Factor V Leiden polymorphism modifies sepsis outcome: evidence from animal studies

The high prevalence of the factor V Leiden mutation in certain populations has prompted speculation that the mutation may have been subject to positive selection during evolution, either by providing a survival benefit or by directly enhancing reproductive performance. We investigated the hypothesis that heterozygous factor V Leiden carrier status might protect against the lethal consequences of severe inflammatory disease.

Two mouse models (thrombomodulin-deficient TMPro mice and factor V Leiden mice), in which the endogenous protein C anticoagulant pathway is disrupted either at the level of protein C activation (TMPro mice) or at the level of factor V proteolysis by activated protein C (factor V Leiden mice), were employed. The mutant mouse strains were subjected to lethal doses of bacterial lipopolysaccharide. The effects of these two mutations on coagulation activation and inflammatory cytokine elaboration were observed and compared with those in wild-type mice.

As has already been shown, heterozygous factor V Leiden carrier status improves the survival of mice subjected to endotoxemia induced by bacterial lipopolysaccharide. The survival of homozygous factor V Leiden mice did not differ from that of normal mice. The survival benefit derived from heterozygous factor V Leiden carrier status was only evident at doses of lipopolysaccharide producing death in approximately 50% of wild-type animals. At higher (LD90) or lower (LD10) doses of lipopolysaccharide, the survival of heterozygous factor V Leiden mice did not differ from that of wild-type mice. Concomitant administration of an LD90 dose of lipopolysaccharide and therapeutic heparin abolished the relative survival advantage of heterozygous factor V Leiden mice. Analysis of systemic coagulation and cytokine variables failed to provide conclusive evidence for altered coagulation activation or inflammatory cytokine production as the basis for the survival advantage associated with heterozygous factor V Leiden carrier status.

The improved survival of mice heterozygous for the factor V Leiden mutation complements results from the analysis of the factor V Leiden subgroup of patients enrolled in the PROWESS trial. Such convergent findings in two different species strongly suggest that the factor V Leiden mutation is indeed a potent modifier of the response to severe inflammatory disease. The striking magnitude of the factor V Leiden survival benefit in the initial PROWESS population, and in mice, suggests that the as-yet unknown mechanism conferring this benefit is a rather potent endogenous modifier of the pathogenic pathways engaged in sepsis. Delineation of this pathway will be important for understanding the therapeutic mechanisms, or absence thereof, of agents designed to act at the interface of coagulation and inflammation.