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

Background

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, activated protein C–protein C inhibitor (APC–PCI), has been investigated in the present study.

Methods

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, moderately activated or highly activated, based on maximum APC–PCI values in relation to the normal range.

Results

The maximum APC–PCI values were 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 and relative mortality (mortality of activation group/overall mortality) of each activation group are presented in Table 1. A bell-shaped mortality relationship was noted, with high mortalities in both the nonactivated and highly activated groups. Notably, the lowest mortality was recorded in the moderately activated group. Subdividing activation groups by the Acute Physiology and Chronic Health Evaluation (APACHE) II score yielded the highest mortality (5/7 = 71%, relative mortality 227.7%) in the nonactivated subgroup with APACHE II score ≥25, whereas the APACHE II score did not influence mortality in the other activation groups. Minimum PC levels did not correlate with APC–PCI and showed no significant differences between the activation groups.

Table 1 Mortality and relative mortality (mortality of activation group/overall mortality) of each activation group

Conclusion

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.