinolytic system and utilization of the coagulation inhibitors in sepsis: comparison with severe sepsis and septic shock. Intensive Care Med 2001; 27 (12) 1853-1859
    CrossrefPubMedGoogle Scholar
  • 44 Delabranche X, Boisramé-Helms J, Asfar P. et al. Microparticles are new biomarkers of septic shock-induced disseminated intravascular coagulopathy. Intensive Care Med 2013; 39 (10) 1695-1703
    CrossrefPubMedGoogle Scholar
  • 45 Dofferhoff AS, Bom VJ, de Vries-Hospers HG. et al. Patterns of cytokines, plasma endotoxin, plasminogen activator inhibitor, and acute-phase proteins during the treatment of severe sepsis in humans. Crit Care Med 1992; 20 (02) 185-192
    CrossrefPubMedGoogle Scholar
  • 46 Suffredini AF, Harpel PC, Parrillo JE. Promotion and subsequent inhibition of plasminogen activation after administration of intravenous endotoxin to normal subjects. N Engl J Med 1989; 320 (18) 1165-1172
    CrossrefPubMedGoogle Scholar
  • 47 Asakura H, Ontachi Y, Mizutani T. et al. Depressed plasma activity of plasminogen or alpha2 plasmin inhibitor is not due to consumption coagulopathy in septic patients with disseminated intravascular coagulation. Blood Coagul Fibrinolysis 2001; 12 (04) 275-281
    CrossrefPubMedGoogle Scholar
  • 48 Hayakawa M, Sawamura A, Gando S, Jesmin S, Naito S, Ieko M. A low TAFI activity and insufficient activation of fibrinolysis by both plasmin and neutrophil elastase promote organ dysfunction in disseminated intravascular coagulation associated with sepsis. Thromb Res 2012; 130 (06) 906-913
    CrossrefPubMedGoogle Scholar
  • 49 Park KJ, Kim HJ, Hwang SC. et al. The imbalance between coagulation and fibrinolysis is related to the severity of the illness and the prognosis in sepsis. Korean J Intern Med (Korean Assoc Intern Med) 1999; 14 (02) 72-77
    CrossrefPubMedGoogle Scholar
  • 50 Kawamura T, Okada N, Okada H. Elastase from activated human neutrophils activates procarboxypeptidase R. Microbiol Immunol 2002; 46 (03) 225-230
    CrossrefPubMedGoogle Scholar
  • 51 Gando S, Hayakawa M, Sawamura A. et al. The activation of neutrophil elastase-mediated fibrinolysis is not sufficient to overcome the fibrinolytic shutdown of disseminated intravascular coagulation associated with systemic inflammation. Thromb Res 2007; 121 (01) 67-73
    CrossrefPubMedGoogle Scholar
  • 52 Adamzik M, Eggmann M, Frey UH. 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 (05) R178
    CrossrefPubMedGoogle Scholar
  • 53 Davies GR, Lawrence M, Pillai S. et al. The effect of sepsis and septic shock on the viscoelastic properties of clot quality and mass using rotational thromboelastometry: a prospective observational study. J Crit Care 2018; 44: 7-11
    CrossrefPubMedGoogle Scholar
  • 54 Sivula M, Pettilä V, Niemi TT, Varpula M, Kuitunen AH. Thromboelastometry in patients with severe sepsis and disseminated intravascular coagulation. Blood Coagul Fibrinolysis 2009; 20 (06) 419-426
    CrossrefPubMedGoogle Scholar
  • 55 Blasi A, Patel VC, Adelmeijer J. et al. Mixed fibrinolytic phenotypes in decompensated cirrhosis and acute-on-chronic liver failure with hypofibrinolysis in those with complications and poor survival. Hepatology 2020; 71 (04) 1381-1390
    CrossrefPubMedGoogle Scholar
  • 56 Schmitt FCF, Manolov V, Morgenstern J. et al. Acute fibrinolysis shutdown occurs early in septic shock and is associated with increased morbidity and mortality: results of an observational pilot study. Ann Intensive Care 2019; 9 (01) 19
    CrossrefPubMedGoogle Scholar
  • 57 Davies GR, Pillai S, Lawrence M. et al. The effect of sepsis and its inflammatory response on mechanical clot characteristics: a prospective observational study. Intensive Care Med 2016; 42 (12) 1990-1998
    CrossrefPubMedGoogle Scholar
  • 58 Zeerleder S, Schroeder V, Lämmle B, Wuillemin WA, Hack CE, Kohler HP. Factor XIII in severe sepsis and septic shock. Thromb Res 2007; 119 (03) 311-318
    CrossrefPubMedGoogle Scholar
  • 59 Gando S. Role of fibrinolysis in sepsis. Semin Thromb Hemost 2013; 39 (04) 392-399
    Article in Thieme ConnectPubMedGoogle Scholar
  • 60 Asakura H. Classifying types of disseminated intravascular coagulation: clinical and animal models. J Intensive Care 2014; 2 (01) 20
    CrossrefPubMedGoogle Scholar
  • 61 Higgins RA, Kitchen S, Chen D. Hemostasis. In: Rifai N. ed. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed.. Amsterdam, the Netherlands: Elsevier; 2017
    Google Scholar
  • 62 Dhainaut JF, Shorr AF, Macias WL. et al. Dynamic evolution of coagulopathy in the first day of severe sepsis: relationship with mortality and organ failure. Crit Care Med 2005; 33 (02) 341-348
    CrossrefPubMedGoogle Scholar
  • 63 Semeraro F, Ammollo CT, Caironi P. et al. Low D-dimer levels in sepsis: good or bad?. Thromb Res 2019; 174: 13-15
    CrossrefPubMedGoogle Scholar
  • 64 Lisman T. Interpreting hemostatic profiles assessed with viscoelastic tests in patients with cirrhosis. J Clin Gastroenterol 2020; 54 (04) 389-391
    CrossrefPubMedGoogle Scholar
  • 65 Koyama K, Madoiwa S, Nunomiya S. et al. Combination of thrombin-antithrombin complex, plasminogen activator inhibitor-1, and protein C activity for early identification of severe coagulopathy in initial phase of sepsis: a prospective observational study. Crit Care 2014; 18 (01) R13
    CrossrefPubMedGoogle Scholar
  • 66 Karamarkovic A, Radenkovic D, Milic N, Bumbasirevic V, Stefanovic B. Protein C as an early marker of severe septic complications in diffuse secondary peritonitis. World J Surg 2005; 29 (06) 759-765
    CrossrefPubMedGoogle Scholar
  • 67 Kinasewitz GT, Yan SB, Basson B. et al; PROWESS Sepsis Study Group. Universal changes in biomarkers of coagulation and inflammation occur in patients with severe sepsis, regardless of causative micro-organism [ISRCTN74215569]. Crit Care 2004; 8 (02) R82-R90
    CrossrefPubMedGoogle Scholar
  • 68 Iba T, Kidokoro A, Fukunaga M, Sugiyama K, Sawada T, Kato H. Association between the severity of sepsis and the changes in hemostatic molecular markers and vascular endothelial damage markers. Shock 2005; 23 (01) 25-29
    CrossrefPubMedGoogle Scholar
  • 69 Wiersinga WJ, Meijers JC, Levi M. et al. Activation of coagulation with concurrent impairment of anticoagulant mechanisms correlates with a poor outcome in severe melioidosis. J Thromb Haemost 2008; 6 (01) 32-39
    CrossrefPubMedGoogle Scholar
  • 70 Semeraro F, Colucci M, Caironi P. et al. Platelet drop and fibrinolytic shutdown in patients with sepsis. Crit Care Med 2018; 46 (03) e221-e228
    CrossrefPubMedGoogle Scholar
  • 71 Voves C, Wuillemin WA, Zeerleder S. International Society on Thrombosis and Haemostasis score for overt disseminated intravascular coagulation predicts organ dysfunction and fatality in sepsis patients. Blood Coagul Fibrinolysis 2006; 17 (06) 445-451
    CrossrefPubMedGoogle Scholar
  • 72 Zeerleder S, Schroeder V, Hack CE, Kohler HP, Wuillemin WA. TAFI and PAI-1 levels in human sepsis. Thromb Res 2006; 118 (02) 205-212
    CrossrefPubMedGoogle Scholar
  • 73 Semeraro F, Ammollo CT, Caironi P. et al. D-dimer corrected for thrombin and plasmin generation is a strong predictor of mortality in patients with sepsis. Blood Transfus 2020; 18 (04) 304-311
    PubMedGoogle Scholar
  • 74 Robbie LA, Dummer S, Booth NA, Adey GD, Bennett B. Plasminogen activator inhibitor 2 and urokinase-type plasminogen activator in plasma and leucocytes in patients with severe sepsis. Br J Haematol 2000; 109 (02) 342-348
    CrossrefPubMedGoogle Scholar
  • 75 Voss R, Matthias FR, Borkowski G, Reitz D. Activation and inhibition of fibrinolysis in septic patients in an internal intensive care unit. Br J Haematol 1990; 75 (01) 99-105
    CrossrefPubMedGoogle Scholar
  • 76 Kelly BJ, Lautenbach E, Nachamkin I. et al; Centers for Disease Control and Prevention (CDC) Prevention Epicenters Program. Combined biomarkers predict acute mortality among critically Ill patients with suspected sepsis. Crit Care Med 2018; 46 (07) 1106-1113
    CrossrefPubMedGoogle Scholar
  • 77 Lorente JA, García-Frade LJ, Landín L. et al. Time course of hemostatic abnormalities in sepsis and its relation to outcome. Chest 1993; 103 (05) 1536-1542
    CrossrefPubMedGoogle Scholar
  • 78 Pregernig A, Müller M, Held U, Beck-Schimmer B. Prediction of mortality in adult patients with sepsis using six biomarkers: a systematic review and meta-analysis. Ann Intensive Care 2019; 9 (01) 125
    CrossrefPubMedGoogle Scholar
  • 79 Huang Q, Xiong H, Yan P. et al. The diagnostic and prognostic value of suPAR in patients with sepsis: a systematic review and meta-analysis. Shock 2020; 53 (04) 416-425
    CrossrefPubMedGoogle Scholar
  • 80 Higazi A, Cohen RL, Henkin J, Kniss D, Schwartz BS, Cines DB. Enhancement of the enzymatic activity of single-chain urokinase plasminogen activator by soluble urokinase receptor. J Biol Chem 1995; 270 (29) 17375-17380
    CrossrefPubMedGoogle Scholar
  • 81 Pawlak K, Pawlak D, Mysliwiec M. Excess soluble urokinase-type plasminogen activator receptor in the plasma of dialysis patients correlates with increased fibrinolytic activity. Thromb Res 2007; 119 (04) 475-480
    CrossrefPubMedGoogle Scholar
  • 82 Wilhelm O, Weidle U, Höhl S, Rettenberger P, Schmitt M, Graeff H. Recombinant soluble urokinase receptor as a scavenger for urokinase-type plasminogen activator (uPA). Inhibition of proliferation and invasion of human ovarian cancer cells. FEBS Lett 1994; 337 (02) 131-134
    CrossrefPubMedGoogle Scholar
  • 83 Gando S, Sawamura A, Hayakawa M, Hoshino H, Kubota N, Nishihira J. High macrophage migration inhibitory factor levels in disseminated intravascular coagulation patients with systemic inflammation. Inflammation 2007; 30 (3-4): 118-124
    CrossrefPubMedGoogle Scholar
  • 84 Hoppensteadt D, Tsuruta K, Hirman J, Kaul I, Osawa Y, Fareed J. Dysregulation of inflammatory and hemostatic markers in sepsis and suspected disseminated intravascular coagulation. Clin Appl Thromb Hemost 2015; 21 (02) 120-127
    CrossrefPubMedGoogle Scholar
  • 85 Hoshino K, Kitamura T, Nakamura Y. et al. Usefulness of plasminogen activator inhibitor-1 as a predictive marker of mortality in sepsis. J Intensive Care 2017; 5: 42
    CrossrefPubMedGoogle Scholar
  • 86 Ikeda M, Matsumoto H, Ogura H. et al. Circulating syndecan-1 predicts the development of disseminated intravascular coagulation in patients with sepsis. J Crit Care 2018; 43: 48-53
    CrossrefPubMedGoogle Scholar
  • 87 Masuda T, Shoko T, Deguchi Y. Clinical investigation of coagulation markers for early detection of sepsis-induced disseminated intravascular coagulation: a single-center, prospective observational study. Clin Appl Thromb Hemost 2018; 24 (07) 1082-1087
    CrossrefPubMedGoogle Scholar
  • 88 Tipoe TL, Wu WKK, Chung L. et al. Plasminogen activator inhibitor 1 for predicting sepsis severity and mortality outcomes: a systematic review and meta-analysis. Front Immunol 2018; 9: 1218
    CrossrefPubMedGoogle Scholar
  • 89 Kazune S, Caica A, Volceka K, Suba O, Rubins U, Grabovskis A. Relationship of mottling score, skin microcirculatory perfusion indices and biomarkers of endothelial dysfunction in patients with septic shock: an observational study. Crit Care 2019; 23 (01) 311
    CrossrefPubMedGoogle Scholar
  • 90 Madách K, Aladzsity I, Szilágyi A. et al. 4G/5G polymorphism of PAI-1 gene is associated with multiple organ dysfunction and septic shock in pneumonia induced severe sepsis: prospective, observational, genetic study. Crit Care 2010; 14 (02) R79
    CrossrefPubMedGoogle Scholar
  • 91 García-Segarra G, Espinosa G, Tassies D. et al. Increased mortality in septic shock with the 4G/4G genotype of plasminogen activator inhibitor 1 in patients of white descent. Intensive Care Med 2007; 33 (08) 1354-1362
    CrossrefPubMedGoogle Scholar
  • 92 Lorente L, Martín MM, Borreguero-León JM. et al. The 4G/4G genotype of PAI-1 polymorphism is associated with higher plasma PAI-1 concentrations and mortality in patients with severe sepsis. PLoS One 2015; 10 (06) e0129565
    CrossrefPubMedGoogle Scholar
  • 93 Perés Wingeyer SD, Cunto ER, Nogueras CM, San Juan JA, Gomez N, de Larrañaga GF. Biomarkers in sepsis at time zero: intensive care unit scores, plasma measurements and polymorphisms in Argentina. J Infect Dev Ctries 2012; 6 (07) 555-562
    CrossrefPubMedGoogle Scholar
  • 94 Wingeyer SP, de Larrañaga G, Cunto E, Fontana L, Nogueras C, San Juan J. Role of 4G/5G promoter polymorphism of plasminogen activator inhibitor-1 (PAI-1) gene in outcome of sepsis. Thromb Res 2010; 125 (04) 367-369
    CrossrefPubMedGoogle Scholar
  • 95 Georgakopoulou A, Papadimitriou-Olivgeris M, Karakantza M, Marangos M. Role of inherited thrombophilic profile on survival of patients with sepsis. J Investig Med 2019; 67 (08) 1131-1135
    CrossrefPubMedGoogle Scholar
  • 96 Jessen K, Lindboe S, Petersen A, Eugen-Olsen J, Benfield T. Common TNF-α, IL-1b, PAI-1, uPA, CD14 and TLR4 polymorphisms are not associated with disease severity or outcome from Gram negative sepsis. BMC Infect Dis 2007; 7 DOI: 10.1186/1471-2334-7-108.
    CrossrefPubMedGoogle Scholar
  • 97 Tsantes AE, Tsangaris I, Bonovas S. et al. The effect of four hemostatic gene polymorphisms on the outcome of septic critically ill patients. Blood Coagul Fibrinolysis 2010; 21 (02) 175-181
    CrossrefPubMedGoogle Scholar
  • 98 Pieters M, Philippou H, Undas A, de Lange Z, Rijken DC, Mutch NJ. Subcommittee on Factor XIII and Fibrinogen, and the Subcommittee on Fibrinolysis. An international study on the feasibility of a standardized combined plasma clot turbidity and lysis assay: communication from the SSC of the ISTH. J Thromb Haemost 2018; 16 (05) 1007-1012
    CrossrefPubMedGoogle Scholar
  • 99 Verheijen JH, Mullaart E, Chang GT, Kluft C, Wijngaards G. A simple, sensitive spectrophotometric assay for extrinsic (tissue-type) plasminogen activator applicable to measurements in plasma. Thromb Haemost 1982; 48 (03) 266-269
    Article in Thieme ConnectPubMedGoogle Scholar
  • 100 Boudjeltia KZ, Ollieuz S, Piagnerelli M. et al. Plasma fibrinolysis is related to the degree of organ dysfunction but not to the concentration of von Willebrand Factor in critically ill patients. Thromb J 2009; 7: 10
    CrossrefPubMedGoogle Scholar
  • 101 Koami H, Sakamoto Y, Ohta M. et al. Can rotational thromboelastometry predict septic disseminated intravascular coagulation?. Blood Coagul Fibrinolysis 2015; 26 (07) 778-783
    CrossrefPubMedGoogle Scholar
  • 102 Koami H, Sakamoto Y, Sakurai R. et al. The thromboelastometric discrepancy between septic and trauma induced disseminated intravascular coagulation diagnosed by the scoring system from the Japanese association for acute medicine. Medicine (Baltimore) 2016; 95 (31) e4514
    CrossrefPubMedGoogle Scholar
  • 103 Koch A, Meesters MI, Scheller B, Boer C, Zacharowski K. Systemic endotoxin activity correlates with clot formation: an observational study in patients with early systemic inflammation and sepsis. Crit Care 2013; 17 (05) R198
    CrossrefPubMedGoogle Scholar
  • 104 Kuiper GJ, Kleinegris MC, van Oerle R. et al. Validation of a modified thromboelastometry approach to detect changes in fibrinolytic activity. Thromb J 2016; 14: 1
    CrossrefPubMedGoogle Scholar
  • 105 Panigada M, Zacchetti L, L'Acqua C. et al. Assessment of fibrinolysis in sepsis patients with urokinase modified thromboelastography. PLoS One 2015; 10 (08) e0136463
    CrossrefPubMedGoogle Scholar
  • 106 Panigada M, Sampietro F, L'Acqua C. et al. Impaired dynamics of clot formation and hypofibrinolysis in severe sepsis are coexisting and strictly related. Intensive Care Med 2016; 42 (04) 622-623
    CrossrefPubMedGoogle Scholar
  • 107 Prakash S, Verghese S, Roxby D, Dixon D, Bihari S, Bersten A. Changes in fibrinolysis and severity of organ failure in sepsis: a prospective observational study using point-of-care test—ROTEM. J Crit Care 2015; 30 (02) 264-270
    CrossrefPubMedGoogle Scholar
  • 108 Scărlătescu E, Lancé MD, White NJ, Tomescu DR. Thromboelastometric prediction of mortality using the kinetics of clot growth in critically ill septic patients. Blood Coagul Fibrinolysis 2018; 29 (06) 533-539
    CrossrefPubMedGoogle Scholar
  • 109 Zhou W, Zhou W, Bai J, Ma S, Liu Q, Ma X. TEG in the monitoring of coagulation changes in patients with sepsis and the clinical significance. Exp Ther Med 2019; 17 (05) 3373-3382
    PubMedGoogle Scholar
  • 110 Biemond BJ, Levi M, Coronel R, Janse MJ, ten Cate JW, Pannekoek H. Thrombolysis and reocclusion in experimental jugular vein and coronary artery thrombosis. Effects of a plasminogen activator inhibitor type 1-neutralizing monoclonal antibody. Circulation 1995; 91 (04) 1175-1181
    CrossrefPubMedGoogle Scholar
  • 111 van Giezen JJ, Wahlund G, Nerme Abrahamsson T. The Fab-fragment of a PAI-1 inhibiting antibody reduces thrombus size and restores blood flow in a rat model of arterial thrombosis. Thromb Haemost 1997; 77 (05) 964-969
    Article in Thieme ConnectPubMedGoogle Scholar
  • 112 Elokdah H, Abou-Gharbia M, Hennan JK. et al. Tiplaxtinin, a novel, orally efficacious inhibitor of plasminogen activator inhibitor-1: design, synthesis, and preclinical characterization. J Med Chem 2004; 47 (14) 3491-3494
    CrossrefPubMedGoogle Scholar
  • 113 Hennan JK, Morgan GA, Swillo RE. et al. Effect of tiplaxtinin (PAI-039), an orally bioavailable PAI-1 antagonist, in a rat model of thrombosis. J Thromb Haemost 2008; 6 (09) 1558-1564
    CrossrefPubMedGoogle Scholar
  • 114 Zhou X, Hendrickx ML, Hassanzadeh-Ghassabeh G, Muyldermans S, Declerck PJ. Generation and in vitro characterisation of inhibitory nanobodies towards plasminogen activator inhibitor 1. Thromb Haemost 2016; 116 (06) 1032-1040
    Article in Thieme ConnectPubMedGoogle Scholar
  • 115 Wang D, Yang Y, Wang Y. et al. Embelin ameliorated sepsis-induced disseminated intravascular coagulation intensities by simultaneously suppressing inflammation and thrombosis. Biomed Pharmacother 2020; 130: 110528
    CrossrefPubMedGoogle Scholar
  • 116 King R, Tiede C, Simmons K, Fishwick C, Tomlinson D, Ajjan R. Inhibition of complement C3 and fibrinogen interaction: a potential novel therapeutic target to reduce cardiovascular disease in diabetes. Lancet 2015; 385 (Suppl. 01) S57
    CrossrefPubMedGoogle Scholar
  • 117 Merle NS, Noe R, Halbwachs-Mecarelli L, Fremeaux-Bacchi V, Roumenina LT. Complement system part II: role in immunity. Front Immunol 2015; 6: 257
    CrossrefPubMedGoogle Scholar
  • 118 Héja D, Harmat V, Fodor K. et al. Monospecific inhibitors show that both mannan-binding lectin-associated serine protease-1 (MASP-1) and -2 are essential for lectin pathway activation and reveal structural plasticity of MASP-2. J Biol Chem 2012; 287 (24) 20290-20300
    CrossrefPubMedGoogle Scholar
  • 119 Jenny L, Dobó J, Gál P, Pál G, Lam WA, Schroeder V. MASP-1 of the complement system enhances clot formation in a microvascular whole blood flow model. PLoS One 2018; 13 (01) e0191292
    CrossrefPubMedGoogle Scholar
  • 120 Jenny L, Noser D, Larsen JB. et al. MASP-1 of the complement system alters fibrinolytic behaviour of blood clots. Mol Immunol 2019; 114: 1-9
    CrossrefPubMedGoogle Scholar
  • 121 Aiuto LT, Barone SR, Cohen PS, Boxer RA. Recombinant tissue plasminogen activator restores perfusion in meningococcal purpura fulminans. Crit Care Med 1997; 25 (06) 1079-1082
    CrossrefPubMedGoogle Scholar
  • 122 Akol H, Boon E, van Haren F, van der Hoeven J. Successful treatment of fulminant pneumococcal sepsis with recombinant tissue plasminogen activator. Eur J Intern Med 2002; 13 (06) 389
    CrossrefPubMedGoogle Scholar
  • 123 Denning DW, Gilliland L, Hewlett A, Hughes LO, Reid CD. Peripheral symmetrical gangrene successfully treated with epoprostenol and tissue plasminogen activator. Lancet 1986; 2 (8520): 1401-1402
    CrossrefPubMedGoogle Scholar
  • 124 Zenz W, Zoehrer B, Levin M. et al; International Paediatric Meningococcal Thrombolysis Study Group. Use of recombinant tissue plasminogen activator in children with meningococcal purpura fulminans: a retrospective study. Crit Care Med 2004; 32 (08) 1777-1780
    CrossrefPubMedGoogle Scholar
  • 125 Henry DA, Carless PA, Moxey AJ. et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2011; 2011 (03) CD001886
    PubMedGoogle Scholar
  • 126 Shakur H, Roberts I, Bautista R. et al; CRASH-2 trial collaborators. 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 (9734): 23-32
    CrossrefPubMedGoogle Scholar
  • 127 Kłak M, Anäkkälä N, Wang W. et al. Tranexamic acid, an inhibitor of plasminogen activation, aggravates staphylococcal septic arthritis and sepsis. Scand J Infect Dis 2010; 42 (05) 351-358
    CrossrefPubMedGoogle Scholar
  • 128 Wada H, Matsumoto T, Yamashita Y. Diagnosis and treatment of disseminated intravascular coagulation (DIC) according to four DIC guidelines. J Intensive Care 2014; 2 (01) 15
    CrossrefPubMedGoogle Scholar
  • 129 Scully M, Levi M. How we manage haemostasis during sepsis. Br J Haematol 2019; 185 (02) 209-218
    CrossrefPubMedGoogle Scholar
  • 130 Hesselvik F, von Schenck H, Berg S, Blombäck M. Influence of plasma protease activation on electroimmunoassay and nephelometry of plasma fibronectin in sepsis. Thromb Res 1989; 56 (06) 731-737
    CrossrefPubMedGoogle Scholar
  • 131 Katayama S, Nunomiya S, Koyama K. et al. Markers of acute kidney injury in patients with sepsis: the role of soluble thrombomodulin. Crit Care 2017; 21 (01) 229
    CrossrefPubMedGoogle Scholar
  • 132 Yang KY, Liu KT, Chen YC. et al. 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 (01) R11
    CrossrefPubMedGoogle Scholar
  • 133 Milbrandt EB, Reade MC, Lee M. et al; GenIMS Investigators. Prevalence and significance of coagulation abnormalities in community-acquired pneumonia. Mol Med 2009; 15 (11-12): 438-445
    CrossrefPubMedGoogle Scholar
  • 134 Kidokoro A, Iba T, Fukunaga M, Yagi Y. Alterations in coagulation and fibrinolysis during sepsis. Shock 1996; 5 (03) 223-228
    CrossrefPubMedGoogle Scholar
  • 135 Madoiwa S, Nunomiya S, Ono T. et al. Plasminogen activator inhibitor 1 promotes a poor prognosis in sepsis-induced disseminated intravascular coagulation. Int J Hematol 2006; 84 (05) 398-405
    CrossrefPubMedGoogle Scholar
  • 136 Kager LM, Weehuizen TA, Wiersinga WJ. et al. Endogenous α2-antiplasmin is protective during severe gram-negative sepsis (melioidosis). Am J Respir Crit Care Med 2013; 188 (08) 967-975
    CrossrefPubMedGoogle Scholar
  • 137 Chen CC, Lee KD, Gau JP. et al. Plasma antigen levels of thrombin-activatable fibrinolysis inhibitor did not differ in patients with or without disseminated intravascular coagulation. Ann Hematol 2005; 84 (10) 675-680
    CrossrefPubMedGoogle Scholar