VPB0316 - Anti-ADAMTS13 IgG in congenital TTP patients

Sunday, July 10, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: Virtual

Presenting Author(s)

Ilaria Mancini, PhD

Post-Doc Research Fellow
Università degli Studi di Milano, Department of Pathophysiology and Transplantation and Fondazione Luigi Villa, Milan, Italy
Milan, Lombardia, Italy

Co-Author(s)

MB

Marina Biganzoli

Lab Technician
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
Milano, Lombardia, Italy
Andrea Cairo

Biologist
Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center
Milan, Lombardia, Italy
MC

Marco Capecchi

Medical Doctor
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Università degli Studi di Milano, Department of Biomedical Sciences for Health, Milan, Italy
Milan, Lombardia, Italy
Andrea Artoni, MD

MD
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
Milano, Lombardia, Italy
BF

Barbara Ferrari

MD
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
Milan, Lombardia, Italy
ST

Silvia Maria Trisolini

Medical Doctor
Hematology, Department of Translational and Precision Medicine, "Sapienza" University of Rome, Rome, Italy
Roma, Lazio, Italy
LF

Luca Facchini

Medical Doctor
Hematology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy
Reggio Emilia, Emilia-Romagna, Italy
GG

Gaetano Giffrida

MD
university hospital of Catania
Catania, Sicilia, Italy
AD

Alessandro De Fanti

Medical Doctor
Departmental Simple Unit of Pediatric Rheumatology, AUSL-IRCSS Reggio Emilia, Reggio Emilia, Italy
Reggio Emilia, Emilia-Romagna, Italy
Pasquale Agosti, MD

MD, PhD
Università degli Studi di Milano, Department of Pathophysiology and Transplantation and Fondazione Luigi Villa, Milan, Italy
Milano, Lombardia, Italy
Flora Peyvandi, MD, PhD

Professor of Internal Medicine; Director of the Angelo Bianchi Bonomi Hemophilia & Thrombosis Center
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
Milan, Lombardia, Italy

Background: Congenital thrombotic thrombocytopenic purpura (cTTP) is an autosomal recessive disease due to mutations in the ADAMTS13 gene. cTTP manifests as acute episodes of thrombotic microangiopathy characterized by ADAMTS13 activity < 10 IU/dl and absence of anti-ADAMTS13 antibodies, which are treated by plasma infusion to replenish the deficient protease. cTTP patients with anti-ADAMTS13 antibodies were rarely described.

Aims: To investigate anti-ADAMTS13 IgG in our cTTP cohort.

Methods: We performed a cross-sectional study of cTTP patients with homozygous or compound-heterozygous ADAMTS13 mutations, enrolled in the Milan TTP registry from 2002 to 2018. Plasma samples collected during the acute or remission phase were tested for anti-ADAMTS13 IgG using an in-house western blot or ELISA-based assay or the Technozym ADAMTS13 Inhibitor ELISA kit (Technoclone). Neutralizing activity of anti-ADAMTS13 antibodies was measured using a FRET-based Bethesda-like assay.

Results: Ninety-one samples from 27 cTTP patients (52% females, median age at onset 6.5 years [interquartile range 1.2–20.1]) were tested for anti-ADAMTS13 IgG (samples per patient, median [range]: 2 [1-13]). Four acute phase samples from four cTTP patients were positive by at least two anti-ADAMTS13 IgG assays. In one case, non-neutralizing anti-ADAMTS13 IgG (83 U/ml) developed during ticlopidine treatment, considered the trigger of the acute event. Two patients presented non-neutralizing anti-ADAMTS13 IgG (33 and 19 U/ml) after infusion of four units of fresh frozen plasma over 33 and 59 days, respectively. The last case presented extremely high titers of anti-ADAMTS13 IgG (8800 U/ml) with neutralizing activity (295 BU/ml) after being misdiagnosed with acquired TTP due to baseline low titer anti-ADAMTS13 IgGs (17 U/ml) and treated with plasma-exchange every other day for nine months, rituximab, vincristine, cyclophosphamide and splenectomy.

Conclusion(s): Neutralizing anti-ADAMTS13 IgG could develop very rarely in cTTP patients after prolonged exposure to plasma, exogenous source of ADAMTS13. Monitoring of anti-ADAMTS13 antibodies in cTTP patients with a reduced therapeutic response is recommended.