{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T04:25:23Z","timestamp":1742963123359,"version":"3.40.3"},"reference-count":45,"publisher":"Georg Thieme Verlag KG","issue":"CP","license":[{"start":{"date-parts":[[2025,3,25]],"date-time":"2025-03-25T00:00:00Z","timestamp":1742860800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH grant","award":["1R43HL149480-01"],"award-info":[{"award-number":["1R43HL149480-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["TH Open"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Patients taking direct oral anticoagulants (DOACs) often present complicated scenarios following major bleeding, stroke, or emergency surgery. Rapid whole blood assays of DOAC levels would aid clinical decisions such as the need for DOAC reversal.<\/jats:p><jats:p>We developed a single-use, storage-stable, eight-channel microfluidic device to estimate factor Xa (FXa) inhibitor (apixaban or rivaroxaban) levels in venous thromboembolism or atrial fibrillation patients. The assay simultaneously measured whole blood clotting dynamics on collagen\/tissue factor (TF; wall shear rate, 200\u22121) under four ex vivo conditions: no-treatment control, high dose Factor Xa inhibition, low dose or high dose FXa reversal agent (andexanet alfa). Fibrin and platelet deposition dynamics were monitored via two-color epifluorescence microscopy. Plasma samples were also evaluated by LC-MS\/MS for DOAC concentrations.<\/jats:p><jats:p>Experiments with healthy volunteer blood spiked with DOAC verified device performance (DOAC IC50 \u223c120\u2009nM) and confirmed that andexanet alfa added to healthy donor blood had no off-target effect on platelet or fibrin signal. Patient whole blood monitored for 15 to 25\u2009minutes (17\u2009minutes mean runtime) allowed calculation of functional DOAC concentrations ranging from 2 to 500\u2009nM that correlated well with LC-MS\/MS determination of apixaban or rivaroxaban (R2\u2009=\u20090.7 or 0.9, respectively). Platelet dysfunction was not observed in any patient on DOAC. For a threshold of 100\u2009nM DOAC, the area under the curve (AUC) was found to be 0.881 for apixaban and 0.933 for rivaroxaban.<\/jats:p><jats:p>Microfluidic testing of whole blood can provide a rapid estimate of DOAC levels over the on-therapy range.<\/jats:p>","DOI":"10.1055\/a-2547-5710","type":"journal-article","created":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T02:44:10Z","timestamp":1742957050000},"source":"Crossref","is-referenced-by-count":0,"special_numbering":"S","title":["Rapid Determination of Xa Inhibitor Activity in Blood Using a Microfluidic Device that Measures Platelet Deposition and Fibrin Generation Under Flow"],"prefix":"10.1055","volume":"09","author":[{"given":"Jason M.","family":"Rossi","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering, Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, Pennsylvania, United States"},{"name":"FloBio LLC, Philadelphia, Pennsylvania, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen A.","family":"Panckeri","sequence":"additional","affiliation":[{"name":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Soumita","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Institute for Translational Medicine and Therapeutics University of Pennsylvania, Philadelphia, Pennsylvania, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tilo","family":"Grosser","sequence":"additional","affiliation":[{"name":"Institute for Translational Medicine and Therapeutics University of Pennsylvania, Philadelphia, Pennsylvania, United States"},{"name":"Department of Translational Pharmacology, Bielefeld University, Bielefeld, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam","family":"Cuker","sequence":"additional","affiliation":[{"name":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States"},{"name":"Department of Pathology & Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott L.","family":"Diamond","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering, Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, Pennsylvania, United States"},{"name":"Institute for Translational Medicine and Therapeutics University of Pennsylvania, Philadelphia, Pennsylvania, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"194","published-online":{"date-parts":[[2025,3,25]]},"reference":[{"issue":"S 04","key":"ref1","first-page":"S67","article-title":"Exploring indications for the use of direct oral anticoagulants and the associated risks of major bleeding","volume":"23","author":"T J Milling Jr","year":"2017","journal-title":"Am J Manag Care"},{"issue":"09","key":"ref2","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1038\/nrd.2018.89","article-title":"The market for oral anticoagulants","volume":"17","author":"S Bielecki","year":"2018","journal-title":"Nat Rev Drug Discov"},{"issue":"19","key":"ref3","doi-asserted-by":"crossref","first-page":"2009","DOI":"10.1182\/blood-2018-04-791541","article-title":"Testing and monitoring direct oral anticoagulants","volume":"132","author":"J M Connors","year":"2018","journal-title":"Blood"},{"issue":"S 01","key":"ref4","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s12959-016-0111-3","article-title":"DOACs - advances and limitations in real world","volume":"14","author":"L H Lee","year":"2016","journal-title":"Thromb J"},{"issue":"01","key":"ref5","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1002\/phar.2350","article-title":"Oral anticoagulant prescription trends, profile use, and determinants of adherence in patients with atrial fibrillation","volume":"40","author":"S Perreault","year":"2020","journal-title":"Pharmacotherapy"},{"issue":"9921","key":"ref6","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1016\/S0140-6736(13)62343-0","article-title":"Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials","volume":"383","author":"C T Ruff","year":"2014","journal-title":"Lancet"},{"issue":"10","key":"ref7","doi-asserted-by":"crossref","first-page":"2383","DOI":"10.1111\/jth.15466","article-title":"Anticoagulant-associated gastrointestinal bleeding: framework for decisions about whether, when and how to resume anticoagulants","volume":"19","author":"Y Xu","year":"2021","journal-title":"J Thromb Haemost"},{"issue":"06","key":"ref8","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1177\/1756283X17702092","article-title":"Direct oral anticoagulants and digestive bleeding: therapeutic management and preventive measures","volume":"10","author":"D Deutsch","year":"2017","journal-title":"Therap Adv Gastroenterol"},{"issue":"01","key":"ref9","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/s12325-022-02333-9","article-title":"Risk and management of bleeding complications with direct oral anticoagulants in patients with atrial fibrillation and venous thromboembolism: a narrative review","volume":"40","author":"S Ballestri","year":"2023","journal-title":"Adv Ther"},{"issue":"01","key":"ref10","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/s40119-020-00171-w","article-title":"Incidence rates of bleeding and emergency surgery due to trauma or fracture among Japanese patients with non-valvular atrial fibrillation receiving oral anticoagulation therapy","volume":"9","author":"M Yasaka","year":"2020","journal-title":"Cardiol Ther"},{"issue":"08","key":"ref11","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1007\/s11739-019-02177-2","article-title":"Reversal agents for oral anticoagulant-associated major or life-threatening bleeding","volume":"14","author":"M Moia","year":"2019","journal-title":"Intern Emerg Med"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ajem.2023.07.042","article-title":"Real world utilization of Andexanet alfa in the management of oral factor Xa inhibitor-associated gastrointestinal bleeding","volume":"73","author":"C S Brown","year":"2023","journal-title":"Am J Emerg Med"},{"issue":"05","key":"ref13","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1002\/phar.2925","article-title":"Andexanet alfa versus PCC products for factor Xa inhibitor bleeding: a systematic review with meta-analysis","volume":"44","author":"C M White","year":"2024","journal-title":"Pharm J Human Pharmacol Drug Ther"},{"issue":"04","key":"ref14","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1097\/FJC.0000000000000870","article-title":"Therapeutic drug monitoring of direct oral anticoagulants may increase their benefit-risk ratio","volume":"76","author":"M Bernier","year":"2020","journal-title":"J Cardiovasc Pharmacol"},{"issue":"01","key":"ref15","doi-asserted-by":"crossref","first-page":"3","DOI":"10.2174\/187152571201141201091848","article-title":"Novel oral anticoagulants in non-valvular atrial fibrillation","volume":"12","author":"R MFL da Silva","year":"2014","journal-title":"Cardiovasc Hematol Agents Med Chem"},{"issue":"02","key":"ref16","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1002\/phar.1884","article-title":"Laboratory and clinical monitoring of direct acting oral anticoagulants: what clinicians need to know","volume":"37","author":"S E Conway","year":"2017","journal-title":"Pharmacotherapy"},{"issue":"02","key":"ref17","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1055\/a-1113-0655","article-title":"Does one dose really fit all? 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anticoagulation in healthy volunteers","volume":"4","author":"G Lu","year":"2020","journal-title":"Blood Adv"},{"key":"ref33","first-page":"SP309","article-title":"Direct oral anticoagulant prescription trends, switching patterns, and adherence in Texas Medicaid","volume":"24","author":"S L Wong","year":"2018","journal-title":"Am J Manag Care"},{"issue":"05","key":"ref34","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1111\/ejh.12610","article-title":"Direct-acting oral anticoagulants: pharmacology, indications, management, and future perspectives","volume":"95","author":"A G\u00f3mez-Outes","year":"2015","journal-title":"Eur J Haematol"},{"issue":"05","key":"ref35","doi-asserted-by":"crossref","first-page":"9","DOI":"10.3390\/biomedicines9050445","article-title":"Laboratory monitoring of direct oral anticoagulants (Doacs)","volume":"9","author":"C Dunois","year":"2021","journal-title":"Biomedicines"},{"issue":"05","key":"ref36","first-page":"462","article-title":"Position paper on laboratory testing for patients on direct oral anticoagulants. a consensus document from the SISET, FCSA, SIBioC and SIPMeL","volume":"16","author":"A Tripodi","year":"2018","journal-title":"Blood Transfus"},{"issue":"S 01","key":"ref37","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1111\/ijlh.12992","article-title":"An update on laboratory assessment for direct oral anticoagulants (DOACs)","volume":"41","author":"R C Gosselin","year":"2019","journal-title":"Int J Lab Hematol"},{"issue":"06","key":"ref38","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1111\/bjh.17470","article-title":"A universal anti-Xa assay for rivaroxaban, apixaban, and edoxaban measurements: method validation, diagnostic accuracy and external validation","volume":"193","author":"G Willekens","year":"2021","journal-title":"Br J Haematol"},{"issue":"02","key":"ref39","doi-asserted-by":"crossref","first-page":"e0171272","DOI":"10.1371\/journal.pone.0171272","article-title":"Determination of rivaroxaban in patient's plasma samples by anti-Xa chromogenic test associated to high performance liquid chromatography tandem mass spectrometry (HPLC-MS\/MS)","volume":"12","author":"P BM Derogis","year":"2017","journal-title":"PLoS One"},{"issue":"11","key":"ref40","doi-asserted-by":"crossref","first-page":"2494","DOI":"10.1111\/jth.15884","article-title":"The myths behind DOAC measurement: analyses of prescribing information from different regulatory bodies and a call for harmonization","volume":"20","author":"R C Gosselin","year":"2022","journal-title":"J Thromb Haemost"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s12959-017-0160-2","article-title":"Detecting clinically relevant rivaroxaban or dabigatran levels by routine coagulation tests or thromboelastography in a cohort of patients with atrial fibrillation","volume":"16","author":"Y MC Henskens","year":"2018","journal-title":"Thromb J"},{"issue":"09","key":"ref42","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1055\/a-1753-2748","article-title":"DOAC dipstick testing can reliably exclude the presence of clinically relevant DOAC concentrations in circulation","volume":"122","author":"S Margeti\u0107","year":"2022","journal-title":"Thromb Haemost"},{"issue":"06","key":"ref43","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1002\/ajh.25475","article-title":"Reversal of direct oral anticoagulants: guidance from the anticoagulation forum","volume":"94","author":"A Cuker","year":"2019","journal-title":"Am J Hematol"},{"issue":"10","key":"ref44","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1007\/s40262-019-00775-z","article-title":"Apixaban: a clinical pharmacokinetic and pharmacodynamic review","volume":"58","author":"W Byon","year":"2019","journal-title":"Clin 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