Vitamin C, Sepsis and Coagulopathy: An Ancillary Study of the CITRIS-ALI Trial

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 DESCRIPTION (provided by applicant): This is an ancillary study associated with a recently funded NIH UM-1 application at our institution [UM1-HL116885-01: Vitamin C: Infusion for the Treatment in Sepsis Induced Acute Lung Injury (CITRIS-ALI)]. The parent UM-1 is a double-blind, randomized, placebo-controlled, multi-center, Phase II clinical trial examining the efficacy of high dose intravenous vitamin C (VitC, ascorbic acid) infusion for 96 hours in human sepsis-associated acute lung injury. The proposed ancillary study will examine the effects of parenteral VitC on sepsis-associated coagulopathy and platelet dysfunction (which is not being evaluated in the parent UM-1). Sepsis provokes intense systemic pro-inflammatory and pro-coagulant responses that arise from dysregulation of host-derived mediators of inflammation and coagulation. As a result, sepsis-driven coagulation induces consumption of coagulation and fibrinolytic factors that lead to Disseminated Intravascular Coagulation (DIC), one of the most feared complications of sepsis that leads to widespread systemic microvascular thrombosis. DIC is a critical mediator of sepsis-associated multiple organ failure. The long range goal of our research team is to develop optimal strategies to reduce the morbidity and mortality associated with human sepsis, specifically targeting the attenuation of DIC and other thrombotic events that lead to end-organ dysfunction. We have preliminary data suggesting Vitamin C significantly attenuates the inflammatory and pro-coagulant cascades in both animal and human sepsis. The Central Hypothesis is that parenteral VitC reduces sepsis-associated coagulopathy in humans by restoration of hemostatic integrity, and by the normalization of platelet function. We believe the molecular basis by which this occurs is through mechanisms attenuating increases in circulating pro-inflammatory mediators (which are being measured in the parent UM-1 study). The rationale is that if Vitamin C attenuates the inflammatory and coagulation pathways in sepsis, the occurrence of end-organ dysfunction can be reduced thereby improving morbidity and mortality. The specific aims will: (1) Determine the effects of parenteral vitamin C on plasma coagulation biomarkers in patients with severe sepsis; (2) Characterize the effect of parenteral vitamin C on platelet function in patients with severe sepsis; and (3) Determine the relationships between Vit C, persistent hypercoagulability, and DIC score in the CITRIS-ALI study. Finally, consistent with the R-15 mechanism, this study will provide pharmacy- and graduate students hands-on experience in clinical and translational research.