Sepsis-induced systemic inflammation results in coagulation abnormalities that may be different in gram-positive and gram-negative infections. We used ciprofloxacin to induce a predominantly gram-positive Enterococcus faecalis polymicrobial sepsis in rats. Ciprofloxacin-untreated rats exhibited a predominantly gram-negative polymicrobial sepsis. Rats were subjected to 30% body surface area burn (B), cecal ligation puncture (CLP) with a 22-gauge needle, and B + CLP. Ciprofloxacin-treated B + CLP rats showed a significant decrease in plasma thrombin activatable fibrinolysis inhibitor (TAFI) levels compared with sham rats. However, plasma tissue factor pathway inhibitor (TFPI) levels decreased significantly in B, CLP, and B + CLP groups compared with sham rats. The ciprofloxacin-untreated group showed a significant decrease in plasma TAFI levels in CLP and B + CLP and plasma TFPI levels decreased in all 3 groups compared with sham rats. Histological changes in the liver and kidney included vascular congestion and parenchyma bleed following B + CLP in ciprofloxacin-untreated rats. These results suggest that plasma TAFI and TFPI levels differ depending on the type of bacteria involved in the septic process.
Thrombin activatable fibrinolytic inhibitor (TAFI) acts as an inhibitor of fibrinolysis by cleaving the arginine and lysine amino acid residues from the carboxy terminus of fibrin, rendering it resistant to digestion by plasmin. This study determines the effect of direct thrombin inhibitors on TAFI functionality and if there is a correlation to their anti‐IIa effects. The following thrombin inhibitors were tested: argatroban, melagatran, angiomax, LU 208791, hirudin and dabigatran. All agents were supplemented to normal human pooled plasma in various concentrations (10–0.16 μg/ml). The functional TAFI levels were determined using a chromogenic substrate based method developed by Pentapharm Inc. (Basel, Switzerland), the Pefakit® TAFI. The anti‐IIa effects were determined using a chromogenic substrate based method by American Diagnostica (Stamford, CN). All of the thrombin inhibitors were capable of inhibiting TAFI functionality; LU 208791 was the strongest inhibitor with an IC50 of 0.09 μg/ml while angiomax was the weakest with an IC50 of 6.6 μg/ml. These results for the most part corresponded to the anti‐IIa results. LU 208791 had the strongest anti‐IIa effects (IC50=0.39 μg/ml), while angiomax had an IC50 >10 μg/ml. The IC50s for TAFI inhibition by argatroban and hirudin were not significantly different (1.3 and 1.2 μg/ml); however, their IC50s for thrombin inhibition were >10 and 3.0 μg/ml respectively. This indicates that argatroban may inhibit TAFIa directly. These results show that the bleeding complications observed when using thrombin inhibitors may be due to the indiscriminate inhibition of TAFI. Persistent inhibition of TAFI by thrombin inhibitors may compromise both their safety and efficacy.
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