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Mechanisms of ADAMTS13 deficiency in thrombotic thrombocytopenic purpura (TTP) and beyond

Applicant Schaller Tschan Monica
Number 139794
Funding scheme Marie Heim-Voegtlin grants
Research institution Universitätsklinik für Hämatologie und Hämatologisches Zentrallabor Inselspital
Institution of higher education University of Berne - BE
Main discipline Immunology, Immunopathology
Start/End 01.02.2012 - 31.01.2014
Approved amount 205'008.00
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Keywords (8)

Thrombotic thrombocytopenic purpura (TTP); ADAMTS13 deficiency; Anti-ADAMTS13; Autoimmune disease; Spleen; Cardiovascular disease; preeclampsia/HELLP; stroke

Lay Summary (English)

Lay summary
Background. The very first case of TTP reported by Eli Moschcowitz in 1924, was a 16 year old girl, presenting with fever and petechia (hematoma). Within a week she developed paralysis of her left arm and leg and died. Autopsy revealed multiple small thrombi, the hallmark of TTP in arterioles and capillaries in heart, kidneys, liver and spleen. Today mortality rate is still 20% with a high relapse rate of 40-50%. TTP is the result of a severe deficiency of ADAMTS13 - the vonWillebrand Factor (VWF) cleaving protease, causing the accumulation of  ultralarge VWF multimers in the microciruclation leading to the observed blood clots and ultimatively to organ ischemia and dysfunction. There are two forms of TTP: (1) hereditary with homozygous or double heterozygous ADAMTS13 gene mutations, and (2) acquired due to anti-ADAMTS13 autoantibodies neutralizing enzymatic activity. Plasma exchange with fresh frozen plasma with the goal to administer ADAMTS13 and to remove neutralizing anti-ADAMTS13 antibodies is the therapy of choice for this life-threatening disease.

Aims. Studying the pathophysiological mechanisms underlying the severely deficient(Part I) or moderately reduced ADAMTS13 activity (Part II) linked to systemic thrombosis in TTP and beyond.

Experimental set-up. (Part I) We have previously isolated mononuclear cells of two spleens donated to our laboratory by patients (A and B) splenectomized for frequently relapsing acute TTP in order to generate human monoclonal anti-ADAMTS13 antibodies. Preliminary genetic and functional characterization of the patient’s entire IgG4 repertoire using phage display technology and Epstein Barr virus (EBV) transformation of switched memory B cells, revealed that the spleen harbors a distinct set of B-cells producing neutralizing anti-ADAMTS13 antibodies, explaining the success of splenectomy, as both patients are in remission for more than 6 years. Detailed sequence analysis most extraordinarily revealed that the ADAMTS13-binding sites (Fab) of the 29 monoclonal antibodies generated from both patients, are characterized by seven unique and novel antigen-binding motifs (Complementarity determinig region 3, CDR3). Strikingly, four of these motifs were shared by both patients. As both patients are neither genetically nor geographically related and taking into account that the probability of two B-cells to produce very similar specific antibodies is less than 10-9, our findings strongly suggest that these motifs are part of the key antigen-binding sites of neutralizing anti-ADAMTS13 antibodies present in relapsing acquired TTP. My goals are twofold, first I aim to confirm these findings in the spleen of two additional relapsing acquired TTP patients and second, to use these anti-ADAMTS13 antibodies as tools to screen a small protein library (DARPin) for high specific binders blocking the neutralizing antibodies.

(Part II) Clinicial consequences include myocardial infaction, stroke or pregnancy related complications such as preeclampsia/HELLP, which are more prevalent in the general population compared to rare TTP disease. In these conditions, there is often an inverse correlation between VWF and ADAMTS13, with elevated VWF levels and midly to moderately reduced ADAMTS13 activites. My goal is to better understand how ADAMTS13 and VWF contribute to these disease using more comprehensive near-physiological systems and ADAMTS13 genotyping of suitable patient groups to evaluate their risk to develop cardiovascular diseases.

Expected impact. Our preliminary findings regarding the unique set of CDR3 signatures that characterize the pathological relevant, neutralizing antibodies paves the road to define their triggering ADAMTS13 epitope(s). Identification of small molecules that neutralize pathogenic anti-ADAMTS13 antibodies are ideal tools to develop new diagnostic tests and therapeutic treatments for acute TTP. Moerever, I hypothesize that unraveling the pathophysiological mechanisms leading to ADAMTS13 deficiency can serve as a model to understand micro- and macrovascular thrombosis in general, beyond the TTP setting.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants



Von Willebrand Factor Interacts with Surface-Bound C1q and Induces Platelet Rolling.
Kölm Robert, Schaller Monica, Roumenina Lubka T, Niemiec Iga, Kremer Hovinga Johanna A, Khanicheh Elham, Kaufmann Beat A, Hopfer Helmut, Trendelenburg Marten (2016), Von Willebrand Factor Interacts with Surface-Bound C1q and Induces Platelet Rolling., in Journal of immunology (Baltimore, Md. : 1950), 197(9), 3669-3679.
Acquired thrombotic thrombocytopenic purpura - Development of an autoimmune respponse
Schaller Monica (2013), Acquired thrombotic thrombocytopenic purpura - Development of an autoimmune respponse, in Hämostaseologie, 33(2), 1-9.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Gesellschaft für Thrombose und Hämostase Poster Presence of circulating anti-ADAMTS13 specific B-cells following acute acquired Thrombotic Thrombocytopenic Purpura (aTTP) 12.02.2014 Wien, Oesterreich, Austria Schaller Tschan Monica;
Gesellschaft für Thrombose und Hämostase (GTH) Talk given at a conference Anti-idiotypic Designed-Ankyrin Repeat molecules (DARPins) universally neutralize plasma-derived autoantibodies in acquired TTP patients 12.02.2014 Wien, Oesterreich, Austria Schaller Tschan Monica;
IBC-Antibody Engineering Conference Poster Spleen - derived anti-ADAMTS13 antibodies compromising four shared CDR3 signatures - promising new tools for therapy in acquired Thrombotic Thromobocytopenic Purpura (aTTP) 07.12.2013 Huntington Beach, CA, USA, United States of America Schaller Tschan Monica;
International Society on Thrombosis and Haemostasis (ISTH) Poster Anti-idiotypic DARPin molecules - potential new treatment tools for acquired thrombotic thrombocytopenic purura (aTTP)? 29.06.2013 Amsterdam, Niederlande, Netherlands Schaller Tschan Monica;
American Association of Immunologist (AAI) Poster Anti-idiotypic small molecules neutralize pathogenic anti-ADAMTS13 autoantibodies in autoimmune Thrombotic Thrombocytopenic Purpura in vitro - new treatment tools in vivo? 03.05.2013 Honolulu, Hawaii, United States of America Schaller Tschan Monica;
Hämostaseclub 2013 Talk given at a conference Erworbene TTP – Mechanismen der Autoimmunität,aktuelle Forschung, therapeutische Ansätze 24.04.2013 Bern, Schweiz, Switzerland Schaller Tschan Monica;
GTH 2013 (Gesellschaft für Thrombose und Hämostase) Talk given at a conference Anti-idiotypic molecules selected from a large combinatorial library of small proteins neutralize human spleen-derived monoclonal anti-ADAMTS13 - potential new treatment tolls for acquired Thrombotic Thrombocytopenic Purpura (TTP)? 20.02.2013 Muenchen, Deutschland, Germany Schaller Tschan Monica;
ASH 2012 (American Society of Hematology) Talk given at a conference High-Throughput screening of a large combinatorial library of small proteins against human spleen-derived monoclonal anti-ADAMTS13 antibodies yields anti-idiotypic molecules - potential tolls for new treatment strategy in acquired TTP 08.12.2012 Atlanta (GA), USA, United States of America Schaller Tschan Monica;
SGH 2012 (Schweizerische Gesellschaft für Hämatologie) Talk given at a conference A limited number of variable heavy chain complementarity determining region (CDR3) sigantures characterize inhibitory spleen-derived anti-ADAMTS13 B-cells in patients with relapsing acquired Thrombotic Thrombocytopenic Purpura 23.05.2012 Basel, Schweiz, Switzerland Schaller Tschan Monica;
GTH 2012 (Gesellschaft für Thrombose und Hämostase) Talk given at a conference The Splee-derived ADAMTS13-spedcific antibody repertoire in two unrelated patients with relapsing acquired TTP reveals two common heavy chain complementarity-determining region 3 (CDR3) motifs 01.02.2012 St. Gallen, Schweiz, Switzerland Schaller Tschan Monica;


Title Year
Best Abstract Award (First of 5 selected from 230) 2013
Best student abstract for my PhD Student Magdalena Skowronska during the meeting of the IBC Antibody Engineering Conference 2013
Best Abstract Award (11/233 ausgewählt) 2012
Travel grant Award 2012

Associated projects

Number Title Start Funding scheme
124892 Acquired and hereditary thrombotic microangiopathies - clinical presentation, pathophysiology and treatment with a focus on ADAMTS13 01.09.2009 Project funding
160269 Acquired and hereditary thrombotic microangiopathies exemplar diseases to understand ADAMTS13 function and pathophysiology 01.01.2016 Project funding
151807 Mechanisms of ADAMTS13 deficiency in thrombotic thrombocytopenic purpura (TTP) and beyond 01.02.2014 Marie Heim-Voegtlin grants


Severe deficiency of ADAMTS13 (a distintegrin and metalloprotease with thrombospondin Type 1 motifs-13), a VWF-cleaving protease, prevents normal processing of large, sticky Willebrand factor (VWF) multimers, thus accumulating in the microcirculation leading to occlusion of the microvasculature especially in the brain and kidneys, the hallmark of thrombotic thrombocytopenic purpura (TTP). Analyzing in a first step, the acute immune response of two relapsing acquired TTP patients, revealed that the spleen harbours an unique set of ADAMTS13 specific memory B-cells of pathological relevance since after splenectomy both patients stayed in remission. I aim therefore to confirm those findings in 2 spleens of acquired TTP patients (part I). To unravel the pathophysiologial mechanisms of ADAMTS13 deficieny in TTP and beyond, the ADAMTS13 genotype in other cardiovascular diseases with different manifestations of microvascular thrombosis will be analyzed (part II) with the goal to develop new tools to improve therapy options in their clinical management.