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Activated protein C–protein C inhibitor complex as a prognostic marker in sepsis


The PROWESS study and later trials of activated protein C (APC) treatment in sepsis have shown only modest reductions in mortality. A recent Cochrane systematic review (CD004388) records doubtful efficacy and serious adverse effects. To optimize the benefit/risk ratio of APC treatment of each patient, a biomarker of protein C (PC) activation is urgently needed, and the use of such a marker, APC–protein C inhibitor (PCI), has been investigated in the present study.


APC–PCI was measured in acid citrate plasma by means of a newly developed sandwich ELISA (median normal value 0.13 ng/ml, range 0.07 to 0.26, n = 16). Levels of APC–PCI and PC were monitored (daily to alternate days) in 135 consecutive critically ill patients, 53 of whom had sepsis during the observation period. The state of PC activation to APC was categorized as nonactivated (APC–PCI < 0.25 ng/ml), moderately activated (APC–PCI = 0.25 to 0.72 ng/ml) or highly activated (APC–PCI > 0.72 ng/ml), based on maximum APC–PCI values in relation to the normal range.


The maximum APC–PCI values ranged from 0.03 to 29 ng/ml, median 0.44 ng/ml. The overall mortality of the 53 sepsis patients was 32% (17/53). The mortality in the PC activation groups was significantly different (P = 0.032, chi-square test): nonactivated 44% (7/16), moderately activated 13% (3/23) and highly activated 50% (7/14). A bell-shaped mortality relationship was noted, with high mortalities in both the nonactivated and highly activated groups, and a much lower mortality in the moderately activated group. Subdividing the PC activation groups according to APACHE II score yielded the highest mortality, 71% (5/7), in the nonactivated subgroup with APACHE II ≥ 25, whereas the APACHE II score showed no relationship with mortality in the other PC activation groups. Minimum PC levels did not correlate with APC–PCI and showed no significant differences between the activation groups.


Nonactivation of PC in sepsis may represent the failure of an appropriate protective response and is therefore associated with increased mortality, especially when the APACHE II score is elevated. Septic patients without PC activation and a high APACHE II score may be those who are most likely to benefit from APC treatment. PC measurements were not predictive of PC activation as indicated by APC–PCI levels.

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Heslet, L., Hald, R., Recke, C. et al. Activated protein C–protein C inhibitor complex as a prognostic marker in sepsis. Crit Care 13 (Suppl 1), P382 (2009).

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  • Septic Patient
  • Sandwich ELISA
  • Sepsis Patient
  • Modest Reduction
  • Inhibitor Complex