{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T18:40:04Z","timestamp":1750876804201,"version":"3.41.0"},"reference-count":54,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2025,7]]},"abstract":"\n BACKGROUND:<\/jats:title>\n TFPI (tissue factor pathway inhibitor) inhibits the initiation of blood coagulation. TFPI\u03b1 (TFPI alpha isoform), the only alternatively spliced TFPI isoform in platelets, is abundant in placenta and uniquely inhibits prothrombinase (FXa [activated factor X]-FVa [activated factor V]). This inhibitory activity is reduced when prothrombinase is assembled with FVL (factor V Leiden).<\/jats:p>\n <\/jats:sec>\n \n METHODS:<\/jats:title>\n \n Effects of TFPI\u03b1 (\n Tfpi<\/jats:italic>\n \u0394\u03b1<\/jats:sup>\n ) and platelet (\n Tfpi<\/jats:italic>\n fl<\/jats:sup>\n ;\n Pf4<\/jats:italic>\n -Cre\n +<\/jats:sup>\n ) specific knockout alleles were characterized in FVL (\n F5<\/jats:italic>\n L<\/jats:sup>\n ) mice to examine the physiological effects of the TFPI\u03b1-FV interaction.\n <\/jats:p>\n <\/jats:sec>\n \n RESULTS:<\/jats:title>\n \n Genotype frequencies were assessed and revealed that\n Tfpi<\/jats:italic>\n +\/\u0394\u03b1<\/jats:sup>\n F5<\/jats:italic>\n L\/L<\/jats:sup>\n mice survive to adulthood. However,\n Tfpi<\/jats:italic>\n \u0394\u03b1<\/jats:sup>\n homozygosity with even a single\n F5<\/jats:italic>\n L<\/jats:sup>\n allele resulted in embryonic lethality during mid-gestation development regardless of maternal FVL status. In contrast,\n F5<\/jats:italic>\n L\/L<\/jats:sup>\n Tfpi<\/jats:italic>\n fl\/fl<\/jats:sup>\n Pf4<\/jats:italic>\n -Cre\n +<\/jats:sup>\n mice were at expected frequencies at weaning, indicating that platelet TFPI\u03b1 loss alone did not cause mid-gestation lethality in\n Tfpi<\/jats:italic>\n \u0394\u03b1\/\u0394\u03b1<\/jats:sup>\n F5<\/jats:italic>\n L<\/jats:sup>\n mice. Histological analyses showed no fibrin deposition in embryonic or extraembryonic tissues but revealed placental vasculature defects in\n Tfpi<\/jats:italic>\n \u0394\u03b1\/\u0394\u03b1<\/jats:sup>\n F5<\/jats:italic>\n L<\/jats:sup>\n genotypes. Treatment with the direct thrombin inhibitor dabigatran partially rescued the lethality and corrected placental defects, implicating excessive thrombin generation as a factor in\n Tfpi<\/jats:italic>\n \u0394\u03b1\/\u0394\u03b1<\/jats:sup>\n F5<\/jats:italic>\n L<\/jats:sup>\n demise.\n <\/jats:p>\n <\/jats:sec>\n \n CONCLUSIONS:<\/jats:title>\n These findings suggest that TFPI\u03b1 and its inhibition of prothrombinase play an important role in placental angiogenesis and embryonic survival.<\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/atvbaha.125.322650","type":"journal-article","created":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T09:01:00Z","timestamp":1747904460000},"page":"1266-1276","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Placental Vascular Defects and Embryonic Lethality Triggered by TFPI\u03b1 Deficiency in Factor V Leiden Mice"],"prefix":"10.1161","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9634-9164","authenticated-orcid":true,"given":"Amy E.","family":"Siebert","sequence":"first","affiliation":[{"name":"Thrombosis and Hemostasis Program, Versiti Blood Research Institute, Milwaukee, WI (A.E.S., S.A.M., N.D.M., A.E.M.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8021-0694","authenticated-orcid":true,"given":"Susan A.","family":"Maroney","sequence":"additional","affiliation":[{"name":"Thrombosis and Hemostasis Program, Versiti Blood Research Institute, Milwaukee, WI (A.E.S., S.A.M., N.D.M., A.E.M.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6540-4076","authenticated-orcid":true,"given":"Nicholas D.","family":"Martinez","sequence":"additional","affiliation":[{"name":"Thrombosis and Hemostasis Program, Versiti Blood Research Institute, Milwaukee, WI (A.E.S., S.A.M., N.D.M., A.E.M.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7158-1592","authenticated-orcid":true,"given":"Michael J.","family":"Soares","sequence":"additional","affiliation":[{"name":"Institute for Reproductive and Developmental Sciences (M.J.S.), University of Kansas Medical Center."},{"name":"Department of Pathology and Laboratory Medicine (M.J.S.), University of Kansas Medical Center."},{"name":"Department of Obstetrics and Gynecology (M.J.S.), University of Kansas Medical Center."},{"name":"Center for Perinatal Research, Children\u2019s Mercy Research Institute, Children\u2019s Mercy, Kansas City, MO (M.J.S.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3740-0318","authenticated-orcid":true,"given":"Alan E.","family":"Mast","sequence":"additional","affiliation":[{"name":"Thrombosis and Hemostasis Program, Versiti Blood Research Institute, Milwaukee, WI (A.E.S., S.A.M., N.D.M., A.E.M.)."},{"name":"Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee 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