Highlights From the 34th Congress of the International Society on Thrombosis and Haemostasis
Histopathological characterization of immune-mediated hepatocellular injury following gene therapy in hemophilia
Presenting Author: Vincenzo La Mura, MD
Vincenzo La Mura1,2, Niccolò Bitto1, Alessandro Ciavarella1, Paola Dongiovanni3, Paola Gruarin4, Miriam Longo3, Laura Maria Napoli5, Marco Maggioni6, Michela Ripolone7, Anna Maria Ierardi8, Anna Fracanzani3, Sergio Abrignani4,9, Flora Peyvandi1,2
1 Foundation I.R.C.C.S. Ca' Granda, Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi and Thrombosis center, Milan, Italy, Milan, Italy; 2 Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy., Milan, Italy; 3 Foundation I.R.C.C.S. Ca' Granda, Ospedale Maggiore Policlinico, Medicine and Metabolic Diseases Unit, Milan, Italy, Milan, Italy; 4 National Institute for Molecular Genetics "Romeo ed Enrica Invernizzi", INGM, Milan, Italy., Milan, Italy; 5 Dino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, Milan, 20135, Italy., Milan, Italy; 6 Foundation I.R.C.C.S. Ca' Granda, Ospedale Maggiore Policlinico, Pathology Division, Milan, Italy., Milan, Italy; 7 Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Neuromuscular and Rare Disease Unit, Milan, Italy, Milan, Italy; 8 Foundation I.R.C.C.S. Ca' Granda, Ospedale Maggiore Policlinico, Interventional radiology Unit, Milan, Italy, Milan, Italy; 9 Department for Clinical Sciences and Community Health (DISCCO), University of Milan, Milan, Italy, Milan, Italy
A 5-year histological analysis presented at ISTH 2026 evaluated the impact of valoctogene roxaparvovec on immune-mediated hepatocellular injury in 5 patients treated with gene therapy for severe hemophilia A. The goal of this study was to explore the mechanisms of alanine transaminase (ALT) elevation in order to personalize corticosteroid therapy. At baseline, 4 (80%) participants had transaminase levels 1.5x the baseline values. Of these 4 participants, 2 (40%) had transaminase levels above the normal laboratory range and lost expression of the therapeutic transgene. Liver biopsies in these 2 patients showed plasma cell and leukocyte infiltrates consistent with immune-mediated hepatitis along with evidence of endoplasmic reticulum stress, another proposed mechanism for post-gene therapy ALT elevation. Immune profiling showed CD4 T-cell exhaustion and CD8 T-cell hyperactivation, suggesting a cytotoxic immune response. The other 2 patients had mild ALT increases that remained within the normal range, without loss of transgene expression. They were not treated and maintained normal transaminases and sustained transgene expression during follow-up. Based on these findings, the proposed management algorithm emphasizes:
- Excluding extrahepatic causes of ALT elevation
- Determining whether ALT is above or within the normal laboratory range
- Assessing factor VIII transgene expression
Figure: Proposed Management Algorithm
