Transient suppression of fibrinolytic potential during cytokine release syndrome after chimeric antigen receptor T-cell therapy in B-cell malignancies.

BACKGROUND: Although chimeric antigen receptor (CAR) T-cell therapy is an established treatment for relapsed or refractory B-cell malignancies, haemostatic abnormalities associated with cytokine release syndrome (CRS) remain incompletely understood. OBJECTIVE: To investigate CRS-associated haemostatic abnormalities using simultaneous thrombin-plasmin generation assay (T/P-GA). METHODS: A total of 43 patients were included, and 37 treated with tisagenlecleucel underwent detailed analyses. Measurements were obtained at eight time points, from before lymphocyte-depleting chemotherapy to 3 weeks post-CAR T-cell infusion. Ratios of endogenous thrombin potential (T-EP) and plasmin peak height (P-Peak) relative to pooled normal plasma were analyzed. RESULTS: The median T-EP ratio remained elevated throughout follow-up (range, 1.12-1.22). Conversely, the median P-Peak ratio decreased below 1.0 during CRS onset (range, 0.89-0.93) and was significantly lower than that before lymphocyte-depleting chemotherapy (p < 0.01). Median plasminogen levels also decreased during the CRS onset period. Patients with prolonged/severe CRS (modified CRS grade 1b-4) showed significantly lower P-Peak ratios than those with mild CRS (grade 0-1a) at CRS onset (p = 0.036). In addition, P-Peak ratios negatively correlated with soluble interleukin-2 receptor (sIL-2R) levels (Spearman's rho = -0.472, p < 0.001). CONCLUSION: CRS after CAR T-cell therapy is associated with transient suppression of fibrinolytic potential during sustained coagulation activation. Suppressed fibrinolytic potential was associated with elevated sIL-2R levels, suggesting a link between immune activation and haemostatic dysregulation during CRS. T/P-GA may provide functional insights beyond conventional haemostatic markers.