Characterization of the coagulation deficit in porcine dilutional coagulopathy and substitution with a prothrombin complex concentrate.
BACKGROUND
In this study, we used a porcine model to investigate whether impaired coagulation and severe arterial or venous bleeding could be normalized by substitution with a prothrombin complex concentrate (PCC), Beriplex P/N, containing coagulation factors II, VII, IX, and X.


METHODS
Dilutional coagulopathy was induced in anesthetized pigs by fractionated blood withdrawal (approximately 65% of total volume), followed by erythrocyte retransfusion and volume substitution with a total of 1000 mL of hydroxyethyl starch (Infukoll 6%). Animals were randomized to no treatment, treatment with placebo, or treatment with 35 U/kg PCC. Arterial (spleen incision) or venous (bone injury) bleeding was inflicted. Thromboelastometry, hematology, and coagulation tests were performed at baseline, after dilution, and after study treatments had been administered and injury inflicted. The primary end-point was postinjury time to hemostasis.


RESULTS
Hemodilution resulted in a decrease in coagulation factor concentrations to approximately 35% and prolonged prothrombin time. Platelet numbers decreased from approximately 400,000 to approximately 100,000/microL, and aggregation and adhesion were impaired. PCC effectively substituted the deficient prothrombin factors (II, VII, IX, and X) and normalized the prolonged prothrombin time. After spleen injury, PCC significantly reduced time to hemostasis versus dilutional control (median, 35 vs 82.5 min; P < 0.0001), and produced a nonsignificant trend towards reduction in blood loss (mean, 275 vs 589 mL). PCC also significantly reduced time to hemostasis (median, 27 vs 97 min; P < 0.0011) and blood loss (mean, 71 vs 589 mL; P < 0.0017) after bone injury.


CONCLUSIONS
Dilutional coagulopathy produced a generalized decrease in coagulation factors and impaired platelet function. Substitution with PCC effectively normalized coagulation and significantly improved hemostasis after venous and arterial bleeding.
Dickneite
Gerhard
G
Department of Pharmacology and Toxicology, CSL Behring GmbH, Marburg, Germany. Gerhard.Dickneite@cslbehring.com
Doerr
Baerbel
B
Kaspereit
Franz
F
D018686:Anesthetics, Intravenous; D000818:Animals; D001778:Blood Coagulation Disorders / Q000188:drug therapy*; D001779:Blood Coagulation Factors / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006438:Hemodilution / Q000379:methods; D006470:Hemorrhage / Q000503:physiopathology; D010974:Platelet Aggregation / Q000187:drug effects; D013552:Swine; D013874:Thiopental
D018686:Anesthetics, Intravenous; D001779:Blood Coagulation Factors; C025667:prothrombin complex concentrates; D013874:Thiopental