Neonatal Exchange Transfusion: When Should We Think about Hereditary Thrombotic Thrombocytopenic Purpura (hTTP)?

Introduction Neonatal exchange transfusion (NExT) is a procedure to treat severe neonatal hyperbilirubinemia persisting despite phototherapy, to remove red cell allo-antibodies associated with excessive neonatal hemolysis and to correct severe anemia. During the past decades, the number of NExT preformed have steadily decreased, particularly since the introduction of rhesus prophylaxis in rhesus negative women.

Hereditary thrombotic thrombocytopenic purpura (hTTP) because of severe congenital ADAMTS13 deficiency is a rare, autosomal recessively inherited disorder with an estimated prevalence of one case per million. Although excessive neonatal hemolysis (often in conjunction with thrombocytopenia) seems to be prevalent in hTTP, patients are seldom diagnosed with hTTP in the neonatal period, possibly because hTTP is not recognized as a differential diagnosis of severe neonatal hyperbilirubinemia and NExT. In this study, we investigated the prevalence of severe neonatal hyperbilirubinemia necessitating NExT among confirmed hTTP patients enrolled in the International Hereditary TTP Registry (www.ttpregistry.net; ClinicalTrials.gov Identifier: NCT01257269), at participating sites and in the literature in the past 20 years.

Methods The International Hereditary TTP Registry is a cohort study for patients with confirmed hTTP and their family members, established in 2006. The hTTP Registry collects clinical and treatment information, as well as laboratory parameters retrospectively up to enrollment (including performance of NExT), and then prospectively during annual follow-up visits. Participating study sites and/or national coordinating centers were asked to provide information on the number of and indication for all NExT performed between January 2001 and July 2022. Finally, we performed a literature search to identify reports on NExT / neonatal exchange blood transfusion over the same 20-year period.

Results At present, the International Hereditary TTP Registry has enrolled 178 confirmed hTTP patients. Forty-two (24%) of them had required NExT because of severe hyperbilirubinemia in the neonatal period, which led to early diagnosis of hTTP in 7/42 (16%) cases. In the remaining 33 patients treated with NExT, hTTP diagnosis was established in infancy/early childhood (between 3 months - ≤6 years of age) in 20 patients, and in 15 instances after 6 years of age. Of the 136 hTTP patients not requiring NExT, 35 (26%) had a disease onset in the neonatal period although only four of them (11%) were diagnosed at this time, while the majority (20/35 patients, 57%) received their hTTP diagnosis following further acute episodes in late adolescence or adulthood.

Twelve of the 20 sites or national coordination centers participating in the International Hereditary TTP Registry answered our survey and reported 70 neonates treated with NExT over a period of 20 years. Indication for NExT were severe hyperbilirubinemia and or severe anemia due to AB0 or Rhesus incompatibility. In none of the cases hTTP was suspected or diagnosed, as immune-hematological findings indicated severe allo-antibody mediated hemolysis.

We retrieved from PubMed 887 publications mentioning NExT or neonatal exchange blood transfusion, of which we excluded 229 papers, that did not describe patients treated with exchange transfusions. In the remaining 658 publications, patients were treated with exchange transfusions because of severe hyperbilirubinemia due to AB0-, Rhesus- or minor blood group incompatibilities, glucose-6-phosphate deficiency, sickle cell disease and severe infections. Only three publications mentioned the indication TTP.

Conclusions Despite increased awareness and tools to diagnose hTTP, prompt recognition and diagnosis remain a critical impediment and result in delayed diagnosis and treatment.

Early and persistent severe hyperbilirubinemia (often in conjunction with thrombocytopenia) necessitating NExT prevalent in newborns later in life diagnosed with hTTP. Differential diagnosis of severe neonatal hyperbilirubinemia should include hTTP and we suggest to determine ADAMTS13 activity together with molecular analysis of the ADAMTS13 gene in case of an ADAMTS13 activity <10% in any newborn requiring NExT for severe hyperbilirubinemia.

Friedman:NovoNordisk: Consultancy; CSL Behring: Consultancy; Shire: Consultancy. Matsumoto:Sanofi K.K.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceutical Co. Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Asahi Kase Pharma Coeporation: Honoraria, Research Funding; Chugai Pharmaceutical Co. Ltd.: Research Funding; Alexion Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alfresa Pharma Corporation: Patents & Royalties: ADAMTS13 activity ELISA kit. Lammle:Takeda: Honoraria, Other: Chairman of Data Safety Monitoring Board for studies investigating recombinant ADAMTS13 for cTTP and iTTP.; Sanofi: Honoraria, Other: I was on the board for development of caplacizumab and gave once a lecture on TTP (preclinical research) for which I received a honararium (November-2019).