{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T05:02:36Z","timestamp":1761541356235},"reference-count":22,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2016,12,8]],"date-time":"2016-12-08T00:00:00Z","timestamp":1481155200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"INSERM (French National Institute for Health and Medical Research)"},{"name":"TC2N (Trans Channel Neuroscience Network)"},{"name":"FP7 NEURON","award":["3-275-006"],"award-info":[{"award-number":["3-275-006"]}]},{"name":"Equipe FRM","award":["N\u00b0DEQ20140329555"],"award-info":[{"award-number":["N\u00b0DEQ20140329555"]}]},{"name":"Regional Council of Lower Normandy"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Haemophilia"],"published-print":{"date-parts":[[2017,3]]},"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Haemophilia is a major bleeding disorder due to a deficiency of procoagulant factor <jats:styled-content style=\"fixed-case\">VIII<\/jats:styled-content> (type A) or <jats:styled-content style=\"fixed-case\">IX<\/jats:styled-content> (type B). The treatment is substitutive and based on infusion of factor concentrates. Main limitations of this therapy are cost, short factor half\u2010life and the development of inhibitors (up to 30% of severe <jats:styled-content style=\"fixed-case\">HA<\/jats:styled-content> patients). An important aggravating factor of haemophilia is due to a premature fibrinolysis, directing attention to the therapeutic potential of suitable antifibrinolytics. Thrombomodulin (<jats:styled-content style=\"fixed-case\">TM<\/jats:styled-content>) is a key player of the coagulation cascade by activating protein C (an inhibitor of thrombin generation, thus antagonizing coagulation) and of the fibrinolytic cascade by activating thrombin activatable fibrinolysis inhibitor <jats:styled-content style=\"fixed-case\">TAFI<\/jats:styled-content> (thus reducing fibrinolysis). Solulin is a soluble form of <jats:styled-content style=\"fixed-case\">TM<\/jats:styled-content> that shows both capabilities.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim<\/jats:title><jats:p>Here, we developed a new generation of solulin variants (F376A\u2010, M388A\u2010 and F376A\/M388A\u2010solulin) with a decreased ability to activate protein C and a conserved capacity to activate <jats:styled-content style=\"fixed-case\">TAFI<\/jats:styled-content>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We produced and characterized solulin variants <jats:italic>in vitro<\/jats:italic>. In addition, F376A\/M388A\u2010solulin was tested <jats:italic>ex vivo<\/jats:italic>, using blood samples of haemophilic A patients, with thromboelastography.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The solulin variants (F376A, M388A and the double\u2010mutant F376A\/M388A) lost their abilities to activate protein C but are still capable to activate <jats:styled-content style=\"fixed-case\">TAFI<\/jats:styled-content>. Thrombelastography showed increased clot firmness and stability, that, as opposed to wild\u2010type solulin, was maintained even at high concentrations of F376A\/M388A\u2010solulin (100 n<jats:sc>m<\/jats:sc>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In sum, these results open new opportunities for the development of specific medication for haemophilic patients.<\/jats:p><\/jats:sec>","DOI":"10.1111\/hae.13126","type":"journal-article","created":{"date-parts":[[2016,12,8]],"date-time":"2016-12-08T06:16:38Z","timestamp":1481177798000},"page":"319-325","source":"Crossref","is-referenced-by-count":1,"title":["F376A\/M388A\u2010solulin, a new promising antifibrinolytic for severe haemophilia A"],"prefix":"10.1111","volume":"23","author":[{"given":"J.","family":"Parcq","sequence":"first","affiliation":[{"name":"Serine Proteases and Pathophysiology of the Neurovascular Unit Normandie Univ UNICAEN INSERM Caen France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"K. U.","family":"Petersen","sequence":"additional","affiliation":[{"name":"PAION Deutchland GmbH Aachen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A.","family":"Borel\u2010Derlon","sequence":"additional","affiliation":[{"name":"Serine Proteases and Pathophysiology of the Neurovascular Unit Normandie Univ UNICAEN INSERM Caen France"},{"name":"Laboratoire d'h\u00e9matologie CHU de Caen Caen France"},{"name":"Centre de Traitement de l'H\u00e9mophilie (CRTH) CHU de Caen Caen France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P.","family":"Gautier","sequence":"additional","affiliation":[{"name":"Laboratoire d'h\u00e9matologie CHU de Caen Caen France"},{"name":"Centre de Traitement de l'H\u00e9mophilie (CRTH) CHU de Caen Caen France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M.","family":"Ebel","sequence":"additional","affiliation":[{"name":"PAION Deutchland GmbH Aachen 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