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

Introduction: 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.

Figure 1

Time course of overt DIC scores and hemostatic biomarkers from baseline to Day 3. Overt disseminated intravascular coagulation (DIC) scores, platelet count, prothrombin time-international normalized ratio (PT-INR), fibrin degradation product (FDP), thrombin-antithrombin complex (TAT), plasminogen activator inhibitor-1 (PAI-1) and protein C (PC) for patients with and without subsequent development of overt DIC (gray vs. white bars), and for survivors (dotted line) and non-survivors (solid line) among patients with overt DIC. Data are expressed as mean and 95% CI. *P <0.05 between patients with and without overt DIC on the same day. **P <0.05 between patients on Day 0 versus Day 2. ⁺P <0.05 between survivors and non-survivors with overt DIC on the same day.

Figure 2

ROC curves of TAT, PAI-1 and PC activity for prediction of overt DIC. Area under the receiver operating characteristic curve (AUROC) for thrombin-antithrombin complex (TAT), 0.77 (95% CI, 0.64 to 0.86), plasminogen activator inhibitor-1 (PAI-1), 0.87 (0.78 to 0.92), protein C (PC), 0.85 (0.76 to 0.91), and combination of these biomarkers are described. Combination of TAT, PAI-1 and PC was superior to each marker alone (AUROC, 0.95 (vs. TAT, P = 0.0004; vs. PAI-1, P = 0.033; vs. PC, P = 0.025)).

Figure 3

Kaplan-Meier survival curves for patients grouped by cutoff points of TAT and PAI-1 at baseline. The cutoff points were set at 18 ng/mL for thrombin-antithrombin complex (TAT) and 270 ng/mL for plasminogen activator inhibitor-1 (PAI-1), based on the best calculated cutoff values that maximize the sum of sensitivity and specificity for 28-day mortality.