Recombinant activated protein C (rhAPC) was recently tested in a large clinical trial for the management of severe sepsis.1  The study revealed that infusion of rhAPC for 96 hours reduced the 28-day mortality rate from 30.8% to 24.7%. In this study group, 70% of patients were in shock and 75% were assisted with mechanical ventilation. This significant advance in the management of sepsis, which afflicts some 750 000 hospitalized patients per year in the United States, has evoked acclaim and new expectations. Indeed, sepsis is the most common cause of death in noncoronary intensive care units (ICUs). Management of patients admitted with severe sepsis consumes an estimated 52% of the ICU total budget.

Severe sepsis consists of local or generalized invasion of the body by pathogenic microorganisms or their toxins. These agents can cause organ dysfunction, hypoperfusion, or hypotension associated with microvascular thrombosis as a consequence of systemic inflammation. One of the agents responsible for this constellation of microvascular changes is the lipopolysaccharide (LPS) component of the outer membrane on Gram-negative bacteria. Systemic response to LPS, also known as endotoxin, fulfills the criteria for an acute inflammatory reaction. This experimental model elicited in humans with injection of exceedingly small amounts of LPS (2-5 ng/kg) provided key insights into the temporal appearance and importance of mediators in the process of inflammation.2 

In this issue, Derhaschnig and colleagues (page 2093) report the effects of rhAPC on coagulation and inflammation parameters in 24 healthy volunteers following acute perturbation with LPS. When infusion of rhAPC reaches steady-state levels (60- to 70-fold higher than baseline), basal levels of tissue factor transcripts and thrombin generation are suppressed. Subsequent challenge with LPS (2 ng/kg) induces a 15-fold increase in tissue factor transcripts and a significant increase in thrombin generation. Surprisingly, these elevated coagulation parameters remain untouched in rhAPC-treated subjects. Similarly, LPS-induced activation and subsequent inhibition of fibrinolysis and a wave of inflammatory cytokines (tumor necrosis factor α [TNFα] and interleukin 6 [IL-6]) remain unchanged by rhAPC. Thus, in this model of LPS-induced acute inflammation and coagulation, beefing up normal levels of APC with recombinant protein seems to leave coagulation and inflammation responses unshaken.

Does this pattern of nonresponsiveness to rhAPC raise questions regarding severe sepsis with shock and microvascular thrombosis? The answer seems to be “no” because LPS-producing Gram-negative bacteria were isolated from 64 of 107 patients with severe sepsis. The remainder of microorganisms was Gram-positive bacteria and Candida albicans.3  These isolated pathogens are known to trigger a large set of distinct Toll-like receptors that function as vanguards of innate immunity. These receptors exhibit genetic polymorphism linked to differences in intracellular signaling required for activation of genes that encode mediators and suppressors of inflammation.4  Furthermore, progression of microvascular changes in severe sepsis usually continues for days and weeks. Thus, it is likely that APC and its receptor, as well as the endothelial thrombin binder and regulator thrombomodulin, undergo dynamic changes induced by multiple waves of inflammatory cytokines and chemokines.

With these considerations in mind, it is difficult to extrapolate the results reported by Derhaschnig and colleagues to critically ill and hemodynamically compromised patients with severe sepsis. To wit, we need comprehensive studies of inflammation and coagulation parameters over the course of sepsis from its early to advanced stages, using genotypic and phenotypic analysis of the host response to a specific pathogen or its product. In such a context, the mechanism of in vivo action of rhAPC in etiologically diverse cases of severe sepsis can be delineated.

Bernard GR, Vincent JL, Laterre PF, et al. Effi-cacy and safety of recombinant human activated protein C for severe sepsis.
N Engl J Med.
Gallin JI, Snyderman R, eds; Fearon DT, Haynes BF, Nathan J, assoc eds.
Inflammation: Basic Principles and Clinical Correlates
. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins,
Stuber F, Petersen M, Bokelmann F, Schade U. A genomic polymorphism within the tumor necrosis factor locus influences plasma tumor necrosis factor-alpha concentrations and outcome of patients with severe sepsis.
Crit Care Med.
Schroder NW, Hermann C, Hamann L, Gobel UB, Hartung T, Schumann RR. High frequency of polymorphism Arg753Gln of the Toll-like receptor-2 gene detected by a novel allele-specific PCR.
J Mol Med.
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