Anticoagulant and anti‐inflammatory effects after peritoneal lavage with antithrombin in experimental polymicrobial peritonitis

Abstract

Summary. Background: In sepsis, coagulation inhibition using high-dose systemic antithrombin (AT) tends to improve survival. However, systemic AT use is complicated by increased risk of bleeding (odds ratio 1,7) and clinically important survival increase is seen only in the non-heparinized subgroup. Local (intra-abdominal) inhibition of coagulation with AT may be more effective. Objectives: To investigate effects of intraabdominal high-dose recombinant human AT (rhAT) lavage on coagulation and inflammation in experimental polymicrobial sepsis. Methods: Murine cecal ligation and puncture model was used with peritoneal lavage after 24 h, containing rhAT (3 IU mL )1 ) or saline. Clotting time, thrombin-antithrombin complexes (TAT), D-dimers, tissue-type plasminogen activator and plasminogen activator inhibitor-1 assessed coagulation and fibrinolysis responses. Inflammation was assessed by keratinocyte-derived chemokine (KC), interleukin-1b (IL-1b), IL-6, tumor necrosis factor-alpha (TNF-a), leukocyte count, myeloperoxidase and bacterial load. Results: rhAT lavage prolonged abdominal clotting times and reduced D-dimers and TAT levels, indicating inhibited abdominal coagulation. Pulmonary clotting time and D-dimers decreased towards normal by rhAT lavage. Abdominal fibrinolysis was reduced after rhAT lavage, as were abdominal IL-1b, KC, leukocytes and bacterial load. Pulmonary TNF-a, KC, myeloperoxidase and histopathological injury were decreased. Survival improved from 62% (saline lavage) to 83% (rhAT lavage, P < 0.05). Conclusions: High-dose rhAT lavage inhibited coagulation activation, and reduced inflammatory responses in both abdominal and pulmonary compartments, ultimately improving survival.

Effect of Vasoactive Intestinal Peptide (VIP) on Cytokine Levels and Haemostatic and Biochemical Parameters in A Rat Endotoxaemic Model

“…In our study, haemostatic disturbances associated with endotoxin-induced DIC were not suppressed as required by treatment with VIP. Some experimental studies have reported that AT is a good predictor of mortality in sepsis patients (9,27). In the present study, the observed decrease in plasma AT activity in LPS group is consistent with the results of previous in vitro and in vivo investigations (4,30).…”

Fibrinogen Is at the Interface of Host Defense and Pathogen Virulence in Staphylococcus aureus Infection

“…diseases. [11][12][13][14] Collectively, the expression and activity changes of coagulation system components following infection favor the rapid generation of fibrin matrices. An uncontrolled coagulation response following infection can lead to disseminated intravascular coagulation (DIC), a consumptive coagulopathy.…”

Human Neutrophils Support Thrombin Generation in Peritonitis

“…It was recently demonstrated that the TF/FVIIa pathway was involved in a mouse model of abdominal sepsis induced by Escherichia coli (9) and that the inhibition of this pathway by recombinant nematode anticoagulant protein c2 (rNAPc2) did reduce thrombin generation and fibrin deposition without affecting the inflammatory or antibacterial response. In experimental polymicrobial peritonitis, it was demonstrated that a peritoneal lavage with recombinant human antithrombin (rhAT) inhibited coagulation and reduced neutrophil recruitment and local cytokine concentrations, ultimately improving survival (10). The inhibition of TF may therefore be useful to avoid fibrin deposition in organs without compromising the host defence.…”