Activated protein C-induced protection from lipopolysaccharide-mediated microcirculatory dysfunction was characterized in vivo for the first time. The impressive modification of leukocyte cross-talk indicates systemic anti-inflammatory activated protein C effects on leukocytes and the endothelium, subsequently improving capillary perfusion. These actions could represent the in vivo mechanism of activated protein C interactions observed in patients with severe sepsis.

IntroductionProthrombin complex concentrates are recommended for rapid reversal of vitamin K anticoagulants. As they normalize levels of vitamin K dependent clotting factors and re-establish hemostasis, they may also be used as adjunctive therapy in patients with major bleeding. The aim of this study was to retrospectively evaluate the efficacy of prothrombin complex concentrates in the surgical setting.MethodsThe case notes of 50 patients requiring urgent oral anticoagulation reversal (n = 12) or with severe perioperative coagulopathic bleeding (n = 38) who received an infusion of prothrombin complex concentrate (Beriplex P/N(R) 500) at the surgical department of the University of Munich Hospital, Germany were retrospectively reviewed. Efficacy of prothrombin complex concentrate application was evaluated using the Quick test, reported as an international normalized ratio, hemodynamic measurements and requirement for blood products. Safety assessments included whole blood hemoglobin levels and specific parameters of organ dysfunction.ResultsBaseline characteristics were comparable, except that mean baseline international normalized ratio and hemoglobin levels were significantly higher (P < 0.01) in anticoagulation reversal than in bleeding patients. In anticoagulation reversal, the international normalized ratio was significantly reduced (from 2.8 +/- 0.2 at baseline to 1.5 +/- 0.1, P < 0.001) after one prothrombin complex concentrate infusion (median dose 1500 IU; lower quartile 1,000, upper quartile 2,000). No major bleeding was observed during surgery after prothrombin complex concentrate administration. Only one patient received platelets and red blood cell transfusion after prothrombin complex concentrate administration. In bleeding patients, infusion of prothrombin complex concentrate (median dose 2,000 IU; lower quartile 2,000, upper quartile 3,000) significantly reduced the INR from 1.7 +/- 0.1 at baseline to 1.4 +/- 0.1 (P < 0.001). This decrease was unrelated to fresh frozen plasma or vitamin K administration. Bleeding stopped after prothrombin complex concentrate administration in 4/11 (36%) patients with surgical bleeding and 26/27 (96%) patients with diffuse bleeding. Hemoglobin levels increased significantly from baseline in bleeding patients (P < 0.05) and mean arterial pressure stabilized (P < 0.05). No thrombotic events or changes in organ function were reported in any patient.ConclusionsProthrombin complex concentrate application effectively reduced international normalized ratios in anticoagulation reversal, allowing surgical procedures and interventions without major bleeding. In bleeding patients, the improvement in coagulation after prothrombin complex concentrate administration was judged to be clinically significant.

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