Better understandanding of rare blood disease TTP

PhD thesis defense Johana Hrdinová

On 29 January 2021 (10:00) Johana Hrdinová will defend her thesis at the University of Amsterdam. Her research aimes to improve our understanding of the pathophysiology of the rare blood disease iTTP, in order to be able to design improved, targeted therapies with fewer side effects. Common treatment includes endless rounds of plasma exchange. 

Immune thrombotic thrombocytopenic purpura (iTTP) is a hematological condition which presents with thrombocytopenia, hemolytic anemia, neurological symptoms and schistocytes on a blood smear. Although being rare, iTTP is a deadly disease with rapid progression when left untreated. In the past few years, the diagnosis and treatment of iTTP patients has been significantly improved. Nevertheless, the majority of patients suffer from relapses, tiredness, neurological disorders after the first iTTP bout, which cannot be overcome by current treatment strategies. 

In the studies included in this thesis we aimed to improve our understanding of the pathophysiology of iTTP in order to be able to design improved, targeted therapies with fewer side effects. In this thesis we discuss the latest advances in our current understanding of the pathophysiology of iTTP. Furthermore, we discuss structural changes in ADAMTS13 and their role in regulation of proteolytic activity towards its substrate von Willebrand factor. Additionally, we discuss possible involvement of ADAMTS13 structural changes in the onset of autoimmunity and place these recent findings into context of other autoimmune diseases.

In our research we also identified ADAMTS13 peptides that are preferentially presented on HLA-DR and HLA-DQ of healthy individuals. Furthermore, the immunogenic potential of the identified HLA-DR- and HLA-DQ-presented ADAMTS13 peptides was assessed using in silico methods. In this thesis we also introduced novel treatment strategies for iTTP; based on additional N-glycan insertion on the major autoantibody epitope in the ADAMTS13 spacer domain and designed novel peptide inhibitors of the VWF A1- platelet GPIbα axis.

The research was part of the Eurpean Horizon 2020 PROFILE project. Read more at Sanquin.org.

Promotores: prof J.J. Voorberg PhD, prof K. Vanhoorelbeke PhD

Co-promotores: prof C.P.M. Reutelingsperger PhD, G.A.F. Nicolaes PhD