Thrombosis,Tthrombophilia and Haemorrhagic Diathesis Research Group

Group leader: Zsuzsanna Bereczky MD, PhD

Members: Gábor Balogh PhD; Nikoletta Gáti MSc; Réka Gindele PhD; Judit Kállai MSc; Éva Katona PhD; Adrienne Kerényi MD, PhD; Réka Bogáti Kiss MSc; László Muszbek MD, full member of The Hungarian Academy of Sciences; Krisztina Pénzes-Daku PhD; Dóra Pituk MSc

Technician: Éva Molnár MSc

Background: Thrombosis is a typical example of complex common diseases, where environmental factors and genetic determinants play a significant role. Different mutations in the genes encoding antithrombin (AT), protein C and S are associated with severe thrombophilia and among them AT deficiency is the so far known most severe condition. Hemorrhagic diatheses can be inherited and acquired with auto-or alloantibodies in the background of the latter. There are still unanswered questions and unresolved problems in terms of structural and functional features of proteins involved in hemostasis and the laboratory diagnosis of their deficiencies.

Areas of interest: Main focus areas of our research group are thrombosis, thrombophilia and haemorrhagic diatheses. Research methodology covers a wide spectrum from basic research to clinical research and laboratory diagnostics development. The group investigates structural-functional associations of proteins involved in hemostasis, the roles of coagulation factors and natural coagulation inhibitors in hemostasis and other physiological processes by molecular biology, biochemical and in silico methods. The group coordinates and plays an active role in clinical research, mainly but not exclusively in the field of coagulopathies, thrombophilias and cardiovascular diseases. We are working in the development and evaluation of laboratory diagnostics, mainly immunoassays and functional tests in hemostasis. Representative examples of our research areas are as follows, development of monoclonal anti-FXIII-B antibody, which inhibits the interaction between FXIII-A and B subunits and the description of the epitope of the antibody on FXIII-B. Furthermore, we demonstrated the importance of FXIII-B polymorphisms in the determination of FXIII complex (FXIII-A2B2) plasma level. We investigated the molecular consequences of antithrombin (AT), protein C and S mutations. Our group confirmed the founder effect of AT Budapest3 (ATBp3) mutation by polymorph genetic markers and determined its age and origin. We described for the first time the mechanism of allosteric activation of AT and the AT-pentasaccharid interaction by using in silico methods. We demonstrated the differences of different frequent AT heparin binding site mutations in their clinical phenotype, laboratory behaviour and heparin interaction by clinical, laboratory, biochemical and in silico studies. The group studied the role of different alpha2 plasmin inhibitor isoforms in thrombotic diseases. Concerning our laboratory diagnostic development, the most recent results are a laboratory reagent kit for the determination of the heparin cofactor and progressive activity of AT, the development of methods and protocols for diagnosis of inherited and acquired FXIII deficiency and inherited AT deficiency and method development for the measurement of beta-AT, development of ELISA kit for the measurement of alpha2 plasmin inhibitor and its isoforms. The group actively takes part in the organisation of scientific conferences and senior members play roles in national and international scientific committees in the field of thrombosis and hemostasis (eg. ISTH SSC Subcommittee on Physiological Anticoagulants and Thrombophilia).

Research techniques applied: We use mostly molecular genetic methods, protein techniques such as Western-blot and ELISA and surface plasmon resonance assays, hemostasis functional tests adapted to different coagulometers and in silico methods.

A kutatómunkához kapcsolódó fontosabb közlemények listája:

1. Kállai, J, Gindele, R, Pénzes-Daku, K, Balogh, G, Bogáti, R, Bécsi, B, Katona, É, Oláh, Z, Ilonczai, P, Boda, Z, Róna-Tas, Á, Nemes, L, Marton, , Bereczky, Zs.  Clinical and Molecular Characterization of Nine Novel Antithrombin Mutations. Int J Mol Sci. 25(5):2893, 2024.
2. Natorska, J., Corral, J., de la Morena, -., Bravo-Pérez, C., Bagoly, Z., Bereczky, Z., Treliński, J., Witkowski, M., Klajmon, A., Undas, A., Ząbczyk, M. Antithrombin Deficiency Is Associated with Prothrombotic Plasma Fibrin Clot Phenotype. Thromb. Haemost. 123 (9), 880-891, 2023.
3. Somodi, L., Horváth, E., Bárdos, H., Baráth, B., Pethő, D., Katona, É., Balla, J., Mutch, N., Muszbek, L. Cellular FXIII in Human Macrophage-Derived Foam Cells. Int. J. Mol. Sci. 24 (5), 1-12, 2023.
4. Pituk, D., Miklós, T., Schlammadinger, Á., Molnárné Rázsó, K., Bereczky, Z. The association between EPCR gene p.Ser219Gly polymorphism and venous thromboembolism risk: a case-control study, meta-analysis, and a reproducibility study. Front. Cardiovasc. Med  10 1-14, 2023.
5. Balogh, G., Bereczky, Z. The Interaction of Factor Xa and IXa with Non-Activated Antithrombin in Michaelis Complex: Insights from Enhanced-Sampling Molecular Dynamics Simulations. Biomolecules 13 (5), 1-21, 2023.
6. Raut, S. Katona, É., Riches-Duit, A., Coxon, C., Muszbek, L., Schroeder, V., Rigsby, P. An international collaborative study to assign value for Total Factor XIII-B Subunit Antigen to the WHO 1st International Standard for Factor XIII Plasma, (02/206): communication from the ISTH SSC Subcommittee on Factor XIII and Fibrinogen. J. Thromb. Haemost. 20 (2), 525-531, 2022.
7. Kissné Bogáti, R., Katona, É. Shemirani, A., Balogh, E., Bárdos, H., Jeney, V., Muszbek, L. The Effect of Activated FXIII, a Transglutaminase, on Vascular Smooth Muscle Cells. Int. J. Mol. Sci  23 (10), 1-15, 2022.
8. Bereczky, Z., Gindele, R., Fiatal, S., Speker, M., Miklós, T., Balogh, L., Mezei, Z., Szabó, Z., Ádány, R. Age and Origin of the Founder Antithrombin Budapest 3 (p.Leu131Phe) Mutation; Its High Prevalence in the Roma Population and Its Association With Cardiovascular Diseases.Front. Cardiovasc. Med 7 1-15, 2021.
9. Balogh, G., Gyöngyösi, T., Timári, I., Herczeg, M., Borbás, A., Sadiq, S., Fehér, K., Kövér, K. Conformational Analysis of Heparin-Analogue Pentasaccharides by Nuclear Magnetic Resonance Spectroscopy and Molecular Dynamics Simulations. J. Chem Inf. Model 61 (6), 2926-2936, 2021.

10. Baráth, B., Kissné Bogáti, R., Miklós, T., Kállai, J., Mezei, Z., Bereczky, Z., Muszbek, L., Katona, É. Effect of [alfa]2-plasmin inhibitor heterogeneity on the risk of venous thromboembolism. Thromb. Res. 203 110-116, 2021.
11. Morena-Barrio, M., Gindele, R., Bravo-Pérez, C., Ilonczai, P., Zuazu, I., Speker, M., Oláh, Z., Rodríguez-Sevilla, J., Entrena, L., Infante, M., Morena-Barrio, B., García, J., Schlammadinger, Á., Cifuentes-Riquelme, R., Mora, -., Miñano, A., Padilla, J., Vicente, V., Corral, J., Bereczky, Z. High penetrance of inferior vena cava system atresia in severe thrombophilia caused by homozygous antithrombin Budapest 3 variant: description of a new syndrome. Am. J. Hematol. 96 (11), 1363-1373, 2021.
12. Pénzes-Daku, K., Vezina, C., Bereczky, Z., Katona, É., Kun, M., Muszbek, L., Rivard, G. Alloantibody developed in a factor XIII A subunit deficient patient during substitution therapy: characterization of the antibody. Haemophilia. 22 (2), 268-275, 2016.