FIBRINOLYSIS DISORDERS IN SEPSIS: THE IMPORTANCE OF EARLY DETECTION OF ABNORMALITIES IN SEPSIS-INDUCED COAGULOPATHY AND AVAILABLE LABORATORY MARKERS OF FIBRINOLYSIS
Keywords:
sepsis-induced coagulopathy; fibrinolysis; fibrinolysis damage; viscoelastic tests.
Abstract
Sepsis is a life-threatening organ dysfunction caused by an ineffective host response to infection. Some of the most prevalent disorders in sepsis are hemostatic disorders. Sepsis often develops a state of impaired anticoagulant activity and fibrinolysis suppression, called sepsis-induced coagulopathy. Damage to the fibrinolytic system is increasingly considered a key factor in sepsis-induced coagulopathy. Impaired fibrinolysis in sepsis can contribute to undesirable outcomes such as microvascular thrombosis, organ dysfunction, and increased mortality. Given that one of the postulates related to sepsis is that prompt diagnosis and quick care are necessary, it would be of great importance to diagnose various forms of coagulopathies in sepsis at the beginning of their occurrence, for an adequate therapeutic approach. In this sense, easily accessible, routine diagnostic tests are necessary. Conventional laboratory tests for coagulopathies so far fail to fully define sepsis-induced coagulopathy. Particularly challenging is the testing of hypofibrinolysis in routine practice. The objectives of our study were to review the available scientific literature to investigate the relationship between inflammation and coagulation in sepsis, fibrinolysis disorders in sepsis-induced coagulopathy, to determine the importance of early recognition of these disorders in sepsis, and to investigate the available laboratory markers of fibrinolysis and coagulopathies.
Key words: sepsis-induced coagulopathy; fibrinolysis; fibrinolysis damage; viscoelastic tests.
References
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36. 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: 1853-59.
37. Ghansah H, Orban-Kalmandi R, Debreceni IB, et al. Low factor XIII levels and altered fibrinolysis in patients with multiple myeloma. Thromb Res 2024; 234: 12-20.
38. Cohen T, Haas T, Cushing MM. The strengths and weaknesses of viscoelastic testing compared to traditional coagulation testing. Transfusion 2020; 6 :S21-8.
39. 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.
40. Kim SM, Kim SI, Yu G, et al. Role of thromboelastography in the evaluation of septic shock patients with normal prothrombin time and activated partial thromboplastin time. Sci Rep 2021; 11: 11833.
41. Enk NM, Kutter APN, Kuemmerle-Fraune C, Sigrist NE. Correlation of plasma coagulation tests and fibrinogen (Clauss) with rotational thromboelastometry parameters and prediction of bleeding in dogs. J Vet Intern Med 2019; 33: 132-40.
42. Moore HB. Fibrinolysis Shutdown and Hypofibrinolysis Are Not Synonymous Terms: The Clinical Significance of Differentiating Low Fibrinolytic States. Semin Thromb Hemost 2023; 49: 433-43.
43. Mohapatra P, Kumar A, Singh RK, et al. The Effect of Sepsis and Septic Shock on the Viscoelastic Properties of Clot Quality and Mass Using Thromboelastometry: A Prospective Observational Study. Indian J Crit Care Med 2023; 27: 625-34.
44. Hans GA, Besser MW. The place of viscoelastic testing in clinical practice. Br J Haematol 2016; 173: 37-48.
45. Borawski J, Myśliwiec M. Plasma fibrinogen level is an important determinant of prolonged euglobulin clot lysis time in hemodialysis patients. Clin Appl Thromb Hemost 2001; 7: 296-9.
2. Rhodes A, Evans LE, Alhazzani W, et al. Surviving sepsis campaign: International guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 2017; 43: 304-77.
3. 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: 200-11.
4. Dimić N, Đurić M, Nenadić I, et al. Razvoj definicije sepse. Srpski medicinski časopis Lekarske komore 2023; 4: 75-81.
5. Kell DB, Pretorius E. To What Extent Are the Terminal Stages of Sepsis, Septic Shock, Systemic Inflammatory Response Syndrome, and Multiple Organ Dysfunction Syndrome Actually Driven by a Prion/Amyloid Form of Fibrin? Semin Thromb Hemost 2018; 44: 224-38.
6. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315: 801-10.
7. Kim HI, Park S. Sepsis: Early Recognition and Optimized Treatment. Tuberc Respir Dis (Seoul) 2019; 82: 6-14.
8. Larsen JB, Aggerbeck MA, Larsen KM, Hvas CL, Hvas AM. Fibrin Network Formation and Lysis in Septic Shock Patients. Int J Mol Sci 2021; 22: 9540.
9. 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: 19.
10. Helms J, Iba T, Connors JM, et al. How to manage coagulopathies in critically ill patients. Intensive Care Med 2023; 49: 273-90.
11. Iba T, Helms J, Levi M, Levy JH. Thromboinflammation in acute injury: infections, heatstroke, and trauma. J Thromb Haemost 2024; 22: 7-22.
12. Iba T, Helms J, Maier CL, Levi M, Scarlatescu E, Levy JH. The role of thromboinflammation in acute kidney injury among patients with septic coagulopathy. J Thromb Haemost 2024; 22: 1530-40.
13. Delano MJ, Ward PA. The immune system's role in sepsis progression, resolution, and long-term outcome. Immunol Rev 2016; 274: 330-53.
14. Medcalf RL, Keragala CB. Fibrinolysis: A Primordial System Linked to the Immune Response. Int J Mol Sci 2021; 22: 3406.
15. Bergmann S, Hammerschmidt S. Fibrinolysis and host response in bacterial infections. Thromb Haemost 2007; 98: 512-20.
16. Williams B, Zou L, Pittet JF, Chao W. Sepsis-Induced Coagulopathy: A Comprehensive Narrative Review of Pathophysiology, Clinical Presentation, Diagnosis, and Management Strategies. Anesth Analg 2024; 138: 696-711.
17. Hvas CL, Larsen JB. The Fibrinolytic System and Its Measurement: History, Current Uses and Future Directions for Diagnosis and Treatment. International Journal of Molecular Sciences 2023; 24: 14179.
18. Rijken DC, Uitte de Willige S. Inhibition of fibrinolysis by coagulation factor XIII. Biomed Res Int 2017; 2017: 1209676.
19. Spasić, I. Specifičnosti hemostaznog mehanizma kod obolelih od SARS-CoV-2 virusne infekcije. Doktorska disertacija, Novi Sad: Medicinski fakultet, 2022.
20. Gando S. Role of Fibrinolysis in Sepsis. Semin Thromb Hemost 2013; 39: 392-99.
21. Degen JL, Bugge TH, Goguen JD. Fibrin and fibrinolysis in infection and host defense. J Thromb Haemost 2007; 5: 24–31.
22. Brewer JS, Hvas CL, Hvas AM, Larsen JB. Impaired Whole-Blood Fibrinolysis is a Predictor of Mortality in Intensive Care Patients. TH Open 2024; 08: 164-74.
23. Coupland LA, Rabbolini DJ, Schoenecker JG, et al. Point-of-care diagnosis and monitoring of fibrinolysis resistance in the critically ill: results from a feasibility study. Crit Care 2023; 27: 55.
24. Singhal S, Ranga S, Chawla AS, Kamra R. Role of Antithrombin III, Plasminogen, Protein C and Protein S in Deep Vein Thrombosis in Indian Population. IJSHR 2019; 4: 54-9.
25. Levi M, Van Der Poll T. Thrombomodulin in sepsis. Minerva Anestesiol 2013; 79: 294-8.
26. Kato H, Hagihara M, Asai N. Efficacy and safety of recombinant human soluble thrombomodulin in patients with sepsis-induced disseminated intravascular coagulation - A meta-analysis. Thromb Res 2023; 226: 165-72.
27. Wang G, Hao C, Yao S, Wang Y, Xu Z, Zhao H, et al. Exploring the Mediating Role of Multiple Organ Dysfunction in Sepsis-Induced Disseminated Intravascular Coagulation and Its Impact on Worsening Prognosis. Clin Appl Thromb Hemost 2024; 30: 10760296241271358.
28. Iba T, Helms J, Levy JH. Sepsis-induced coagulopathy (SIC) in the management of sepsis. Ann Intensive Care 2024; 14: 148.
29. Egi M, Ogura H, Yatabe T, et al. The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020). Acute Med Surg 2021; 8: e659.
30. Larsen JB, Aggerbeck MA, Granfeldt A, Schmidt M, Hvas AM, Adelborg K. Disseminated intravascular coagulation diagnosis: Positive predictive value of the ISTH score in a Danish population. Res Pract Thromb Haemost 2021; 5: e12636.
31. Hartmann J, Hermelin D, Levy JH. Viscoelastic testing: an illustrated review of technology and clinical applications. Res Pract Thromb Haemost 2022; 7:100031.
32. Govil D, Pal D. Point-of-care testing of coagulation in intensive care unit: Role of thromboelastography. Indian J Crit Care Med 2019; 23: S202-6.
33. Zátroch I, Dinya E, Fazakas J. New under the sun: ClotPro's ECA-test detects hyperfibrinolysis in a higher number of patients, more frequently and 9 min earlier. Blood Coagul Fibrinolysis 2023; 34: 99-104.
34. Bui-Thi HD, Kien To Gia, Le Minh K. Coagulation profiles in patients with sepsis/septic shock identify mixed hypo-hypercoagulation patterns based on rotational thromboelastometry: A prospective observational study. Thromb Res 2023; 227: 51-9.
35. Zheng Z, Mukhametova L, Boffa MB, et al. Assays to quantify fibrinolysis: strengths and limitations. Communication from the International Society on Thrombosis and Haemostasis Scientific and Standardization Committee on fibrinolysis. J Thromb Haemost 2023; 21: 1043-54.
36. 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: 1853-59.
37. Ghansah H, Orban-Kalmandi R, Debreceni IB, et al. Low factor XIII levels and altered fibrinolysis in patients with multiple myeloma. Thromb Res 2024; 234: 12-20.
38. Cohen T, Haas T, Cushing MM. The strengths and weaknesses of viscoelastic testing compared to traditional coagulation testing. Transfusion 2020; 6 :S21-8.
39. 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.
40. Kim SM, Kim SI, Yu G, et al. Role of thromboelastography in the evaluation of septic shock patients with normal prothrombin time and activated partial thromboplastin time. Sci Rep 2021; 11: 11833.
41. Enk NM, Kutter APN, Kuemmerle-Fraune C, Sigrist NE. Correlation of plasma coagulation tests and fibrinogen (Clauss) with rotational thromboelastometry parameters and prediction of bleeding in dogs. J Vet Intern Med 2019; 33: 132-40.
42. Moore HB. Fibrinolysis Shutdown and Hypofibrinolysis Are Not Synonymous Terms: The Clinical Significance of Differentiating Low Fibrinolytic States. Semin Thromb Hemost 2023; 49: 433-43.
43. Mohapatra P, Kumar A, Singh RK, et al. The Effect of Sepsis and Septic Shock on the Viscoelastic Properties of Clot Quality and Mass Using Thromboelastometry: A Prospective Observational Study. Indian J Crit Care Med 2023; 27: 625-34.
44. Hans GA, Besser MW. The place of viscoelastic testing in clinical practice. Br J Haematol 2016; 173: 37-48.
45. Borawski J, Myśliwiec M. Plasma fibrinogen level is an important determinant of prolonged euglobulin clot lysis time in hemodialysis patients. Clin Appl Thromb Hemost 2001; 7: 296-9.