Recombinant human activated protein C resets thrombin generation in patients with severe sepsis - a case control study

Abstract

Introduction: Recombinant human activated protein C (rhAPC) is the first drug for which a reduction of mortality in severe sepsis has been demonstrated. However, the mechanism by which this reduction in mortality is achieved is still not clearly defined. The aim of the present study was to evaluate the dynamics of the anticoagulant, anti-inflammatory and pro-fibrinolytic action of rhAPC in patients with severe sepsis, by comparing rhAPC-treated patients with case controls.

Methods: In this prospectively designed multicenter case control study, 12 patients who were participating in the ENHANCE study, an open-label study of rhAPC in severe sepsis, were treated intravenously with rhAPC at a constant rate of 24 microg/kg/h for a total of 96 h. Twelve controls with severe sepsis matching the inclusion criteria received standard therapy. The treatment was started within 48 h after the onset of organ failure. Blood samples were taken before the start of the infusion and at 4, 8, 24, 48, 96 and 168 h, for determination of parameters of coagulation and inflammation.

Results: Sepsis-induced thrombin generation as measured by thrombin-antithrombin complexes and prothrombin fragment F1+2, was reset by rhAPC within the first 8 h of infusion. The administration of rhAPC did not influence parameters of fibrinolysis and inflammation. There was no difference in outcome or occurrence of serious adverse events between the treatment group and the control group.

Conclusion: Sepsis-induced thrombin generation in severely septic patients is reset by rhAPC within the first 8 h of infusion without influencing parameters of fibrinolysis and inflammation.

Figure 1

Levels of TAT and F1+2. Plasma levels of (a) TAT and (b) F1+2 in the rhAPC group (▴) and the control group (○). Data represent mean ± SD. F1+2, prothrombin fragment F1+2; rhAPC, recombinant human activated protein C; TAT, thrombin-antithrombin complexes.

Figure 2

Levels of protein C and protein C inhibitor. Plasma levels of (a) protein C and (b) protein C inhibitor in the rhAPC group (▴) and the control group (○). The levels of protein C and protein C inhibitor are expressed as the percentage of the level measured in normal pool plasma. Data represent mean ± SD. rhAPC, recombinant human activated protein C.

Figure 3

Levels of total and free protein S. Plasma levels of (a) total protein S and (b) free protein S in the rhAPC group (▴) and the control group (○). The levels of total protein S are expressed as the percentage of the level measured in normal pool plasma. The levels of free protein S are expressed as a percentage of total protein S. Data represent mean ± SD. rhAPC, recombinant human activated protein C.

Figure 4

Fibrinolysis. Plasma levels of (a) D-dimer, (b) PAP and (c)TAFI-Ag in the rhAPC group (▴) and the control group (○). TAFI levels are expressed as the percentage of the level measured in normal pool plasma. Data represent mean ± SD. PAP, plasmin-antiplasmin complexes; TAFI-Ag, thrombin-activatable fibrinolysis inhibitor antigen; rhAPC, recombinant human activated protein C.

Figure 5

Cytokines. Plasma levels of (a) TNF-alpha, (b) IL-6 and (c) IL-10 in the rhAPC group (▴) and the control group (○). Assay detection limits were 3.0 pg/ml for TNF-alpha, 0.6 pg/ml for IL-6 and 1.2 pg/ml for IL-10. Data represent mean ± SD. IL, interleukin; rhAPC, recombinant human activated protein C; TNF, tumor necrosis factor.