A retrospective study was performed examining the trend of inflammatory markers, including D-dimers, in 29 COVID-19 patients requiring veno-venous (VV) extracorporeal membrane oxygenation (ECMO) support. We observed that COVID-19 patients with pre-cannulation D-dimer levels >3,000 ng/mL had a significantly shorter time from admission to cannulation (4.78 vs. 8.44 days, p = 0.049) compared to those with D-dimer <3,000 ng/mL. Furthermore, patients with D-dimer >3,000 ng/mL had a trend of lower pH (7.24 vs. 7.33), higher pCO₂ (61.33 vs. 50.69), and higher vasoactive inotropic score (7.23 vs. 3.97) at time of cannulation, however, these were not statistically significant. This cohort of patients also required a longer duration of ECMO support (51.44 vs. 31.25 days). However, 13 patients required at least one ECMO-circuit exchange and 16 patients did not require any exchanges. There was a consistent drop in D-dimer values after every circuit exchange, which was not observed in any of the other examined inflammatory markers, including ferritin, lactate dehydrogenase, or C-reactive protein. We propose that elevated D-dimer levels (>3,000 ng/mL) reflect increased disease severity in COVID-19, and predict a longer ECMO course. Once on ECMO, however, the D-Dimer level consistently decreased with every circuit exchange, which may reflect thrombus within the oxygenator rather than just disease severity.