{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T19:49:24Z","timestamp":1760644164668,"version":"build-2065373602"},"reference-count":34,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,4,1]],"date-time":"2020-04-01T00:00:00Z","timestamp":1585699200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Spontaneous abortion is a common complication in early pregnancy, with an incidence of around 20%. Ultrasound scan and measurement of human chorionic gonadotropin are used to identify patients at risk of spontaneous abortion; however, there is a clinical need to find new biomarkers to prospectively identify patients before the onset of clinical symptoms. Here, we aim to investigate potential biomarkers of spontaneous abortion taken in the first clinical appointment of pregnancy. A case\u2013control study was conducted based on a prospectively collected cohort in which cases and controls were retrospectively stratified based on pregnancy outcome: normal healthy pregnancies (controls = 33) and pregnancies that ended in spontaneous abortion (cases = 10). We evaluated extracellular vesicles isolated by precipitation with ExoQuick\u2122 and protein concentrations of tissue plasminogen activator, leptin, and adiponectin measured by ELISA. The extracellular vesicles showed the typical morphology and membrane proteins: CD63, Alix, and Flotilin-1. The size distributions of the isolated extracellular vesicles were 112 \u00b1 27 and 118 \u00b1 28 nm in diameter for controls and spontaneous abortion, respectively, and the total amount of extracellular vesicles did not show any difference between controls and the spontaneous abortion group. The tissue plasminogen activator showed a significant difference (p = 0.0004) between both groups, although neither adiponectin nor leptin revealed significant changes, indicating that women who had spontaneous abortions have significantly higher levels of tissue plasminogen activator than women who had normal pregnancies.<\/jats:p>","DOI":"10.3390\/diagnostics10040197","type":"journal-article","created":{"date-parts":[[2020,4,1]],"date-time":"2020-04-01T15:37:21Z","timestamp":1585755441000},"page":"197","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Increased Circulating Levels of Tissue-Type Plasminogen Activator Are Associated with the Risk of Spontaneous Abortion During the First Trimester of Pregnancy"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2078-380X","authenticated-orcid":false,"given":"Lara J.","family":"Monteiro","sequence":"first","affiliation":[{"name":"Centre for Biomedical Research, Laboratory of Reproductive Biology, Faculty of Medicine, Universidad de Los Andes, Santiago 7620001, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5857-4793","authenticated-orcid":false,"given":"Manuel","family":"Varas-Godoy","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Research, Laboratory of Reproductive Biology, Faculty of Medicine, Universidad de Los Andes, Santiago 7620001, Chile"},{"name":"Cancer Cell Biology Lab., Centre of Celullar Biology and Biomedicine (CEBICEM), Faculty of Medicine and Science, Universidad San Sebasti\u00e1n, Santiago 7510157, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Acu\u00f1a-Gallardo","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Research, Laboratory of Reproductive Biology, Faculty of Medicine, Universidad de Los Andes, Santiago 7620001, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paula","family":"Correa","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Faculty of Medicine, Universidad de los Andes, Santiago 7620001, Chile"},{"name":"Department of Maternal-Fetal Medicine, Cl\u00ednica D\u00e1vila, Santiago 8420384, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gianluca","family":"Passalacqua","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Research, Laboratory of Reproductive Biology, Faculty of Medicine, Universidad de Los Andes, Santiago 7620001, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Max","family":"Monckeberg","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Faculty of Medicine, Universidad de los Andes, Santiago 7620001, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7177-0246","authenticated-orcid":false,"given":"Gregory E.","family":"Rice","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Research, Laboratory of Reproductive Biology, Faculty of Medicine, Universidad de Los Andes, Santiago 7620001, Chile"},{"name":"Centre for Clinical Research, University of Queensland, QLD 4029 Herston, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5433-9315","authenticated-orcid":false,"given":"Sebasti\u00e1n E.","family":"Illanes","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Research, Laboratory of Reproductive Biology, Faculty of Medicine, Universidad de Los Andes, Santiago 7620001, Chile"},{"name":"Department of Obstetrics and Gynecology, Faculty of Medicine, Universidad de los Andes, Santiago 7620001, Chile"},{"name":"Department of Maternal-Fetal Medicine, Cl\u00ednica D\u00e1vila, Santiago 8420384, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.bpobgyn.2013.08.012","article-title":"Pregnancy loss","volume":"28","author":"Robinson","year":"2014","journal-title":"Best Pract. Res. Clin. Obstet. Gynaecol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/S0015-0282(02)04694-0","article-title":"Conception, early pregnancy loss, and time to clinical pregnancy: A population-based prospective study","volume":"79","author":"Wang","year":"2003","journal-title":"Fertil. Steril."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1093\/humupd\/dmv041","article-title":"The role of infection in miscarriage","volume":"22","author":"Giakoumelou","year":"2016","journal-title":"Hum. Reprod. Update"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1016\/j.fertnstert.2012.09.017","article-title":"When is a pregnancy nonviable and what criteria should be used to define miscarriage?","volume":"98","author":"Bourne","year":"2012","journal-title":"Fertil. Steril."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1016\/j.fertnstert.2012.09.014","article-title":"What serial hcg can tell you, and cannot tell you, about an early pregnancy","volume":"98","author":"Seeber","year":"2012","journal-title":"Fertil. Steril."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1111\/j.1471-0528.2000.tb11618.x","article-title":"First trimester maternal serum free beta human chorionic gonadotrophin and pregnancy associated plasma protein a as predictors of pregnancy complications","volume":"107","author":"Ong","year":"2000","journal-title":"BJOG"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3220","DOI":"10.1093\/humrep\/13.11.3220","article-title":"The accuracy of single serum progesterone measurement in the diagnosis of ectopic pregnancy: A meta-analysis","volume":"13","author":"Mol","year":"1998","journal-title":"Hum. Reprod."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e6077","DOI":"10.1136\/bmj.e6077","article-title":"Accuracy of single progesterone test to predict early pregnancy outcome in women with pain or bleeding: Meta-analysis of cohort studies","volume":"345","author":"Verhaegen","year":"2012","journal-title":"BMJ"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1016\/j.clinthera.2014.05.008","article-title":"Diagnostic and prognostic potential of extracellular vesicles in peripheral blood","volume":"36","author":"Revenfeld","year":"2014","journal-title":"Clin. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Ghiran, I., and Kuo, W.P. (2010). Examining the role of microvesicles to develop prognostic and diagnostic assays. J. Appl. Oral. Sci., 18.","DOI":"10.1590\/S1678-77572010000500001"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1002\/pmic.201300389","article-title":"The roles of extracellular vesicles in cancer biology: Toward the development of novel cancer biomarkers","volume":"14","author":"Katsuda","year":"2014","journal-title":"Proteomics"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1124\/pr.112.005983","article-title":"Classification, functions, and clinical relevance of extracellular vesicles","volume":"64","author":"Boing","year":"2012","journal-title":"Pharmacol. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Sarker, S., Scholz-Romero, K., Perez, A., Illanes, S.E., Mitchell, M.D., Rice, G.E., and Salomon, C. (2014). Placenta-derived exosomes continuously increase in maternal circulation over the first trimester of pregnancy. J. Transl. Med., 12.","DOI":"10.1186\/1479-5876-12-204"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"598","DOI":"10.2337\/db15-0966","article-title":"Gestational diabetes mellitus is associated with changes in the concentration and bioactivity of placenta-derived exosomes in maternal circulation across gestation","volume":"65","author":"Salomon","year":"2016","journal-title":"Diabetes"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3182","DOI":"10.1210\/jc.2017-00672","article-title":"Placental exosomes as early biomarker of preeclampsia: Potential role of exosomal micrornas across gestation","volume":"102","author":"Salomon","year":"2017","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1002\/oby.20250","article-title":"Maternal and fetal leptin, adiponectin levels and associations with fetal insulin sensitivity","volume":"21","author":"Luo","year":"2013","journal-title":"Obesity"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1038\/sj.jp.7211639","article-title":"Maternal serum adiponectin levels during human pregnancy","volume":"27","author":"Kanety","year":"2007","journal-title":"J. Perinatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1046\/j.1365-2265.1999.00637.x","article-title":"Serum leptin levels in women throughout pregnancy and the postpartum period and in women suffering spontaneous abortion","volume":"50","author":"Lage","year":"1999","journal-title":"Clin. Endocrinol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.1093\/humrep\/16.9.2008","article-title":"Leptin and leptin-binding activity in women with recurrent miscarriage: Correlation with pregnancy outcome","volume":"16","author":"Laird","year":"2001","journal-title":"Hum. Reprod."},{"key":"ref_20","first-page":"225","article-title":"Insulin resistance in first-trimester pregnant women with pre-pregnant glucose tolerance and history of recurrent spontaneous abortion","volume":"27","author":"Hong","year":"2013","journal-title":"J. Biol. Regul. Homeost. Agents"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"274","DOI":"10.2337\/diacare.27.1.274","article-title":"Plasma adiponectin and pregnancy-induced insulin resistance","volume":"27","author":"Cseh","year":"2004","journal-title":"Diabetes Care"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Gris, J.C., Schved, J.F., Neveu, S., Mares, P., Aguilar-Martinez, P., and Dupaigne, D. (1990). Impaired fibrinolytic capacity and early recurrent spontaneous abortion. BMJ, 300.","DOI":"10.1136\/bmj.300.6738.1500"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1159\/000077821","article-title":"Recurrent pregnancy loss and its relation to fv leiden, fii g20210a and polymorphisms of plasminogen activator and plasminogen activator inhibitor","volume":"33","author":"Wolf","year":"2003","journal-title":"Pathophysiol. Haemost. Thromb."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1055\/s-0038-1661167","article-title":"Haemostasis in normal pregnancy","volume":"52","author":"Stirling","year":"1984","journal-title":"Thromb. Haemost."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1016\/S0002-9378(98)70389-8","article-title":"Hemostasis in the uteroplacental and peripheral circulations in normotensive and pre-eclamptic pregnancies","volume":"179","author":"Higgins","year":"1998","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_26","first-page":"1250","article-title":"Elevated tissue plasminogen activator as a potential marker of endothelial dysfunction in pre-eclampsia: Correlation with proteinuria","volume":"109","author":"Belo","year":"2002","journal-title":"BJOG"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1111\/j.1365-2249.2007.03382.x","article-title":"Autoantibodies to plasminogen and tissue plasminogen activator in women with recurrent pregnancy loss","volume":"149","author":"Bu","year":"2007","journal-title":"Clin. Exp. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"S173","DOI":"10.1016\/j.ajog.2015.07.001","article-title":"Placental exosomes in normal and complicated pregnancy","volume":"213","author":"Mitchell","year":"2015","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Chong, S.Y., Lee, C.K., Huang, C., Ou, Y.H., Charles, C.J., Richards, A.M., Neupane, Y.R., Pavon, M.V., Zharkova, O., and Pastorin, G. (2019). Extracellular vesicles in cardiovascular diseases: Alternative biomarker sources, therapeutic agents, and drug delivery carriers. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20133272"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Mustapic, M., Eitan, E., Werner, J.K., Berkowitz, S.T., Lazaropoulos, M.P., Tran, J., Goetzl, E.J., and Kapogiannis, D. (2017). Plasma extracellular vesicles enriched for neuronal origin: A potential window into brain pathologic processes. Front. Neurosci., 11.","DOI":"10.3389\/fnins.2017.00278"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.placenta.2018.02.006","article-title":"Placental exosomes profile in maternal and fetal circulation in intrauterine growth restriction \u2014Liquid biopsies to monitoring fetal growth","volume":"64","author":"Miranda","year":"2018","journal-title":"Placenta"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1530\/ror.0.0050018","article-title":"Placental leptin","volume":"5","author":"Ashworth","year":"2000","journal-title":"Rev. Reprod."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3427","DOI":"10.1210\/jc.2013-4074","article-title":"Patterns of adiponectin expression in term pregnancy: Impact of obesity","volume":"99","author":"Haghiac","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.2337\/dc12-2532","article-title":"Adiponectin: Are measurements clinically useful in pregnancy?","volume":"36","author":"Catalano","year":"2013","journal-title":"Diabetes Care"}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/10\/4\/197\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:14:28Z","timestamp":1760174068000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/10\/4\/197"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,1]]},"references-count":34,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2020,4]]}},"alternative-id":["diagnostics10040197"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics10040197","relation":{},"ISSN":["2075-4418"],"issn-type":[{"type":"electronic","value":"2075-4418"}],"subject":[],"published":{"date-parts":[[2020,4,1]]}}}