Fibrinogen in dilutional coagulopathy: a dose study in pigs

Introduction

Dilutional coagulopathy following massive bleeding is the result of clotting factor dilution and impaired fibrin polymerization after infusion of colloidal plasma expanders. Although fibrinogen has been clinically used to treat dilutional coagulopathy [1, 2], the effects of fibrinogen dosages on normalizing coagulation function is unclear. This study investigated the effect of six different fibrinogen dosages (range: 37.5 to 600 mg/kg) on ROTEM^® parameters and overall blood loss in a pig model for dilutional coagulopathy.

Methods

Forty-two pigs underwent a 60% hemodilution with Voluven^® (HES130/0.4). A standardized bone injury was performed after the completion of hemodilution. Animals were then randomized to receive 37.5, 75, 150, 300, 450 or 600 mg/kg fibrinogen (FGTW, LFB, France) or 500 ml saline. Four hours after fibrinogen administration a standardized liver injury was performed. Animals were then observed for 2 hours or until death. Blood loss was measured and tissue samples were collected at the end of the study. Hemodynamic and coagulation parameters were measured at baseline (BL), after hemodilution, 15 minutes, 1, 2 and 4 hours after drug infusion and 2 hours after liver injury or right before the animal's death. Statistical significance was set at P < 0.05.

Results

Fibrinogen dosages of 150 mg/kg and higher completely reversed dilutional coagulopathy: the maximum clot firmness (MCF) which was decreased after hemodilution (36 ± 3 vs 65 ± 4 mm at BL, P < 0.05), returned to BL levels after fibrinogen administration (69 ± 5 mm). Blood loss from bone and liver injury significantly decreased with increased fibrinogen dosages: 42 ± 19 (sham), 34 ± 14 (75 mg/kg), 29 ± 13 (150 mg/kg) and 28 ± 10 ml/kg BW (600 mg/kg). No thrombotic events occurred.

Conclusions

In a swine model of 60% hemodilution with bone and liver injury, fibrinogen administration (150 mg/kg and above) normalized MCF and decreased blood loss. Infusions of 12 times the dosage recommended in humans did not induce hypercoagulability.