{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T11:04:52Z","timestamp":1774609492922,"version":"3.50.1"},"reference-count":27,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","award":["NNF22SA0079901"],"award-info":[{"award-number":["NNF22SA0079901"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","award":["NNF15OC0016474"],"award-info":[{"award-number":["NNF15OC0016474"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","award":["NNF20OC0060610"],"award-info":[{"award-number":["NNF20OC0060610"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015223","name":"Danish Diabetes and Endocrine Academy","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015223","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004836","name":"Danmarks Frie Forskningsfond","doi-asserted-by":"publisher","award":["2096\u201000165A"],"award-info":[{"award-number":["2096\u201000165A"]}],"id":[{"id":"10.13039\/501100004836","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Andrology"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Klinefelter syndrome is associated with a markedly increased risk of venous thrombosis. While hypogonadism and metabolic dysfunction are known contributors, the role of the contact activation system in Klinefelter syndrome remains unexplored. contact activation system mediates crosstalk between coagulation, fibrinolysis, and inflammation and may contribute to thromboinflammatory risk.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To investigate whether contact activation system is dysregulated in Klinefelter syndrome and assess the influence of hypogonadism, body composition, and testosterone replacement therapy on contact activation system activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a longitudinal study including 22 testosterone\u2010treated Klinefelter syndrome, 15 untreated Klinefelter syndrome, and 14 age\u2010matched controls. Untreated Klinefelter syndrome initiated testosterone replacement therapy at baseline. Plasma levels of contact activation system proteins (coagulation factor XII, prekallikrein, high\u2010molecular\u2010weight kininogen, cleaved high\u2010molecular\u2010weight kininogen, and C1 esterase inhibitor were measured by enzyme\u2010linked immunosorbent assays. Contact activation system activity was assessed functional assays describing the endogenous kallikrein potential and contact\u2010induced thrombin generation. Associations with sex hormones and body composition were analyzed using mixed\u2010effects models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>At baseline, untreated Klinefelter syndrome exhibited coagulation factor XII, prekallikrein, and C1 esterase inhibitor levels compared with controls. Following testosterone replacement therapy, untreated\u2010Klinefelter syndrome showed significant reductions in coagulation factor XII and C1 esterase inhibitor. Testosterone was inversely associated with coagulation factor XII, while body fat correlated positively with prekallikrein, endogenous kallikrein potential, and contact\u2010induced thrombin generation. Endogenous kallikrein potential and contact\u2010induced thrombin generation were not correlated, suggesting a bias toward inflammatory rather than procoagulant contact activation system activation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Contact activation system is dysregulated in hypogonadal Klinefelter syndrome and partially normalized by testosterone replacement therapy. contact activation system dysregulation in Klinefelter syndrome appears multifactorial, involving both hormonal and metabolic components. The strongest associations were with body fat, indicating that metabolic dysfunction may be a key regulator of contact activation system activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Inflammatory skew in contact activation system activation may contribute to thromboinflammatory risk in Klinefelter syndrome.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial Registration<\/jats:title>\n                    <jats:p>Clinicaltrials.gov identifier: NCT02526628<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/andr.70220","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T10:13:48Z","timestamp":1774606428000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Contact Activation Is Alleviated by Testosterone Replacement Therapy in Klinefelter Syndrome: Evidence of Hormonal and Metabolic Modulation"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1130-3659","authenticated-orcid":false,"given":"Simon","family":"Chang","sequence":"first","affiliation":[{"name":"Department of Endocrinology Aarhus University Hospital  Aarhus Denmark"},{"name":"Unit for Thrombosis Research Esbjerg Hospital\u2014University Hospital of Southern Denmark  Esbjerg Denmark"},{"name":"Department of Molecular Medicine Aarhus University Hospital  Aarhus Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5924-1720","authenticated-orcid":false,"given":"Claus H.","family":"Gravholt","sequence":"additional","affiliation":[{"name":"Department of Endocrinology Aarhus University Hospital  Aarhus Denmark"},{"name":"Department of Molecular Medicine Aarhus University Hospital  Aarhus Denmark"},{"name":"Department of Clinical Medicine Aarhus University  Aarhus Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9178-4901","authenticated-orcid":false,"given":"Anne","family":"Skakkeb\u00e6k","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Aarhus University Hospital  Aarhus Denmark"},{"name":"Department of Clinical Medicine Aarhus University  Aarhus Denmark"},{"name":"Department of Clinical Genetics Aarhus University Hospital  Aarhus Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3398-3977","authenticated-orcid":false,"given":"Anna\u2010Marie Bloch","family":"M\u00fcnster","sequence":"additional","affiliation":[{"name":"Unit for Thrombosis Research Esbjerg Hospital\u2014University Hospital of Southern Denmark  Esbjerg Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9337-0232","authenticated-orcid":false,"given":"Yaseelan","family":"Palarasah","sequence":"additional","affiliation":[{"name":"Unit for Thrombosis Research Esbjerg Hospital\u2014University Hospital of Southern Denmark  Esbjerg Denmark"},{"name":"Inflammation Research, Institute for Molecular Medicine University of Southern Denmark  Odense 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