Metabolic acidosis has been implicated in the development of coagulopathy, although the specific mechanisms have not been well characterized. We sought to explore whether resuscitation of injured patients with a balanced crystalloid solution affects coagulation, as measured by endogenous thrombin potential (ETP) and thromboelastography (TEG). We performed an exploratory analysis of a subset of subjects enrolled in a randomized trial comparing the effect of resuscitation with isotonic saline versus Plasma-Lyte A (PLA) on acidosis and electrolyte abnormalities. We collected plasma at admission and 6 h later for subsequent ETP and TEG analysis and compared subjects receiving isotonic saline to those receiving PLA. Among 18 evaluated subjects, baseline characteristics, including ETP and TEG parameters, were similar between the two arms. At 6 h, subjects receiving isotonic saline were more acidemic. At 6 h, there were no differences in ETP parameters between groups; however, TEG results showed the time from initial clot formation to an amplitude of 20 mm (K) was shorter (3.8 ± 2.1 vs. 7.2 ± 2.8 s) and the rapidity of fibrin build-up and cross-linking (α angle) was significantly greater (41 ± 8 vs. 24 ± 15 deg) for the PLA group than in the isotonic saline group. Relative to PLA, isotonic saline does not alter thrombin generation, but isotonic saline and PLA may differentially impact clotting factor availability. The shorter time to reach prespecified clot amplitude and the increased rate of fibrin generation imply faster amplification of clotting factors with PLA without effect on latency time or clot strength.