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 intra-abdominal 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-1beta (IL-1beta), IL-6, tumor necrosis factor-alpha (TNF-alpha), 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-1beta, KC, leukocytes and bacterial load. Pulmonary TNF-alpha, 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.
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 intra-abdominal 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-1beta (IL-1beta), IL-6, tumor necrosis factor-alpha (TNF-alpha), 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-1beta, KC, leukocytes and bacterial load. Pulmonary TNF-alpha, 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.