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Dissecting the pathophysiology of immune thrombotic thrombocytopenic purpura: interplay between genes and environmental triggers
Johana Hrdinová,1,2,3 Silvia D’Angelo,4,5 Nuno A. G. Graça,1,6 Bogac Ercig,1,2,3 Karen Vanhoorelbeke,4 Agnès Veyradier,7,8 Jan Voorberg 1and Paul Coppo8,9,10
1Department of Plasma Proteins, Sanquin-Academic Medical Center Landsteiner Laboratory, Amsterdam, the Netherlands; 2PharmaTarget B.V., Maastricht, the Netherlands; 3Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands; 4Laboratory for Thrombosis Research, IRF Life Sciences, KU Leuven Campus Kulak Kortrijk, Belgium; 5Protobios LLC, Tallinn, Estonia; 6Icosagen Cell Factory OÜ, Ülenurme Vald, Tartumaa, Estonia; 7Service d'Hématologie Biologique and EA3518, Groupe Hospitalier Saint Louis- Lariboisière, Assistance Publique - Hôpitaux de Paris, Université Paris Diderot, France; 8Centre de Référence des Microangiopathies Thrombotiques, Hôpital Saint-Antoine, AP- HP, Paris, France; 9Service d’Hématologie, Assistance Publique – Hôpitaux de Paris, France and 10Sorbonne Université, UPMC Univ Paris 06, France
ABSTRACT
Although outstanding progress has been made in understanding the pathophysiology of thrombotic thrombocytopenic purpura (TTP), knowledge of the immunopathogenesis of the disease is only at an early stage. Anti-ADAMTS13 auto-antibodies were shown to block proteolysis of von Willebrand factor and/or induce ADAMTS13 clearance from the circulation. However, it still remains to identify which immune cells are involved in the production of anti- ADAMTS13 autoantibodies, and therefore account for the remarkable efficacy of the B-cell depleting agents in this disease. The mechanisms leading to the loss of tolerance of the immune system towards ADAMTS13 involve the predisposing genetic factors of the human leukocyte antigen class II locus DRB1*11 and DQB1*03 alleles as well as the protective allele DRB1*04, and modifying factors such as ethnic- ity, sex and obesity. Future studies have to identify why these identi- fied genetic risk factors are also frequently to be found in the healthy population although the incidence of immune-mediated thrombotic thrombocytopenic purpura (iTTP) is extremely low. Moreover, the development of recombinant ADAMTS13 opens a new therapeutic era in the field. Interactions of recombinant ADAMTS13 with the immune system of iTTP patients will require intensive investigation, especially for its potential immunogenicity. Better understanding of iTTP immunopathogenesis should, therefore, provide a basis for the devel- opment of novel therapeutic approaches to restore immune tolerance towards ADAMTS13 and thereby better prevent refractoriness and relapses in patients with iTTP. In this review, we address these issues and the related challenges in this field.
Introduction
Thrombotic thrombocytopenic purpura (TTP) is a devastating disease resulting from a severe deficiency in the von Willebrand factor (VWF)-cleaving protease ADAMTS13. This deficiency causes the accumulation of ultra-large VWF multi- mers in the circulation and the formation of thrombi in the microvasculature under high shear stress conditions. When left untreated, these microthrombi cause multi-organ failure and lead to death. In the acquired immune-mediated form of
Ferrata Storti Foundation
Haematologica 2018 Volume 103(2):1099-1109
Correspondence:
paul.coppo@aphp.fr
Received: January11,2018. Accepted: April 13, 2018. Pre-published: April 19, 2018.
doi:10.3324/haematol.2016.151407
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/7/1099
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