{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T06:29:58Z","timestamp":1790922598597,"version":"4.1.0"},"reference-count":63,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2019,12,30]],"date-time":"2019-12-30T00:00:00Z","timestamp":1577664000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Platelet-dependent thrombin generation is a helpful tool to assess ex vivo the interaction between platelets and plasma coagulation factors in the initiation, amplification, and inhibition of thrombin generation (TG). This review article discusses the most relevant available data on the clinical applications of fluorogenic TG, the most widely used TG assay, performed in the presence of platelets, i.e., in platelet-rich plasma. With respect to prothrombotic states, arterial hypertension and obesity were the most prominent cardiovascular conditions linked to increased platelet-dependent TG. In addition, platelet-associated hypercoagulability, assessed by the TG assay, has been shown in individuals with active cancer. In terms of bleeding, platelet-dependent TG has been applied to assess bleeding risk in individuals with hemophilia, von Willebrand disease, and Glanzmann thrombasthenia as well as in subjects with other congenital or acquired coagulation factor deficiencies. In addition to risk prediction, a role of the TG assay has been suggested in monitoring antiplatelet therapy in prothrombotic conditions and replacement therapy in bleeding diathesis. Finally, for the routine clinical use and as a biomarker of disease development and progression, better standardization and clinical validation of platelet-dependent TG are still needed.<\/jats:p>","DOI":"10.3390\/jcm9010092","type":"journal-article","created":{"date-parts":[[2019,12,30]],"date-time":"2019-12-30T05:49:41Z","timestamp":1577684981000},"page":"92","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Clinical Applications, Pitfalls, and Uncertainties of Thrombin Generation in the Presence of Platelets"],"prefix":"10.3390","volume":"9","author":[{"given":"Marina","family":"Panova-Noeva","sequence":"first","affiliation":[{"name":"Clinical Epidemiology and Systems Medicine, Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola E.J.","family":"van der Meijden","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, 6200 Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7796-4463","authenticated-orcid":false,"given":"Hugo","family":"ten Cate","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Laboratory of Clinical Thrombosis and Haemostasis, and Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, 6200 Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1001\/jama.2018.14346","article-title":"Venous Thromboembolism: Advances in Diagnosis and Treatment","volume":"320","author":"Tritschler","year":"2018","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1111\/jth.13368","article-title":"A diagnostic approach to mild bleeding disorders","volume":"14","author":"Boender","year":"2016","journal-title":"J. Thromb. Haemost."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1159\/000073575","article-title":"The calibrated automated thrombogram (CAT): A universal routine test for hyper- and hypocoagulability","volume":"32","author":"Hemker","year":"2002","journal-title":"Pathophysiol. Haemost. Thromb."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1055\/s-0037-1613868","article-title":"The thrombogram: Monitoring thrombin generation in platelet-rich plasma","volume":"83","author":"Hemker","year":"2000","journal-title":"Thromb. Haemost."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1016\/j.thromres.2012.07.017","article-title":"Evaluation of a standardized protocol for thrombin generation measurement using the calibrated automated thrombogram: An international multicentre study","volume":"130","author":"Dargaud","year":"2012","journal-title":"Thromb. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1159\/000071636","article-title":"Calibrated automated thrombin generation measurement in clotting plasma","volume":"33","author":"Hemker","year":"2003","journal-title":"Pathophysiol. Haemost. Thromb."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2544","DOI":"10.1111\/jth.12012","article-title":"Preanalytic variables of thrombin generation: Towards a standard procedure and validation of the method","volume":"10","author":"Loeffen","year":"2012","journal-title":"J. Thromb. Haemost."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Kossmann, S., Lagrange, J., Jackel, S., Jurk, K., Ehlken, M., Schonfelder, T., Weihert, Y., Knorr, M., Brandt, M., and Xia, N. (2017). Platelet-localized FXI promotes a vascular coagulation-inflammatory circuit in arterial hypertension. Sci. Transl. Med., 9.","DOI":"10.1126\/scitranslmed.aah4923"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1055\/s-0038-1641565","article-title":"Clinical Determinants of Thrombin Generation Measured in Presence and Absence of Platelets-Results from the Gutenberg Health Study","volume":"118","author":"Schulz","year":"2018","journal-title":"Thromb. Haemost."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Panova-Noeva, M., Neu, M.A., Eckerle, S., Spix, C., Schneider, A., Schmidtmann, I., Spronk, H.M., Pfeiffer, N., Beutel, M., and Lackner, K.J. (2018). Cardiovascular risk factors are important determinants of platelet-dependent thrombin generation in adult survivors of childhood cancer. Clin. Res. Cardiol.","DOI":"10.1007\/s00392-018-1374-4"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1093\/eurheartj\/ehy026","article-title":"Burden of cardiovascular risk factors and cardiovascular disease in childhood cancer survivors: Data from the German CVSS-study","volume":"39","author":"Faber","year":"2018","journal-title":"Eur. Heart J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1111\/j.1467-789X.2011.00930.x","article-title":"Platelet activation in obesity and metabolic syndrome","volume":"13","author":"Santilli","year":"2012","journal-title":"Obes. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.thromres.2005.12.013","article-title":"Impact of weight reduction on production of platelet-derived microparticles and fibrinolytic parameters in obesity","volume":"119","author":"Murakami","year":"2007","journal-title":"Thromb. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1097\/MBC.0b013e32835f93d5","article-title":"Obesity and thrombin-generation profiles in women with venous thromboembolism","volume":"24","author":"Sonnevi","year":"2013","journal-title":"Blood Coagul. Fibrinolysis"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1160\/TH14-02-0156","article-title":"Hypercoagulability in overweight and obese subjects who are asymptomatic for thrombotic events","volume":"113","author":"Campello","year":"2015","journal-title":"Thromb. Haemost."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1007\/s11239-019-01818-9","article-title":"Body mass index reduction improves the baseline procoagulant imbalance of obese subjects","volume":"48","author":"Tripodi","year":"2019","journal-title":"J. Thromb. Thrombolysis"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"944","DOI":"10.2337\/dc08-1308","article-title":"Association between increased platelet P-selectin expression and obesity in patients with type 2 diabetes: A BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) substudy","volume":"32","author":"Schneider","year":"2009","journal-title":"Diabetes Care"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2482","DOI":"10.1056\/NEJMra071014","article-title":"Platelet activation and atherothrombosis","volume":"357","author":"Davi","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Ten Cate, H., and Hemker, H.C. (2016). Thrombin Generation and Atherothrombosis: What Does the Evidence Indicate?. J. Am. Heart Assoc., 5.","DOI":"10.1161\/JAHA.116.003553"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1159\/000071642","article-title":"Thrombin generation in platelet-rich plasma as a tool for the detection of hypercoagulability in young stroke patients","volume":"33","author":"Faber","year":"2003","journal-title":"Pathophysiol. Haemost. Thromb."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.thromres.2017.05.008","article-title":"Thrombin generation and intracranial atherosclerotic disease in patients with a transient ischaemic attack","volume":"155","author":"Favaretto","year":"2017","journal-title":"Thromb. Res."},{"key":"ref_22","first-page":"547","article-title":"Thrombin generation assessed as endogenous thrombin potential in patients with hyper- or hypo-coagulability","volume":"88","author":"Chantarangkul","year":"2003","journal-title":"Haematologica"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1111\/j.1538-7836.2008.03117.x","article-title":"High rate of unprovoked recurrent venous thrombosis is associated with high thrombin-generating potential in a prospective cohort study","volume":"6","author":"Besser","year":"2008","journal-title":"J. Thromb. Haemost."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1160\/TH08-02-0099","article-title":"Thrombin generation in patients after acute deep-vein thrombosis","volume":"100","author":"Dielis","year":"2008","journal-title":"Thromb. Haemost."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1001\/jama.296.4.397","article-title":"Identification of patients at low risk for recurrent venous thromboembolism by measuring thrombin generation","volume":"296","author":"Hron","year":"2006","journal-title":"JAMA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1111\/j.1365-2141.2007.06732.x","article-title":"Thrombin generation: A comparison of assays using platelet-poor and -rich plasma and whole blood samples from healthy controls and patients with a history of venous thromboembolism","volume":"139","author":"Tappenden","year":"2007","journal-title":"Br. J. Haematol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1002\/ajh.21974","article-title":"Platelet-induced thrombin generation by the calibrated automated thrombogram assay is increased in patients with essential thrombocythemia and polycythemia vera","volume":"86","author":"Marchetti","year":"2011","journal-title":"Am. J. Hematol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.thromres.2013.05.003","article-title":"ADP-induced platelet aggregation and thrombin generation are increased in Essential Thrombocythemia and Polycythemia Vera","volume":"132","author":"Marchetti","year":"2013","journal-title":"Thromb. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/1477-9560-4-5","article-title":"Thrombin generation by activated factor VII on platelet activated by different agonists. Extending the cell-based model of hemostasis","volume":"4","author":"Altman","year":"2006","journal-title":"Thromb. J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2022","DOI":"10.1111\/j.1538-7836.2006.02088.x","article-title":"Recombinant factor VIIa reverses the inhibitory effect of aspirin or aspirin plus clopidogrel on in vitro thrombin generation","volume":"4","author":"Altman","year":"2006","journal-title":"J. Thromb. Haemost."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1160\/TH04-09-0597","article-title":"Platelet P2Y12 receptors enhance signalling towards procoagulant activity and thrombin generation. A study with healthy subjects and patients at thrombotic risk","volume":"93","author":"Feijge","year":"2005","journal-title":"Thromb. Haemost."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1080\/09537104.2017.1294680","article-title":"Thrombin generation test for evaluation of antiplatelet treatment in patients with coronary artery disease after percutaneous coronary intervention","volume":"29","author":"Berezovskaya","year":"2018","journal-title":"Platelets"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Consolo, F., Pozzi, L., Pieri, M., Valle, P.D., Redaelli, A., D\u2019Angelo, A., and Pappalardo, F. (2019). Influence of Different Antithrombotic Regimens on Platelet-Mediated Thrombin Generation in Patients with Left Ventricular Assist Devices. ASAIO J.","DOI":"10.1097\/MAT.0000000000001064"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"566","DOI":"10.3324\/haematol.12364","article-title":"The effect of platelet activation on the hypercoagulability induced by murine monoclonal antiphospholipid antibodies","volume":"93","author":"Membre","year":"2008","journal-title":"Haematologica"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e89373","DOI":"10.1172\/jci.insight.89373","article-title":"Protein disulfide isomerase inhibition blocks thrombin generation in humans by interfering with platelet factor V activation","volume":"2","author":"Stopa","year":"2017","journal-title":"JCI Insight"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Zwicker, J.I., Schlechter, B.L., Stopa, J.D., Liebman, H.A., Aggarwal, A., Puligandla, M., Caughey, T., Bauer, K.A., Kuemmerle, N., and Wong, E. (2019). Targeting protein disulfide isomerase with the flavonoid isoquercetin to improve hypercoagulability in advanced cancer. JCI Insight, 4.","DOI":"10.1172\/jci.insight.125851"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Makhoul, S., Panova-Noeva, M., Regnault, V., Ruf, W., Wenzel, P., and Lagrange, J. (2019). Rivaroxaban Effects Illustrate the Underestimated Importance of Activated Platelets in Thrombin Generation Assessed by Calibrated Automated Thrombography. J. Clin. Med., 8.","DOI":"10.3390\/jcm8111990"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1111\/j.1365-2516.2011.02601.x","article-title":"Platelets significantly modify procoagulant activities in haemophilia A","volume":"17","author":"Ilveskero","year":"2011","journal-title":"Haemophilia"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1111\/j.1538-7836.2010.03767.x","article-title":"Severe hemophilia with mild bleeding phenotype: Molecular characterization and global coagulation profile","volume":"8","author":"Santagostino","year":"2010","journal-title":"J. Thromb. Haemost."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1160\/TH03-01-0027","article-title":"Thrombin generation in severe haemophilia A and B: The endogenous thrombin potential in platelet-rich plasma","volume":"90","author":"Siegemund","year":"2003","journal-title":"Thromb. Haemost."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.3324\/haematol.11460","article-title":"Thrombin-generating capacity in patients with von Willebrand\u2019s disease","volume":"92","author":"Rugeri","year":"2007","journal-title":"Haematologica"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1055\/s-0037-1614080","article-title":"The effect of DDAVP infusion on thrombin generation in platelet-rich plasma of von Willebrand type 1 and in mild haemophilia A patients","volume":"84","author":"Keularts","year":"2000","journal-title":"Thromb. Haemost."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Szanto, T., Nummi, V., Jouppila, A., Brinkman, H.J.M., and Lassila, R. (2019). Platelets compensate for poor thrombin generation in type 3 von Willebrand disease. Platelets, 1\u20139.","DOI":"10.1080\/09537104.2019.1581922"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1182\/blood-2009-08-237719","article-title":"Residual platelet factor V ensures thrombin generation in patients with severe congenital factor V deficiency and mild bleeding symptoms","volume":"115","author":"Duckers","year":"2010","journal-title":"Blood"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1111\/j.1538-7836.2011.04237.x","article-title":"Homozygous F5 deep-intronic splicing mutation resulting in severe factor V deficiency and undetectable thrombin generation in platelet-rich plasma","volume":"9","author":"Castoldi","year":"2011","journal-title":"J. Thromb. Haemost."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1111\/j.1365-2516.2010.02246.x","article-title":"Thrombin generation in patients with factor XI deficiency and clinical bleeding risk","volume":"16","author":"Rugeri","year":"2010","journal-title":"Haemophilia"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1111\/j.1365-2141.2011.08945.x","article-title":"Biological determinants of bleeding in patients with heterozygous factor XI deficiency","volume":"156","author":"Gueguen","year":"2012","journal-title":"Br. J. Haematol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1182\/blood-2014-12-616565","article-title":"Sample conditions determine the ability of thrombin generation parameters to identify bleeding phenotype in FXI deficiency","volume":"126","author":"Pike","year":"2015","journal-title":"Blood"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1111\/j.1365-2141.2007.06722.x","article-title":"Measurement of global haemostasis in severe haemophilia A following factor VIII infusion","volume":"138","author":"Lewis","year":"2007","journal-title":"Br. J. Haematol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"604","DOI":"10.3109\/09537104.2011.642031","article-title":"The in vivo effect of fibrinogen and factor XIII on clot formation and fibrinolysis in Glanzmann\u2019s thrombasthenia","volume":"23","author":"Shenkman","year":"2012","journal-title":"Platelets"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1055\/s-0038-1676348","article-title":"Low Concentrations of Recombinant Factor VIIa May Improve the Impaired Thrombin Generation of Glanzmann Thrombasthenia Patients","volume":"119","author":"Levy","year":"2019","journal-title":"Thromb. Haemost."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1160\/TH13-06-0493","article-title":"Additive roles of platelets and fibrinogen in whole-blood fibrin clot formation upon dilution as assessed by thromboelastometry","volume":"111","author":"Ninivaggi","year":"2014","journal-title":"Thromb. Haemost."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1160\/TH07-07-0438","article-title":"Increased thrombin generation and fibrinogen level after therapeutic plasma transfusion: Relation to bleeding","volume":"99","author":"Schols","year":"2008","journal-title":"Thromb. Haemost."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1016\/j.thromres.2013.12.017","article-title":"Measurement of thrombin generation intra-operatively and its association with bleeding tendency after cardiac surgery","volume":"133","author":"Bosch","year":"2014","journal-title":"Thromb. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1159\/000071638","article-title":"Calibrated automated thrombin generation in frozen-thawed platelet-rich plasma to detect hypercoagulability","volume":"33","author":"Regnault","year":"2003","journal-title":"Pathophysiol. Haemost. Thromb."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"e214","DOI":"10.1111\/hae.13180","article-title":"Low agreement between fresh and frozen-thawed platelet-rich plasma in the calibrated automated thrombogram assay","volume":"23","author":"Ljungkvist","year":"2017","journal-title":"Haemophilia"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1111\/j.1538-7836.2011.04427.x","article-title":"Towards a recommendation for the standardization of the measurement of platelet-dependent thrombin generation","volume":"9","author":"Baglin","year":"2011","journal-title":"J. Thromb. Haemost."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/1477-9560-3-16","article-title":"Towards a standardization of thrombin generation assessment: The influence of tissue factor, platelets and phospholipids concentration on the normal values of Thrombogram-Thrombinoscope assay","volume":"3","author":"Gerotziafas","year":"2005","journal-title":"Thromb. J."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.thromres.2010.08.007","article-title":"Monitoring platelet dependent thrombin generation in mice","volume":"126","author":"Dargaud","year":"2010","journal-title":"Thromb. Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1111\/j.1538-7836.2012.04758.x","article-title":"Platelet- and erythrocyte-derived microparticles trigger thrombin generation via factor XIIa","volume":"10","author":"Renne","year":"2012","journal-title":"J. Thromb. Haemost."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1111\/j.1538-7836.2006.01905.x","article-title":"Elimination of contact factor activation improves measurement of platelet-dependent thrombin generation by calibrated automated thrombography at low-concentration tissue factor","volume":"4","author":"Dargaud","year":"2006","journal-title":"J. Thromb. Haemost."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1002\/rth2.12238","article-title":"Thrombin generation measurement using the ST Genesia Thrombin Generation System in a cohort of healthy adults: Normal values and variability","volume":"3","author":"Calzavarini","year":"2019","journal-title":"Res. Pract. Thromb. Haemost."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1111\/jth.14470","article-title":"Assessment of the analytical performances and sample stability on ST Genesia system using the STG-DrugScreen application","volume":"17","author":"Douxfils","year":"2019","journal-title":"J. Thromb. Haemost."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/1\/92\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:46:40Z","timestamp":1760190400000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/1\/92"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,30]]},"references-count":63,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,1]]}},"alternative-id":["jcm9010092"],"URL":"https:\/\/doi.org\/10.3390\/jcm9010092","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,30]]}}}