Proteomic signatures of fibrinolytic activity and neovascularization (NV) in patients with chronic limb-threatening ischemia (CLTI) receiving a novel combinatorial therapy. Six CLTI patients underwent treatment for 30 days with subcutaneous filgrastim (10 µg/kg every 72 hours; Amgen Inc.) in conjunction with a Programmed Infra-Geniculate Compression Pump (PCP) applied 3 hours daily. Blood samples were collected at baseline (day 1) and on days 15 and 30, 24 hours after the fifth and tenth filgrastim doses, respectively. On each collection day, samples were taken before and after 2 hours of supervised PCP. Serum concentrations of plasmin, fibrin degradation products (FDP), vascular endothelial growth factor-A (VEGF-A), hepatocyte growth factor (HGF), and matrix metalloproteinase-9 (MMP-9) were quantified using ELISA. Filgrastim administration consistently induced significant increases in plasmin and FDP levels (p < 0.001), independent of PCP application, without hemorrhagic complications. Similarly, levels of VEGF-A, HGF, and MMP-9 were significantly elevated post-treatment, indicating enhanced neovascular signaling. These changes occurred independently of the compression pump, suggesting systemic fibrinolytic and angiogenic effects mediated primarily by filgrastim. The study demonstrates proteomic evidence supporting fibrinolysis and neovascularization induced by this novel filgrastim-based therapy in CLTI. These findings corroborate prior angiographic and hemodynamic observations and provide a rationale for further clinical evaluation of this cell therapy in ischemic conditions.