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CC BY-NC-ND 4.0 · Thromb Haemost 2025; 125(06): 513-522
DOI: 10.1055/a-2413-4345
Review Article

Emerging Thrombotic Disorders Associated with Virus-Based Innovative Therapies: From VITT to AAV Gene Therapy–Related Thrombotic Microangiopathy

Silvia Benemei
1   Medical Affairs, Pfizer Italia, Rome, Italy
,
Francesca Gatto
1   Medical Affairs, Pfizer Italia, Rome, Italy
,
Rossella Marcucci   *
2   Department of Experimental and Clinical Medicine, University of Florence and Azienda Ospedaliero-Universitaria Careggi, Firenze, Italy
,
Paolo Gresele    *
3   Section of Internal and Cardiovascular Medicine, Department of Medicine, University of Perugia, Perugia, Italy
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Abstract

Gene therapy is a promising therapeutic approach for treating life-threatening disorders. Despite the clinical improvements observed with gene therapy, immune responses either innate or adaptive against the vector used for gene delivery, can affect treatment efficacy and lead to adverse reactions. Thrombotic microangiopathy (TMA) is a thrombosis with thrombocytopenia syndrome (TTS) characterized by microangiopathic hemolytic anemia, thrombocytopenia, and small vessel occlusion known to be elicited by several drugs, that has been recently reported as an adverse event of adeno-associated virus (AAV)-based gene therapy. TMA encompasses a heterogenous group of disorders, its classification and underlining mechanisms are still uncertain, and still lacks validated biomarkers. The identification of predictors of TMA, such as vector dose and patient characteristics, is a pressing need to recognize patients at risk before and after AAV-based gene therapy administration. This review aims to explore the literature on TMA associated with AAV-based gene therapy in the larger context of TMA (i.e., hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura, and other drug-related TMAs). Considering the wide attention recently gained by another TTS associated with a non-gene therapy viral platform (adenovirus, AV COVID-19 vaccine), namely vaccine-induced immune thrombocytopenia and thrombosis (VITT), AAV gene therapy–related TMA mechanisms will be discussed and differentiated from those of VITT to avoid recency bias and favor a correct positioning of these two recently emerged syndromes within the heterogenous group of drug-related TTS. Finally, the review will discuss strategies for enhancing the safety and optimize the management of AAV-based gene therapy that is emerging as an efficacious therapeutic option for disparate, severe, and often orphan conditions.

Keywords

adeno-associated virus (AAV) - biomarkers - gene therapy - thrombotic microangiopathy (TMA) - vaccine-induced immune thrombocytopenia and thrombosis (VITT)

Authors' Contribution

All authors conceived the project, wrote, edited, and revised the manuscript critically. All authors approved the final version of the manuscript.


* These authors share senior authorship.


Supplementary Material



Publication History

Received: 02 February 2024

Accepted: 04 August 2024

Accepted Manuscript online:
11 September 2024

Article published online:
03 October 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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