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Acquired and hereditary thrombotic microangiopathies - clinical presentation, pathophysiology and treatment with a focus on ADAMTS13

Applicant Kremer Hovinga Strebel Johanna Anne
Number 124892
Funding scheme Project funding
Research institution Universitätsklinik für Hämatologie und Hämatologisches Zentrallabor Inselspital
Institution of higher education University of Berne - BE
Main discipline Clinical Cardiovascular Research
Start/End 01.09.2009 - 31.08.2012
Approved amount 250'000.00
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All Disciplines (2)

Discipline
Clinical Cardiovascular Research
Clinical Pathophysiology

Keywords (9)

ADAMTS13; Thrombotic thrombocytopenic purpura; von Willebrand factor; Thrombotic microangiopathy; hereditary; Upshaw-Schulman syndrome; TTP; VWF; acquired

Lay Summary (English)

Lead
Lay summary
Background. Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia and variable ischemic organ damage, primarily in the brain, heart and the kidneys as the result of Von Willebrand factor (VWF) - platelet thrombi in the microvasculature. In the majority of cases, acute TTP bouts are the result of a severe deficiency of the VWF-cleaving protease, ADAMTS13 (A disintegrin and metalloprotease with thrombospondin type 1 motifs13). Severe ADAMTS13 deficiency (<5% of the normal) prevents normal processing of unusually large VWF multimers and their persistence in the circulation is held responsible for the formation of platelet thrombi in the microvasculature. In acquired TTP severe ADAMTS13 deficiency is the result of circulating autoantibodies inhibiting or enhancing clearance of ADAMTS13, while in hereditary TTP (Upshaw-Schulman syndrome) compound heterozygous or homozygous ADAMTS13 gene mutations lead to severe ADAMTS13 deficiency. Aims. In this project we address several topics with the overall goal to better understand pathophysiological mechanisms underlying the clinical pictures of acquired and hereditary TTP. Specific goals are: 1. Identification of the role of ADAMTS13 and possible other (co)factors in acute TTP without severe ADAMTS13 deficiency (about one third of patients) as well as identification of predictors of severe clinical courses and disease relapses in survivors of a first acute bout. 2. Identification of genetic factors contributing to the development of anti-ADAMTS13 autoantibodies. 3. Study of the natural history in hereditary TTP with the aim to establish evidence based guidelines for prophylactic measures and treatment (e.g. during pregnancy) in these patients. For this we have set up an international prospective observational study (Upshaw-Schulman syndrome registry). Comparison of clinical courses among affected siblings or patients with the same ADAMTS13 mutations will help to identify additional factors contributing to the clinical picture in hereditary TTP. 4. Through the study of recombinant ADAMTS13 mutants, in vivo ADAMTS13 parameters and the clinical course we will try to establish a genotype-phenotype correlation in hereditary TTP. 5. Search for other proteases involved in size VWF regulation and VWF processing.Outlook. Although rare TTP is a model disorder of small and large vessel thrombosis and an exemplar autoimmune disease. Data obtained within the framework of this project will enhance our understanding of pathophysiologically related, but much more frequent diseases such as myocardial infarction and stroke.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Indications for a protective function of beta2-glycoprotein I in thrombotic thrombocytopenic purpura
Du VX, von Os G, Kremer Hovinga JA, Dienava-Verdoold I, Wollersheim J, Ruggeri ZM, Fijnheer R, de Groot PG, de Laat B (2012), Indications for a protective function of beta2-glycoprotein I in thrombotic thrombocytopenic purpura, in Br J Haematol, 159(1), 94-103.
Circulating DNA and myeloperoxidase indicate disease activity in patients with thrombotic microangiopathies.
Fuchs Tobias A, Kremer Hovinga Johanna A, Schatzberg Daphne, Wagner Denisa D, Lämmle Bernhard (2012), Circulating DNA and myeloperoxidase indicate disease activity in patients with thrombotic microangiopathies., in Blood, 120(6), 1157-64.
Initial experience from a double-blind, placebo-controlled, clinical outcome study of ARC1779 in patients with thrombotic thrombocytopenic purpura.
Cataland Spero R, Peyvandi Flora, Mannucci Pier M, Lämmle Bernhard, Kremer Hovinga Johanna A, Machin Samuel J, Scully Marie, Rock Gail, Gilbert James C, Yang Shangbin, Wu Haifeng, Jilma Bernd, Knoebl Paul (2012), Initial experience from a double-blind, placebo-controlled, clinical outcome study of ARC1779 in patients with thrombotic thrombocytopenic purpura., in American journal of hematology, 87(4), 430-2.
Improving on nature: redesigning ADAMTS13
Kremer Hovinga JA, Voorberg J (2012), Improving on nature: redesigning ADAMTS13, in BLOOD, 119(16), 3654-3655.
Thrombotic microangiopathic syndromes associated with drugs, HIV infection, hematopoietic stem cell transplantation and cancer.
George James N, Terrell Deirdra R, Vesely Sara K, Kremer Hovinga Johanna A, Lämmle Bernhard (2012), Thrombotic microangiopathic syndromes associated with drugs, HIV infection, hematopoietic stem cell transplantation and cancer., in Presse médicale (Paris, France : 1983), 41, e177-e188.
Evidence for a role of anti-ADAMTS13 autoantibodies despite normal ADAMTS13 activity in recurrent thrombotic thrombocytopenic purpura
Froehlich-Zahnd R, George JN, Vesely SK, Terrell DR, Aboulfatova K, Dong JF, Luken BM, Voorberg J, Budde U, Sulzer I, Lammle B, Hovinga JAK (2012), Evidence for a role of anti-ADAMTS13 autoantibodies despite normal ADAMTS13 activity in recurrent thrombotic thrombocytopenic purpura, in HAEMATOLOGICA-THE HEMATOLOGY JOURNAL, 97(2), 297-303.
Humoral immune response to ADAMTS13 in acquired thrombotic thrombocytopenic purpura.
Pos W, Luken B M, Sorvillo N, Hovinga J A Kremer, Voorberg J (2011), Humoral immune response to ADAMTS13 in acquired thrombotic thrombocytopenic purpura., in Journal of thrombosis and haemostasis : JTH, 9(7), 1285-91.
Recombinant ADAMTS13 normalizes von Willebrand factor-cleaving activity in plasma of acquired TTP patients by overriding inhibitory antibodies.
Plaimauer B, Kremer Hovinga J A, Juno C, Wolfsegger M J, Skalicky S, Schmidt M, Grillberger L, Hasslacher M, Knöbl P, Ehrlich H, Scheiflinger F (2011), Recombinant ADAMTS13 normalizes von Willebrand factor-cleaving activity in plasma of acquired TTP patients by overriding inhibitory antibodies., in Journal of thrombosis and haemostasis : JTH, 9(5), 936-44.
Blood group O and black race are independent risk factors for thrombotic thrombocytopenic purpura associated with severe ADAMTS13 deficiency.
Terrell Deirdra R, Motto David G, Kremer Hovinga Johanna A, Lämmle Bernhard, George James N, Vesely Sara K (2011), Blood group O and black race are independent risk factors for thrombotic thrombocytopenic purpura associated with severe ADAMTS13 deficiency., in Transfusion, 51, 2237-2243.
von Willebrand factor-mediated platelet adhesion is critical for deep vein thrombosis in mouse models.
Brill Alexander, Fuchs Tobias A, Chauhan Anil K, Yang Janie J, De Meyer Simon F, Köllnberger Maria, Wakefield Thomas W, Lämmle Bernhard, Massberg Steffen, Wagner Denisa D (2011), von Willebrand factor-mediated platelet adhesion is critical for deep vein thrombosis in mouse models., in Blood, 117(4), 1400-7.
Different disparities of gender and race among the thrombotic thrombocytopenic purpura and hemolytic-uremic syndromes.
Terrell Deirdra R, Vesely Sara K, Hovinga Johanna A Kremer, Lämmle Bernhard, George James N (2010), Different disparities of gender and race among the thrombotic thrombocytopenic purpura and hemolytic-uremic syndromes., in American journal of hematology, 85(11), 844-7.
Survival and relapse in patients with thrombotic thrombocytopenic purpura.
Hovinga Johanna A Kremer, Vesely Sara K, Terrell Deirdra R, Lämmle Bernhard, George James N (2010), Survival and relapse in patients with thrombotic thrombocytopenic purpura., in Blood, 115(8), 1500-1511.
IgG subclass distribution of anti-ADAMTS13 antibodies in patients with acquired thrombotic thrombocytopenic purpura.
Ferrari S, Mudde G C, Rieger M, Veyradier A, Kremer Hovinga J A, Scheiflinger F (2009), IgG subclass distribution of anti-ADAMTS13 antibodies in patients with acquired thrombotic thrombocytopenic purpura., in Journal of thrombosis and haemostasis : JTH, 7(10), 1703-10.
Decreasing frequency of plasma exchange complications in patients treated for thrombotic thrombocytopenic purpura-hemolytic uremic syndrome, 1996 to 2011.
Som Sumit, Deford Cassandra C, Kaiser Mandi L, Terrell Deirdra R, Kremer Hovinga Johanna A, Lämmle Bernhard, George James N, Vesely Sara K, Decreasing frequency of plasma exchange complications in patients treated for thrombotic thrombocytopenic purpura-hemolytic uremic syndrome, 1996 to 2011., in Transfusion.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
80th Annual Meeting, Swiss Society of Hematology 24.05.2012 Basel
12th Annual Meeting American Society for Apheresis (ASFA) 12.04.2012 Atlanta, GA, USA
TTP Consensus Conference of the American Society for Apheresis 10.04.2012 Atlanta, GA, USA
14th ADAMTS13 Meeting 29.07.2011 Nara, Japan
XXIIrd Congress of the International Society on Thrombosis and Haemostasis (ISTH) 23.07.2011 Kyoto, Japan
7th Bari International Conference on Hemophilia, von Willebrand factor and ADAMTS13 21.05.2011 Pugnochiuso del Vieste, Italien
21st International Congress on Thrombosis 2010 06.07.2010 Milano, Italien
Annual Meeting of the Swedish Society of Nephrology 03.05.2010 Kalmar, Schweden
1st European Thrombotic Microangiopathy Meeting 25.03.2010 Paris, Frankreich
13th International Congress of the World Apheresis Association WAA 02.09.2009 Interlaken


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Schweizerische Informationswoche für Labor und Medizin, Silamed 2012 26.04.2012 Horgen
Swiss Hemophilia Symposium - Von Willebrand Syndrom: Klinisches Bild und Behandlung 06.11.2011 Zürich
16. Fortbildungskurs Schweizerischen Gesellschaft für Hämatologie 22.10.2010 Bern, Schweiz


Self-organised

Title Date Place
ADAMTS13 und andere therapeutische Fortschritte in der Hämostaseologie 22.09.2011 Bern, Schweiz

Awards

Title Year
2. Fakultätspreis für die Dissertation, Medizinische Fakultät, Universität Bern 2012
GTH – Award of the best congress abstract 2012 2012
Marie Heim-Vögtlin Stipendium 2012
American Society of Hematology Abstract Achievment Award 2011 2011
Best Abstract-Preis 2011 Gesellschaft für Thrombose- und Hämostaseforschung (Rang 1/384 Abstracts) 2011
Best Abstract-Preis 2011 Gesellschaft für Thrombose- und Hämostaseforschung (Rang 5/384 Abstracts) 2011
Co-Chair, ISTH SSC Von Willebrand 2011
Roche Hämostase Förderpreis 2011 2011
Vorstand, Gesellschaft für Thrombose und Hämostaseforschung 2011
Stipendium Josephine Clark-Fonds, Universität Bern 2009

Associated projects

Number Title Start Funding scheme
151807 Mechanisms of ADAMTS13 deficiency in thrombotic thrombocytopenic purpura (TTP) and beyond 01.02.2014 Marie Heim-Voegtlin grants
108261 ADAMTS-13 and thrombotic microangiopathies: Pathophysiology, diagnosis and treatment 01.07.2005 Project funding
139794 Mechanisms of ADAMTS13 deficiency in thrombotic thrombocytopenic purpura (TTP) and beyond 01.02.2012 Marie Heim-Voegtlin grants
160269 Acquired and hereditary thrombotic microangiopathies exemplar diseases to understand ADAMTS13 function and pathophysiology 01.01.2016 Project funding
185233 Thrombotic thrombocytopenic purpura - role of ADAMTS13 and long-term outcome 01.07.2019 Project funding

Abstract

Thrombotic thrombocytopenic purpura (TTP) is a rare disorder characterized by thrombocytopenia due to microvascular platelet clumping, microangiopathic hemolytic anemia, often accompanied by ischemic organ dysfunctions such as neurological abnormalities, renal insufficiency, and fever. In 1924 Moschcowitz first described TTP in a 16-year-old girl who died within a fortnight of abrupt onset of petechiae, anemia, micro-hematuria, fever and coma. Until the seventies of the 20th century, acute TTP remained an almost universally fatal disorder when the empirical introduction of plasma therapy dramatically improved survival from <10% to about 80-90%. During the past decade remarkable advances in understanding the pathogenesis of TTP have been achieved. The condition is often associated with insufficient processing of newly secreted, unusually large von Willebrand factor (VWF) multimers as a result of a severe deficiency of the von VWF-cleaving protease (<5% of normal plasma), now denoted as ADAMTS13.Nowadays two major forms of classical TTP are distinguished, an acquired as well as a hereditary form. Hereditary TTP ( also known as Upshaw-Schulman syndrome) is caused by severe congenital ADAMTS13 deficiency due to compound heterozygous or homozygous ADAMTS13 mutations. The pathophysiology underlying acquired TTP is not completely understood, although 60% of patients have a severe ADAMTS13 deficiency as a result of circulating anti-ADAMTS13 autoantibodies, either inhibiting ADAMTS13 or enhancing its clearance. In the majority of patients with this form normalization of ADAMTS13 activity and disappearance of the inhibiting antibodies is observed when remission is achieved. Despite these advances to which we have greatly contributed by the discovery and partial purification of the VWF-cleaving protease in our laboratory, through establishing the link between severe VWF-cleaving protease deficiency and a disorder most often clinically diagnosed as TTP, as well as by distinguishing two separate forms of ADAMTS13 deficiency, acquired autoantibody-mediated and constitutional deficiency, respectively, many questions remain as yet unanswered and will be addressed in the present research proposal.1. We will address peculiarities of ADAMTS13 in acquired idiopathic TTP: Severe ADAMTS13 deficiency is a specific finding of acute TTP bouts, still about one third of patients clinically diagnosed with TTP have normal or only moderately decreased ADAMTS13 activities. What is the underlying pathophysiology in these patients? Is there a pathophysiological role for ADAMTS13 in this situation? The relapse rate in survivors of acute TTP bouts has been reported to be 30-50%, with the highest rates among patients severe ADAMTS13 deficiency. Are ADAMTS13 parameters during relapse similar as during a first acute TTP bout? Is it possible to identify imminent relapses by regular ADAMTS13 activity measurements? During the last two years, we have developed and implemented new assays to address these question in a large cohort of patients suffering from acquired idiopathic TTP form the Oklahoma TTP-HUS registry. Using these new assays, we have observed that in a few patients ADAMTS13 activities determined by different assays don’t correlate well and we will explore reasons for the observed discrepancies in addition.2. It s now well recognized, that in most adult cases of TTP severe ADAMTS13 deficiency is the result of circulating autoantibodies, however, insights into the basis of ADAMTS13 autoimmunity are still limited. The occurrence of acquired TTP with severe autoantibody-mediated ADAMTS13 deficiency in identical twin sisters set us off to speculate on so far unrecognized genetic determinants increasing susceptibility for acquired TTP and pathogenic ADAMTS13 autoantibody formation. Our primary focus is on ADAMTS13 itself, which contains a large number of coding single nucleotide polymorphisms, which cluster in exons encoding the ADAMTS13 cys-rich and spacer domains, which in turn contain the primary anti-ADAMTS13 antibody epitopes. Molecular analyses of the ADAMTS13 gene in a first cohort of 37 patients with acute TTP and severe acquired ADAMTS13 deficiency revealed that ADAMTS13 itself may indeed be the immunological culprit, as we observed ADAMTS13 mutations, a definite disease-associated ADAMTS13 haplotype and most strikingly an increased interallelic variability specific for the ADAMTS13 locus in these patients. These spectacular findings need to be confirmed in a second patient cohort. In a nex step, we will extend our search for genetic determinants of ADAMTS13 autoimmunity to the major histocompatibility complex, other candidate proteins and eventually the whole genome.3. Little is know on the natural history and treatment requirements in hereditary TTP patients. In addition there are no data on the prevalence of this syndrome, except that it is considered extremely rare. There are several indications, however, that hereditary TTP is under-recognized, e.g. in many families (several) siblings of index patients have died of a TTP-like disorder without a formally established diagnosis, or there are frequently recurring mutations which have spread over a large area in Europe. With our registry for Upshaw-Schulman syndrome patients and a population screening for known ADMATS13 mutations using a DNA chip, we hope to gain insights in the clinical questions and the prevalence of this disorder. Furthermore, these studies aim at increasing knowledge and awareness for a disorder that can be treated with simple infusions of fresh frozen plasma ever 2-3 weeks, but leads to considerable morbidity and mortality in many cases if left untreated.4. To establish a causal relationship between identified ADAMTS13 mutations and clinical phenotype, the impact of the mutations on protein production, secretion and function have to be studied by site- directed mutagensis and transfection of mutant ADAMTS13 cDNA into mammalian cell lines. These technologies have been established in our laboratory during the last 12-18 months and studies initiated on the first five ADAMTS13 mutations observed in homozygous form will be continued. Eventually, further ADAMTS13 mutations found in our patients (so far we have found 30 different mutations in 51 families) will be chosen for investigation. These studies will shed light on structure-function relationship and help to better understand ADAMTS13 properties.5. Finally, we attempt to identify other proteases possibly involved in VWF size regulation under certain conditions.In summary, our ongoing research in the field, started more than 10 years ago, has contributed substantially to the understanding of a rare, though exemplar disorder of micro- and macrovascular thrombosis, and has likely implications for other more frequent disorders, such as stroke or myocardial infarction where adhesion of platelets on large VWF multimers is a primary event. Moreover, our current research provides a new model for pathogenic autoantibody formation with importance beyond acquired TTP. We hope that we can pursue our research with the help of the Swiss National Research Foundation over the next three years.
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