Neurological Impact of Caplacizumab in Refractory iTTP Survivors: A Comparative Study of Blood-Brain-Barrier Integrity and Cognitive Outcomes.

BACKGROUND

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) causes systemic microvascular thrombosis, often leading to long-term neurological complications and cognitive decline despite achieving hematologic remission. Persistent blood-brain barrier (BBB) dysfunction is a suspected driver of these chronic sequelae. This study investigated whether adding caplacizumab to standard of care (SOC) improves long-term BBB integrity and cognitive outcomes in refractory iTTP survivors compared with SOC alone.

METHODS

We analyzed 16 patients with iTTP categorized into SOC-only (n=7) or SOC plus caplacizumab (n=9) cohorts. Patients underwent computed tomography perfusion imaging to measure BBB permeability (PS product), blood flow, and blood volume at baseline (30 days postremission) and 12-month follow-up. Cognitive function was assessed using Creyos (URL: https://www.clinicaltrials.gov; Unique identifier: NCT03187652).

RESULTS

At baseline, the caplacizumab group, composed largely of refractory cases, exhibited nominally higher BBB permeability than the SOC-only group (0.48±0.11 mL/min per 100 grams versus 0.38±0.14 mL/min per 100 grams, P=0.048, Cohen d=0.73 [95% CI, -0.277 to -0.001]), an exploratory finding. The primary outcome, within-group BBB-PS reduction in the SOC plus caplacizumab group at 12 months, was significant (0.37±0.09 mL/min per 100 grams, P=0.027, Cohen d=0.90 [95% CI, 0.016-0.203]), while the SOC-only group showed minimal change. Despite variations in rituximab administration due to regional funding restrictions, higher BBB permeability was moderately to strongly correlated with lower scores across all cognitive domains and lower ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 repeats 13) activity (q<0.05, Benjamini-Hochberg corrected).

CONCLUSIONS

Caplacizumab may provide a neuroprotective benefit by facilitating BBB repair, even in initially refractory patients. These findings suggest that targeting microvascular integrity during acute episodes can mitigate long-term cognitive decline in iTTP survivors. By facilitating long-term BBB repair, caplacizumab may mitigate chronic cognitive decline and improve the quality of life for refractory iTTP survivors.