PMID- 30275110 OWN - NLM STAT- MEDLINE DCOM- 20190716 LR - 20240207 IS - 1528-0020 (Electronic) IS - 0006-4971 (Print) IS - 0006-4971 (Linking) VI - 132 IP - 24 DP - 2018 Dec 13 TI - A synthesis approach of mouse studies to identify genes and proteins in arterial thrombosis and bleeding. PG - e35-e46 LID - 10.1182/blood-2018-02-831982 [doi] AB - Antithrombotic 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 (FeCl(3) 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. CI - (c) 2018 by The American Society of Hematology. FAU - Baaten, Constance C F M J AU - Baaten CCFMJ AD - Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands. AD - Institute for Molecular Cardiovascular Research (IMCAR), University Hospital Aachen, RWTH Aachen University, Aachen, Germany. FAU - Meacham, Stuart AU - Meacham S AD - Department of Haematology, University of Cambridge and NHS Blood and Transplant, Cambridge, United Kingdom. FAU - de Witt, Susanne M AU - de Witt SM AD - Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands. FAU - Feijge, Marion A H AU - Feijge MAH AD - Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands. FAU - Adams, David J AU - Adams DJ AD - Wellcome Sanger Institute, Hinxton, Cambridge, United Kingdom. FAU - Akkerman, Jan-Willem N AU - Akkerman JN AD - Laboratory of Clinical Chemistry and Haematology, University Medical Centre Utrecht, Utrecht, The Netherlands. FAU - Cosemans, Judith M E M AU - Cosemans JMEM AD - Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands. FAU - Grassi, Luigi AU - Grassi L AD - Department of Haematology, University of Cambridge and NHS Blood and Transplant, Cambridge, United Kingdom. FAU - Jupe, Steve AU - Jupe S AD - EMBL-European Bioinformatics Institute, Cambridge, United Kingdom. FAU - Kostadima, Myrto AU - Kostadima M AD - Department of Haematology, University of Cambridge and NHS Blood and Transplant, Cambridge, United Kingdom. FAU - Mattheij, Nadine J A AU - Mattheij NJA AD - Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands. FAU - Prins, Martin H AU - Prins MH AD - Department of Clinical Epidemiology, Maastricht University Medical Centre, Maastricht, The Netherlands. FAU - Ramirez-Solis, Ramiro AU - Ramirez-Solis R AD - Wellcome Sanger Institute, Hinxton, Cambridge, United Kingdom. FAU - Soehnlein, Oliver AU - Soehnlein O AD - Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilians University, Munich, Germany. AD - DZHK, Partner Site Munich Heart Alliance, Munich, Germany; and. AD - Department of Pathology, AMC, Amsterdam, The Netherlands. FAU - Swieringa, Frauke AU - Swieringa F AD - Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands. FAU - Weber, Christian AU - Weber C AD - Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilians University, Munich, Germany. AD - DZHK, Partner Site Munich Heart Alliance, Munich, Germany; and. FAU - White, Jacqueline K AU - White JK AD - Wellcome Sanger Institute, Hinxton, Cambridge, United Kingdom. FAU - Ouwehand, Willem H AU - Ouwehand WH AD - Department of Haematology, University of Cambridge and NHS Blood and Transplant, Cambridge, United Kingdom. AD - Wellcome Sanger Institute, Hinxton, Cambridge, United Kingdom. FAU - Heemskerk, Johan W M AU - Heemskerk JWM AD - Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands. LA - eng GR - U41 HG003751/HG/NHGRI NIH HHS/United States GR - RG/09/12/28096/BHF_/British Heart Foundation/United Kingdom PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20181001 PL - United States TA - Blood JT - Blood JID - 7603509 SB - IM CIN - Blood. 2018 Dec 13;132(24):2532-2534. PMID: 30545893 MH - Animals MH - Disease Models, Animal MH - *Hemorrhage/genetics/metabolism/pathology MH - Humans MH - Mice MH - Mice, Knockout MH - *Thrombosis/genetics/metabolism/pathology PMC - PMC6293874 COIS- Conflict-of-interest disclosure: The authors declare no competing financial interests. EDAT- 2018/10/03 06:00 MHDA- 2019/07/17 06:00 PMCR- 2019/12/13 CRDT- 2018/10/03 06:00 PHST- 2018/02/14 00:00 [received] PHST- 2018/09/19 00:00 [accepted] PHST- 2018/10/03 06:00 [pubmed] PHST- 2019/07/17 06:00 [medline] PHST- 2018/10/03 06:00 [entrez] PHST- 2019/12/13 00:00 [pmc-release] AID - S0006-4971(20)42940-4 [pii] AID - 2018/831982 [pii] AID - 10.1182/blood-2018-02-831982 [doi] PST - ppublish SO - Blood. 2018 Dec 13;132(24):e35-e46. doi: 10.1182/blood-2018-02-831982. Epub 2018 Oct 1.