Bio sketch Prof. Johanna Anna Kremer Hovinga
I am a physician-scientist with a strong interest in bringing clinical observations to the research laboratory to unravel underlying pathophysiological mechanisms.
Following graduation from medical school, I started my research career with a fellowship from the Swiss National Science Foundation working in the field of blood coagulation, which has remained my fascination. Since 2003 I have focused on Von Willebrand factor (VWF), its principal size regulator ADAMTS13 and on disorders were the interplay between these two proteins is perturbed: Von Willebrand Disease, a bleeding diathesis, and life-threatening thrombotic thrombocytopenic purpura (TTP) characterized by microvascular thrombosis throughout the body.
In my clinical work, the certification of the hemophilia consultation at Bern University Hospital as European Hemophilia Comprehensive Care Center (EHCCC) in 2015 was important. Together, with my role in the routine laboratory of the Bern University Hospital, I have established this center as a national reference center for VWF diagnostics and treatment of patients with Von Willebrand Disease over the past 10 years. Further important to my clinical work is my role as principal investigator in clinical trials with innovative investigational compounds: Caplacizumab (TITAN and HERCULES trials) for immune-mediated TTP and rADAMTS13 for hereditary TTP; or Emicizumab (STASEY) in hemophilia A with high-titer inhibitors.
Contribution to science & major achievements of the last 5 years
The pathophysiology underlying immune-mediated thrombotic thrombocytopenic purpura (TTP) is a severe acquired ADAMST13 deficiency due to circulating anti-ADAMTS13 autoantibodies while hereditary TTP is the result of an autosomal recessively inherited severe congenital ADAMTS13 deficiency.
My laboratory is one of the world leading reference centers. I have a long-standing interest in ADAMTS13 assays and the role of ADAMTS13 in the pathophysiology of TTP. My research laboratory was the first to develop ADAMTS13 assays to accreditation, and recapitulated their high quality performance in multicenter studies. This was instrumental in / for
- the assignment of the International Society on Thrombosis and Haemostasis (ISTH) to develop the first international plasma ADAMTS13 standard, which was approved by the WHO in 2014 .
- the close collaboration with James N. George and the Oklahoma TTP-HUS registry, the largest and oldest cohort study on TTP. This collaboration has resulted in a number of important observations. We found, that relapses in TTP survivors occur almost exclusively in patients initially presenting a severe acquired ADAMTS13 deficiency . We were the first to document the maturation of the autoimmune response to ADAMTS13 over time and the presence of circulating ADAMTS13 immune complexes during acute TTP episodes and in remission . Or that reappearance of severe acquired ADAMTS13 deficiency in the absence of overt TTP may be reversible without treatment in a relevant number of patients .
- establishing the inhibitory effect of hemoglobin on VWF-cleavage by ADAMTS13 (relevant besides TTP possibly also in (cerebral) malaria, paroxysmal nocturnal hemoglobinuria, etc.) .
- the participation and selection as central laboratory for the randomized phase 2 clinical trial on Caplacizumab in acquired TTP (TITAN trial) [6, 7], which together with the phase 3 HERCULES trial  was instrumental for the approval of Caplacizumab by the FDA, EMA and SwissMedic.
- the International Hereditary TTP Registry (www.ttpregistry.net; NCT01257269), an international multicentre study for long-term follow-up of patients with hereditary TTP and their family members, which has today more than 210 participants [9, 10]. The New England Journal of Medicine recognized this work by the invitation to write a review article on hereditary TTP together with James N. George [11, 12]. Also in 2019, this project received the Günter Landbeck Excellence Award (GLEA) 2019.
- With a number of studies, my team contributed to the picture of a baseline risk, e.g. conferred by a severe ADAMTS13 deficiency, which leads to a common final pathway of thrombotic microangiopathies. Other risk factors and factors contributing to the of the common final pathway explored are freshly released ultra-large VWF multimers, Neutrophil Extracellular Traps (NETs) and free DNA , DNAse1 , free hemoglobin , or the complement system .
- The close link between offering advice and complete ADAMTS13 diagnostics for physicians taking care of patients with rare TTP or VWD at Bern University Hospital, in many countries in Europe and overseas, as well as the contribution of patients e.g. in the form of tissue donations (spleens), make my translational research possible [16, 17].
In the center of my research projects are the immune response to ADAMTS13 in acquired TTP and in hereditary TTP, and the (long-term) course and burden of hereditary TTP. Tracing the onset of the autoimmune response to ADAMTS13 to its beginnings is so far not possible, as the first acute TTP episode usually sets in like a bolt out of the blue sky. Therefore, we focus on survivors and on patients with a relapsing disease course to understand mechanisms that lead to remission, reversing and keeping the autoimmune response in check, and that interrupt the established balance.
With new approaches, we study the ADAMTS13 antibody response in plasma of well-defined patients (i.e. siblings suffering from acquired TTP; hereditary TTP patients having allo-antibodies to ADAMTS13; patients demonstrating inhibitor boosting during plasma exchange treatment).
Using selected monoclonal ADAMTS13 antibodies from the splenic antibody repertoire of eight iTTP patients, we aim at the generation of small anti-idiotypic molecules that are able to neutralize ADAMTS13 inhibitors present in acute TTP episodes and to track and eliminate anti-ADAMTS13 specific B-cells in the circulation and in secondary lymphoid organs of iTTP patients.
The International Hereditary TTP registry, an open and ambi-directional cohort study, has enrolled so far more than 140 hereditary TTP patients, and 40 obligatory heterozygous mutation carriers. A first dataset is now ready for analysis and we aim at the identification of factors influencing the clinical course and long-term outcome in affected patients. The goal is to understand unmet needs, prevent delayed diagnosis and establish criteria for treatment decisions.
List of collaborators
- James N. George, Oklahoma, US
- Karen Vanhoorelbeke, Leuven, Belgium
- Jan J Voorberg, Amsterdam, The Netherlands
- Steering committee and Advisory Board members International Hereditary TTP Registry
Swiss National Science Foundation (Grant 310030-185233)
Baxter, a Takeda company BioScience Grant (H16-36165)
GTH Congress President Fund
Answering T.T.P. Thrombotic Thrombocytopenic Purpura Foundation (Project ID 1009)
- Link to publication list in pubmed (descending order): Johanna A. Kremer Hovinga in PubMed
- List of all publications can be found here: Publication List Kremer Hovinga
- Hubbard AR, Heath AB, Kremer Hovinga JA. Establishment of the WHO 1st International Standard ADAMTS13, plasma (12/252): communication from the SSC of the ISTH. J Thromb Haemost. 2015;13:1151-3.
- Kremer Hovinga JA, Vesely SK, Terrell DR, Lämmle B, George JN. Survival and relapse in patients with thrombotic thrombocytopenic purpura. Blood. 2010;115:1500-11.
- Froehlich-Zahnd R, George JN, Vesely SK, Terrell DR, Aboulfatova K, Dong JF, Luken BM, Voorberg J, Budde U, Sulzer I, Lämmle B, Kremer Hovinga JA. Evidence for a role of anti-ADAMTS13 autoantibodies despite normal ADAMTS13 activity in recurrent thrombotic thrombocytopenic purpura. Haematologica. 2012;97:297-303.
- Page EE, Kremer Hovinga JA, Terrell DR, Vesely SK, George JN. Clinical importance of ADAMTS13 activity during remission in patients with acquired thrombotic thrombocytopenic purpura. Blood. 2016;128:2175-8.
- Studt JD, Kremer Hovinga JA, Antoine G, Hermann M, Rieger M, Scheiflinger F, Lämmle B. Fatal congenital thrombotic thrombocytopenic purpura with apparent ADAMTS13 inhibitor: in vitro inhibition of ADAMTS13 activity by hemoglobin. Blood. 2005;105:542-4.
- Peyvandi F, Scully M, Kremer Hovinga JA, Cataland S, Knöbl P, Wu H, Artoni A, Westwood JP, Mansouri Taleghani M, Jilma B, Callewaert F, Ulrichts H, Duby C, Tersago D, Investigators T. Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura. N Engl J Med. 2016;374:511-22.
- Peyvandi F, Scully M, Kremer Hovinga JA, Knöbl P, Cataland S, De Beuf K, Callewaert F, De Winter H, Zeldin RK. Caplacizumab reduces the frequency of major thromboembolic events, exacerbations and death in patients with acquired thrombotic thrombocytopenic purpura. J Thromb Haemost. 2017;15:1448-52.
- Scully M, Cataland SR, Peyvandi F, Coppo P, Knobl P, Kremer Hovinga JA, Metjian A, de la Rubia J, Pavenski K, Callewaert F, Biswas D, De Winter H, Zeldin RK, Investigators H. Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura. N Engl J Med. 2019;380:335-46.
- Mansouri Taleghani M, von Krogh AS, Fujimura Y, George JN, Hrachovinova I, Knöbl PN, Quist-Paulsen P, Schneppenheim R, Lämmle B, Kremer Hovinga JA. Hereditary thrombotic thrombocytopenic purpura and the hereditary TTP registry. Hamostaseologie. 2013;33:138-43.
- van Dorland HA, Taleghani MM, Sakai K, Friedman KD, George JN, Hrachovinova I, Knöbl PN, von Krogh AS, Schneppenheim R, Aebi-Huber I, Bütikofer L, Largiader CR, Cermakova Z, Kokame K, Miyata T, Yagi H, Terrell DR, Vesely SK, Matsumoto M, Lämmle B, et al. The International Hereditary Thrombotic Thrombocytopenic Purpura Registry: key findings at enrollment until 2017. Haematologica. 2019;104:2107-15.
- Kremer Hovinga JA, George JN. Hereditary Thrombotic Thrombocytopenic Purpura. N Engl J Med. 2019;381:1653-62.
- Kremer Hovinga JA, George JN. Hereditary Thrombotic Thrombocytopenic Purpura. Reply. N Engl J Med. 2020;382:394-5.
- Fuchs TA, Kremer Hovinga JA, Schatzberg D, Wagner DD, Lämmle B. Circulating DNA and myeloperoxidase indicate disease activity in patients with thrombotic microangiopathies. Blood. 2012;120:1157-64.
- Jiménez-Alcázar M, Napirei M, Panda R, Köhler EC, Kremer Hovinga JA, Mannherz HG, Peine S, Renné T, Lämmle B, Fuchs TA. Impaired DNase1-mediated degradation of neutrophil extracellular traps is associated with acute thrombotic microangiopathies. J Thromb Haemost. 2015;13:732-42.
- Fan X, Kremer Hovinga JA, Shirotani-Ikejima H, Eura Y, Hirai H, Honda S, Kokame K, Taleghani MM, von Krogh AS, Yoshida Y, Fujimura Y, Lämmle B, Miyata T. Genetic variations in complement factors in patients with congenital thrombotic thrombocytopenic purpura with renal insufficiency. Int J Hematol. 2016;103:283-91.
- Schaller M, Vogel M, Kentouche K, Lämmle B, Kremer Hovinga JA. The splenic autoimmune response to ADAMTS13 in thrombotic thrombocytopenic purpura contains recurrent antigen-binding CDR3 motifs. Blood. 2014;124:3469-79.
- von Krogh AS, Quist-Paulsen P, Waage A, Langseth OO, Thorstensen K, Brudevold R, Tjonnfjord GE, Largiadèr CR, Lämmle B, Kremer Hovinga JA. High prevalence of hereditary thrombotic thrombocytopenic purpura in central Norway: from clinical observation to evidence. J Thromb Haemost. 2016;14:73-82.