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dc.contributor.authorBaaten, Constance CFMJ
dc.contributor.authorMeacham, Stuart
dc.contributor.authorde Witt, Susanne M
dc.contributor.authorFeijge, Marion AH
dc.contributor.authorAdams, David J
dc.contributor.authorAkkerman, Jan-Willem N
dc.contributor.authorCosemans, Judith MEM
dc.contributor.authorGrassi, Luigi
dc.contributor.authorJupe, Steve
dc.contributor.authorKostadima, Myrto
dc.contributor.authorMattheij, Nadine JA
dc.contributor.authorPrins, Martin H
dc.contributor.authorRamirez-Solis, Ramiro
dc.contributor.authorSoehnlein, Oliver
dc.contributor.authorSwieringa, Frauke
dc.contributor.authorWeber, Christian
dc.contributor.authorWhite, Jacqueline K
dc.contributor.authorOuwehand, Willem
dc.contributor.authorHeemskerk, Johan WM
dc.date.accessioned2018-11-23T00:32:34Z
dc.date.available2018-11-23T00:32:34Z
dc.date.issued2018-12-13
dc.identifier.issn0006-4971
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/285824
dc.description.abstractAntithrombotic therapies reduce cardiovascular diseases by preventing arterial thrombosis and thromboembolism, but at expense of increased bleeding risks. Arterial thrombosis studies using genetically modified mice have been invaluable for identification of new molecular targets. Because of low sample sizes and heterogeneity in approaches or methodologies, a formal meta-analysis to compare studies of mice with single-gene defects encountered major limitations. To overcome these, we developed a novel synthesis approach to quantitatively scale 1514 published studies of arterial thrombus formation (in vivo and in vitro), thromboembolism, and tail-bleeding of genetically modified mice. Using a newly defined consistency parameter (CP), indicating the strength of published data, comparisons were made of 431 mouse genes, of which 17 consistently contributed to thrombus formation without affecting hemostasis. Ranking analysis indicated high correlations between collagen-dependent thrombosis models in vivo (FeCl3 injury or ligation/compression) and in vitro. Integration of scores and CP values resulted in a network of protein interactions in thrombosis and hemostasis (PITH), which was combined with databases of genetically linked human bleeding and thrombotic disorders. The network contained 2946 nodes linked to modifying genes of thrombus formation, mostly with expression in megakaryocytes. Reactome pathway analysis and network characteristics revealed multiple novel genes with potential contribution to thrombosis/hemostasis. Studies with additional knockout mice revealed that 4 of 8 (Apoe, Fpr2, Ifnar1, Vps13a) new genes were modifying in thrombus formation. The PITH network further: (i) revealed a high similarity of murine and human hemostatic and thrombotic processes and (ii) identified multiple new candidate proteins regulating these processes.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherAmerican Society of Hematology
dc.subjectAnimals
dc.subjectMice, Knockout
dc.subjectHumans
dc.subjectMice
dc.subjectThrombosis
dc.subjectDisease Models, Animal
dc.subjectHemorrhage
dc.titleA synthesis approach of mouse studies to identify genes and proteins in arterial thrombosis and bleeding.
dc.typeArticle
prism.endingPagee46
prism.issueIdentifier24
prism.publicationDate2018
prism.publicationNameBlood
prism.startingPagee35
prism.volume132
dc.identifier.doi10.17863/CAM.33168
dcterms.dateAccepted2018-09-19
rioxxterms.versionofrecord10.1182/blood-2018-02-831982
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-12
dc.contributor.orcidOuwehand, Willem [0000-0002-7744-1790]
dc.identifier.eissn1528-0020
rioxxterms.typeJournal Article/Review
rioxxterms.freetoread.startdate2019-10-31


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