title: 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.
abstract: BACKGROUND
  Current criteria for early diagnosis of coagulopathy in sepsis are limited. We postulated that coagulopathy is already complicated with sepsis in the initial phase, and severe coagulopathy or disseminated intravascular coagulation (DIC) becomes overt after progressive consumption of platelet and coagulation factors. To determine early diagnostic markers for severe coagulopathy, we evaluated plasma biomarkers for association with subsequent development of overt DIC in patients with sepsis.
  
  
  METHODS
  A single-center, prospective observational study was conducted in an adult ICU at a university hospital. Plasma samples were obtained from patients with sepsis at ICU admission. Fourteen biomarkers including global markers (platelet count, prothrombin time, activated partial thromboplastin time, fibrinogen and fibrin degradation product (FDP)); markers of thrombin generation (thrombin-antithrombin complex (TAT) and soluble fibrin); markers of anticoagulants (protein C (PC) and antithrombin); markers of fibrinolysis (plasminogen, α2-plasmin inhibitor (PI), plasmin-α2-PI complex, and plasminogen activator inhibitor (PAI)-1); and a marker of endothelial activation (soluble E-selectin) were assayed. Patients who had overt DIC at baseline were excluded, and the remaining patients were followed for development of overt DIC in 5 days, and for mortality in 28 days.
  
  
  RESULTS
  A total of 77 patients were enrolled, and 37 developed overt DIC within the following 5 days. Most patients demonstrated hemostatic abnormalities at baseline with 98.7% TAT, 97.4% FDP and 88.3% PC. Most hemostatic biomarkers at baseline were significantly associated with subsequent development of overt DIC. Notably, TAT, PAI-1 and PC discriminated well between patients with and without developing overt DIC (area under the receiver operating characteristic curve (AUROC), 0.77 (95% confidence interval, 0.64 to 0.86); 0.87 (0.78 to 0.92); 0.85 (0.76 to 0.91), respectively), and using the three together, significantly improved the AUROC up to 0.95 (vs. TAT, PAI-1, and PC). Among the significant diagnostic markers for overt DIC, TAT and PAI-1 were also good predictors of 28-day mortality (AUROC, 0.77 and 0.81, respectively).
  
  
  CONCLUSIONS
  Severe coagulation and fibrinolytic abnormalities on ICU admission were associated with subsequent development of overt DIC. A single measurement of TAT, PAI-1, and PC activity could identify patients with ongoing severe coagulopathy, early in the course of sepsis.
authors.forename: Kansuke
authors.initials: K
authors.lastname: Koyama
authors.forename: Seiji
authors.initials: S
authors.lastname: Madoiwa
authors.forename: Shin
authors.initials: S
authors.lastname: Nunomiya
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Koinuma
authors.forename: Masahiko
authors.initials: M
authors.lastname: Wada
authors.forename: Asuka
authors.initials: A
authors.lastname: Sakata
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Ohmori
authors.forename: Jun
authors.initials: J
authors.lastname: Mimuro
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Sakata
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000990:Antithrombin III; D015415:Biomarkers / Q000097:blood; D001777:Blood Coagulation / Q000502:physiology; D001778:Blood Coagulation Disorders / Q000097:blood* / Q000175:diagnosis / Q000453:epidemiology; D042241:Early Diagnosis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010447:Peptide Hydrolases / Q000097:blood*; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood*; D011446:Prospective Studies; D011486:Protein C / Q000378:metabolism*; D018805:Sepsis / Q000097:blood* / Q000175:diagnosis / Q000453:epidemiology; D012720:Severity of Illness Index
chemical_list: D015415:Biomarkers; D017395:Plasminogen Activator Inhibitor 1; D011486:Protein C; C046193:antithrombin III-protease complex; D000990:Antithrombin III; D010447:Peptide Hydrolases