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


CONCLUSIONS
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.
de Pont
Anne-Cornélie J M
AC
Department of Intensive Care, Academic Medical Center, University of Amsterdam, The Netherlands. a.c.depont@amc.uva.nl
Bakhtiari
Kamran
K
Hutten
Barbara A
BA
de Jonge
Evert
E
Vroom
Margreeth B
MB
Meijers
Joost C M
JC
Büller
Harry R
HR
Levi
Marcel
M
D000704:Analysis of Variance; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D000925:Anticoagulants / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects*; D016022:Case-Control Studies; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005342:Fibrinolysis / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011486:Protein C / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D018805:Sepsis / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D013917:Thrombin / Q000096:biosynthesis* / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000925:Anticoagulants; D011486:Protein C; D011994:Recombinant Proteins; D013917:Thrombin; C421124:drotrecogin alfa activated