Characterization and Usefulness of Clot-Fibrinolysis Waveform Analysis in Critical Care Patients with Enhanced or Suppressed Fibrinolysis

Abstract

Introduction Recently, clot-fibrinolysis waveform analysis (CFWA), which is a coagulation and fibrinolysis global assay based on assessing the activated partial thromboplastin time with tissue-type plasminogen activator, was developed. This study aimed to investigate the characteristics of CFWA using plasma samples from patients in the critical care unit.

Materials and Methods The fibrinolysis times using CFWA were measured in 298 plasma samples. These samples were divided into three groups based on the reference interval (RI) of fibrinolysis time using CFWA: shortened group, less than RI; within group, within RI; prolonged group, more than RI. The coagulation and fibrinolysis markers, including D-dimer, plasmin–α₂ plasmin inhibitor complex (PIC), fibrin monomer complex (FMC), plasmin–α₂ plasmin inhibitor (α₂-PI), plasminogen (Plg), and fibrinogen (Fbg) were analyzed and compared among the three groups.

Results The FMC level decreased in the order of shortened, within, and prolonged groups, and the decrease was statistically significant among all three group pairs. The opposite tendency was observed for Fbg and fibrinolysis-related markers of α₂-PI and Plg, and significant differences were recognized in all pair comparisons except for between within and prolonged groups in Plg. The mean values of the fibrinolysis markers D-dimer and PIC in all three groups were higher than the cut-off values, and the PIC value differed significantly between the within and prolonged groups.

Conclusion The fibrinolysis reaction was detected in all three groups, but the status differed. CFWA has the potential to reflect the fibrinolysis status in one global assay.

Keywords

clot-fibrinolysis waveform analysis - coagulation and fibrinolysis - fibrin - tissue-type plasminogen activator - fibrinolysis

Data Availability Statement

The corresponding author can disclose the data on request.

Authors' Contribution

T.T. contributed to the conception of the study and manuscript preparation. O.K. contributed to the sample measurements, data analysis, creation of figures, and revision of the intellectual content. M.H. contributed to the sample collection, manuscript preparation, and revision of the intellectual content. All authors have read and approved the final manuscript version before submission.

Publikationsverlauf

Eingereicht: 05. März 2023

Angenommen: 10. Juli 2023

Accepted Manuscript online:
01. August 2023

Artikel online veröffentlicht:
05. September 2023

• References

• 1 Gando S, Sawamura A, Hayakawa M. Trauma, shock, and disseminated intravascular coagulation: lessons from the classical literature. Ann Surg 2011; 254 (01) 10-19
• 2 Moore HB, Gando S, Iba T. et al; Subcommittees on Fibrinolysis, Disseminated Intravascular Coagulation, and Perioperative and Critical Care Thrombosis and Hemostasis. Defining trauma-induced coagulopathy with respect to future implications for patient management: communication from the SSC of the ISTH. J Thromb Haemost 2020; 18 (03) 740-747
• 3 Wada T, Shiraishi A, Gando S. et al. Disseminated intravascular coagulation immediately after trauma predicts a poor prognosis in severely injured patients. Sci Rep 2021; 11 (01) 11031
• 4 Hayakawa M, Maekawa K, Kushimoto S. et al. High D-dimer levels predict a poor outcome in patients with severe trauma, even with high fibrinogen levels on arrival: a multicenter retrospective study. Shock 2016; 45 (03) 308-314
• 5 Sawamura A, Hayakawa M, Gando S. et al. Disseminated intravascular coagulation with a fibrinolytic phenotype at an early phase of trauma predicts mortality. Thromb Res 2009; 124 (05) 608-613
• 6 Hotchkiss RS, Moldawer LL, Opal SM, Reinhart K, Turnbull IR, Vincent JL. Sepsis and septic shock. Nat Rev Dis Primers 2016; 2: 16045
• 7 Levi M, Schultz M, van der Poll T. Sepsis and thrombosis. Semin Thromb Hemost 2013; 39 (05) 559-566
• 8 Umemura Y, Yamakawa K, Hayakawa M, Hamasaki T, Fujimi S. Japan Septic Disseminated Intravascular Coagulation (J-Septic DIC) study group. Screening itself for disseminated intravascular coagulation may reduce mortality in sepsis: a nationwide multicenter registry in Japan. Thromb Res 2018; 161: 60-66
• 9 Asakura H. Classifying types of disseminated intravascular coagulation: clinical and animal models. J Intensive Care 2014; 2 (01) 20
• 10 Lee DH, Lee BK, Jeung KW. et al. Disseminated intravascular coagulation is associated with the neurologic outcome of cardiac arrest survivors. Am J Emerg Med 2017; 35 (11) 1617-1623
• 11 Tsuchida T, Wada T, Gando S. Coagulopathy induced by veno-arterial extracorporeal membrane oxygenation is associated with a poor outcome in patients with out-of-hospital cardiac arrest. Front Med (Lausanne) 2021; 8: 651832
• 12 Ono Y, Hayakawa M, Maekawa K. et al. Fibrin/fibrinogen degradation products (FDP) at hospital admission predict neurological outcomes in out-of-hospital cardiac arrest patients. Resuscitation 2017; 111: 62-67
• 13 Wada H, Matsumoto T, Ohishi K, Shiraki K, Shimaoka M. Update on the clot waveform analysis. Clin Appl Thromb Hemost 2020; 26: 1076029620912027
• 14 Suzuki K, Wada H, Matsumoto T. et al. Usefulness of the APTT waveform for the diagnosis of DIC and prediction of the outcome or bleeding risk. Thromb J 2019; 17: 12
• 15 Shimonishi N, Nogami K, Ogiwara K. et al. Emicizumab improves the stability and structure of fibrin clot derived from factor VIII-deficient plasma, similar to the addition of factor VIII. Haemophilia 2020; 26 (03) e97-e105
• 16 Nogami K, Matsumoto T, Tabuchi Y. et al. Modified clot waveform analysis to measure plasma coagulation potential in the presence of the anti-factor IXa/factor X bispecific antibody emicizumab. J Thromb Haemost 2018; 16 (06) 1078-1088
• 17 Fan BE, Ng J, Chan SSW. et al. COVID-19 associated coagulopathy in critically ill patients: a hypercoagulable state demonstrated by parameters of haemostasis and clot waveform analysis. J Thromb Thrombolysis 2021; 51 (03) 663-674
• 18 Oka S, Wakui M, Fujimori Y. et al. Application of clot-fibrinolysis waveform analysis to assessment of in vitro effects of direct oral anticoagulants on fibrinolysis. Int J Lab Hematol 2020; 42 (03) 292-298
• 19 Nogami K, Matsumoto T, Sasai K, Ogiwara K, Arai N, Shima M. A novel simultaneous clot-fibrinolysis waveform analysis for assessing fibrin formation and clot lysis in haemorrhagic disorders. Br J Haematol 2019; 187 (04) 518-529
• 20 Matsumoto T, Wada H, Fujimoto N. et al. An evaluation of the activated partial thromboplastin time waveform. Clin Appl Thromb Hemost 2018; 24 (05) 764-770
• 21 Shima M, Matsumoto T, Fukuda K. et al. The utility of activated partial thromboplastin time (aPTT) clot waveform analysis in the investigation of hemophilia A patients with very low levels of factor VIII activity (FVIII:C). Thromb Haemost 2002; 87 (03) 436-441
• 22 Matsumoto T, Nogami K, Ogiwara K, Shima M. A putative inhibitory mechanism in the tenase complex responsible for loss of coagulation function in acquired haemophilia A patients with anti-C2 autoantibodies. Thromb Haemost 2012; 107 (02) 288-301
• 23 Matsumoto T, Nogami K, Shima M. A combined approach using global coagulation assays quickly differentiates coagulation disorders with prolonged aPTT and low levels of FVIII activity. Int J Hematol 2017; 105 (02) 174-183
• 24 Matsumoto T, Nogami K, Tabuchi Y. et al. Clot waveform analysis using CS-2000i™ distinguishes between very low and absent levels of factor VIII activity in patients with severe haemophilia A. Haemophilia 2017; 23 (05) e427-e435
• 25 Onishi T, Shimonishi N, Takeyama M. et al. The balance of comprehensive coagulation and fibrinolytic potential is disrupted in patients with moderate to severe COVID-19. Int J Hematol 2022; 115 (06) 826-837
• 26 Onishi T, Nogami K, Ishihara T. et al. A pathological clarification of sepsis-associated disseminated intravascular coagulation based on comprehensive coagulation and fibrinolysis function. Thromb Haemost 2020; 120 (09) 1257-1269
• 27 Sidelmann JJ, Gram J, Jespersen J, Kluft C. Fibrin clot formation and lysis: basic mechanisms. Semin Thromb Hemost 2000; 26 (06) 605-618
• 28 Ieko M, Nakabayashi T, Tarumi T. et al. Soluble fibrin monomer degradation products as a potentially useful marker for hypercoagulable states with accelerated fibrinolysis. Clin Chim Acta 2007; 386 (1–2): 38-45
• 29 Kumano O, Ieko M, Komiyama Y. et al. Basic evaluation of the newly developed “Lias Auto P-FDP” assay and the influence of plasmin-α2 plasmin inhibitor complex values on discrepancy in the comparison with “Lias Auto D-Dimer Neo” assay. Clin Lab 2018; 64 (04) 433-442
• 30 Gando S, Kameue T, Nanzaki S, Nakanishi Y. Massive fibrin formation with consecutive impairment of fibrinolysis in patients with out-of-hospital cardiac arrest. Thromb Haemost 1997; 77 (02) 278-282
• 31 Saito T, Hayakawa M, Honma Y. et al. Relationship between severity of fibrinolysis based on rotational thromboelastometry and conventional fibrinolysis markers. Clin Appl Thromb Hemost 2020; 26: 1076029620933003
• 32 Gando S, Tedo I, Kubota M. Posttrauma coagulation and fibrinolysis. Crit Care Med 1992; 20 (05) 594-600
• 33 Chapman MP, Moore EE, Moore HB. et al. Overwhelming tPA release, not PAI-1 degradation, is responsible for hyperfibrinolysis in severely injured trauma patients. J Trauma Acute Care Surg 2016; 80 (01) 16-23 , discussion 23–25
• 34 Hayakawa M, Tsuchida T, Honma Y. et al. Fibrinolytic system activation immediately following trauma was quickly and intensely suppressed in a rat model of severe blunt trauma. Sci Rep 2021; 11 (01) 20283
• 35 Chandler WL, Jascur ML, Henderson PJ. Measurement of different forms of tissue plasminogen activator in plasma. Clin Chem 2000; 46 (01) 38-46
• 36 Shapiro NI, Schuetz P, Yano K. et al. The association of endothelial cell signaling, severity of illness, and organ dysfunction in sepsis. Crit Care 2010; 14 (05) R182
• 37 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
• 38 Ware LB, Matthay MA, Parsons PE, Thompson BT, Januzzi JL, Eisner MD. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Clinical Trials Network. Pathogenetic and prognostic significance of altered coagulation and fibrinolysis in acute lung injury/acute respiratory distress syndrome. Crit Care Med 2007; 35 (08) 1821-1828
• 39 Wada T, Gando S, Mizugaki A. et al. Coagulofibrinolytic changes in patients with disseminated intravascular coagulation associated with post-cardiac arrest syndrome–fibrinolytic shutdown and insufficient activation of fibrinolysis lead to organ dysfunction. Thromb Res 2013; 132 (01) e64-e69
• 40 Mertens I, Verrijken A, Michiels JJ, Van der Planken M, Ruige JB, Van Gaal LF. Among inflammation and coagulation markers, PAI-1 is a true component of the metabolic syndrome. Int J Obes 2006; 30 (08) 1308-1314
• 41 Sprengers ED, Kluft C. Plasminogen activator inhibitors. Blood 1987; 69 (02) 381-387
• 42 Gando S, Levi M, Toh CH. Disseminated intravascular coagulation. Nat Rev Dis Primers 2016; 2: 16037