Management and follow-up of pregnancy-onset thrombotic thrombocytopenic purpura: the French experience.

"Conflict-of-interest disclosure: N.B. received speaker fees from Sanofi. V.T. is a member of the advisory board, and received speaker fees from Roche diagnosis and grants for a clinical trial (Precog Trial). P.C. is a member of advisory boards and received speaker fees from Sanofi, Alexion, Octapharma, and Takeda. Y.D. is a member of advisory boards of, and received speaker fees from, Sanofi, Takeda, and Alexion. A.V. is a member of the French advisory boards for Sanofi and Takeda and received speaker fees from Sanofi, Octapharma, LFB-Biomédicaments, and Takeda. B.S.J. received speaker fees from Sanofi, Takeda, and LFB-Biomédicaments."

"This work was partly funded by a grant from the Délégation Régionale à la Recherche Clinique, Assistance Publique-Hôpitaux de Paris (PHRC AOM05012) and have been registered at www.ClinicalTrials.gov as # NCT00426686 (http://clinicaltrials.gov/show/NCT00426686, study ID number: P051064, Health Authority: France, Ministry of Health); and by a grant from the French healthcare network for rare immuno-hematological diseases (Maladies Rares Immuno-Hématologiques, MaRIH) in 2020."

"This work was partly funded by a grant from the Délégation Régionale à la Recherche Clinique, Assistance Publique-Hôpitaux de Paris (PHRC AOM05012) and have been registered at www.ClinicalTrials.gov as # NCT00426686 (http://clinicaltrials.gov/show/NCT00426686, study ID number: P051064, Health Authority: France, Ministry of Health); and by a grant from the French healthcare network for rare immuno-hematological diseases (Maladies Rares Immuno-Hématologiques, MaRIH) in 2020. AuthorshipContribution: N.B. did the cross-sectional analysis of the French Registry for Thrombotic Microangiopathies with a severe ADAMTS13 deficiency, did the phenotypic analysis, interpreted the results, and wrote the manuscript; B.S.J., A.V., and P.C. designed the study, interpreted the results, and wrote and critically reviewed the report; B.S.J. and A.V. supervised the phenotypic analysis and the database analysis; P.C., V.T., F.P., Y.D., and P.P. enrolled most patients, collected clinical and laboratory information, and critically reviewed the report; P.B. performed genetic analysis and critically reviewed the manuscript; K.V. provided monoclonal antibodies, interpreted data, and reviewed the manuscript for scientific content; and the final version of the manuscript was read and approved by all authors. Since 2000, all patients with a presumptive diagnosis of TMA (microangiopathic hemolytic anemia, severe thrombocytopenia, and organ ischemia) have been prospectively enrolled in the registry of the French Reference Center for TMA qualified by the National Plan for Rare Diseases of the French Health Ministry. ADAMTS13 investigation (activity, antigen, anti-ADAMTS13 immunoglobulin G [IgG], ADAMTS13 gene sequencing) is carried out in the central French reference laboratory. This study is a retrospective observational multicenter study focusing on patients presenting with their first TTP episode (ADAMTS13 activity of <10 IU/dL, associated or not with anti-ADAMTS13 IgG or bi-allelic deleterious ADAMTS13 sequence variations) during either pregnancy, postpartum, or in the aftermath of an abortion, from 1 January 2000 to 30 September 2020. All women with a history of TTP who became pregnant afterward were intentionally excluded from the study. We also investigated the follow-up (including future pregnancies) of the patients included in the study over the same time period. Our strategy for the differential diagnosis between cTTP and aTTP (iTTP and uTTP) is depicted in . Clinical and biological data at acute phase and during follow-up, with a specific focus on subsequent pregnancies, were gathered through hospital reports. Placental histology reports, when available, were also collected. Written informed consent was obtained from all patients in accordance with the Declaration of Helsinki. This study was approved by the ethics committee of Hospital Pitié-Salpêtrière (Paris, France), and is registered at www.clinicaltrials.gov under identifier NCT00426686 and at the Health Authority and the French Ministry of Heath under the number P051064/PHRC AOM05012. Pregnancy-onset thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening disease of which diagnosis and management requires experienced multidisciplinary teams. The mechanisms responsible for a deficiency in the disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 (ADAMTS13) leading to pregnancy-onset TTP may be congenital or acquired, and studying ADAMTS13 conformation could be of interest. The differential diagnosis between TTP and other pregnancy-associated thrombotic microangiopathies (TMA) is often challenging. Our retrospective multicenter study highlights the significance and the challenges associated with pregnancy-onset TTP and childbirth in terms of diagnosis, obstetric management, and follow-up aspects. Among 1174 pregnancy-onset TMA enrolled in the French Registry for TMA from 2000 to 2020, we identified 108 pregnancy-onset TTP: 52 immune-mediated TTP (iTTP, 48.1%), 27 acquired TTP of unidentified mechanism (uTTP, 25%), and 29 congenital TTP (cTTP, 26.9%). Data show that maternal outcome is good (survival rate: 95%) and fetal outcome is linked to the gestational age at the onset of the disease (survival rate: 75.5%). Three distinct entities with different natural histories emerged: pregnancy-onset iTTP appears similar to idiopathic iTTP, with an open ADAMTS13 conformation, and is marked by a relapse risk independent of subsequent pregnancies; pregnancy-onset uTTP appears to have a different pathophysiology with an unexpected open ADAMTS13 conformation and a very low relapse risk independent of subsequent pregnancies; finally, pregnancy-onset cTTP is characterized by the necessity of pregnancy as a systematic and specific trigger and a need for prophylactic plasmatherapy for subsequent pregnancies. This trial was registered at www.clinicaltrials.gov as #NCT00426686, and at the Health Authority and the French Ministry of Health (P051064/PHRC AOM05012)."