{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T23:26:04Z","timestamp":1787095564816,"version":"build-2736575974"},"reference-count":12,"publisher":"Georg Thieme Verlag KG","issue":"CP","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["TH Open"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Introduction Predicting bleeding in hemophilia A is difficult due to limitations of existing factor VIII (FVIII) activity assays, which correlate poorly with clinical bleeding tendency. Measurement of thrombin generation (TG) by calibrated automated thrombography (CT) may be an alternative to predict bleeding as it measures an individual\u2019s complete plasma derived coagulation potential, rather than just focusing on one part of the coagulation cascade. However, lack of standardization limits its applicability.<\/jats:p>\n                  <jats:p>Objective To evaluate the ability of our standardized tissue factor (TF)\/factor XI (FXI) a dual-activated thrombin generation assay (TGA) to assess TG across severe, moderate, and mild hemophilia A. Secondarily, we evaluate whether varying TG levels at similar FVIII concentrations translate to different clinical bleeding tendencies.<\/jats:p>\n                  <jats:p>Materials and Methods Plasma samples from 657 adult patients with hemophilia A of all severities included in the Hemophilia in the Netherlands 6 (HiN6) study were used. Samples were collected through standardized protocols from six Dutch hemophilia treatment centers, and stored in a centralized biobank. FVIII activity was centrally measured using one-stage assays. Thrombin generation was measured using our in-house TF\/FXIa TGA protocol using 1 pm TF, 100 pm FXIa, and 30 \u03bcM phospholipids. Bleeding tendencies were analyzed based on patient questionnaires.<\/jats:p>\n                  <jats:p>Results The TF\/FXIa dual-activated TGA protocol was able to measure thrombin generation across all severities of hemophilia A. Median peak heights (PH) were 119.5, 98.9, and 214.7 nM for severe, moderate, and mild, respectively. Moreover, the assay showed substantial variation in interindividual TG levels among patients with comparable FVIII activity levels (coefficient of variance of 99%, 83%, and 47% for severe, moderate, and mild hemophilia A, respectively). However, TG did not differentiate between patients with and without self-reported bleeding in this study.<\/jats:p>\n                  <jats:p>Conclusion The standardized TF\/FXIa dual-activated TGA represents a tool for assessing individual coagulation potential in hemophilia A. More research is needed to further characterize the interindividual differences in thrombin generations at similar FVIII levels and possibly link these results to bleeding tendency.<\/jats:p>","DOI":"10.1055\/a-2916-8837","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T23:31:28Z","timestamp":1785886288000},"source":"Crossref","is-referenced-by-count":0,"special_numbering":"S","title":["Tissue Factor\/Factor XIa Dual-activated Thrombin Generation is Able to Reliably Measure Thrombin Generation at All Hemophilia A Disease Severities"],"prefix":"10.1055","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7069-7590","authenticated-orcid":false,"given":"Tom William","family":"van de Berg","sequence":"additional","affiliation":[{"name":"Maastricht University Medical Centre (MUMC+), Limburg, Netherlands","place":["Maastricht"],"department":["Department of Hematology"]},{"name":"Maastricht University, Cardiovascular Research Institute Maastricht (CARIM), Limburg, Netherlands","place":["Maastricht"],"department":["Department of Biochemistry"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Heinzmann","sequence":"additional","affiliation":[{"name":"Maastricht University, Cardiovascular Research Institute Maastricht (CARIM), Limburg, Netherlands","place":["Maastricht"],"department":["Department of Biochemistry"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stella","family":"Thomassen","sequence":"additional","affiliation":[{"name":"Maastricht University, Cardiovascular Research Institute Maastricht (CARIM), Limburg, Netherlands","place":["Maastricht"],"department":["Department of Biochemistry"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saskia E.M.","family":"Schols","sequence":"additional","affiliation":[{"name":"Radboud University Medical Center, GE, Netherlands","place":["Nijmegen"],"department":["Department of Hematology"]},{"name":"Hemophilia Treatment Centre Nijmegen-Eindhoven-Maastricht, Netherlands","place":["Maastricht"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Floor C.J.I.","family":"Heubel-Moenen","sequence":"additional","affiliation":[{"name":"Maastricht University Medical Centre (MUMC+), Limburg, Netherlands","place":["Maastricht"],"department":["Department of Hematology"]},{"name":"Maastricht University, Cardiovascular Research Institute Maastricht (CARIM), Limburg, Netherlands","place":["Maastricht"],"department":["Department of Biochemistry"]},{"name":"Hemophilia Treatment Centre Nijmegen-Eindhoven-Maastricht, Netherlands","place":["Maastricht"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick","family":"van Es","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, University of Amsterdam, North-Holland, Netherlands","place":["Amsterdam"],"department":["Department of Vascular Medicine"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2558-7496","authenticated-orcid":false,"given":"Frits R.","family":"Rosendaal","sequence":"additional","affiliation":[{"name":"Leiden University Medical Center, ZH, Netherlands","place":["Leiden"],"department":["Department of Clinical Epidemiology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Gouw","sequence":"additional","affiliation":[{"name":"Leiden University Medical Center, ZH, Netherlands","place":["Leiden"],"department":["Department of Clinical Epidemiology"]},{"name":"Amsterdam UMC location University of Amsterdam, Noord-Holland, Netherlands","place":["Amsterdam"],"department":["Department of Pediatric Hematology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tilman Mathias","family":"Hackeng","sequence":"additional","affiliation":[{"name":"Maastricht University, Cardiovascular Research Institute Maastricht (CARIM), 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