ADAMTS13; Thrombotic thrombocytopenic purpura; von Willebrand factor; Thrombotic microangiopathy; hereditary; Upshaw-Schulman syndrome; TTP; VWF; acquired
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.
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.
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.
Kremer Hovinga JA, Voorberg J (2012), Improving on nature: redesigning ADAMTS13, in BLOOD
, 119(16), 3654-3655.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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.