{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T02:44:42Z","timestamp":1785465882233,"version":"3.56.0"},"reference-count":34,"publisher":"Georg Thieme Verlag KG","issue":"11","license":[{"start":{"date-parts":[[2020,8,15]],"date-time":"2020-08-15T00:00:00Z","timestamp":1597449600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009425","name":"Landsteiner Foundation for Blood Transfusion Research","doi-asserted-by":"crossref","award":["grant 1504"],"award-info":[{"award-number":["grant 1504"]}],"id":[{"id":"10.13039\/100009425","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Thromb Haemost"],"published-print":{"date-parts":[[2020,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Von Willebrand disease (VWD) is the most common inherited bleeding disorder and is mainly caused by dominant-negative mutations in the multimeric protein von Willebrand factor (VWF). These mutations may either result in quantitative or qualitative defects in VWF. VWF is an endothelial protein that is secreted to the circulation upon endothelial activation. Once secreted, VWF multimers bind platelets and chaperone coagulation factor VIII in the circulation. Treatment of VWD focuses on increasing VWF plasma levels, but production and secretion of mutant VWF remain uninterrupted. Presence of circulating mutant VWF might, however, still affect normal hemostasis or functionalities of VWF beyond hemostasis. We hypothesized that inhibition of the production of mutant VWF improves the function of VWF overall and ameliorates VWD phenotypes. We previously proposed the use of allele-specific small-interfering RNAs (siRNAs) that target frequent VWF single nucleotide polymorphisms to inhibit mutant VWF. The aim of this study is to prove the functionality of these allele-specific siRNAs in endothelial colony-forming cells (ECFCs). We isolated ECFCs from a VWD type 2A patient with an intracellular multimerization defect, reduced VWF collagen binding, and a defective processing of proVWF to VWF. After transfection of an allele-specific siRNA that specifically inhibited expression of mutant VWF, we showed amelioration of the laboratory phenotype, with normalization of the VWF collagen binding, improvement in VWF multimers, and enhanced VWF processing. Altogether, we prove that allele-specific inhibition of the production of mutant VWF by siRNAs is a promising therapeutic strategy to improve VWD phenotypes.<\/jats:p>","DOI":"10.1055\/s-0040-1715442","type":"journal-article","created":{"date-parts":[[2020,8,15]],"date-time":"2020-08-15T22:31:15Z","timestamp":1597530675000},"page":"1569-1579","source":"Crossref","is-referenced-by-count":29,"title":["Ex vivo Improvement of a von Willebrand Disease Type 2A Phenotype Using an Allele-Specific Small-Interfering RNA"],"prefix":"10.1055","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6124-535X","authenticated-orcid":false,"given":"Annika","family":"de Jong","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Thrombosis and Hemostasis, Einthoven laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9626-9925","authenticated-orcid":false,"given":"Richard J.","family":"Dirven","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Thrombosis and Hemostasis, Einthoven laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"Boender","sequence":"additional","affiliation":[{"name":"Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3769-9148","authenticated-orcid":false,"given":"Ferdows","family":"Atiq","sequence":"additional","affiliation":[{"name":"Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seyed Yahya","family":"Anvar","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank W. G.","family":"Leebeek","sequence":"additional","affiliation":[{"name":"Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart J. M.","family":"van Vlijmen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Thrombosis and Hemostasis, Einthoven laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3268-5759","authenticated-orcid":false,"given":"Jeroen","family":"Eikenboom","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Thrombosis and Hemostasis, Einthoven laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"194","published-online":{"date-parts":[[2020,8,15]]},"reference":[{"issue":"21","key":"ref1","doi-asserted-by":"crossref","first-page":"2067","DOI":"10.1056\/NEJMra1601561","article-title":"Von Willebrand's disease","volume":"375","author":"F W Leebeek","year":"2016","journal-title":"N Engl J Med"},{"issue":"04","key":"ref2","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1111\/j.1538-7836.2006.01847.x","article-title":"A quantitative analysis of bleeding symptoms in type 1 von Willebrand disease: results from a multicenter European study (MCMDM-1 VWD)","volume":"4","author":"A Tosetto","year":"2006","journal-title":"J Thromb Haemost"},{"issue":"09","key":"ref3","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1182\/blood-2014-05-378638","article-title":"von Willebrand factor, Jedi knight of the bloodstream","volume":"124","author":"T A Springer","year":"2014","journal-title":"Blood"},{"issue":"02","key":"ref4","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1172\/JCI108788","article-title":"Stabilization of factor VIII in plasma by the von Willebrand factor. 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