{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T23:59:05Z","timestamp":1783814345439,"version":"3.55.0"},"reference-count":44,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T00:00:00Z","timestamp":1729123200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medical Directorate (HMD, Forschungskonto) of the Austrian Worker\u2019s Compensation Board (AUVA)","award":["P-35425"],"award-info":[{"award-number":["P-35425"]}]},{"name":"Austrian Science Fund","award":["P-35425"],"award-info":[{"award-number":["P-35425"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Extracorporeal membrane oxygenation (ECMO) provides critical support for patients with severe cardiopulmonary dysfunction. Unfractionated heparin (UFH) is used for anticoagulation to maintain circuit patency and avoid thrombotic complications, but it increases the risk of bleeding. Extracellular vesicles (EVs), nano-sized subcellular spheres with potential pro-coagulant properties, are released during cellular stress and may serve as potential targets for monitoring anticoagulation, particularly in thromboinflammation. We investigated the impact of UFH dose during ECMO therapy at the coagulation\u2013inflammation interface level, focusing on complement activation and changes in circulating large EV (lEV) subsets. In a post hoc analysis of a multicenter randomized controlled trial comparing two anticoagulation management algorithms, we examined lEV levels and complement activation in 23 veno-venous-ECMO patients stratified by UFH dose. Blood samples were collected at different time points and grouped into three phases of ECMO therapy: initiation (day 1), mid (days 3\u20134), and late (days 6\u20137). Immunoassays detected complement activation, and flow cytometry analyzed lEV populations with an emphasis on mitochondria-carrying subsets. Patients receiving &lt;15 IU\/kg\/h UFH exhibited higher levels of the complement activation product C5a and soluble terminal complement complex (sC5b-9). Lower UFH doses were linked to increased endothelial-derived lEVs, while higher doses were associated with elevated RBC-derived and mitochondria-positive lEVs. Our findings suggest the potential theranostic relevance of EV detection at the coagulation\u2013inflammation interface. Further research is needed to standardize EV detection methods and validate these findings in larger ECMO patient cohorts.<\/jats:p>","DOI":"10.3390\/ijms252011166","type":"journal-article","created":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T08:56:32Z","timestamp":1729155392000},"page":"11166","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Effect of Unfractionated Heparin Dose on Complement Activation and Selected Extracellular Vesicle Populations during Extracorporeal Membrane Oxygenation"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8222-3413","authenticated-orcid":false,"given":"Johannes","family":"Zipperle","sequence":"first","affiliation":[{"name":"Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, 1200 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4780-2569","authenticated-orcid":false,"given":"Laurenz","family":"Vock","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, 1200 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4795-6662","authenticated-orcid":false,"given":"Gerhard","family":"Fritsch","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, 1200 Vienna, Austria"},{"name":"AUVA Trauma Center Salzburg, Department of Anaesthesiology and Intensive Care Medicine, Academic Teaching Hospital of the Paracelsus Medical University, 5010 Salzburg, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5474-6332","authenticated-orcid":false,"given":"Johannes","family":"Grillari","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, 1200 Vienna, Austria"},{"name":"Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria"},{"name":"Institute for Molecular Biotechnology, Department for Biotechnology, BOKU University, 1190 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1321-9883","authenticated-orcid":false,"given":"Marcin F.","family":"Osuchowski","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, 1200 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6425-9028","authenticated-orcid":false,"given":"Wolfgang","family":"Holnthoner","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, 1200 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6028-1551","authenticated-orcid":false,"given":"Herbert","family":"Sch\u00f6chl","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, 1200 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8060-2076","authenticated-orcid":false,"given":"Rebecca","family":"Halbgebauer","sequence":"additional","affiliation":[{"name":"Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, University Hospital of Ulm, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2359-6516","authenticated-orcid":false,"given":"Markus","family":"Huber-Lang","sequence":"additional","affiliation":[{"name":"Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, University Hospital of Ulm, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaus","family":"Hofmann","sequence":"additional","affiliation":[{"name":"Department of Anaesthesia, Intensive Care Medicine and Pain Medicine, Division of General Anaesthesia and Intensive Care Medicine, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenz","family":"Scharner","sequence":"additional","affiliation":[{"name":"Department of Anaesthesia, Intensive Care Medicine and Pain Medicine, Division of General Anaesthesia and Intensive Care Medicine, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro","family":"Panigada","sequence":"additional","affiliation":[{"name":"Department of Anaesthesia, Critical Care and Emergency Medicine, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"},{"name":"Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8717-0544","authenticated-orcid":false,"given":"Johannes","family":"Gratz","sequence":"additional","affiliation":[{"name":"Department of Anaesthesia, Intensive Care Medicine and Pain Medicine, Division of General Anaesthesia and Intensive Care Medicine, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7972-1569","authenticated-orcid":false,"given":"Giacomo","family":"Iapichino","sequence":"additional","affiliation":[{"name":"Department of Anesthesia and Intensive Care Medicine, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1007\/s00134-021-06593-x","article-title":"Bleeding and thrombotic events in adults supported with venovenous extracorporeal membrane oxygenation: An ELSO registry analysis","volume":"48","author":"Nunez","year":"2022","journal-title":"Intensive Care Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/S0022-3476(96)70252-4","article-title":"Activation of the clotting system during extracorporeal membrane oxygenation in term newborn infants","volume":"129","author":"Urlesberger","year":"1996","journal-title":"J. Pediatr."},{"key":"ref_3","first-page":"170","article-title":"Hemostasis changes during veno-venous extracorporeal membrane oxygenation for respiratory support in adults","volume":"82","author":"Panigada","year":"2016","journal-title":"Minerva Anestesiol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Lim, G.B. (Nat. Rev. Cardiol., 2017). Milestone 1: Discovery and purification of heparin, Nat. Rev. Cardiol., ahead of print.","DOI":"10.1038\/nrcardio.2017.171"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2698","DOI":"10.1161\/01.CIR.0000131660.51520.9A","article-title":"Bidirectional Relation between Inflammation and Coagulation","volume":"109","author":"Levi","year":"2004","journal-title":"Circulation"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1160\/TH15-08-0687","article-title":"Antithrombin: Anti-inflammatory properties and clinical applications","volume":"115","author":"Levy","year":"2016","journal-title":"Thromb. Haemost."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1213\/ANE.0000000000000115","article-title":"Extracorporeal membrane oxygenation in the adult: A review of anticoagulation monitoring and transfusion","volume":"118","author":"Esper","year":"2014","journal-title":"Anesth. Analg."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1056\/NEJM199105303242206","article-title":"Heparin","volume":"324","author":"Hirsh","year":"1991","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13613-017-0352-8","article-title":"Thromboelastography-based anticoagulation management during extracorporeal membrane oxygenation: A safety and feasibility pilot study","volume":"8","author":"Panigada","year":"2018","journal-title":"Ann. Intensive Care"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1007\/s00134-017-4725-0","article-title":"What do sepsis-induced coagulation test result abnormalities mean to intensivists?","volume":"43","author":"Levi","year":"2017","journal-title":"Intensive Care Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1186\/s13054-016-1570-4","article-title":"The inflammatory response to extracorporeal membrane oxygenation (ECMO): A review of the pathophysiology","volume":"20","author":"Millar","year":"2016","journal-title":"Crit. Care"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s13054-020-03444-x","article-title":"Venoarterial extracorporeal membrane oxygenation induces early immune alterations","volume":"25","author":"Frerou","year":"2021","journal-title":"Crit. Care"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1007\/s11239-021-02562-9","article-title":"Early platelet dysfunction in patients receiving extracorporeal membrane oxygenation is associated with mortality","volume":"53","author":"Siegel","year":"2022","journal-title":"J. Thromb. Thrombolysis"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.smim.2016.04.006","article-title":"Complement inhibition in biomaterial- and biosurface-induced thromboinflammation","volume":"28","author":"Ekdahl","year":"2016","journal-title":"Semin. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.it.2007.02.006","article-title":"Complement and coagulation: Strangers or partners in crime?","volume":"28","author":"Markiewski","year":"2007","journal-title":"Trends Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1038\/ni.1923","article-title":"Complement\u2014A key system for immune surveillance and homeostasis","volume":"11","author":"Ricklin","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"289","DOI":"10.2741\/e376","article-title":"Tissue factor in blood cells and endothelial cells","volume":"4","author":"Osterud","year":"2012","journal-title":"Front. Biosci. Elite Ed."},{"key":"ref_18","first-page":"4794","article-title":"A novel C5a receptor-tissue factor cross-talk in neutrophils links innate immunity to coagulation pathways","volume":"177","author":"Ritis","year":"2006","journal-title":"J. Immunol. Baltim. Md. 1950"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1055\/s-0038-1655974","article-title":"C5a induces tissue factor activity on endothelial cells","volume":"77","author":"Ikeda","year":"1997","journal-title":"Thromb. Haemost."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Karasu, E., Eisenhardt, S.U., Harant, J., and Huber-Lang, M. (2018). Extracellular Vesicles: Packages Sent with Complement. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.00721"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e2103471","DOI":"10.1002\/adma.202103471","article-title":"Engineering Extracellular Vesicles Enriched with Palmitoylated ACE2 as COVID-19 Therapy","volume":"33","author":"Xie","year":"2021","journal-title":"Adv. Mater. Deerfield Beach Fla"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1182\/bloodadvances.2020003308","article-title":"Dissemination of extreme levels of extracellular vesicles: Tissue factor activity in patients with severe COVID-19","volume":"5","author":"Guervilly","year":"2021","journal-title":"Blood Adv."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Cappellano, G., Raineri, D., Rolla, R., Giordano, M., Puricelli, C., Vilardo, B., Manfredi, M., Cantaluppi, V., Sainaghi, P.P., and Castello, L. (2021). Circulating Platelet-Derived Extracellular Vesicles Are a Hallmark of SARS-CoV-2 Infection. Cells, 10.","DOI":"10.3390\/cells10010085"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1186\/s40635-023-00567-7","article-title":"Circulating endothelial extracellular vesicle signatures correspond with ICU requirement: An exploratory study in COVID-19 patients","volume":"11","author":"Zipperle","year":"2023","journal-title":"Intensive Care Med. Exp."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.ceb.2014.05.004","article-title":"Biogenesis and secretion of exosomes","volume":"29","author":"Kowal","year":"2014","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1016\/j.cell.2019.02.029","article-title":"Reassessment of Exosome Composition","volume":"177","author":"Jeppesen","year":"2019","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1038\/s41577-022-00763-8","article-title":"The roles of extracellular vesicles in the immune system","volume":"23","author":"Buzas","year":"2023","journal-title":"Nat. Rev. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e12404","DOI":"10.1002\/jev2.12404","article-title":"Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches","volume":"13","author":"Welsh","year":"2024","journal-title":"J. Extracell. Vesicles"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1160\/TH12-10-0767","article-title":"A novel coagulation assay incorporating adherent endothelial cells in thromboelastometry","volume":"109","author":"Zipperle","year":"2013","journal-title":"Thromb. Haemost."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Holnthoner, W., Bonstingl, C., Hromada, C., Muehleder, S., Zipperle, J., Stojkovic, S., Redl, H., Wojta, J., Sch\u00f6chl, H., and Grillari, J. (2017). Endothelial Cell-Derived Extracellular Vesicles Size-Dependently Exert Procoagulant Activity Detected by Thromboelastometry. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-03159-0"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3348","DOI":"10.7150\/thno.23453","article-title":"Extracellular Vesicles as Markers and Mediators in Sepsis","volume":"8","author":"Raeven","year":"2018","journal-title":"Theranostics"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5031","DOI":"10.1038\/s41467-023-40680-5","article-title":"Mitochondria are secreted in extracellular vesicles when lysosomal function is impaired","volume":"14","author":"Liang","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e14186","DOI":"10.1111\/acel.14186","article-title":"Elimination of damaged mitochondria during UVB-induced senescence is orchestrated by NIX-dependent mitophagy","volume":"23","author":"Cavinato","year":"2024","journal-title":"Aging Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.cell.2020.08.031","article-title":"A Network of Macrophages Supports Mitochondrial Homeostasis in the Heart","volume":"183","author":"Santiago","year":"2020","journal-title":"Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1016\/j.cmet.2021.08.002","article-title":"Extracellular vesicle-based interorgan transport of mitochondria from energetically stressed adipocytes","volume":"33","author":"Crewe","year":"2021","journal-title":"Cell Metab."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1161\/CIRCRESAHA.118.314601","article-title":"Mitochondria Are a Subset of Extracellular Vesicles Released by Activated Monocytes and Induce Type I IFN and TNF Responses in Endothelial Cells","volume":"125","author":"Puhm","year":"2019","journal-title":"Circ. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"8472","DOI":"10.1038\/ncomms9472","article-title":"Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs","volume":"6","author":"Phinney","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1016\/j.imbio.2016.06.005","article-title":"Complement-coagulation crosstalk on cellular and artificial surfaces","volume":"221","author":"Wiegner","year":"2016","journal-title":"Immunobiology"},{"key":"ref_39","first-page":"598","article-title":"Mechanism of complement activation during extracorporeal blood-biomaterial interaction: Effects of heparin coated and uncoated surfaces","volume":"48","author":"Kopp","year":"2002","journal-title":"ASAIO J. Am. Soc. Artif. Intern. Organs 1992"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2020","DOI":"10.1007\/s00134-015-4015-7","article-title":"Low-dose heparin during extracorporeal membrane oxygenation treatment in adults","volume":"41","author":"Yeo","year":"2015","journal-title":"Intensive Care Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.jss.2019.05.050","article-title":"Heparin-Sparing Anticoagulation Strategies Are Viable Options for Patients on Veno-Venous ECMO","volume":"243","author":"Carter","year":"2019","journal-title":"J. Surg. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e563","DOI":"10.1097\/CCM.0000000000003780","article-title":"Low-Dose Versus Therapeutic Anticoagulation in Patients on Extracorporeal Membrane Oxygenation: A Pilot Randomized Trial","volume":"47","author":"Aubron","year":"2019","journal-title":"Crit. Care Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1177\/0267659119850024","article-title":"Pilot study evaluating a non-titrating, weight-based anticoagulation scheme for patients on veno-venous extracorporeal membrane oxygenation","volume":"35","author":"Deatrick","year":"2020","journal-title":"Perfusion"},{"key":"ref_44","first-page":"S53","article-title":"Activation and control of complement, inflammation, and infection associated with the use of biomedical polymers","volume":"46","author":"Janatova","year":"2000","journal-title":"ASAIO J. Am. Soc. Artif. Intern. Organs 1992"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/20\/11166\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:15:11Z","timestamp":1760112911000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/20\/11166"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,17]]},"references-count":44,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["ijms252011166"],"URL":"https:\/\/doi.org\/10.3390\/ijms252011166","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,17]]}}}