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PS and PROS have distinct, yet overlapping clinical findings and are caused by somatic pathogenic variants in the PI3K\/AKT gene signaling pathway. PS is caused by a single somatic activating <jats:italic>AKT1<\/jats:italic> c.49G\u2009&gt;\u2009A p.E17K variant while PROS can be caused one of multiple variants in <jats:italic>PIK3CA<\/jats:italic>. The role of prothrombotic factors, endothelial cell adhesion molecules, and vascular malformations in both PS and PROS have not been previously investigated. A pilot study of prospective clinical and laboratory evaluations with the purposes of identifying potential risk factors for thrombosis was conducted. Doppler ultrasounds and magnetic resonance angiogram\/ venography (MRA\/MRV) scans identified vascular malformations in PS and PROS that were not appreciated on physical examination. Abnormal D\u2010dimers (0.60\u20132.0 mcg\/ml) occurred in half of individuals, many having vascular malformations, but no thromboses. Soluble vascular endothelial markers, including thrombomodulin, soluble vascular adhesion molecule (sVCAM), soluble intercellular adhesion molecule (sICAM), E\u2010selectin, and P\u2010selectin were significantly higher in PS and PROS compared to controls. However, no single attribute was identified that explained the risk of thrombosis. Predisposition to thrombosis is likely multifactorial with risk factors including chronic stasis within vascular malformations, stasis from impaired mobility (e.g., following surgery), decreased anticoagulant proteins, and effects of <jats:italic>AKT1<\/jats:italic> and <jats:italic>PIK3CA<\/jats:italic> variants on vascular endothelium. Based on our findings, we propose clinical recommendations for surveillance of thrombosis in PS and PROS.<\/jats:p>","DOI":"10.1002\/ajmg.c.31735","type":"journal-article","created":{"date-parts":[[2019,9,6]],"date-time":"2019-09-06T14:09:57Z","timestamp":1567778997000},"page":"571-581","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Thrombosis risk factors in PIK3CA\u2010related overgrowth spectrum and Proteus syndrome"],"prefix":"10.1002","volume":"181","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8250-164X","authenticated-orcid":false,"given":"Kim M.","family":"Keppler\u2010Noreuil","sequence":"first","affiliation":[{"name":"Medical Genomics and Metabolic Genetics Branch National Human Genome Research Institute, National Institutes of Health  Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay","family":"Lozier","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine Warren Magnuson Clinical Center, National Institutes of Health  Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neal","family":"Oden","sequence":"additional","affiliation":[{"name":"Department of Biostatistics The EMMES Corporation  Rockville Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anjali","family":"Taneja","sequence":"additional","affiliation":[{"name":"Medical Genomics and Metabolic Genetics Branch National Human Genome Research Institute, National Institutes of Health  Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmine","family":"Burton\u2010Akright","sequence":"additional","affiliation":[{"name":"Medical Genomics and Metabolic Genetics Branch National Human Genome Research Institute, National Institutes of Health  Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie C.","family":"Sapp","sequence":"additional","affiliation":[{"name":"Medical Genomics and Metabolic Genetics Branch National Human Genome Research Institute, National Institutes of Health  Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0197-3811","authenticated-orcid":false,"given":"Leslie G.","family":"Biesecker","sequence":"additional","affiliation":[{"name":"Medical Genomics and Metabolic Genetics Branch National Human Genome Research Institute, National Institutes of Health  Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,9,6]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2141.2002.03614.x"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtcvs.2010.04.023"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-2648"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/bjs.1800720331"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9149(02)02963-6"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5201638"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19990611)84:5<389::AID-AJMG1>3.0.CO;2-O"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2141.2000.01813.x"},{"key":"e_1_2_6_10_1","first-page":"134","article-title":"Release of thrombomodulin from endothelial cells by concerted action of TNF\u2010\u03b1 and neutrophils: in vivo and in vitro studies","volume":"87","author":"Boehme M. 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