Effect of factor V Leiden polymorphism in severe sepsis and on treatment with recombinant human activated protein C

Objective: Coagulation activation is part of the acute innate host response to infection that, when uncontrolled, may contribute to organ dysfunction and death. Activated protein C limits excessive coagulation activation by inactivating factors Va and Villa. The factor V Leiden mutation (R5060), a prothrombotic gene polymorphism, disrupts the activity of this natural anticoagulant by rendering factor Va partially resistant to inactivation by activated protein C. Previous findings in the mouse factor V Leiden endotoxemia model and in patients with severe sepsis suggest that factor V Leiden constitutes a rare example of a balanced gene polymorphism that may provide a survival advantage for heterozygous carriers with severe sepsis. We sought to confirm that carriers of this prothrombotic factor V Leiden mutation do not have an increased risk of developing severe sepsis and that carriers with severe sepsis derive similar treatment benefit from recombinant human activated protein C (drotrecogin alfa [activated]) as non-factor V Leiden carriers. Design: Prospective collection of factor V Leiden status from two clinical studies of severe sepsis (PROWESS and ENHANCE). Setting: A total of 447 clinical sites across 25 countries. Patients: A total of 3,894 adult patients with severe sepsis. Intervention: Either 24 mug.kg(-1).hr(-1) drotrecogin alfa (activated) (n = 3063) or placebo (n = 800) for 96 hrs or no exposure to the study drug (n = 31). Main Results. The effect of the factor V Leiden carrier status in severe sepsis in the PROWESS study has been previously reported. The combined data on factor V Leiden status from 3,894 adult patients with severe sepsis from the PROWESS and ENHANCE (a single-arm, open-label study of drotrecogin alfa [activated]) studies are reported here. At study entry, 3.9% of patients (150/3894) presenting with severe sepsis were heterozygous carriers. No homozygous factor V Leiden carriers were identified. The proportion of factor V Leiden carriers in patients with severe sepsis differs slightly from that predicted (allelic frequency of 2.5%) by the Hardy-Weinberg equation for the general white population (p =.05). There was no significant difference in baseline disease severity (Acute Physiology and Chronic Health Evaluation II score or number of organ dysfunctions) between heterozygous carriers and non-Leiden carriers. There was no significant difference in serious bleeding or thrombotic event rates with drotrecogin alfa (activated) treatment between heterozygous carriers and non-Leiden carriers. The 28-day mortality rates for heterozygous carriers and non-Leiden carriers with drotrecogin alfa (activated) treatment were 20.3% and 24.9%, respectively (risk ratio, 0.82; 95% confidence interval, 0.57-1.17). Conclusions. Compared with non-Leiden carriers, factor V Leiden heterozygous carriers may have a slightly decreased risk of developing severe sepsis from infection, do not seem to have increased mortality in severe sepsis, and derive similar benefit and risk profiles from drotrecogin alfa (activated) treatment. Therefore, factor V Leiden carriers should not be excluded from this new sepsis therapy.