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How to manage coagulopathies in critically ill patients

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Abstract

Coagulopathy is a severe and frequent complication in critically ill patients, for which the pathogenesis and presentation may be variable depending on the underlying disease. Based on the dominant clinical phenotype, the current review differentiates between hemorrhagic coagulopathies, characterized by a hypocoagulable and hyperfibrinolysis state, and thrombotic coagulopathies with a systemic prothrombotic and antifibrinolytic phenotype. We discuss the differences in pathogenesis and treatment of the common coagulopathies.

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References

  1. Hjorleifsson E, Sigurdsson MI, Gudmundsdottir BR, Sigurdsson GH, Onundarson PT (2015) Prediction of survival in patients suspected of disseminated intravascular coagulation. Acta Anaesthesiol Scand 59:870–880. https://doi.org/10.1111/aas.12537

    Article  CAS  PubMed  Google Scholar 

  2. Kleinveld DJB, Hamada SR, Sandroni C (2022) Trauma-induced coagulopathy. Intensive Care Med. https://doi.org/10.1007/s00134-022-06834-7

    Article  PubMed  Google Scholar 

  3. Callcut RA, Kornblith LZ, Conroy AS, Robles AJ, Meizoso JP, Namias N, Meyer DE, Haymaker A, Truitt MS, Agrawal V, Haan JM, Lightwine KL, Porter JM, San Roman JL, Biffl WL, Hayashi MS, Sise MJ, Badiee J, Recinos G, Inaba K, Schroeppel TJ, Callaghan E, Dunn JA, Godin S, McIntyre RC Jr, Peltz ED, O’Neill PJ, Diven CF, Scifres AM, Switzer EE, West MA, Storrs S, Cullinane DC, Cordova JF, Moore EE, Moore HB, Privette AR, Eriksson EA, Cohen MJ, Western Trauma Association Multicenter Study G (2019) The why and how our trauma patients die: a prospective Multicenter Western Trauma Association study. J Trauma Acute Care Surg 86:864–870. https://doi.org/10.1097/TA.0000000000002205

    Article  PubMed Central  PubMed  Google Scholar 

  4. McLintock C (2020) Prevention and treatment of postpartum hemorrhage: focus on hematological aspects of management. Hematol Am Soc Hematol Educ Progr 2020:542–546. https://doi.org/10.1182/hematology.2020000139

    Article  Google Scholar 

  5. Raza I, Davenport R, Rourke C, Platton S, Manson J, Spoors C, Khan S, De’Ath HD, Allard S, Hart DP, Pasi KJ, Hunt BJ, Stanworth S, MacCallum PK, Brohi K (2013) The incidence and magnitude of fibrinolytic activation in trauma patients. J Thromb Haemost 11:307–314. https://doi.org/10.1111/jth.12078

    Article  CAS  PubMed  Google Scholar 

  6. Moore HB, Moore EE, Morton AP, Gonzalez E, Fragoso M, Chapman MP, Dzieciatkowska M, Hansen KC, Banerjee A, Sauaia A, Silliman CC (2015) Shock-induced systemic hyperfibrinolysis is attenuated by plasma-first resuscitation. J Trauma Acute Care Surg 79:897–903. https://doi.org/10.1097/TA.0000000000000792

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Gando S, Levi M, Toh CH (2016) Disseminated intravascular coagulation. Nat Rev Dis Primers 2:16037. https://doi.org/10.1038/nrdp.2016.37

    Article  PubMed  Google Scholar 

  8. Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, Brohi K, Itagaki K, Hauser CJ (2010) Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464:104–107. https://doi.org/10.1038/nature08780

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Vulliamy P, Kornblith LZ, Kutcher ME, Cohen MJ, Brohi K, Neal MD (2021) Alterations in platelet behavior after major trauma: adaptive or maladaptive? Platelets 32:295–304. https://doi.org/10.1080/09537104.2020.1718633

    Article  CAS  PubMed  Google Scholar 

  10. Kutcher ME, Redick BJ, McCreery RC, Crane IM, Greenberg MD, Cachola LM, Nelson MF, Cohen MJ (2012) Characterization of platelet dysfunction after trauma. J Trauma Acute Care Surg 73:13–19. https://doi.org/10.1097/TA.0b013e318256deab

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Starr NE, Matthay ZA, Fields AT, Nunez-Garcia B, Callcut RA, Cohen MJ, Kornblith LZ (2020) Identification of injury and shock driven effects on ex vivo platelet aggregometry: a cautionary tale of phenotyping. J Trauma Acute Care Surg 89:20–28. https://doi.org/10.1097/TA.0000000000002707

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Zhang J, Zhang F, Dong JF (2018) Coagulopathy induced by traumatic brain injury: systemic manifestation of a localized injury. Blood 131:2001–2006. https://doi.org/10.1182/blood-2017-11-784108

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Erez O (2017) Disseminated intravascular coagulation in pregnancy: clinical phenotypes and diagnostic scores. Thromb Res 151(Suppl 1):S56–S60. https://doi.org/10.1016/S0049-3848(17)30069-5

    Article  CAS  PubMed  Google Scholar 

  14. Kashuk JL, Moore EE, Millikan JS, Moore JB (1982) Major abdominal vascular trauma–a unified approach. J Trauma 22:672–679. https://doi.org/10.1097/00005373-198208000-00004

    Article  CAS  PubMed  Google Scholar 

  15. Moore HB, Tessmer MT, Moore EE, Sperry JL, Cohen MJ, Chapman MP, Pusateri AE, Guyette FX, Brown JB, Neal MD, Zuckerbraun B, Sauaia A (2020) Forgot calcium? Admission ionized-calcium in two civilian randomized controlled trials of prehospital plasma for traumatic hemorrhagic shock. J Trauma Acute Care Surg 88:588–596. https://doi.org/10.1097/TA.0000000000002614

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Ditzel RM Jr, Anderson JL, Eisenhart WJ, Rankin CJ, DeFeo DR, Oak S, Siegler J (2020) A review of transfusion- and trauma-induced hypocalcemia: Is it time to change the lethal triad to the lethal diamond? J Trauma Acute Care Surg 88:434–439. https://doi.org/10.1097/TA.0000000000002570

    Article  PubMed  Google Scholar 

  17. Morton AP, Moore EE, Wohlauer MV, Lo K, Silliman CC, Burlew CC, Banerjee A (2013) Revisiting early postinjury mortality: are they bleeding because they are dying or dying because they are bleeding? J Surg Res 179:5–9. https://doi.org/10.1016/j.jss.2012.05.054

    Article  PubMed  Google Scholar 

  18. Mitrophanov AY, Szlam F, Sniecinski RM, Levy JH, Reifman J (2020) Controlled multifactorial coagulopathy: effects of dilution, hypothermia, and acidosis on thrombin generation in vitro. Anesth Analg 130:1063–1076. https://doi.org/10.1213/ANE.0000000000004479

    Article  CAS  PubMed  Google Scholar 

  19. Moore HB, Moore EE, Gonzalez E, Chapman MP, Chin TL, Silliman CC, Banerjee A, Sauaia A (2014) Hyperfibrinolysis, physiologic fibrinolysis, and fibrinolysis shutdown: the spectrum of postinjury fibrinolysis and relevance to antifibrinolytic therapy. J Trauma Acute Care Surg 77:811–817. https://doi.org/10.1097/TA.0000000000000341

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Zipperle J, Altenburger K, Ponschab M, Schlimp CJ, Spittler A, Bahrami S, Redl H, Schochl H (2017) Potential role of platelet-leukocyte aggregation in trauma-induced coagulopathy: ex vivo findings. J Trauma Acute Care Surg 82:921–926. https://doi.org/10.1097/TA.0000000000001410

    Article  PubMed  Google Scholar 

  21. Barrett CD, Moore HB, Banerjee A, Silliman CC, Moore EE, Yaffe MB (2017) Human neutrophil elastase mediates fibrinolysis shutdown through competitive degradation of plasminogen and generation of angiostatin. J Trauma Acute Care Surg 83:1053–1061. https://doi.org/10.1097/TA.0000000000001685

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Wang TF, Makar RS, Antic D, Levy JH, Douketis JD, Connors JM, Carrier M, Zwicker JI (2020) Management of hemostatic complications in acute leukemia: guidance from the SSC of the ISTH. J Thromb Haemost 18:3174–3183. https://doi.org/10.1111/jth.15074

    Article  PubMed Central  PubMed  Google Scholar 

  23. Ten Cate H, Leader A (2021) Management of disseminated intravascular coagulation in acute leukemias. Hamostaseologie 41:120–126. https://doi.org/10.1055/a-1393-8302

    Article  PubMed  Google Scholar 

  24. Sanz MA, Montesinos P (2020) Advances in the management of coagulopathy in acute promyelocytic leukemia. Thromb Res 191(Suppl 1):S63–S67. https://doi.org/10.1016/S0049-3848(20)30399-6

    Article  CAS  PubMed  Google Scholar 

  25. Mitrovic M, Suvajdzic N, Elezovic I, Bogdanovic A, Djordjevic V, Miljic P, Djunic I, Gvozdenov M, Colovic N, Virijevic M, Lekovic D, Vidovic A, Tomin D (2015) Thrombotic events in acute promyelocytic leukemia. Thromb Res 135:588–593. https://doi.org/10.1016/j.thromres.2014.11.026

    Article  CAS  PubMed  Google Scholar 

  26. Stein E, McMahon B, Kwaan H, Altman JK, Frankfurt O, Tallman MS (2009) The coagulopathy of acute promyelocytic leukaemia revisited. Best Pract Res Clin Haematol 22:153–163. https://doi.org/10.1016/j.beha.2008.12.007

    Article  CAS  PubMed  Google Scholar 

  27. Bennett B, Booth NA, Croll A, Dawson AA (1989) The bleeding disorder in acute promyelocytic leukaemia: fibrinolysis due to u-PA rather than defibrination. Br J Haematol 71:511–517. https://doi.org/10.1111/j.1365-2141.1989.tb06311.x

    Article  CAS  PubMed  Google Scholar 

  28. Graf M, Reif S, Hecht K, Pelka-Fleischer R, Pfister K, Schmetzer H (2005) High expression of urokinase plasminogen activator receptor (UPA-R) in acute myeloid leukemia (AML) is associated with worse prognosis. Am J Hematol 79:26–35. https://doi.org/10.1002/ajh.20337

    Article  CAS  PubMed  Google Scholar 

  29. Wang P, Zhang Y, Yang H, Hou W, Jin B, Hou J, Li H, Zhao H, Zhou J (2018) Characteristics of fibrinolytic disorders in acute promyelocytic leukemia. Hematology 23:756–764. https://doi.org/10.1080/10245332.2018.1470069

    Article  CAS  PubMed  Google Scholar 

  30. Kwaan HC, Weiss I, Tallman MS (2019) The role of abnormal hemostasis and fibrinolysis in morbidity and mortality of acute promyelocytic leukemia. Semin Thromb Hemost 45:612–621. https://doi.org/10.1055/s-0039-1693478

    Article  Google Scholar 

  31. Bonlokke ST, Ommen HB, Hvas AM (2021) Altered fibrinolysis in hematological malignances. Semin Thromb Hemost 47:569–580. https://doi.org/10.1055/s-0041-1725099

    Article  CAS  Google Scholar 

  32. Boisrame-Helms J, Kremer H, Schini-Kerth V, Meziani F (2013) Endothelial dysfunction in sepsis. Curr Vasc Pharmacol 11:150–160

    CAS  Google Scholar 

  33. Fourrier F (2012) Severe sepsis, coagulation, and fibrinolysis: dead end or one way? Crit Care Med 40:2704–2708. https://doi.org/10.1097/CCM.0b013e318258ff30

    Article  Google Scholar 

  34. Lane DA, Philippou H, Huntington JA (2005) Directing thrombin. Blood 106:2605–2612. https://doi.org/10.1182/blood-2005-04-1710

    Article  CAS  Google Scholar 

  35. van der Poll T, Herwald H (2014) The coagulation system and its function in early immune defense. Thromb Haemost. https://doi.org/10.1160/TH14-01-0053

    Article  Google Scholar 

  36. Delabranche X, Helms J, Meziani F (2017) Immunohaemostasis: a new view on haemostasis during sepsis. Ann Intensive Care 7:117. https://doi.org/10.1186/s13613-017-0339-5

    Article  CAS  PubMed Central  Google Scholar 

  37. Levi M (2010) The coagulant response in sepsis and inflammation. Hamostaseologie 30:10–16

    Article  CAS  Google Scholar 

  38. Pfeiler S, Massberg S, Engelmann B (2014) Biological basis and pathological relevance of microvascular thrombosis. Thromb Res 133(Suppl 1):S35-37. https://doi.org/10.1016/j.thromres.2014.03.016

    Article  Google Scholar 

  39. Gould TJ, Lysov Z, Liaw PC (2015) Extracellular DNA and histones: double-edged swords in immunothrombosis. J Thromb Haemost 13(Suppl 1):S82-91. https://doi.org/10.1111/jth.12977

    Article  CAS  Google Scholar 

  40. Yang H, Biermann MH, Brauner JM, Liu Y, Zhao Y, Herrmann M (2016) New insights into neutrophil extracellular traps: mechanisms of formation and role in inflammation. Front Immunol 7:302. https://doi.org/10.3389/fimmu.2016.00302

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Stiel L, Meziani F, Helms J (2018) Neutrophil activation during septic shock. Shock 49:371–384. https://doi.org/10.1097/SHK.0000000000000980

    Article  CAS  PubMed  Google Scholar 

  42. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y, Zychlinsky A (2004) Neutrophil extracellular traps kill bacteria. Science 303:1532–1535. https://doi.org/10.1126/science.1092385

    Article  CAS  PubMed  Google Scholar 

  43. Yipp BG, Kubes P (2013) NETosis: how vital is it? Blood 122:2784–2794. https://doi.org/10.1182/blood-2013-04-457671

    Article  CAS  PubMed  Google Scholar 

  44. Meziani F, Delabranche X, Asfar P, Toti F (2010) Bench-to-bedside review: circulating microparticles–a new player in sepsis? Crit Care 14:236. https://doi.org/10.1186/cc9231

    Article  PubMed Central  Google Scholar 

  45. Mortaza S, Martinez MC, Baron-Menguy C, Burban M, de la Bourdonnaye M, Fizanne L, Pierrot M, Cales P, Henrion D, Andriantsitohaina R, Mercat A, Asfar P, Meziani F (2009) Detrimental hemodynamic and inflammatory effects of microparticles originating from septic rats. Crit Care Med 37:2045–2050. https://doi.org/10.1097/CCM.0b013e3181a00629

    Article  CAS  Google Scholar 

  46. Lacroix R, Plawinski L, Robert S, Doeuvre L, Sabatier F, Martinez de Lizarrondo S, Mezzapesa A, Anfosso F, Leroyer AS, Poullin P, Jourde N, Njock MS, Boulanger CM, Angles-Cano E, Dignat-George F (2012) Leukocyte- and endothelial-derived microparticles: a circulating source for fibrinolysis. Haematologica 97:1864–1872. https://doi.org/10.3324/haematol.2012.066167

    Article  CAS  PubMed Central  Google Scholar 

  47. Engelmann B, Massberg S (2013) Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 13:34–45. https://doi.org/10.1038/nri3345

    Article  CAS  Google Scholar 

  48. Massberg S, Grahl L, von Bruehl ML, Manukyan D, Pfeiler S, Goosmann C, Brinkmann V, Lorenz M, Bidzhekov K, Khandagale AB, Konrad I, Kennerknecht E, Reges K, Holdenrieder S, Braun S, Reinhardt C, Spannagl M, Preissner KT, Engelmann B (2010) Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med 16:887–896. https://doi.org/10.1038/nm.2184

    Article  CAS  Google Scholar 

  49. Levi M (2019) Disseminated intravascular coagulation in cancer: an update. Semin Thromb Hemost 45:342–347. https://doi.org/10.1055/s-0039-1687890

    Article  Google Scholar 

  50. Leiva O, Newcomb R, Connors JM, Al-Samkari H (2020) Cancer and thrombosis: new insights to an old problem. J Med Vasc 45:6S8-6S16. https://doi.org/10.1016/S2542-4513(20)30514-9

    Article  CAS  PubMed  Google Scholar 

  51. Levi M, Sivapalaratnam S (2020) An overview of thrombotic complications of old and new anticancer drugs. Thromb Res 191(Suppl 1):S17–S21. https://doi.org/10.1016/S0049-3848(20)30391-1

    Article  CAS  PubMed  Google Scholar 

  52. Rickles FR, Brenner B (2008) Tissue factor and cancer. Semin Thromb Hemost 34:143–145. https://doi.org/10.1055/s-2008-1079253

    Article  PubMed  Google Scholar 

  53. Falanga A, Marchetti M, Vignoli A (2013) Coagulation and cancer: biological and clinical aspects. J Thromb Haemost 11:223–233. https://doi.org/10.1111/jth.12075

    Article  CAS  PubMed  Google Scholar 

  54. Kwaan HC, McMahon B (2009) The role of plasminogen-plasmin system in cancer. Cancer Treat Res 148:43–66. https://doi.org/10.1007/978-0-387-79962-9_4

    Article  CAS  PubMed  Google Scholar 

  55. Sallah S, Wan JY, Nguyen NP, Hanrahan LR, Sigounas G (2001) Disseminated intravascular coagulation in solid tumors: clinical and pathologic study. Thromb Haemost 86:828–833

    Article  CAS  PubMed  Google Scholar 

  56. Weng J, Chen M, Fang D, Liu D, Guo R, Yang S (2021) Therapeutic Plasma exchange protects patients with sepsis-associated disseminated intravascular coagulation by improving endothelial function. Clin Appl Thromb Hemost 27:10760296211053312. https://doi.org/10.1177/10760296211053313

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. El-Nawawy AA, Elshinawy MI, Khater DM, Moustafa AA, Hassanein NM, Wali YA, Nazir HF (2021) Outcome of early hemostatic intervention in children with sepsis and nonovert disseminated intravascular coagulation admitted to PICU: a randomized controlled trial. Pediatr Crit Care Med 22:e168–e177. https://doi.org/10.1097/PCC.0000000000002578

    Article  PubMed  Google Scholar 

  58. Stahl K, Schmidt JJ, Seeliger B, Schmidt BMW, Welte T, Haller H, Hoeper MM, Budde U, Bode C, David S (2020) Effect of therapeutic plasma exchange on endothelial activation and coagulation-related parameters in septic shock. Crit Care 24:71. https://doi.org/10.1186/s13054-020-2799-5

    Article  PubMed Central  PubMed  Google Scholar 

  59. Vincent JL, Francois B, Zabolotskikh I, Daga MK, Lascarrou JB, Kirov MY, Pettila V, Wittebole X, Meziani F, Mercier E, Lobo SM, Barie PS, Crowther M, Esmon CT, Fareed J, Gando S, Gorelick KJ, Levi M, Mira JP, Opal SM, Parrillo J, Russell JA, Saito H, Tsuruta K, Sakai T, Fineberg D, Group ST (2019) Effect of a recombinant human soluble thrombomodulin on mortality in patients with sepsis-associated coagulopathy: the SCARLET randomized clinical trial. JAMA 321:1993–2002. https://doi.org/10.1001/jama.2019.5358

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Levi M, Vincent JL, Tanaka K, Radford AH, Kayanoki T, Fineberg DA, Hoppensteadt D, Fareed J (2020) Effect of a recombinant human soluble thrombomodulin on baseline coagulation biomarker levels and mortality outcome in patients with sepsis-associated coagulopathy. Crit Care Med 48:1140–1147. https://doi.org/10.1097/CCM.0000000000004426

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. François B, Fiancette M, Helms J, Mercier E, Lascarrou JB, Kayanoki T, Tanaka K, Fineberg D, Vincent JL, Wittebole X (2021) Efficacy and safety of human soluble thrombomodulin (ART-123) for treatment of patients in France with sepsis-associated coagulopathy: post hoc analysis of SCARLET. Ann Intensive Care 11:53. https://doi.org/10.1186/s13613-021-00842-4

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Hayakawa M, Katabami K, Wada T, Sugano M, Hoshino H, Sawamura A, Gando S (2010) Sivelestat (selective neutrophil elastase inhibitor) improves the mortality rate of sepsis associated with both acute respiratory distress syndrome and disseminated intravascular coagulation patients. Shock 33:14–18. https://doi.org/10.1097/SHK.0b013e3181aa95c4

    Article  CAS  PubMed  Google Scholar 

  63. Hazelton JP, Ssentongo AE, Oh JS, Ssentongo P, Seamon MJ, Byrne JP, Armento IG, Jenkins DH, Braverman MA, Mentzer C, Leonard GC, Perea LL, Docherty CK, Dunn JA, Smoot B, Martin MJ, Badiee J, Luis AJ, Murray JL, Noorbakhsh MR, Babowice JE, Mains C, Madayag RM, Kaafarani HMA, Mokhtari AK, Moore SA, Madden K, Tanner A 2nd, Redmond D, Millia DJ, Brandolino A, Nguyen U, Chinchilli V, Armen SB, Porter JM (2022) Use of cold-stored whole blood is associated with improved mortality in hemostatic resuscitation of major bleeding: a multicenter study. Ann Surg 276:579–588. https://doi.org/10.1097/SLA.0000000000005603

    Article  PubMed  Google Scholar 

  64. Crombie N, Doughty HA, Bishop JRB, Desai A, Dixon EF, Hancox JM, Herbert MJ, Leech C, Lewis SJ, Nash MR, Naumann DN, Slinn G, Smith H, Smith IM, Wale RK, Wilson A, Ives N, Perkins GD, Pcg Re (2022) Resuscitation with blood products in patients with trauma-related haemorrhagic shock receiving prehospital care (RePHILL): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Haematol 9:e250–e261. https://doi.org/10.1016/S2352-3026(22)00040-0

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  65. Moore HB, Moore EE, Chapman MP, McVaney K, Bryskiewicz G, Blechar R, Chin T, Burlew CC, Pieracci F, West FB, Fleming CD, Ghasabyan A, Chandler J, Silliman CC, Banerjee A, Sauaia A (2018) Plasma-first resuscitation to treat haemorrhagic shock during emergency ground transportation in an urban area: a randomised trial. Lancet 392:283–291. https://doi.org/10.1016/S0140-6736(18)31553-8

    Article  PubMed Central  PubMed  Google Scholar 

  66. Sperry JL, Guyette FX, Brown JB, Yazer MH, Triulzi DJ, Early-Young BJ, Adams PW, Daley BJ, Miller RS, Harbrecht BG, Claridge JA, Phelan HA, Witham WR, Putnam AT, Duane TM, Alarcon LH, Callaway CW, Zuckerbraun BS, Neal MD, Rosengart MR, Forsythe RM, Billiar TR, Yealy DM, Peitzman AB, Zenati MS, Group PAS (2018) Prehospital plasma during air medical transport in trauma patients at risk for hemorrhagic shock. N Engl J Med 379:315–326. https://doi.org/10.1056/NEJMoa1802345

    Article  PubMed  Google Scholar 

  67. Holcomb JB, Tilley BC, Baraniuk S, Fox EE, Wade CE, Podbielski JM, del Junco DJ, Brasel KJ, Bulger EM, Callcut RA, Cohen MJ, Cotton BA, Fabian TC, Inaba K, Kerby JD, Muskat P, O’Keeffe T, Rizoli S, Robinson BR, Scalea TM, Schreiber MA, Stein DM, Weinberg JA, Callum JL, Hess JR, Matijevic N, Miller CN, Pittet JF, Hoyt DB, Pearson GD, Leroux B, van Belle G, Group PS (2015) Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA 313:471–482. https://doi.org/10.1001/jama.2015.12

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  68. Collaborators WT (2017) Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet 389:2105–2116. https://doi.org/10.1016/S0140-6736(17)30638-4

    Article  Google Scholar 

  69. Collaborators C-T, Shakur H, Roberts I, Bautista R, Caballero J, Coats T, Dewan Y, El-Sayed H, Gogichaishvili T, Gupta S, Herrera J, Hunt B, Iribhogbe P, Izurieta M, Khamis H, Komolafe E, Marrero MA, Mejia-Mantilla J, Miranda J, Morales C, Olaomi O, Olldashi F, Perel P, Peto R, Ramana PV, Ravi RR, Yutthakasemsunt S (2010) 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 376:23–32. https://doi.org/10.1016/S0140-6736(10)60835-5

    Article  CAS  Google Scholar 

  70. Estcourt LJ, McQuilten Z, Powter G, Dyer C, Curnow E, Wood EM, Stanworth SJ, Collaboration TT (2019) The TREATT Trial (TRial to EvaluAte Tranexamic acid therapy in Thrombocytopenia): safety and efficacy of tranexamic acid in patients with haematological malignancies with severe thrombocytopenia: study protocol for a double-blind randomised controlled trial. Trials 20:592. https://doi.org/10.1186/s13063-019-3663-2

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Saito H, Maruyama I, Shimazaki S, Yamamoto Y, Aikawa N, Ohno R, Hirayama A, Matsuda T, Asakura H, Nakashima M, Aoki N (2007) Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trial. J Thromb Haemost 5:31–41. https://doi.org/10.1111/j.1538-7836.2006.02267.x

    Article  CAS  PubMed  Google Scholar 

  72. Taniguchi K, Ohbe H, Yamakawa K, Matsui H, Fushimi K, Yasunaga H (2021) Recombinant thrombomodulin in disseminated intravascular coagulation associated with stage IV solid tumors: a nationwide observational study in Japan. Thromb Haemost 121:36–45. https://doi.org/10.1055/s-0040-1715840

    Article  PubMed  Google Scholar 

  73. Taniguchi K, Ohbe H, Yamakawa K, Matsui H, Fushimi K, Yasunaga H (2020) Antithrombin use and mortality in patients with stage IV solid tumor-associated disseminated intravascular coagulation: a nationwide observational study in Japan. BMC Cancer 20:867. https://doi.org/10.1186/s12885-020-07375-2

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  74. Bianchini EP, Razanakolona M, Helms J, Zouiti F, Couteau-Chardon A, Marin-Esteban V, Chaisemartin L, De-Carvalho A, Bironien R, Chollet-Martin S, Denis CV, Diehl JL, Vasse M, Meziani F, Borgel D (2021) The proteolytic inactivation of protein z-dependent protease inhibitor by neutrophil elastase might promote the procoagulant activity of neutrophil extracellular traps in sepsis. Thromb Haemost. https://doi.org/10.1055/a-1530-3980

    Article  PubMed  Google Scholar 

  75. Clere-Jehl R, Merdji H, Kassem M, Macquin C, De Cauwer A, Sibony A, Kurihara K, Minniti L, Abou Fayçal C, Bahram S, Meziani F, Helms J, Georgel P (2021) A translational investigation of IFN-α and STAT1 signaling in endothelial cells during septic shock provides therapeutic perspectives. Am J Respir Cell Mol Biol 65:167–175. https://doi.org/10.1165/rcmb.2020-0401OC

    Article  CAS  PubMed  Google Scholar 

  76. Stiel L, Mayeur-Rousse C, Helms J, Meziani F, Mauvieux L (2019) First visualization of circulating neutrophil extracellular traps using cell fluorescence during human septic shock-induced disseminated intravascular coagulation. Thromb Res 183:153–158. https://doi.org/10.1016/j.thromres.2019.09.036

    Article  CAS  PubMed  Google Scholar 

  77. Barbosa da Cruz D, Helms J, Aquino LR, Stiel L, Cougourdan L, Broussard C, Chafey P, Riès-Kautt M, Meziani F, Toti F, Gaussem P, Anglés-Cano E (2019) DNA-bound elastase of neutrophil extracellular traps degrades plasminogen, reduces plasmin formation, and decreases fibrinolysis: proof of concept in septic shock plasma. FASEB J 33:14270–14280. https://doi.org/10.1096/fj.201901363RRR

    Article  CAS  Google Scholar 

  78. Helms J, Clere-Jehl R, Bianchini E, Le Borgne P, Burban M, Zobairi F, Diehl JL, Grunebaum L, Toti F, Meziani F, Borgel D (2017) Thrombomodulin favors leukocyte microvesicle fibrinolytic activity, reduces NETosis and prevents septic shock-induced coagulopathy in rats. Ann Intensive Care 7:118. https://doi.org/10.1186/s13613-017-0340-z

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  79. Delabranche X, Stiel L, Severac F, Galoisy AC, Mauvieux L, Zobairi F, Lavigne T, Toti F, Angles-Cano E, Meziani F, Boisrame-Helms J (2017) Evidence of netosis in septic shock-induced disseminated intravascular coagulation. Shock 47:313–317. https://doi.org/10.1097/SHK.0000000000000719

    Article  CAS  PubMed  Google Scholar 

  80. Stiel L, Delabranche X, Galoisy AC, Severac F, Toti F, Mauvieux L, Meziani F, Boisrame-Helms J (2016) Neutrophil fluorescence: a new indicator of cell activation during septic shock-induced disseminated intravascular coagulation. Crit Care Med 44:e1132–e1136. https://doi.org/10.1097/CCM.0000000000001851

    Article  CAS  PubMed  Google Scholar 

  81. Vlaar APJ (2022) Blood transfusion: the search for the sweet spot. Intensive Care Med. https://doi.org/10.1007/s00134-022-06799-7

    Article  PubMed Central  PubMed  Google Scholar 

  82. Vlaar APJ, Dionne JC, de Bruin S, Wijnberge M, Raasveld SJ, van Baarle F, Antonelli M, Aubron C, Duranteau J, Juffermans NP, Meier J, Murphy GJ, Abbasciano R, Muller MCA, Lance M, Nielsen ND, Schochl H, Hunt BJ, Cecconi M, Oczkowski S (2021) Transfusion strategies in bleeding critically ill adults: a clinical practice guideline from the European Society of Intensive Care Medicine. Intensive Care Med 47:1368–1392. https://doi.org/10.1007/s00134-021-06531-x

    Article  PubMed Central  PubMed  Google Scholar 

  83. Levy JH (2010) Antifibrinolytic therapy: new data and new concepts. Lancet 376:3–4. https://doi.org/10.1016/S0140-6736(10)60939-7

    Article  PubMed  Google Scholar 

  84. Baksaas-Aasen K, Gall LS, Stensballe J, Juffermans NP, Curry N, Maegele M, Brooks A, Rourke C, Gillespie S, Murphy J, Maroni R, Vulliamy P, Henriksen HH, Pedersen KH, Kolstadbraaten KM, Wirtz MR, Kleinveld DJB, Schafer N, Chinna S, Davenport RA, Naess PA, Goslings JC, Eaglestone S, Stanworth S, Johansson PI, Gaarder C, Brohi K (2021) Viscoelastic haemostatic assay augmented protocols for major trauma haemorrhage (ITACTIC): a randomized, controlled trial. Intensive Care Med 47:49–59. https://doi.org/10.1007/s00134-020-06266-1

    Article  CAS  PubMed  Google Scholar 

  85. Li X, Ma X (2017) The role of heparin in sepsis: much more than just an anticoagulant. Br J Haematol 179:389–398. https://doi.org/10.1111/bjh.14885

    Article  CAS  PubMed  Google Scholar 

  86. Helms J, Middeldorp S, Spyropoulos AC (2022) Thromboprophylaxis in critical care. Intensive Care Med. https://doi.org/10.1007/s00134-022-06850-7

    Article  PubMed Central  PubMed  Google Scholar 

  87. Duranteau J, Taccone FS, Verhamme P, Ageno W, Force EVGT (2018) European guidelines on perioperative venous thromboembolism prophylaxis: intensive care. Eur J Anaesthesiol 35:142–146. https://doi.org/10.1097/EJA.0000000000000707

    Article  PubMed  Google Scholar 

  88. Schunemann HJ, Cushman M, Burnett AE, Kahn SR, Beyer-Westendorf J, Spencer FA, Rezende SM, Zakai NA, Bauer KA, Dentali F, Lansing J, Balduzzi S, Darzi A, Morgano GP, Neumann I, Nieuwlaat R, Yepes-Nunez JJ, Zhang Y, Wiercioch W (2018) American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients. Blood Adv 2:3198–3225. https://doi.org/10.1182/bloodadvances.2018022954

    Article  PubMed Central  PubMed  Google Scholar 

  89. Wang C, Chi C, Guo L, Wang X, Guo L, Sun J, Sun B, Liu S, Chang X, Li E (2014) Heparin therapy reduces 28-day mortality in adult severe sepsis patients: a systematic review and meta-analysis. Crit Care 18:563. https://doi.org/10.1186/s13054-014-0563-4

    Article  PubMed Central  PubMed  Google Scholar 

  90. Sakuragawa N, Hasegawa H, Maki M, Nakagawa M, Nakashima M (1993) Clinical evaluation of low-molecular-weight heparin (FR-860) on disseminated intravascular coagulation (DIC)–a multicenter co-operative double-blind trial in comparison with heparin. Thromb Res 72:475–500. https://doi.org/10.1016/0049-3848(93)90109-2

    Article  CAS  PubMed  Google Scholar 

  91. Fourrier F, Jourdain M, Tournois A, Caron C, Goudemand J, Chopin C (1995) Coagulation inhibitor substitution during sepsis. Intensive Care Med 21(2):S264-268

    Article  PubMed  Google Scholar 

  92. Giebler R, Schmidt U, Koch S, Peters J, Scherer R (1999) Combined antithrombin III and C1-esterase inhibitor treatment decreases intravascular fibrin deposition and attenuates cardiorespiratory impairment in rabbits exposed to Escherichia coli endotoxin. Crit Care Med 27:597–604

    Article  CAS  PubMed  Google Scholar 

  93. Allingstrup M, Wetterslev J, Ravn FB, Moller AM, Afshari A (2016) Antithrombin III for critically ill patients: a systematic review with meta-analysis and trial sequential analysis. Intensive Care Med 42:505–520. https://doi.org/10.1007/s00134-016-4225-7

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  94. Warren BL, Eid A, Singer P, Pillay SS, Carl P, Novak I, Chalupa P, Atherstone A, Penzes I, Kubler A, Knaub S, Keinecke HO, Heinrichs H, Schindel F, Juers M, Bone RC, Opal SM, KyberSept Trial Study G (2001) Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 286:1869–1878

    Article  CAS  PubMed  Google Scholar 

  95. Dhainaut JF, Laterre PF, Janes JM, Bernard GR, Artigas A, Bakker J, Riess H, Basson BR, Charpentier J, Utterback BG, Vincent JL, Recombinant Human Activated Protein CWEISSG (2003) Drotrecogin alfa (activated) in the treatment of severe sepsis patients with multiple-organ dysfunction: data from the PROWESS trial. Intensive Care Med 29:894–903. https://doi.org/10.1007/s00134-003-1731-1

    Article  PubMed  Google Scholar 

  96. Levi M (2015) Recombinant soluble thrombomodulin: coagulation takes another chance to reduce sepsis mortality. J Thromb Haemost 13:505–507. https://doi.org/10.1111/jth.12868

    Article  CAS  PubMed  Google Scholar 

  97. Levi M, van der Poll T (2013) Endothelial injury in sepsis. Intensive Care Med 39:1839–1842. https://doi.org/10.1007/s00134-013-3054-1

    Article  PubMed  Google Scholar 

  98. Weiler H, Isermann BH (2003) Thrombomodulin. J Thromb Haemost 1:1515–1524. https://doi.org/10.1046/j.1538-7836.2003.00306.x

    Article  CAS  PubMed  Google Scholar 

  99. Ito T, Maruyama I (2011) Thrombomodulin: protectorate God of the vasculature in thrombosis and inflammation. J Thromb Haemost 9(Suppl 1):168–173. https://doi.org/10.1111/j.1538-7836.2011.04319.x

    Article  CAS  PubMed  Google Scholar 

  100. Li YH, Kuo CH, Shi GY, Wu HL (2012) The role of thrombomodulin lectin-like domain in inflammation. J Biomed Sci 19:34. https://doi.org/10.1186/1423-0127-19-34

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  101. Umemura Y, Yamakawa K (2016) Efficacy and safety of anticoagulant therapy in three specific populations with sepsis: a meta-analysis of randomized controlled trials: reply. J Thromb Haemost. https://doi.org/10.1111/jth.13473

    Article  PubMed  Google Scholar 

  102. Hsu C, Hutt E, Bloomfield DM, Gailani D, Weitz JI (2021) Factor XI inhibition to uncouple thrombosis from hemostasis: JACC review topic of the week. J Am Coll Cardiol 78:625–631. https://doi.org/10.1016/j.jacc.2021.06.010

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  103. Preis M, Hirsch J, Kotler A, Zoabi A, Stein N, Rennert G, Saliba W (2017) Factor XI deficiency is associated with lower risk for cardiovascular and venous thromboembolism events. Blood 129:1210–1215. https://doi.org/10.1182/blood-2016-09-742262

    Article  CAS  PubMed  Google Scholar 

  104. Gailani D, Gruber A (2016) Factor XI as a therapeutic target. Arterioscler Thromb Vasc Biol 36:1316–1322. https://doi.org/10.1161/ATVBAHA.116.306925

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  105. Li T, Liu J, Wu W (2022) Factor XI, a potential target for anticoagulation therapy for venous thromboembolism. Front Cardiovasc Med 9:975767. https://doi.org/10.3389/fcvm.2022.975767

    Article  PubMed Central  PubMed  Google Scholar 

  106. Fredenburgh JC, Weitz JI (2021) Factor XI as a target for new anticoagulants. Hamostaseologie 41:104–110. https://doi.org/10.1055/a-1384-3715

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Université de Strasbourg (UNISTRA), Faculté de Médecine, Hôpitaux Universitaires de Strasbourg, Service de Médecine Intensive-Réanimation, Nouvel Hôpital Civil, 1, place de l’Hôpital, 67091, Strasbourg Cedex, France

    Julie Helms & Ferhat Meziani

  2. INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine (RNM), FMTS, Strasbourg, France

    Julie Helms & Ferhat Meziani

  3. Department of Emergency and Disaster Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

    Toshiaki Iba

  4. Hematology Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Jean Marie Connors

  5. Department of Acute and Critical Care Medicine, Sapporo Higashi Tokushukai Hospital, Sapporo, USA

    Satoshi Gando

  6. Division of Acute and Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, Hokkaido University Faculty of Medicine, Sapporo, Japan

    Satoshi Gando

  7. Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands

    Marcel Levi

  8. Department of Medicine, University College London Hospitals NHS Foundation Trust, and Cardio-Metabolic Programme-NIHR UCLH/UCL BRC London, London, UK

    Marcel Levi

  9. Department of Anesthesiology, Critical Care, and Surgery, Duke University School of Medicine, Durham, NC, USA

    Jerrold H. Levy

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  1. Julie Helms
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  2. Toshiaki Iba
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  5. Marcel Levi
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Conflicts of interest

SG has no conflict of interest to declare. JH has received honoraria for lectures from Diagnostica Stago, Pfizer PFE France, Sanofi Aventis France, Inotrem, MSD, and Shionogi. TI participated in advisory boards of Japan Blood Products Organization, Asahi Kasei Pharmaceuticals, and Toray Medical. JMC reports personal fees for scientific advisory boards and consulting from Abbott, Anthos, Alnylam, Bristol Myers Squibb, Five Prime Therapeutics, Pfizer, Roche, and Sanofi, and research funding from CSL Behring. ML has received grants and has participated in advisory boards of NovoNordisk, Eli Lilly, Asahi Kasei Pharmaceuticals America, and Johnson & Johnson. FM has received funding from Diagnostica Stago and Octapharma. JHL serves on the Steering Committees for Instrumentation Laboratories, Merck, and Octapharma.

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Helms, J., Iba, T., Connors, J.M. et al. How to manage coagulopathies in critically ill patients. Intensive Care Med 49, 273–290 (2023). https://doi.org/10.1007/s00134-023-06980-6

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