{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T20:56:16Z","timestamp":1765486576896},"reference-count":96,"publisher":"Georg Thieme Verlag KG","issue":"02","funder":[{"name":"Science Foundation","award":["16\/SPP3303"],"award-info":[{"award-number":["16\/SPP3303"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Semin Thromb Hemost"],"published-print":{"date-parts":[[2021,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>People with hemophilia (PWH) have an increased tendency to bleed, often into their joints, causing debilitating joint disease if left untreated. To reduce the incidence of bleeding events, PWH receive prophylactic replacement therapy with recombinant factor VIII (FVIII) or FIX. Bleeding events in PWH are typically proportional to their plasma FVIII or IX levels; however, in many PWH, bleeding tendency and the likelihood of developing arthropathy often varies independently of endogenous factor levels. Consequently, many PWH suffer repeated bleeding events before correct dosing of replacement factor can be established. Diagnostic approaches to define an individual's bleeding tendency remain limited. Multiple modulators of bleeding phenotype in PWH have been proposed, including the type of disease-causing variant, age of onset of bleeding episodes, plasma modifiers of blood coagulation or clot fibrinolysis pathway activity, interindividual differences in platelet reactivity, and endothelial anticoagulant activity. In this review, we summarize current knowledge of established factors modulating bleeding tendency and discuss emerging concepts of additional biological elements that may contribute to variable bleeding tendency in PWH. Finally, we consider how variance in responses to new gene therapies may also necessitate consideration of patient-specific tailoring of treatment. Cumulatively, these studies highlight the need to reconsider the current \u201cone size fits all\u201d approach to treatment regimens for PWH and consider therapies guided by the bleeding phenotype of each individual PWH at the onset of therapy. Further characterization of the biological bases of bleeding heterogeneity in PWH, combined with the development of novel diagnostic assays to identify those factors that modulate bleeding risk in PWH, will be required to meet these aspirations.<\/jats:p>","DOI":"10.1055\/s-0041-1723769","type":"journal-article","created":{"date-parts":[[2021,2,27]],"date-time":"2021-02-27T00:31:57Z","timestamp":1614385917000},"page":"183-191","source":"Crossref","is-referenced-by-count":7,"title":["Heterogeneity in Bleeding Tendency and Arthropathy Development in Individuals with Hemophilia"],"prefix":"10.1055","volume":"47","author":[{"given":"Aisling M.","family":"Rehill","sequence":"additional","affiliation":[{"name":"Irish Centre for Vascular Biology, Royal College of Surgeons in Ireland, Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Se\u00e1n","family":"McCluskey","sequence":"additional","affiliation":[{"name":"Irish Centre for Vascular Biology, Royal College of Surgeons in Ireland, Dublin, Ireland"},{"name":"National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James S.","family":"O'Donnell","sequence":"additional","affiliation":[{"name":"Irish Centre for Vascular Biology, Royal College of Surgeons in Ireland, Dublin, Ireland"},{"name":"National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland"},{"name":"St James' Hospital, Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Dockal","sequence":"additional","affiliation":[{"name":"Baxalta Innovations GmbH, A Member of the Takeda Group of Companies, Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roger J.S.","family":"Preston","sequence":"additional","affiliation":[{"name":"Irish Centre for Vascular Biology, Royal College of Surgeons in Ireland, Dublin, Ireland"},{"name":"National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"on behalf of the iPATH Study Group","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"194","published-online":{"date-parts":[[2021,2,26]]},"reference":[{"issue":"03","key":"ref1","first-page":"181","article-title":"Role of platelets in hemostasis and thrombosis","volume":"125","author":"R Rodvien","year":"1976","journal-title":"West J Med"},{"issue":"03","key":"ref2","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.thromres.2011.11.036","article-title":"Platelets and primary haemostasis","volume":"129","author":"K J Clemetson","year":"2012","journal-title":"Thromb Res"},{"issue":"02","key":"ref3","first-page":"162","article-title":"New concepts and mechanisms of platelet activation signaling","volume":"32","author":"B 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