{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T04:05:29Z","timestamp":1784261129349,"version":"3.55.0"},"reference-count":35,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The global transition away from di(2-ethylhexyl) phthalate (DEHP)-plasticized blood storage systems has raised important questions regarding platelet storage biology, transfusion performance, and recipient exposure to plasticizer-derived compounds. This systematic review evaluated platelet quality, plasticizer migration, and modeled transfusion exposure associated with DEHP-containing and DEHP-free platelet storage systems, including di(2-ethylhexyl) terephthalate (DEHT), diisononyl cyclohexane-1,2-dicarboxylate (DINCH), butyryl trihexyl citrate (BTHC), and tri(2-ethylhexyl) trimellitate (TOTM). English-language studies reporting quantitative platelet storage, migration, or exposure endpoints were identified through structured Google Scholar searches through 1 May 2025, supplemented by manual reference screening. Eligible studies were required to specify plasticizer composition and report quantitative biologic, migration, or exposure outcomes. Narrative reviews, opinion articles, and studies lacking extractable quantitative data were excluded. The risk of bias and the certainty of the evidence were assessed using adapted domain- and GRADE-based frameworks for mechanistic and preclinical studies. A random-effects meta-analysis was performed for day 7 platelet pH, while the remaining endpoints were synthesized descriptively. Thirty-three studies were included, comprising experimental platelet storage studies, biomaterial migration analyses, toxicologic investigations, and exposure-modeling studies. Platelet metabolic stability, including pH, glucose consumption, lactate accumulation, and mitochondrial membrane potential, was preserved across plasticizer systems. Meta-analysis demonstrated no significant difference in pooled day 7 platelet pH between DEHP and non-DEHP systems (mean difference +0.025; 95% confidence interval \u22120.081 to +0.131). Platelet aggregation and agonist-induced activation responses were maintained in DEHP-free systems. Selected activation and apoptotic markers, including CD62P expression and Annexin V binding, were reduced in fully DEHP-free systems, suggesting decreased storage-related membrane stress. Migration studies consistently demonstrated substantially greater DEHP leaching than DINCH and DEHT, resulting in higher modeled cumulative transfusion exposure, particularly among pediatric and neonatal recipients. Evidence further indicated that DEHP-containing whole-blood collection systems contribute to downstream contamination of platelet products with DEHP and mono(2-ethylhexyl) phthalate (MEHP). Interpretation is limited by heterogeneity in study design, storage platforms, assay methodologies, and the predominance of in vitro evidence. Overall, replacing DEHP with modern alternative plasticizers helps preserve transfusion-relevant platelet quality while potentially reducing plasticizer migration and modeled recipient exposure, thereby supporting the biologic and toxicologic rationale for transitioning to phthalate-free blood collection and storage systems.<\/jats:p>","DOI":"10.3390\/cells15141276","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T08:08:34Z","timestamp":1784189314000},"page":"1276","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Platelet Storage Quality, Plasticizer Migration, and Transfusion Exposure Risk in DEHP Versus Non-DEHP Blood Storage Systems: A Mechanistic and Quantitative Comparative Analysis"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6860-3156","authenticated-orcid":false,"given":"Ludwig Rayner","family":"Frontier Ramos","sequence":"first","affiliation":[{"name":"Medical Affairs, Macopharma USA, 3075 Breckinridge Blvd, Suite 405, Duluth, GA 30096, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1251-0441","authenticated-orcid":false,"given":"Wouter","family":"Van\u2019t Hof","sequence":"additional","affiliation":[{"name":"Cleveland Cord Blood Center, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8616-7054","authenticated-orcid":false,"given":"Quentin","family":"Brebant","sequence":"additional","affiliation":[{"name":"Research and Development Department, Macopharma, 200 Chauss\u00e9e Fernand Forest, 59200 Tourcoing, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1175-9579","authenticated-orcid":false,"given":"Richard R.","family":"Gammon","sequence":"additional","affiliation":[{"name":"Department of Hematopathology, Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA"},{"name":"Department of Oncologic Services, University of South Florida, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3210","DOI":"10.1182\/blood-2006-04-020131","article-title":"A Multicenter Randomized Study of the Efficacy of Transfusions with Platelets Stored in Platelet Additive Solution II versus Plasma","volume":"108","author":"Kerkhoffs","year":"2006","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1111\/trf.12498","article-title":"The Impact of Platelet Additive Solution Apheresis Platelets on Allergic Transfusion Reactions and Corrected Count Increment (CME)","volume":"54","author":"Tobian","year":"2014","journal-title":"Transfusion"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1111\/vox.13446","article-title":"Migration of Di(2-ethylhexyl) Phthalate, Diisononylcyclohexane-1,2-dicarboxylate and Di(2-ethylhexyl) Terephthalate from Transfusion Medical Devices in Labile Blood Products: A Comparative Study","volume":"118","author":"Thelliez","year":"2023","journal-title":"Vox Sang."},{"key":"ref_4","unstructured":"European Commission (2015). Opinion on the Safety of Medical Devices Containing DEHP Plasticized PVC or Other Plasticizers on Neonates and Other Groups Possibly at Risk (2015 Update)."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1002\/1097-0274(200101)39:1<100::AID-AJIM10>3.0.CO;2-Q","article-title":"Health Risks Posed by Use of Di-2-Ethylhexyl Phthalate (DEHP) in PVC Medical Devices: A Critical Review","volume":"39","author":"Tickner","year":"2001","journal-title":"Am. J. Ind. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1046\/j.1537-2995.1976.16476247053.x","article-title":"Fate in Humans of the Plasticizer, Di-2-Ethylhexyl Phthalate, Arising from Transfusion of Platelets Stored in Vinyl Plastic Bags","volume":"16","author":"Rubin","year":"1976","journal-title":"Transfusion"},{"key":"ref_7","unstructured":"U.S. Food and Drug Administration (2026, March 24). PVC Devices Containing the Plasticizer DEHP\u2014Potential Safety Risks for Certain Patient Populations, Available online: http:\/\/accessmedicalusa.com\/pdf\/fda-dehp-letter.pdf."},{"key":"ref_8","unstructured":"World Health Organization (2012). World Health Organization Blood Donor Selection: Guidelines on Assessing Donor Suitability for Blood Donation, World Health Organization."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1111\/trf.12870","article-title":"In Vitro Evaluation of the Quality of Blood Products Collected and Stored in Systems Completely Free of Di(2-ethylhexyl)Phthalate\u2013Plasticized Materials","volume":"55","author":"Lagerberg","year":"2015","journal-title":"Transfusion"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1111\/vox.12982","article-title":"Non-phthalate Plasticizer DEHT Preserves Adequate Blood Component Quality during Storage in PVC Blood Bags","volume":"116","author":"Larsson","year":"2021","journal-title":"Vox Sang."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1046\/j.1537-2995.1992.32893032101.x","article-title":"Five-day Storage of Platelets in a Non-diethylhexyl Phthalate-plasticized Container","volume":"32","author":"Snyder","year":"1992","journal-title":"Transfusion"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1007\/s12288-021-01408-x","article-title":"Comparison of Quality and Efficacy of Apheresis Platelets Stored in Platelet Additive Solution Vis a Vis Plasma","volume":"37","author":"Basu","year":"2021","journal-title":"Indian. J. Hematol. Blood Transfus."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1111\/vox.70087","article-title":"In Vitro Quality of Whole Blood-derived Red Cell Concentrates Collected, Processed and Stored in a Blood Bag Set Plasticized with Di (2-ethylhexyl) Terephthalate","volume":"120","author":"Stephenson","year":"2025","journal-title":"Vox Sang."},{"key":"ref_14","unstructured":"(2026, May 26). Guide to the Preparation, Use and Quality Assurance of Blood Components-European Directorate for the Quality of Medicines & HealthCare-EDQM. Available online: https:\/\/www.edqm.eu\/en\/blood-guide."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 Statement: An Updated Guideline for Reporting Systematic Reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_16","first-page":"424","article-title":"Platelet Additive Solutions SSP+ and T-PAS+ Are Interchangeable for Platelet Concentrate Storage despite Differences in Composition and Plasticizer","volume":"51","author":"Bens","year":"2024","journal-title":"Transfus. Med. Hemother"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2652","DOI":"10.1111\/trf.15356","article-title":"In Vitro Quality and Platelet Function of Cold and Delayed Cold Storage of Apheresis Platelet Concentrates in Platelet Additive Solution for 21 Days","volume":"59","author":"Braathen","year":"2019","journal-title":"Transfusion"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1974","DOI":"10.1111\/trf.13631","article-title":"Metabolites in Stored Platelets Associated with Platelet Recoveries and Survivals","volume":"56","author":"Zimring","year":"2016","journal-title":"Transfusion"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1007\/s00204-004-0642-4","article-title":"New Metabolites of Di(2-Ethylhexyl)Phthalate (DEHP) in Human Urine and Serum after Single Oral Doses of Deuterium-Labelled DEHP","volume":"79","author":"Koch","year":"2005","journal-title":"Arch. Toxicol."},{"key":"ref_20","unstructured":"U.S. Food and Drug Administration (2026, March 24). Safety Assessment of Di(2-Ethylhexyl)Phthalate Released from PVC Medical Devices, Available online: https:\/\/www.fda.gov\/media\/71183\/download."},{"key":"ref_21","unstructured":"European Chemicals Agency (2026, March 24). Bis(2-Ethylhexyl)Phthalate (DEHP): Substance of Very High Concern (SVHC) Identified under Regulation (EC) No 1907\/2006 (REACH), Available online: https:\/\/echa.europa.eu\/substance-information\/-\/substanceinfo\/100.001.285."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"10","DOI":"10.4103\/1658-5127.131819","article-title":"Comparison of Changes in Platelet Count, Mean Platelet Volume and Swirling in Stored Platelet Concentrates with and without Platelet Additive Solution","volume":"5","author":"Bashir","year":"2014","journal-title":"J. Appl. Hematol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1111\/vox.70151","article-title":"In Vitro Quality Assessment of Red Blood Cells and Plasma Units in DEHT\/SAGM Bags and DEHT\/PAGGSM Bags during Storage","volume":"121","author":"Lotens","year":"2026","journal-title":"Vox Sang."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"P\u00f6tzl, B., K\u00fcrzinger, L., Kendl, S., Stopper, H., Kurlbaum, M., Fassnacht, M., and Dischinger, U. (2024). Disruptive Effects of Plasticizers Bisphenol A, F, and S on Steroidogenesis of Adrenocortical Cells. Front. Endocrinol., 15.","DOI":"10.3389\/fendo.2024.1387133"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1046\/j.1537-2995.2003.00479.x","article-title":"Donor Exposure to the Plasticizer Di(2-ethylhexyl)Phthalate during Plateletpheresis","volume":"43","author":"Buchta","year":"2003","journal-title":"Transfusion"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1159\/000487513","article-title":"Platelet Additive Solutions: A Review of the Latest Developments and Their Clinical Implications","volume":"45","year":"2018","journal-title":"Transfus. Med. Hemother"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Couvidou, A., Rojas-Jim\u00e9nez, G., Dupuis, A., and Ma\u00eetre, B. (2023). Anti-HLA Class I Alloantibodies in Platelet Transfusion Refractoriness: From Mechanisms and Determinants to Therapeutic Prospects. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1125367"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"28","DOI":"10.21037\/aob-20-93","article-title":"Incidence and Management of Non-Immune Platelet Transfusion Refractoriness: A Narrative Review","volume":"6","author":"Hagino","year":"2021","journal-title":"Ann. Blood"},{"key":"ref_29","first-page":"480","article-title":"Evaluation of Platelet Function during Extended Storage in Additive Solution, Prepared in a New Container That Allows Manual Buffy-Coat Platelet Pooling and Leucoreduction in the Same System","volume":"10","author":"Plaza","year":"2012","journal-title":"Blood Transfus."},{"key":"ref_30","first-page":"247","article-title":"A Mini-Review on Platelet Refractoriness","volume":"90","author":"Rebulla","year":"2005","journal-title":"Haematologica"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1016\/j.hoc.2016.01.008","article-title":"Management of the Platelet Refractory Patient","volume":"30","author":"Forest","year":"2016","journal-title":"Hematol.\/Oncol. Clin. N. Am."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1136\/oem.2004.017590","article-title":"PHTHALATES AND HUMAN HEALTH","volume":"62","author":"Hauser","year":"2005","journal-title":"Occup. Environ. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1182\/hematology.2020000137","article-title":"Platelet Transfusion Refractoriness: How Do I Diagnose and Manage?","volume":"2020","author":"Cohn","year":"2020","journal-title":"Hematology"},{"key":"#cr-split#-ref_34.1","unstructured":"European Union (2017). Regulation"},{"key":"#cr-split#-ref_34.2","unstructured":"(EU) 2017\/745 of the European Parliament and of the Council of 5 April 2017 on Medical Devices. Off. J. Eur. Union, L117, 1-175."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/14\/1276\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T03:42:26Z","timestamp":1784259746000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/14\/1276"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,16]]},"references-count":35,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["cells15141276"],"URL":"https:\/\/doi.org\/10.3390\/cells15141276","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,16]]}}}