Retrospective Epidemiological Study of Patients in the National Cohort of the French TMA Center

Official title

Auto-immune Thrombotic Thrombocytopenic Purpura : Retrospective Epidemiological Study of Patients in the National Cohort of the French TMA Center, TWI-LIGHT

Overview

Immune thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening disorder characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, and ischemic organ damage due to microvascular thrombosis. It results from a severe deficiency in the von Willeband factor (vWF)-cleaving protease ADAMTS13, primarily caused by autoantibodies that inhibit its activity. This deficiency leads to accumulation of ultra-large vWF multimers, triggering pathological platelet aggregation and widespread microthrombi. iTTP typically presents with acute neurological symptoms (e.g., confusion, seizures, coma), cardiac events (e.g., myocardial infarction), and multiorgan dysfunction. Without prompt treatment-plasma exchange, immunosuppression, and the vWF inhibitor caplacizumab-mortality exceeds 90%. Survivors face long-term risks, including cardiovascular complications, cognitive impairment, and reduced life expectancy. The TWI-LIGHT protocol is a national retrospective epidemiological study coordinated by the French Reference Center for Thrombotic Microangiopathies (CNR-MAT). It aims to analyze long-term outcome in \>1,200 iTTP patients diagnosed between October 2000 and June 2024. The study leverages pseudonymized data from the CNR-MAT registry, collected via a secure REDCap database. Key Objectives: 1. Primary: Assess the impact of cardiovascular risk factors (e.g., hypertension, diabetes) and ADAMTS13 activity on life expectancy in iTTP survivors. 2. Secondary: * Evaluate disease burden in underrepresented groups (pregnant/postpartum women, children, elderly patients). * Analyze the influence of new therapies (caplacizumab, rituximab, recombinant ADAMTS13) on care pathways. * Identify prognostic factors and treatment practices. * Characterize neurocognitive outcomes and quality of life post-iTTP. Methodology: * Design: Non-interventional, retrospective (MR-004 compliance), using data from standard care. * Inclusion: Patients with confirmed iTTP (thrombocytopenia, hemolytic anemia, ADAMTS13 \<10%), diagnosed within the study period, and ≥1 year of follow-up. * Exclusion: Cancer-associated iTTP, severe sepsis, or patient opposition to data reuse. * Data Collection: Clinical, biological, and therapeutic variables from hospital/consultation records, including cardiovascular events, ADAMTS13 activity, and neurocognitive assessments. * Analysis: Kaplan-Meier survival curves and Cox regression models to identify risk factors for non-iTTP-related death. Expected Outcomes: * Prevalence of cardiovascular comorbidities and their correlation with ADAMTS13 activity. * Insights into iTTP subtypes (e.g., gestational, pediatric) and therapeutic efficacy. * Evidence-based strategies for personalized long-term management. Ethical Framework: * AP-HP-sponsored, with oversight from Sorbonne University's ethics committee. * Patients informed of data reuse with opt-out rights; data archived for 15 years. This landmark study will inform clinical guidelines, optimize survivor care, and address unmet needs in iTTP management through comprehensive, real-world data analysis.

Detailed description

The TWI-LIGHT protocol is a retrospective, non-interventional epidemiological study coordinated by the French National Reference Center for Thrombotic Microangiopathies (CNR-MAT). It leverages the CNR-MAT registry to analyze long-term outcomes in over 1,200 patients diagnosed with autoimmune thrombotic thrombocytopenic purpura (iTTP) between October 1, 2000, and June 1, 2024.

Background and Rationale iTTP is a rare, life-threatening disorder caused by severe ADAMTS13 deficiency, leading to microvascular thrombosis, multiorgan damage, and high mortality without prompt treatment. Survivors face long-term risks, including cardiovascular complications, cognitive impairment, and reduced life expectancy. Despite therapeutic advances (e.g., caplacizumab, rituximab), data on late complications, risk factors, and disease burden in underrepresented subgroups (e.g., pregnant women, children, elderly patients) remain limited. This study addresses critical gaps in understanding iTTP's natural history, treatment efficacy, and survival.

Study Design

* Type: Retrospective, multicenter, non-interventional (MR-004 compliance). * Data Collected:

* Acute Phase: Clinical presentation, lab results (standard biology, including ADAMTS13 activity, troponin), treatments (plasma exchange, immunosuppressants, caplacizumab). * Long-Term Follow-Up: Cardiovascular events (major adverse cardiovascular events, including ischemic stroke, myocardial infarction and angioplasty) and cardiovascular risk factors (hypertension, diabetes, weight and body mass index, dyslipidemia, smoking), ADAMTS13 activity trends, neurocognitive outcomes (quality-of-life scales: SF36, HADS), relapse rates, and mortality. * Biobanking: ADAMTS13 samples stored at Hôpital Lariboisière (Prof. Veyradier's lab) under ethical approval (AC-2023-6021).

Expected Outcomes and Impact

* Clinical Insights:

* Personalized cardiovascular risk profiles for iTTP survivors. * Evidence-based guidelines for pregnancy, elderly, and pediatric iTTP management. * Optimization of long-term monitoring (e.g., rituximab frequency). * Health System Impact:

* Cost-benefit analysis of novel therapies (e.g., caplacizumab, recombinant ADAMTS13). * Strategies to reduce diagnostic delays and hospitalizations. Real-World Relevance: Focus on underrepresented groups and long-term survival, with the goal to improve life expectancy of iTTP patients. This protocol represents a landmark effort to transform iTTP management through comprehensive real-world data, directly impacting clinical practice. * Methodological Rigor: Centralized data auditing, ISO/IEC 17025-compliant biobanking.

Primary outcome measures

• prevalence of major cardiovascular events [Time frame: from diagnosis to last follow- up, up to 3 years]

Secondary outcome measures (5)

• Incidence of cardiovascular risk factors [Time frame: from diagnosis to last follow- up, up to 3 years]
• correlation between ADMTS13 activity during remission and incidence of cardiovascular events and life expectancy [Time frame: from remission to last follow- up, up to 3 years]
• characterization of pregnancy onset iTTP [Time frame: from diagnosis to last follow- up, up to 3 years]
• characterization of childhood onset iTTP [Time frame: from diagnosis to last follow- up, up to 3 years]
• characterization of elderly onset iTTP [Time frame: from diagnosis to last follow- up, up to 3 years]

Eligibility criteria

Inclusion criteria

-Patients with a diagnosis of immune mediated TTP

Exclusion criteria

• Cancer- associated iTTP and HIV-associated iTTP
• Severe sepsis
• Disseminated intravascular coagulation with consumption of coagulation factors;
• Transplant-associated TTP
• HIV-associated TTP (AIDS stage)
• Patient not affiliated with a social security scheme
• Patient or parent's objection to the reuse of their healthcare data for research

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

France · 1 center

• Service d'Hématologie Hôpital Saint-Antoine — Paris

Identifiers

NCT: NCT07205861 · APHP240960

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗