Temporal profile of the pro- and anti-inflammatory responses to severe hemorrhage in patients with venous thromboembolism: Findings from the PROPPR trial.

McCully, Belinda H; Wade, Charlie E; Fox, Erin E; Inaba, Kenji; Cohen, Mitchell J; Holcomb, John B; Schreiber, Martin A

BACKGROUND The Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial showed that 15% of patients developed venous thromboembolism (VTE) following hemorrhage, but the mechanisms are unknown. Since inflammation is associated with hypercoagulability and thrombosis, our goal was to compare the temporal inflammatory profile following hemorrhagic shock in patients with and without VTE. STUDY DESIGN Secondary analysis was performed on data collected from PROPPR. Blood samples collected at 0, 2, 4, 6, 12, 24, 48 and 72 hours following admission were assayed on a 27-target cytokine panel, and compared between VTE (n=83) and non-VTE (n=475) patients. p<0.05 indicated significance. RESULTS Over time, both groups exhibited elevations in pro-inflammatory mediators interleukin (IL)-6, IL-8, IL-10, granulocyte colony-stimulating (G-CSF) 57, monocyte chemoattractant protein (MCP)-1 and macrophage inflammatory protein (MIP)-1β, and anti-inflammatory mediators IL-1ra and IL-10 (P<0.05 vs admission). VTE patients showed amplified responses for IL-6 (6-72 hours) and IL-8 (6-24 hours), which peaked at later time points, and GCSF-57 (12-24 hours), MCP-1 (6-72 hours), and MIP-1β (2-12 hours) (P<0.05 vs non-VTE per time point) that peaked at similar time points to non-VTE patients. The anti-inflammatory responses were similar between groups, but the interleukin-mediated pro-inflammatory responses continued to rise after the peak anti-inflammatory response in the VTE group. The occurrence rate of adverse events was higher in VTE (97%) versus non-VTE (87%, p=0.009) and was associated with higher inflammation. CONCLUSION Patients with VTE following hemorrhagic shock exhibited a prolonged and amplified pro-inflammatory responses mediated by select interleukin, chemotactic, and glycoprotein cytokines that are not antagonized by anti-inflammatory mediators. This response is not related to randomization group, injury severity or degree of shock, but may be linked to adverse events. LEVEL OF EVIDENCE Prognostic, Level III.