Early Inhibition of Activated Fibrinolysis Predicts Microbial Infection, Shock and Mortality in Febrile Medical Patients

Summary

To evaluate the contribution of an imbalance between coagulation activation and fibinolysis activation and inhibition to morbidity and mortality in sepsis, we determined in medical hospitalized patients at inclusion (day 0) for fever (temperature above 38.0° C axillary or 38.3° C rectally), and daily thereafter for two days, circulating thrombin-antithrombin III (TAT) complexes, plasmin- ₂-antiplasmin (PAP) complexes (day 0 only), tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) and interleukin (IL)-6, the latter as a marker of the inflammatory host response. Study variables were 1) positive microbiological results for specimens from local sites associated with a clinical infection, positive blood cultures (including parasitemia) or both, within 7 days after inclusion, 2) development of shock, i.e. systolic blood pressure <90 mmHg or a reduction of 40 mmHg from baseline within 7 days after inclusion, and 3) death related to febrile illness within 28 days after inclusion. The peak plasma levels of TAT complexes were elevated in 44% and the PAP complexes in all patients. The t-PA and PAI-1 levels were elevated in 74 and 94% of patients, respectively. Values for TAT and PAP did not differ among subgroups, while peak t-PA and IL-6 levels were higher in patients with positive microbiological results, developing shock or ultimately dying than in those without the complications (p <0.005). Peak PAI-1 levels were elevated in patients developing shock and ultimate death versus those with an uncomplicated course (p <0.05). Peak IL-6 related to PAI-1 and t-PA levels, which interrelated. Patients with elevated TAT levels had increased plasma levels of IL-6, PAP, PAI-1 and t-PA versus those with normal TAT (p <0.05). Our data indicate that inhibition of activated fibrinolysis, which may partly depend on both cytokinemia and activation of coagulation, predicts microbial infection, septic shock and mortality of febrile medical patients. This suggests an early pathogenic role of inhibition of activated fibrinolysis in the downhill course of serious microbial infection.

Keywords

Fever - coagulation - fibrinolysis - septic shock - death - PAI-1 - t-PA - TAT

• References

• 1 Vervloet MG, Thijs LG, Hack CE. Derangements of coagulation and fibrinolysis in critically ill patients with sepsis and septic shock. Sem Thromb Hemost 1998; 24: 33-44.
• 2 Levi M, De Jonge E, Van der Poll T, Ten Cate H. Disseminated intravascular coagulation. Thromb Haemost 1999; 82: 695-705.
• 3 Páramo JA, Fernández Diaz FJ, Rocha E. Plasminogen activator inhibitor activity in bacterial infection. Thromb Haemost 1988; 59: 451-4.
• 4 Hesselvik JF, Blömback M, Brodin B, Maller R. Coagulation, fibrinolysis and kallikrein systems in sepsis: relation to outcome. Crit Care Med 1989; 17: 724-33.
• 5 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: 99-102.
• 6 Philippé J, Offner F, Declerck PJ, Leroux-Roels G, Vogelaers D, Baele G, Collen D. Fibrinolysis and coagulation in patients with infectious disease and sepsis. Thromb Haemost 1991; 65: 291-5.
• 7 Dofferhoff ASM, Bom VJJ, De Vries-Hospers HG, Van Ingen J, Van der Meer J, Hazenberg BPC, Mulder SOM, Weits J. 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: 185-92.
• 8 Lorente JA, Garcia-Frade LJ, Landin L, de Pablo R, Torrado C, Renes E, Garcia Avello A. Time course of hemostatic abnormalities in sepsis and its relation to outcome. Chest 1993; 103: 1536-42.
• 9 Saito M, Asakura H, Jokaji H, Uotani C, Kumabashiri I, Morishita E, Yamazaki M, Yoshida T, Aoshima K, Matsuda T. Haemostatic and fibrinolytic parameters in septic patients with leukopenia or leukocytosis. Eur J Haematol 1995; 54: 176-9.
• 10 Kidokoro A, Iba T, Fukunaga M, Yagi Y. Alterations in coagulation and fibrinolysis during sepsis. Shock 1996; 5: 223-8.
• 11 Leithäuser B, Matthias FR, Nicolai U, Voss R. Hemostatic abnormalities and the severity of illness in patients at the onset of clinically defined sepsis. Intensive Care Med 1996; 22: 631-6.
• 12 Gando S, Kameue T, Nanzaki S, Nakanishi Y. Disseminated intravascular coagulation is a frequent complication of systemic inflammatory response syndrome. Thromb Haemost 1996; 75: 224-8.
• 13 Pralong G, Calandra T, Glauser M-P, Schellekens J, Verhoef J, Bachmann F, Kruithof EKO. Plasminogen activator inhibitor 1: a new prognostic marker in septic shock. Thromb Haemost 1989; 61: 459-62.
• 14 Mesters RM, Flörke N, Ostermann H, Kienast J. Increase of plasminogen activator inhibitor levels predicts outcome of leukocytopenic patients with sepsis. Thromb Haemost 1996; 75: 902-7.
• 15 Groeneveld ABJ, Kindt I, Raijmakers PGHM, Hack CE, Thijs LG. Systemic coagulation and fibrinolysis in patients with or at risk for the adult respiratory distress syndrome. Thromb Haemost 1997; 78: 1444-9.
• 16 Suffredini AF, Harpel PC, Parrillo JE. Promotion and subsequent inhibition of plasminogen activator after administration of intravenous endotoxin to normal subjects. N Engl J Med 1989; 320: 1165-72.
• 17 Van Deventer SJH, 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: 2520-6.
• 18 Biemond BJ, Levi M, Ten Cate H, Van der Poll T, Büller HR, Hack CE, Ten Cate JW. Plasminogen activator and plasminogen activator inhibitor I release during experimental endotoxaemia in chimpanzees: effect of interventions in the cytokine and coagulation cascades. Clin Sci 1995; 88: 587-94.
• 19 Bernard G, Vincent J-L, Laterre P-F, LaRosa SP, Dhainaut J-F, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344: 699-709.
• 20 Stouthard JML, Levi M, Hack CE, Veenhof CHN, Romijn HA, Sauerwein HP, Van der Poll T. Interleukin-6 stimulates coagulation, not fibrinolysis, in humans. Thromb Haemost 1996; 76: 738-42.
• 21 Hack CE, De Groot ER, Felt-Bersma RJF, Nuijens JH, Strack van Schijndel RJM, Eerenberg-Belmer AJM, Thijs LG, Aarden LA. Increased plasma levels of interleukin 6 in sepsis. Blood 1989; 74: 1704-10.
• 22 Wada H, Tanigawa M, Wakita Y, Nakase T, Minamikawa K, Kaneko T, Ohiwa M, Kageyama S, Kobayashi T, Noguchi T, Deguchi K, Shirakawa S. Increased plasma level of interleukin-6 in disseminated intravascular coagulation. Blood Coagulat Fibrinol 1993; 4: 583-90.
• 23 Mestries J-C, Kruithof EKO, Gascon M-P, Herodin F, Agay D, Ythier A. In vivo modulation of coagulation and fibrinolysis by recombinant glycosylated human interleukin-6 in baboons. Eur Cytokine Netw 1994; 5: 275-81.
• 24 Presterl E, Staudinger T, Petterman M, Lassnigg A, Burgmann H, Winkler S, Frass M, Graninger W. Cytokine profile and correlation to the APACHE III and MPM II scores in patients with sepsis. Am J Respir Crit Care Med 1997; 156: 825-32.
• 25 Bossink AWJ, Groeneveld ABJ, Hack CE, Thijs LG. The clinical host response to microbial infection in medical patients with fever. Chest 1999; 116: 380-90.
• 26 Hanss M, Collen D. Secretion of tissue-type plasminogen activator and plasminogen activator inhibitor by cultured human endothelial cells: modulation by thrombin, endotoxin, and histamine. J Lab Clin Med 1987; 109: 97-104.
• 27 Haj MA, Neilly IJ, Robbie LA, Adey GD, Bennett B. Influence of white blood cells on the fibrinolytic response to sepsis: studies of septic patients with or without severe leucopenia. Br J Haematol 1995; 90: 541-7.