Henri Spronk

Associate professor

Initially trained in Biochemistry and Molecular Biology at Nijmegen University, Dr Henri Spronk obtained a PhD in Biochemistry on the effects of impaired vitamin K-dependent protein carboxylation.

The focus of his current work is on the bidirectional relation between coagulation and inflammation, as well as on the applicability of functional plasma assays such as thrombin generation, for atherothrombotic risk prediction. He has a special interest in the role of active coagulation factors, mainly thrombin, in activation of protein-activated receptors (PARs) which can regulate the balance between vascular protective and disruptive. Overall, knowledge on the non-haemostatic functions of thrombin and factor Xa enables pharmacological interference in cellular processes contributing to the the development and progression of atherosclerosis or atrial fibrillation.

Department of Biochemistry
Department of Internal Medicine
Universiteitssingel 50, 6229 ER Maastricht
PO Box 616, 6200 MD Maastricht
Room number: 4.326
T: +31(0)43 388 42 61

2024
- Velt, M. J. H., Crijns, H. J. G. M., van Gelder, I. C., Linz, D., van de Lande, M. E., Ten Cate, H., Spronk, H. M. H., de Melis, M., Rienstra, M., & Mulder, B. A. (2024). Dynamic biomarker profiles in patients with paroxysmal atrial fibrillation: Assessing the differences between sinus rhythm and acute atrial fibrillation episode. International Journal of Cardiology, 417, Article 132526. https://doi.org/10.1016/j.ijcard.2024.132526
- Baaten, C. C. F. M. J., Nagy, M., Spronk, H. M. H., Ten Cate, H., & Kietselaer, B. L. J. H. (2024). NETosis in Cardiovascular Disease: An Opportunity for Personalized Antithrombotic Treatments?Arteriosclerosis Thrombosis and Vascular Biology, 44(12), 2366-2370. https://doi.org/10.1161/ATVBAHA.124.320150
- Monegatti, S., Martinelli, N., Friso, S., Spronk, H. M., & Ten Cate, H. (2024). Mechanisms and management of thrombosis in cancer: focus on gastrointestinal malignancies. Journal of Pharmacology and Experimental Therapeutics, 390(2). https://doi.org/10.1124/jpet.124.002203
- Ceulemans, A., Spronk, H. M. H., Ten Cate, H., van Zwam, W. H., van Oostenbrugge, R. J., & Nagy, M. (2024). Current and potentially novel antithrombotic treatment in acute ischemic stroke. Thrombosis Research, 236, 74-84. https://doi.org/10.1016/j.thromres.2024.02.009
- Busch, M. H., Ysermans, R., Aendekerk, J., Timmermans, S. A., Potjewijd, J., Damoiseaux, J., Spronk, H. M. H., Ten Cate, H., Reutelingsperger, C., Nagy, M., & van Paassen, P. (2024). The intrinsic coagulation pathway plays a dominant role in driving hypercoagulability in ANCA-Associated Vasculitis. Blood advances, 8(5), 1295-1304. https://doi.org/10.1182/bloodadvances.2023011937
- Reutelingsperger, C. P. M., Gijbels, M. J., Spronk, H., Van Oerle, R., Schrijver, R., Ekhart, P., de Kimpe, S., & Nicolaes, G. A. F. (2024). M6229 Protects against Extracellular-Histone-Induced Liver Injury, Kidney Dysfunction, and Mortality in a Rat Model of Acute Hyperinflammation. International Journal of Molecular Sciences, 25(3), Article 1376. https://doi.org/10.3390/ijms25031376
- Baaten, C. C. F. M. J., Nagy, M., Bergmeier, W., Spronk, H. M. H., & van der Meijden, P. E. J. (2024). Platelet biology and function: plaque erosion vs. rupture. European Heart Journal, 45(1), 18-31. https://doi.org/10.1093/eurheartj/ehad720
- Hansildaar, R., Raadsen, R., Gerritsen, M., Nagy, M., Dijkshoorn, B., Spronk, H. M. H., Ten Cate, H., & Nurmohamed, M. T. (2024). Comparative Analysis of Coagulation Activation in Rheumatoid Arthritis Patients Treated With TNF Inhibitors Versus JAK Inhibitors: A Prospective Study. Journal of Clinical Rheumatology, Article 002136. Advance online publication. https://doi.org/10.1097/RHU.0000000000002136
2023
- Mulder, M. M. G., Schellens, J., Sels, J.-W. E. M., van Rosmalen, F., Hulshof, A.-M., de Vries, F., Segers, R., Mihl, C., van Mook, W. N. K. A., Bast, A., Spronk, H. M. H., Henskens, Y. M. C., van der Horst, I. C. C., ten Cate, H., Schurgers, L. J., Drent, M., & van Bussel, B. C. T. (2023). Higher levels of circulating desphospho-uncarboxylated matrix Gla protein over time are associated with worse survival: the prospective Maastricht Intensive Care COVID cohort. Journal of Intensive Care, 11(1), Article 63. https://doi.org/10.1186/s40560-023-00712-0
- Jacobs, L. M. C., Wintjens, M. S. J. N., Nagy, M., Willems, L., ten Cate, H., Spronk, H. M. H., van Kuijk, S. M. J., Ghossein-Doha, C., Netea, M. G., Groh, L. A., van Petersen, A. S., & Warle, M. C. (2023). Biomarkers of sustained systemic inflammation and microvascular dysfunction associated with post-COVID-19 condition symptoms at 24 months after SARS-CoV-2-infection. Frontiers in Immunology, 14(1), Article 1182182. https://doi.org/10.3389/fimmu.2023.1182182
- Baidildinova, G., Pallares Robles, A., ten Cate, V., Kremers, B. M. M., Heitmeier, S., ten Cate, H., Mees, B. M. E., Spronk, H. M. H., Wild, P. S., ten Cate-Hoek, A. J., & Jurk, K. (2023). Plasma protein signatures for high on-treatment platelet reactivity to aspirin and clopidogrel in peripheral artery disease. Thrombosis Research, 230(1), 105-118. https://doi.org/10.1016/j.thromres.2023.08.017
- Alnima, T., Meijer, R. I., Spronk, H. M. H., Warlé, M., & Cate, H. T. (2023). Diabetes- versus smoking-related thrombo-inflammation in peripheral artery disease. Cardiovascular Diabetology, 22(1), Article 257. https://doi.org/10.1186/s12933-023-01990-6
- Musgrave, K. M., Scott, J., Sendama, W., Gardner, A. I., Dewar, F., Lake, C. J., Spronk, H. M. H., van Oerle, R., Visser, M., ten Cate, H., Kesteven, P., Fuller, A., McDonald, D., Knill, C., Hulme, G., Filby, A., Wright, S. E., Roy, A. I., Ruchaud-Sparagano, M.-H., ... Rostron, A. J. (2023). Tissue factor expression in monocyte subsets during human immunothrombosis, endotoxemia and sepsis. Thrombosis Research, 228(1), 10-20. https://doi.org/10.1016/j.thromres.2023.05.018
- Nagy, M., Robles, A. P., Visser, M., Koeck, T., ten Cate, V., ten Cate-Hoek, A. J., Schwers, S., Heitmeier, S., ten Cate, H., Wild, P. S., & Spronk, H. M. H. (2023). Predictive value for increased activated factor XI activity in acute venous thromboembolism. Journal of Thrombosis and Haemostasis, 21(6), 1610-1622. https://doi.org/10.1016/j.jtha.2023.02.031
- Akbalut, C., Arisz, R., Baaten, C., Baildildinova, G., Barakzie, A., Bauersachs, R., Ten Berg, J. M., van den Broek, W., de Boer, H. C., Broker, V., Buka, R., Ten Cate, H., Cate, A. T., De Luca, C., De Simone, I., Dignat-George, F., Freson, K., Gazzaniga, G., van Gorp, E., ... van Zonneveld, A.-J. (2023). Blood coagulation and beyond: Position paper from the Fourth Maastricht Consensus Conference on Thrombosis. Thrombosis and Haemostasis, 123(8), 808-839. https://doi.org/10.1055/a-2052-9175
- Busch, M. H., Timmermans, S. A. M. E. G., Van Kuijk, S. M. J., Aendekerk, J. P., Ysermans, R., Van Doorn, D. P. C., Potjewijd, J., Van de Poll, M. C. G., Van der Horst, I. C. C., Damoiseaux, J. G. M. C., Spronk, H. M. H., Cate, H. T., Reutelingsperger, C. P., Nagy, M., & Van Paassen, P. (2023). Thrombin formation via the intrinsic coagulation pathway and von Willebrand factor reflect disease severity in COVID-19. Haematologica-the Hematology Journal, 108(5), 1417-1422. https://doi.org/10.3324/haematol.2022.281693
- Kearney, K. J., Spronk, H. M. H., Emsley, J., Key, N. S., & Philippou, H. (2023). Plasma Kallikrein as a Forgotten Clotting Factor. Seminars in Thrombosis and Hemostasis, 50(7), 953-961. https://doi.org/10.1055/s-0043-57034
- Arita, V. A., Van de Lande, M. E., Ekrami, N. K., Nguyen, B. O., Van Melle, J. M., Geelhoed, B., De With, R. R., Weberndorfer, V., Erkuner, O., Hillege, H., Linz, D., Ten Cate, H., Spronk, H. M. H., Koldenhof, T., Tieleman, R. G., Schotten, U., Crijns, H. J. G. M., Van Gelder, I. C., & Rienstra, M. (2023). Clinical utility of the 4S-AF scheme in predicting progression of atrial fibrillation: data from the RACE V study. EP Europace, 25(4), 1323-1331. https://doi.org/10.1093/europace/euac268
- Willems, L. H., Jacobs, L. M. C., Groh, L. A., ten Cate, H., Spronk, H. M. H., Wilson-Storey, B., Hannink, G., van Kuijk, S. M. J., Ghossein-Doha, C., Nagy, M., Thijssen, D. H. J., van Petersen, A. S., & Warle, M. C. (2023). Vascular Function, Systemic Inflammation, and Coagulation Activation 18 Months after COVID-19 Infection: An Observational Cohort Study. Journal of Clinical Medicine, 12(4), Article 1413. https://doi.org/10.3390/jcm12041413
- Nguyen, B. O., Weberndorfer, V., Crijns, H. J. G. M., Geelhoed, B., Ten Cate, H., Spronk, H., Kroon, A., De With, R., Al-Jazairi, M., Maass, A. H., Blaauw, Y., Tieleman, R. G., Hemels, M. E. W., Luermans, J., de Groot, J., Allaart, C. P., Elvan, A., De Melis, M., Scheerder, C., ... Rienstra, M. (2023). Prevalence and determinants of atrial fibrillation progression in paroxysmal atrial fibrillation. Heart, 109(3), 186-194. https://doi.org/10.1136/heartjnl-2022-321027
- Kremers, B. M. M., Daemen, J. H. C., ten Cate, H., Spronk, H. M. H., Mees, B. M. E., & Cate-Hoek, A. J. T. (2023). Inadequate response to antiplatelet therapy in patients with peripheral artery disease: a prospective cohort study. Thrombosis Journal, 21(1), Article 5. https://doi.org/10.1186/s12959-022-00445-4
- Iding, A. F. J., Kremers, B. M. M., Nagy, M., Robles, A. P., Ten Cate, H., Spronk, H. M. H., & Ten Cate-Hoek, A. J. (2023). Translational insights into mechanisms underlying residual venous obstruction and the role of factor XI, P-selectin and GPVI in recurrent venous thromboembolism. Thrombosis Research, 221(1), 58-64. https://doi.org/10.1016/j.thromres.2022.11.023
2022
- Baidildinova, G., Ten Cate, V., Nagler, M., Panova-Noeva, M., Rapp, S., Köck, T., Prochaska, J. H., Heitmeier, S., Gerdes, C., Schwers, S., Konstantinides, S. V., Münzel, T., Espinola-Klein, C., Lackner, K. J., Spronk, H. M. N., Ten Cate, H., van der Meijden, P. E. J., Leineweber, K., Wild, P. S., & Jurk, K. (2022). Subtype-specific plasma signatures of platelet-related protein releasate in acute pulmonary embolism. Thrombosis Research, 220, 75-87. https://doi.org/10.1016/j.thromres.2022.10.005
- Nagy, M., van der Meijden, P. E. J., Glunz, J., Schurgers, L., Lutgens, E., Ten Cate, H., Heitmeier, S., & Spronk, H. M. H. (2022). Integrating Mechanisms in Thrombotic Peripheral Arterial Disease. Pharmaceuticals, 15(11), Article 1428. https://doi.org/10.3390/ph15111428
- Kremers, B. M. M., Posma, J. N., Heitmeier, S., Glunz, J., Ten Cate, H., Pallares Robles, A., Daemen, J. H. C., Ten Cate-Hoek, A. J., Mees, B. M. E., & Spronk, H. M. H. (2022). Discovery of four plasmatic biomarkers potentially predicting cardiovascular outcome in peripheral artery disease. Scientific Reports, 12(1), Article 18388. https://doi.org/10.1038/s41598-022-23260-3
- Willems, L. H., Thijssen, D. H. J., Groh, L. A., Kooijman, N. I., Ten Cate, H., Spronk, H. M. H., Donders, A. R. T., Van der Vijver-Coppen, R. J., van Hoek, F., Nagy, M., Reijnen, M. M. P. J., & Warle, M. C. (2022). Dual pathway inhibition as compared to acetylsalicylic acid monotherapy in relation to endothelial function in peripheral artery disease, a phase IV clinical trial. Frontiers in Cardiovascular Medicine, 9, Article 979819. https://doi.org/10.3389/fcvm.2022.979819
- van de Berg, T. W., Mulder, M. M. G., Alnima, T., Nagy, M., van Oerle, R., Beckers, E. A. M., Hackeng, T. M., Hulshof, A. M., Sels, J. W. E. M., Henskens, Y. M. C., van der Horst, I. C. C., ten Cate, H., Spronk, H. M. H., van Bussel, B. C. T., & Dutch COVID & Thrombosis Coalition (2022). Serial thrombin generation and exploration of alternative anticoagulants in critically ill COVID-19 patients: Observations from Maastricht Intensive Care COVID Cohort. Frontiers in Cardiovascular Medicine, 9, Article 929284. https://doi.org/10.3389/fcvm.2022.929284
- van Paridon, P. C. S., Panova-Noeva, M., van Oerle, R., Schulz, A., Prochaska, J. H., Arnold, N., Schmidtmann, I., Beutel, M., Pfeiffer, N., Munzel, T., Lackner, K. J., ten Cate, H., Wild, P. S., & Spronk, H. M. H. (2022). Lower levels of vWF are associated with lower risk of cardiovascular disease. Research and practice in thrombosis and haemostasis, 6(7), Article e12797. https://doi.org/10.1002/rth2.12797
- Bochenek, M. L., Gogiraju, R., Grossmann, S., Krug, J., Orth, J., Reyda, S., Georgiadis, G. S., Spronk, H. M., Konstantinides, S., Munzel, T., Griffin, J. H., Wild, P., Espinola-Klein, C., Ruf, W., & Schafer, K. (2022). EPCR-PAR1 biased signaling regulates perfusion recovery and neovascularization in peripheral ischemia. JCI INSIGHT, 7(14), Article e157701. https://doi.org/10.1172/jci.insight.157701
- Robles, A. P., ten Cate, V., Schulz, A., Prochaska, J. H., Rapp, S., Koeck, T., Panova-Noeva, M., Heitmeier, S., Schwers, S., Leineweber, K., Seyfarth, H. J., Opitz, C. F., Spronk, H., Espinola-Klein, C., Lackner, K. J., Munzel, T., Andrade-Navarro, M. A., Konstantinides, S. V., ten Cate, H., & Wild, P. S. (2022). Association of FXI activity with thrombo-inflammation, extracellular matrix, lipid metabolism and apoptosis in venous thrombosis. Scientific Reports, 12(1), Article 9761. https://doi.org/10.1038/s41598-022-13174-5
- van Paridon, P. C. S., Panova-Noeva, M., van Oerle, R., Schulz, A., Prochaska, J. H., Arnold, N., Schmidtmann, I., Beutel, M., Pfeiffer, N., Münzel, T., Lackner, K. J., Ten Cate, H., Wild, P. S., & Spronk, H. M. H. (2022). Relationships between coagulation factors and thrombin generation in a general population with arterial and venous disease background. Thrombosis Journal, 20(1), Article 32. https://doi.org/10.1186/s12959-022-00392-0
- Dolleman, S. C., Agten, S. M., Spronk, H. M. H., Hackeng, T. M., Bos, M. H. A., Versteeg, H. H., van Zonneveld, A. J., & de Boer, H. C. (2022). Thrombin in complex with dabigatran can still interact with PAR-1 via exosite-I and instigate loss of vascular integrity. Journal of Thrombosis and Haemostasis, 20(4), 996-1007. https://doi.org/10.1111/jth.15642
- Dauwerse, S., ten Cate, H., Spronk, H. M. H., & Nagy, M. (2022). The Composition and Physical Properties of Clots in COVID-19 Pathology. Diagnostics, 12(3), Article 580. https://doi.org/10.3390/diagnostics12030580
- Grover, S. P., Coughlin, T., Fleifil, S. M., Posma, J. J. N., Spronk, H. H. M., Heitmeier, S., Owens, A. P., & Mackman, N. (2022). Effect of combining aspirin and rivaroxaban on atherosclerosis in mice. Atherosclerosis, 345, 7-14. https://doi.org/10.1016/j.atherosclerosis.2022.02.010
- Panova-Noeva, M., Wagner, B., Nagler, M., Koeck, T., Ten Cate, V., Eggebrecht, L., Prochaska, J. H., Meyer, I., Gerdes, C., Spronk, H. M., Lackner, K. J., Ten Cate, H., Leineweber, K., Heitmeier, S., Konstantinides, S., & Wild, P. S. (2022). Variation of platelet function in clinical phenotypes of acute venous thromboembolism - Results from the GMP-VTE project. Journal of Thrombosis and Haemostasis, 20(3), 705-715. https://doi.org/10.1111/jth.15595
- De With, R. R., Artola Arita, V., Nguyen, B.-O., Linz, D., Ten Cate, H., Spronk, H., Schotten, U., van Zonneveld, A. J., Erküner, Ö., Bayón, M. A., Schmidt, A. S., Luermans, J. G. L. M., Crijns, H. J. G. M., Van Gelder, I. C., & Rienstra, M. (2022). Different circulating biomarkers in women and men with paroxysmal atrial fibrillation: results from the AF-RISK and RACE V studies. EP Europace, 24(2), 193-201. https://doi.org/10.1093/europace/euab179
- Brouns, S. L. N., Tullemans, B. M. E., Bulato, C., Perrella, G., Campello, E., Spiezia, L., van Geffen, J. P., Kuijpers, M. J. E., van Oerle, R., Spronk, H. M. H., van der Meijden, P. E. J., Simioni, P., & Heemskerk, J. W. M. (2022). Protein C or Protein S deficiency associates with paradoxically impaired platelet-dependent thrombus and fibrin formation under flow. Research and practice in thrombosis and haemostasis, 6(2), Article e12678. https://doi.org/10.1002/rth2.12678
- Willems, L. H., Nagy, M., Ten Cate, H., Spronk, H. M. H., Groh, L. A., Leentjens, J., Janssen, N. A. F., Netea, M. G., Thijssen, D. H. J., Hannink, G., van Petersen, A. S., & Warle, M. C. (2022). Sustained inflammation, coagulation activation and elevated endothelin-1 levels without macrovascular dysfunction at 3 months after COVID-19. Thrombosis Research, 209, 106-114. https://doi.org/10.1016/j.thromres.2021.11.027
2021
- Willems, L. H., Nagy, M., Ten Cate, H., Spronk, H. M. H., Jacobs, L. M. C., Kranendonk, J., van Leeuwen, M., Meijer, D., Middeldorp, S., Groh, L. A., & Warle, M. C. (2021). ChAdOx1 vaccination, blood coagulation, and inflammation: No effect on coagulation but increased interleukin-6. Research and practice in thrombosis and haemostasis, 5(8), Article e12630. https://doi.org/10.1002/rth2.12630
- D'Alessandro, E., Scaf, B., van Oerle, R., van Nieuwenhoven, F. A., van Hunnik, A., Verheule, S., Schotten, U., Ten Cate, H., & Spronk, H. M. H. (2021). Thrombin generation by calibrated automated thrombography in goat plasma: Optimization of an assay. Research and practice in thrombosis and haemostasis, 5(8), Article e12620. https://doi.org/10.1002/rth2.12620
- van der Beelen, S. H. E., Agten, S. M., Suylen, D. P. L., Wichapong, K., Hrdinova, J., Mees, B. M. E., Spronk, H. M. H., & Hackeng, T. M. (2021). Letter: In response to a recent letter by Prior et al.Thrombosis Research, 207, 66-66. https://doi.org/10.1016/j.thromres.2021.06.017
- van Gorp, R. H., Baaten, C. C. F. M. J., Habibi, A., Jaminon, A. M. G., Peeters, F. E. C. M., Leenders, P., Crijns, H. J. G. M. C., Heemskerk, J. W. M., Reutelingsperger, C. P., Spronk, H. M., & Schurgers, L. J. (2021). Vitamin K antagonist use induces calcification and atherosclerotic plaque progression resulting in increased hypercoagulability. European heart journal open, 1(2), Article oeab017. https://doi.org/10.1093/ehjopen/oeab017
- Giesen, P. L. A., Gulpen, A. J. W., van Oerle, R., ten Cate, H., Nagy, M., & Spronk, H. M. H. (2021). Calibrated automated thrombogram II: removing barriers for thrombin generation measurements. Thrombosis Journal, 19(1), Article 60. https://doi.org/10.1186/s12959-021-00312-8
- Ten Cate, H., Guzik, T. J., Eikelboom, J., & Spronk, H. M. H. (2021). Pleiotropic actions of factor Xa inhibition in cardiovascular prevention - mechanistic insights and implications for anti-thrombotic treatment. Cardiovascular Research, 117(9), 2030-2044. https://doi.org/10.1093/cvr/cvaa263
- Aarsetøy, R., Ten Cate, H., Spronk, H., Van Oerle, R., Aarsetøy, H., Staines, H., & Nilsen, D. W. T. (2021). Activated factor XI-antithrombin complex presenting as an independent predictor of 30-days mortality in out-of-hospital cardiac arrest patients. Thrombosis Research, 204, 1-8. https://doi.org/10.1016/j.thromres.2021.05.014
- Dahlen, B., Schulz, A., Göbel, S., Tröbs, S.-O., Schwuchow-Thonke, S., Spronk, H. M., Prochaska, J. H., Arnold, N., Lackner, K. J., Gori, T., Ten Cate, H., Münzel, T., Wild, P. S., & Panova-Noeva, M. (2021). The impact of platelet indices on clinical outcome in heart failure: results from the MyoVasc study. Esc heart failure, 8(4), 2991-3001. https://doi.org/10.1002/ehf2.13390
- Hisada, Y., Moser, B., Kawano, T., Revenko, A. S., Crosby, J. R., Spronk, H. M., & Mackman, N. (2021). The Intrinsic Pathway does not Contribute to Activation of Coagulation in Mice Bearing Human Pancreatic Tumors Expressing Tissue Factor. Thrombosis and Haemostasis, 121(07), 967-970. https://doi.org/10.1055/s-0040-1722193
- Ford, D. J., Duggan, N. M., Fry, S. E., Ripoll-Rozada, J., Agten, S. M., Liu, W., Corcilius, L., Hackeng, T. M., van Oerle, R., Spronk, H. M. H., Ashhurst, A. S., Mini Sasi, V., Kaczmarski, J. A., Jackson, C. J., Pereira, P. J. B., Passioura, T., Suga, H., & Payne, R. J. (2021). Potent Cyclic Peptide Inhibitors of FXIIa Discovered by mRNA Display with Genetic Code Reprogramming. Journal of Medicinal Chemistry, 64(11), 7853-7876. https://doi.org/10.1021/acs.jmedchem.1c00651
- Mulder, M. M. G., Brandts, LI., Brüggemann, R. A. G., Koelmann, M., Streng, A. S., Olie, R. H., Gietema, H. A., Spronk, H. M. H., van der Horst, I. C. C., Sels, J.-W. E. M., Wildberger, J. E., van Kuijk, S. M. J., Schnabel, R. M., Ten Cate, H., Henskens, Y. M. C., & van Bussel, B. C. T. (2021). Serial markers of coagulation and inflammation and the occurrence of clinical pulmonary thromboembolism in mechanically ventilated patients with SARS-CoV-2 infection; the prospective Maastricht intensive care COVID cohort. Thrombosis Journal, 19(1), Article 35. https://doi.org/10.1186/s12959-021-00286-7

Overview

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Team Science grant Uyen Nguyen and Roel Meiburg

18 December 2024

ZonMw grant on appropriate palliative care

10 December 2024

Henri Spronk

Associate professor