Acute fibrinolysis shutdown occurs early in septic shock and is associated with increased morbidity and mortality: results of an observational pilot study

Abstract

Background: Septic coagulopathy represents a very dynamic disease entity, tilting from initial hypercoagulability towards a subsequent hypocoagulable disease state, entitled overt disseminated intravascular coagulation. Acute fibrinolysis shutdown has recently been described to be a crucial component of initial hypercoagulability in critically ill patients, although the underlying pathomechanisms, the specific temporal kinetics and its outcome relevance in patients with sepsis remain to be determined.

Methods: In total, 90 patients (30 with septic shock, 30 surgical controls and 30 healthy volunteers) were enrolled. Blood samples were collected at sepsis onset or prior and immediately after the surgical procedure as well as 3 h, 6 h, 12 h, 24 h, 48 h and 7 d later, whereas blood samples from healthy volunteers were collected once. Besides viscoelastic and aggregometric point-of-care testing (POCT), enzyme-linked immunosorbent and thrombin generation assays and liquid chromatography-mass spectrometry-based measurements were performed.

Results: As assessed by viscoelastic POCT, fibrinolysis shutdown occurred early in sepsis. Significant increases in tissue plasminogen activator had no effect on thromboelastometrical lysis indices (LIs). Contrariwise, plasminogen activator inhibitor-1 was already significantly increased at sepsis onset, which was paralleled by significantly increased LIs in patients suffering from septic shock in comparison with both control groups. This effect persisted throughout the 7-day observation period and was most pronounced in severely ill as well as non-surviving septic patients. Thromboelastometrical LI, therefore, proved to be suitable for early diagnosis [e.g. LI 45 min: area under the curve (AUC) up to 0.933] as well as prognosis (e.g. LI 60 min: AUC up to 1.000) of septic shock.

Conclusions: Early inhibition of plasminogen activation leads to acute fibrinolysis shutdown with improved clot stability and is associated with increased morbidity and mortality in septic patients. Trial registration This study was approved by the local ethics committee (Ethics Committee of the Medical Faculty of Heidelberg; Trial-Code No. S247-2014/German Clinical Trials Register (DRKS)-ID: DRKS00008090; retrospectively registered: 07.05.2015). All study patients or their legal representatives signed written informed consent.

Keywords: Fibrinolysis shutdown; Plasminogen activator inhibitor 1; Point-of-care testing; Rotational thromboelastometry; Thrombin generation assay; Thrombin–antithrombin; Tissue plasminogen activator.

Fig. 1

Plasma levels of antithrombin (AT) III (a), protein S (b) and protein C (c) in healthy volunteers (n = 30; striped bars), surgical patients (n = 30; white bars) and patients with septic shock (n = 30; squared bars). Data of patients with septic shock and surgical patients are presented for the timepoints onset (sepsis onset or immediately after the surgical procedure) as well as 24 h, 48 h and 7 d later, whereas blood samples from healthy volunteers were collected only once. Data in box plots are given as median, 25th percentile, 75th percentile with the 10th and 90th percentile at the end of the whiskers. A P value < 0.05 was considered statistically significant

Fig. 2

Total thrombin plasminogen activator (total tPA) (a), free thrombin plasminogen activator (tPA) (b) and plasminogen activator inhibitor-1 (PAI-1) plasma levels (c) of healthy volunteers (n = 30; striped bars), surgical patients (n = 30; white bars) and patients with septic shock (n = 30; squared bars). Data of patients with septic shock and surgical patients are presented for the timepoints onset (sepsis onset or immediately after the surgical procedure) as well as 24 h, 48 h and 7 d later, whereas blood samples from healthy volunteers were collected only once. Data in box plots are given as median, 25th percentile, 75th percentile with the 10th and 90th percentile at the end of the whiskers. A P value < 0.05 was considered statistically significant

Fig. 3

EXTEM lysis indices (LIs) at 45 min (a) and 60 min (b) in blood samples of healthy volunteers (n = 30; green dots), surgical patients (n = 30; blue dots) and patients with septic shock (n = 30; red dots). Data of patients with septic shock and surgical patients are presented for the timepoints onset (sepsis onset or immediately after the surgical procedure) as well as 3 h, 6 h, 12 h, 24 h, 48 h and 7 d later, whereas blood samples from healthy volunteers were collected only once. A P value < 0.05 was considered statistically significant

Fig. 4

Thrombin generation assay (TGA) lag time (a), time to peak (b) and  peak height (c) in healthy volunteers (n = 30; striped bars), surgical patients (n = 30; white bars) and patients with septic shock (n = 30; squared bars). Data of patients with septic shock and surgical patients are presented for the timepoints onset (sepsis onset or immediately after the surgical procedure) as well as 24 h, 48 h and 7 d later, whereas blood samples from healthy volunteers were collected only once. Data in box plots are given as median, 25th percentile, 75th percentile with the 10th and 90th percentile at the end of the whiskers. A P value < 0.05 was considered statistically significant

Fig. 5

EXTEM lysis index (LI) at 45 min in blood samples of healthy volunteers (n = 30; green dots), patients with septic shock and a sepsis-related organ failure assessment (SOFA) score ≥ 18 (n = 5 at onset; blue dots) and patients with septic shock and a SOFA score < 18 (n = 25 at sepsis onset; red dots). Blood samples from healthy volunteers were collected once, whereas samples from patients with septic shock were collected at sepsis onset as well as 3 h, 6 h, 12 h, 24 h, 48 h and 7 d later. A P value < 0.05 was considered statistically significant

Fig. 6

This graphical summary clarifies the most important findings of the presented investigation within the context of septic coagulopathy. PRR pattern recognition receptor, PAMP pathogen-associated molecular pattern, AT III antithrombin III, TF tissue factor, TAT thrombin–antithrombin complex, tPA tissue plasminogen activator, PAI-1 plasminogen activator inhibitor 1, TGA thrombin generation assay, COX cyclooxygenase