Abstract Rationale A subset of patients critically ill with COVID-19 experience hyperfibrinogenemia with measured levels up to 3 times the upper limit of normal. This drives blood hyperviscosity that we have previously shown induces red blood cell (RBC) aggregation into clusters and leads to endothelial injury. A recent clinical trial demonstrated the safety and efficacy of therapeutic plasma exchange (TPE) to significantly reduce fibrinogen levels and blood viscosity in patients with COVID-19 compared with the standard of care (SOC) approach. Here, we seek to understand how TPE in these patients affects RBC aggregation and endothelial injury. Methods Plasma samples from seven patients with similar illness severity enrolled in the COVID-19 PLasma EXchange (COPLEX) randomized control trial were collected at time of enrollment and after 48 hours of randomization to receiving either TPE (n = 4) or SOC (n = 3). We quantified aggregation of healthy donor RBCs by patient plasma before and after therapy across a range of shear rates (300s-1 to 100s-1) approximating the microvascular environment using a validated microfluidics-based video microscopy assay. We compared RBC cluster count and size between the cohorts. Additionally, we quantified the change in six markers of thromboinflammation and endothelial injury: IL-6, syndecan-1, PAI-1, thrombomodulin, E-selectin, and P-selectin. Results All comparisons between the two groups and time points were made using a two-way ANOVA. Patients treated with TPE demonstrated a trend towards a reduction in the number of measured RBC clusters (p = 0.071) compared with SOC. Additionally there was a trend towards reduction in median and upper quartile cluster size in the TPE group with all 4 patients showing a decrease compared with only 1 of 3 patients in the SOC cohort (p = 0.13 and p = 0.12 respectively). As expected there was a significant reduction in total fibrinogen levels (p = 0.0022) in the TPE group. There was a trend towards significance in syndecan-1 level reduction (p = 0.053) as well as thrombomodulin (p = 0.15). Similar trends were not seen in the other markers of endothelial injury and activation. Conclusions Total plasma exchange in patients with COVID associated hyperfibrinogenemia reduces RBC aggregation and results in more favorable microvascular rheology. This is associated with a reduction in markers of thromboinflammation and endothelial injury, a findng which aligns with the hypothesis that red cell aggregation in critical illness directly influences endothelial cell dysfunction and represents an important target for therapeutic intervention. However, more work is needed to understand the clinical implications of these findings. This abstract is funded by: Hemostasis and Thrombosis Research Society, National Institute of Health
Iffrig et al. (Fri,) studied this question.