{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T12:11:13Z","timestamp":1760703073835,"version":"build-2065373602"},"reference-count":45,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T00:00:00Z","timestamp":1760659200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University Research Institute of Maternal"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pediatric thrombosis (PT) represents a rare condition that can manifest from neonatal life to adolescence, encompassing life-threatening complications. Its pathogenesis is attributed to immature hemostasis in conjunction with environmental and genetic factors, predominantly including those resulting in increased levels of plasminogen activator inhibitor 1 (PAI-1), the principal inhibitor of fibrinolysis, which is subject to upstream regulation by angiotensin-converting enzyme (ACE). Although the implication of microRNAs (miRNAs), epigenetic modulators of gene expression, has been demonstrated in adult thrombosis, evidence is lacking in the pediatric setting. Here, we investigated the involvement of two miRNA regulators of PAI-1 (SERPINE1 gene) in PT, in relation to clinical and genetic parameters that induce PAI-1 fluctuations. Following bioinformatic target-prediction, miRNA expression was assessed by quantitative real-time PCR in serum-samples of 19 pediatric patients with thrombosis (1\u201318 months post-incident), and 19 healthy controls. Patients were genotyped for the SERPINE1-4G\/5G and ACE-I\/D polymorphisms by PCR-based assays. Genotypic and thrombosis-related clinical data were analyzed in relation to miRNA-expression. Two miRNAs (miR-145-5p, miR-34a-5p) were identified to target SERPINE1 mRNA, with miR-34a additionally targeting the mRNA of ACE. The expression of miR-34a was significantly decreased in patients compared to controls (p = 0.029), while no difference was observed in miR-145 expression. Within patients, miR-34a expression demonstrated a peak 1\u20133 months post-thrombosis and was diminished upon treatment completion (p = 0.031), followed by a slight long-term increase. MiR-34a levels differed significantly by thrombosis site (p = 0.019), while a significant synergistic interaction between site and onset type (provoked\/unprovoked) was detected (p = 0.016). Finally, an epistatic modification was observed in cerebral cases, since double homozygosity (4G\/4G + D\/D) led to a miR-34 decrease, with D\/D carriership reversing the 4G\/4G-induced upregulation of miR-34a (p = 0.006). Our findings suggest that in pediatric thrombosis, downregulation of miR-34a is indicative of impaired fibrinolytic capacity, attributed to deficient regulation of the inhibitory ACE\/PAI-1 axis.<\/jats:p>","DOI":"10.3390\/ijms262010110","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T11:39:34Z","timestamp":1760701174000},"page":"10110","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Serum miR-34a as Indicator of Impaired Fibrinolytic Capacity in Pediatric Thrombosis Through Inadequate Regulation of the ACE\/PAI-1 Axis"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-2561-9595","authenticated-orcid":false,"given":"Iphigenia","family":"Gintoni","sequence":"first","affiliation":[{"name":"Unit of Orofacial Genetics, 1st Department of Pediatrics, School of Medicine, National Kapodistrian University of Athens, \u201cAghia Sophia\u201d Children\u2019s Hospital, 115 27 Athens, Greece"},{"name":"University Research Institute of Maternal and Child Health and Precision Medicine, National Kapodistrian University of Athens, Choremion Laboratory, \u201cAghia Sophia\u201d Children\u2019s Hospital, 115 27 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kleoniki","family":"Baldouni","sequence":"additional","affiliation":[{"name":"Unit of Orofacial Genetics, 1st Department of Pediatrics, School of Medicine, National Kapodistrian University of Athens, \u201cAghia Sophia\u201d Children\u2019s Hospital, 115 27 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8232-3767","authenticated-orcid":false,"given":"Athina","family":"Dettoraki","sequence":"additional","affiliation":[{"name":"Haemophilia Center for Children and Adolescents, Haemostasis and Thrombosis Unit, \u201cAghia Sophia\u201d Children\u2019s Hospital, 115 27 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aikaterini","family":"Michalopoulou","sequence":"additional","affiliation":[{"name":"Haemophilia Center for Children and Adolescents, Haemostasis and Thrombosis Unit, \u201cAghia Sophia\u201d Children\u2019s Hospital, 115 27 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ioanna","family":"Papathanasiou","sequence":"additional","affiliation":[{"name":"Laboratory of Cytogenetics and Molecular Genetics, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, 41500 Larissa, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aspasia","family":"Tsezou","sequence":"additional","affiliation":[{"name":"Laboratory of Cytogenetics and Molecular Genetics, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, 41500 Larissa, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1823-6102","authenticated-orcid":false,"given":"Dimitrios","family":"Vlachakis","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 11855 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1792-0597","authenticated-orcid":false,"given":"Helen","family":"Pergantou","sequence":"additional","affiliation":[{"name":"Haemophilia Center for Children and Adolescents, Haemostasis and Thrombosis Unit, \u201cAghia Sophia\u201d Children\u2019s Hospital, 115 27 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3098-5264","authenticated-orcid":false,"given":"George P.","family":"Chrousos","sequence":"additional","affiliation":[{"name":"University Research Institute of Maternal and Child Health and Precision Medicine, National Kapodistrian University of Athens, Choremion Laboratory, \u201cAghia Sophia\u201d Children\u2019s Hospital, 115 27 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6695-186X","authenticated-orcid":false,"given":"Christos","family":"Yapijakis","sequence":"additional","affiliation":[{"name":"Unit of Orofacial Genetics, 1st Department of Pediatrics, School of Medicine, National Kapodistrian University of Athens, \u201cAghia Sophia\u201d Children\u2019s Hospital, 115 27 Athens, Greece"},{"name":"University Research Institute of Maternal and Child Health and Precision Medicine, National Kapodistrian University of Athens, Choremion Laboratory, \u201cAghia Sophia\u201d Children\u2019s Hospital, 115 27 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.5152\/TurkPediatriArs.2018.2586","article-title":"Thrombosis in Children: Which Test to Whom, When and How Much Necessary?","volume":"53","author":"Celkan","year":"2018","journal-title":"Turk. 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