{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T22:01:13Z","timestamp":1788818473598,"version":"build-2803163510"},"reference-count":37,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,4,19]],"date-time":"2024-04-19T00:00:00Z","timestamp":1713484800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Faculty of Medicine, University of Debrecen"},{"name":"University of Debrecen"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>BCR-ABL tyrosine kinase inhibitors (TKIs) are effective drugs in the treatment of patients with chronic myeloid leukemia. However, based on clinical studies, ponatinib was associated with the development of thrombotic complications. Since endothelial cells (ECs) regulate blood coagulation, their abnormal phenotype may play a role in the development of thrombotic events. We here aimed to investigate the effect of ponatinib on the procoagulant activity of cultured endothelial cells in vitro. Human coronary artery endothelial cells (HCAECs) were incubated with 50, 150, and 1000 nM of ponatinib. Subsequently, phosphatidylserine (PS) exposure and endothelial microvesicles (EMVs) were measured by flow cytometry. In addition, EC- and EMV-dependent thrombin generation was analyzed. To investigate pro-apoptotic effects of ponatinib, the level of Bax and Bcl-xL proteins were studied using Western blot and F3, THBD, and VCAM1 mRNAs were quantified by qPCR. Therapeutic concentrations of ponatinib significantly increased PS expression on ECs and the amount of EMVs which significantly shortened the time parameters of thrombin generation. In addition, these changes were associated with an increased ratio of Bax and Bcl-xL proteins in the presence of the decreased THBD mRNA level. Overall, ponatinib enhances the procoagulant activity of ECs via inducing apoptosis, which may contribute to thrombotic events.<\/jats:p>","DOI":"10.3390\/pharmaceutics16040559","type":"journal-article","created":{"date-parts":[[2024,4,19]],"date-time":"2024-04-19T10:53:17Z","timestamp":1713523997000},"page":"559","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Ponatinib Induces a Procoagulant Phenotype in Human Coronary Endothelial Cells via Inducing Apoptosis"],"prefix":"10.3390","volume":"16","author":[{"given":"B\u00e1lint","family":"Krajcsir","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"},{"name":"Laki K\u00e1lm\u00e1n Doctoral School, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"P\u00f3csi","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1387-2970","authenticated-orcid":false,"given":"Zsolt","family":"Fejes","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5700-3267","authenticated-orcid":false,"suffix":"Jr.","given":"B\u00e9la","family":"Nagy","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e1nos","family":"Kappelmayer","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ildik\u00f3","family":"Beke Debreceni","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1056\/NEJMoa022457","article-title":"Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia","volume":"348","author":"Guilhot","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2457","DOI":"10.21873\/anticanres.14215","article-title":"ABL1-directed inhibitors for CML: Efficacy, resistance and future perspectives","volume":"40","author":"Massimino","year":"2020","journal-title":"Anticancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.1056\/NEJMoa1205127","article-title":"Ponatinib in refractory Philadelphia chromosome-positive leukemias","volume":"367","author":"Cortes","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"7374","DOI":"10.1158\/1078-0432.CCR-06-1516","article-title":"Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: By the GIMEMA Working Party on Chronic Myeloid Leukemia","volume":"12","author":"Soverini","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Musumeci, F., Greco, C., Grossi, G., Molinari, A., and Schenone, S. (2018). Recent studies on ponatinib in cancers other than chronic myeloid leukemia. Cancers, 10.","DOI":"10.3390\/cancers10110430"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e68","DOI":"10.1055\/s-0038-1624566","article-title":"BCR-ABL tyrosine kinase inhibitors: Which mechanism(s) may explain the risk of thrombosis?","volume":"2","author":"Haguet","year":"2018","journal-title":"TH Open"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1182\/blood-2016-09-739086","article-title":"Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: Final 5-year results of the phase 2 PACE trial","volume":"132","author":"Cortes","year":"2018","journal-title":"Blood"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1182\/bloodadvances.2018025874","article-title":"Analysis of cardiovascular and arteriothrombotic adverse events in chronic-phase CML patients after frontline TKIs","volume":"3","author":"Jain","year":"2019","journal-title":"Blood Adv."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.3324\/haematol.2012.064618","article-title":"Platelet dysfunction associated with ponatinib, a new pan BCR-ABL inhibitor with efficacy for chronic myeloid leukemia resistant to multiple tyrosine kinase inhibitor therapy","volume":"97","author":"Neelakantan","year":"2012","journal-title":"Haematologica"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.thromres.2014.11.009","article-title":"The BCR-ABL inhibitor ponatinib inhibits platelet immunoreceptor tyrosine-based activation motif (ITAM) signaling, platelet activation and aggregate formation under shear","volume":"135","author":"Loren","year":"2015","journal-title":"Thromb. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4867","DOI":"10.21873\/anticanres.15300","article-title":"Ponatinib exerts an inhibitory effect on collagen-induced platelet aggregation and generation of coated-platelets","volume":"41","author":"Mezei","year":"2021","journal-title":"Anticancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1182\/blood-2018-10-881557","article-title":"Thrombotic microangiopathy as a cause of cardiovascular toxicity from the BCR-ABL1 tyrosine kinase inhibitor ponatinib","volume":"133","author":"Latifi","year":"2019","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2312","DOI":"10.1182\/bloodadvances.2019000034","article-title":"Ponatinib treatment promotes arterial thrombosis and hyperactive platelets","volume":"3","author":"Merkulova","year":"2019","journal-title":"Blood Adv."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1080\/10428194.2016.1239258","article-title":"Ponatinib reduces viability, migration, and functionality of human endothelial cells","volume":"58","author":"Granot","year":"2017","journal-title":"Leuk. Lymphoma"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"31958","DOI":"10.18632\/oncotarget.24110","article-title":"Ponatinib exerts anti-angiogenic effects in the zebrafish and human umbilical vein endothelial cells via blocking VEGFR signaling pathway","volume":"9","author":"Ai","year":"2018","journal-title":"Oncotarget"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Madonna, R., Pieragostino, D., Cufaro, M.C., Doria, V., Del Boccio, P., Deidda, M., Pierdomenico, S.D., Dessalvi, C.C., De Caterina, R., and Mercuro, G. (2020). Ponatinib-induced vascular toxicity. J. Clin. Med., 9.","DOI":"10.3390\/jcm9030820"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.3389\/fphar.2020.01007","article-title":"The risk of arterial thrombosis in patients with chronic myeloid leukemia treated with second and third generation BCR-ABL tyrosine kinase inhibitors may be explained by their impact on endothelial cells: An in-vitro study","volume":"11","author":"Haguet","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1093\/bja\/aeh163","article-title":"Physiology of the endothelium","volume":"93","author":"Galley","year":"2004","journal-title":"Br. J. Anaesth."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Kr\u00fcger-Genge, A., Blocki, A., Franke, R.P., and Jung, F. (2019). Vascular endothelial cell biology: An update. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20184411"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1055\/s-0038-1675614","article-title":"Role of endothelial cells in acute and chronic thrombosis","volume":"39","author":"Bochenek","year":"2019","journal-title":"Hamostaseologie"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1007\/s00441-021-03471-2","article-title":"Endothelial cells and coagulation","volume":"387","author":"Neubauer","year":"2022","journal-title":"Cell Tissue Res."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Yau, J.W., Teoh, H., and Verma, S. (2015). Endothelial cell control of thrombosis. BMC Cardiovasc. Disord., 15.","DOI":"10.1186\/s12872-015-0124-z"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Fejes, Z., Czimmerer, Z., Sz\u00fck, T., P\u00f3liska, S., Horv\u00e1th, A., Balogh, E., Jeney, V., V\u00e1radi, J., Fenyvesi, F., and Balla, G. (2018). Endothelial cell activation is attenuated by everolimus via transcriptional and post-transcriptional regulatory mechanisms after drug-eluting coronary stenting. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0197890"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"106949","DOI":"10.1016\/j.vph.2021.106949","article-title":"Sodium-glucose cotransporter type 2 inhibitors prevent ponatinib-induced endothelial senescence and disfunction: A potential rescue strategy","volume":"142","author":"Madonna","year":"2022","journal-title":"Vascul. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1680","DOI":"10.1182\/bloodadvances.2018020396","article-title":"A phosphoproteomic signature in endothelial cells predicts vascular toxicity of tyrosine kinase inhibitors used in CML","volume":"2","author":"Gopal","year":"2018","journal-title":"Blood Adv."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2429","DOI":"10.1182\/blood.V89.7.2429","article-title":"Apoptotic vascular endothelial cells become procoagulant","volume":"89","author":"Bombeli","year":"1997","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1177\/0192623310378866","article-title":"Biomarkers of endothelial cell activation serve as potential surrogate markers for drug-induced vascular injury","volume":"38","author":"Zhang","year":"2010","journal-title":"Toxicol. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1007\/s00018-018-2983-9","article-title":"Endothelial cell apoptosis and the role of endothelial cell-derived extracellular vesicles in the progression of atherosclerosis","volume":"76","author":"Paone","year":"2019","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"116397","DOI":"10.1016\/j.jep.2023.116397","article-title":"Qilong capsule alleviates ponatinib-induced ischemic stroke in a zebrafish model by regulating coagulation, inflammation and apoptosis","volume":"314","author":"Lin","year":"2023","journal-title":"J. Ethnopharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"464","DOI":"10.3389\/fphar.2017.00464","article-title":"Attenuation of TNF-\u03b1 induced inflammatory injury in endothelial cells by ginsenoside Rb1 via inhibiting NF-\u03baB, JNK and p38 signaling pathways","volume":"8","author":"Zhou","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Bacci, M., Cancellara, A., Ciceri, R., Romualdi, E., Pessi, V., Tumminello, F., Fantuzzi, M., Donadini, M.P., Lodigiani, C., and Della Bella, S. (2023). Development of personalized thrombogenesis and thrombin generation assays to assess endothelial dysfunction in cardiovascular diseases. Biomedicines, 11.","DOI":"10.3390\/biomedicines11061669"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1161\/01.RES.0000171805.24799.fa","article-title":"Procoagulant soluble tissue factor is released from endothelial cells in response to inflammatory cytokines","volume":"96","author":"Szotowski","year":"2005","journal-title":"Circ. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.thromres.2004.10.010","article-title":"Effects of TNF-\u03b1 and curcumin on the expression of thrombomodulin and endothelial protein C receptor in human endothelial cells","volume":"115","author":"Nan","year":"2005","journal-title":"Thromb. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2042","DOI":"10.1111\/j.1538-7836.2010.03936.x","article-title":"Tissue factor up-regulation in proinflammatory conditions confers thrombin generation capacity to endothelial colony-forming cells without influencing non-coagulant properties in vitro","volume":"8","author":"Cuccuini","year":"2010","journal-title":"J. Thromb. Haemost."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.ejphar.2013.11.041","article-title":"Inhibitory effect of Malvidin on TNF-\u03b1-induced inflammatory response in endothelial cells","volume":"723","author":"Huang","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Wang, Y., Travers, R.J., Farrell, A., Lu, Q., Bays, J.L., Stepanian, A., Chen, C., and Jaffe, I.Z. (2023). Differential vascular endothelial cell toxicity of established and novel BCR-ABL tyrosine kinase inhibitors. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0294438"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"125","DOI":"10.3389\/fcvm.2018.00125","article-title":"Ponatinib activates an inflammatory response in endothelial cells via ERK5 SUMOylation","volume":"5","author":"Chen","year":"2018","journal-title":"Front. Cardiovasc. Med."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/16\/4\/559\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:31:12Z","timestamp":1760106672000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/16\/4\/559"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,19]]},"references-count":37,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2024,4]]}},"alternative-id":["pharmaceutics16040559"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics16040559","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,19]]}}}