Evaluating Neuroprotective Effects of Caplacizumab in Immune-Mediated Thrombotic Thrombocytopenic Purpura

Objective:

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening disease characterized by inhibition of the enzyme ADAMTS13 (A Disintegrin-like And Metalloprotease with Thrombospondin type 1 repeats 13). This leads to widespread formation of platelet clotting/aggregation in the small blood vessels, resulting in thrombosis and end-organ ischemia. Despite standard of care (SOC) treatment involving the use of plasma exchange and immunosuppressants, patients often suffer increased risks of cerebrovascular disease, cognitive decline, and depression. Caplacizumab has shown to be an effective treatment for iTTP by targeting binding zones on ultra-large von Willebrand factors, preventing platelets from aggregating and forming clots. This study investigates whether Caplacizumab can provide a potential neuroprotective effect in preventing/reducing brain tissue damage compared to SOC treatment.

Methods:

We conducted a multi-center study involving 13 iTTP patients, six of whom were refractory to SOC treatment and received Caplacizumab. Participants underwent MRI and a contrast-enhanced dynamic CT perfusion scan to assess gross pathology, blood-brain barrier (BBB) permeability, cerebral blood flow, and volume. Additionally, a comprehensive cognitive and neuropsychiatric assessment was conducted to evaluate reasoning, short-term memory, verbal memory, concentration, and depression scores. Data collection was conducted at two timepoints; baseline, 30-days post remission, and follow-up in one year.

Results:

BBB disruption was evident in all patients. Baseline whole brain mean permeability surface (PS) product for patients receiving Caplacizumab was 0.35 +/- 0.09 mL/min/100g, compared to SOC at 0.27 +/- 0.10 mL/min/100g. A significant reduction (p = 0.047) in the BBB integrity to 0.24 +/- 0.08 mL/min/100g was found in the Caplacizumab group at the follow-up visit. Cognitive scores presented low for all patients with verbal memory and concentration related test being one standard deviation below normative data. All patients have persistent white matter hyperintensities observed on MRI scans. No significant increases or decreases were found in follow-up cognitive scores in both groups but a significant inverse correlation with whole brain mean PS was found across all four cognitive domains, r (26) = -0.51, p = 0.007. Depression assessments revealed consistent concentration difficulties across all participants.

Conclusion:

Compromised BBB integrity observed in patients, regardless of remission or treatment, stresses the chronic nature of iTTP's impact on the brain. Despite patients receiving Caplacizumab having a higher whole-brain mean PS product at baseline, likely due to patients being refractory, follow-up scans show a significant reduction in whole-brain mean PS product. This highlights Caplacizumab's potential neuroprotective capabilities. However, no improvement was seen in patient cognitive scores suggesting that, while Caplacizumab may mitigate some aspects of BBB disruption, it does not reverse any cognitive impairment already developed due to iTTP. In addition, baseline cognitive scores for Caplacizumab were lower than SOC possibly as a result of higher baseline BBB permeability leading more damage of brain tissue. While Caplacizumab shows promise in reducing BBB permeability and potentially offering a neuroprotective effect, further longitudinal studies are needed to fully understand its long-term effects. These findings suggest the inclusion of Caplacizumab in standard iTTP treatment protocols with the potential to improve overall patient outcomes by mitigating some of the neurocognitive complications associated with the disease.

Lee:GE Healthcare: Research Funding. Patriquin:Apellis: Consultancy, Honoraria, Other: Served as a clinical site investigator ; Amgen: Consultancy, Honoraria; BioCryst: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Other: Served as a clinical site investigator ; Sobi: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Pavenski:Sanofi: Other: Clinical Trails; Takeda: Other: Clinical Trails.