Hospital-acquired infection (HAI) is a major complication in pediatric patients on extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT). Infection detection is challenging, as traditional inflammatory markers such as C-reactive protein (CRP) and procalcitonin (PCT) are unreliable. Coagulopathy, common in both sepsis and extracorporeal life support (ELS), may serve as an early infection signal on ELS, but has not been explored. We conducted a single-center, retrospective, propensity-matched, case-control study comparing 62 pediatric patients with 85 HAIs to 169 matched controls without HAIs. Patients with HAIs had more ECMO circuit changes (20 vs. 3, p < 0.001) and greater anticoagulation variability. They required more heparin adjustments on ECMO (p < 0.001) and CRRT monotherapy (p = 0.002), and more bivalirudin adjustments on CRRT monotherapy (p = 0.014) and tandem therapy (p = 0.012). Absolute neutrophil count (ANC) was higher in infected patients (7.0 × 10³/µl vs. 4.8 × 10³/µl, p = 0.003), whereas CRP, PCT, and white blood cell count did not differ. Anticoagulation variability and ECMO circuit instability may represent early physiologic signals of HAIs in pediatric ELS. These may complement traditional laboratory tests, enabling earlier detection and intervention, and warrant prospective multicenter validation.