{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T20:52:20Z","timestamp":1778532740273,"version":"3.51.4"},"reference-count":0,"publisher":"Georg Thieme Verlag KG","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Thromb Haemost"],"published-print":{"date-parts":[[2008]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>Ectopic delivery of factor VIII (FVIII) to megakaryocytes (Mk) represents a viable approach for localized tenase generation by concentrating the FVIIIa\/FIXa enzymecofactor complex onto activated platelet membranes. We utilized a core rat platelet factor 4 (PF4) promoter for Mk\/platelet-restricted expression of human B-domain-deleted (hBDD) FVIII within the background of a haemophilia A mouse (rPF4\/hBDD\/FVIII-\/-). Platelets from rPF4\/hBDD\/FVIII-\/- mice contained \u223c122 mU FVIII:C\/1x109 platelets\/ml with no detectable plasmatic FVIII:C,and with no effect on \u03b1-granule-derived platelet factorV\/Va function.Paired tenase assays (\u00b1 thrombin) confirmed that platelet (pt) FVIII (unlike platelet FV) required thrombin cleavage for complete activation. rPF4\/hBDD\/FVIII-\/- mice exposed to a thrombocytotic stimulus (thrombopoietin, TPO) demonstrated a statistically-significant 66% reduction in molar ptFVIII activity with a non-significant reduction in total ptFVIII biomass. Decreased molar ptFVIII concentration correlated with loss of phenotypic correction as evaluated using a haemostatic tail-snip assay. Comparative studies using a transgenic mouse expressing human amyloid-\u03b2-precursor protein (hA\u03b2PP) from the rPF4 promoter confirmed diminished hA\u03b2PP expression without affecting endogenous \u03b1-granule PF4, establishing generalizability of these observations.While Mk\/plateletreleased ptFVIII (unlike pFV) is proteolytically inactive, we also conclude that thrombocytotic stimuli negatively affect ptFVIII bioavailability and phenotypic efficacy, results which correlate best with molar ptFVIII concentration, and not systemically available ptFVIII.<\/jats:p>","DOI":"10.1160\/th08-04-0242","type":"journal-article","created":{"date-parts":[[2008,11,17]],"date-time":"2008-11-17T08:24:37Z","timestamp":1226910277000},"page":"1111-1122","source":"Crossref","is-referenced-by-count":16,"title":["Altered bioavailability of platelet-derived factor VIII during thrombocytosis reverses phenotypic efficacy in haemophilic mice"],"prefix":"10.1160","volume":"100","author":[{"given":"Andrea L.","family":"Damon","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lesley E.","family":"Scudder","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dmitri V.","family":"Gnatenko","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Varsha","family":"Sitaraman","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick","family":"Hearing","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jolyon","family":"Jesty","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wadie F.","family":"Bahou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"194","published-online":{"date-parts":[[2017,11,23]]},"container-title":["Thrombosis and Haemostasis"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.thieme-connect.de\/products\/ejournals\/pdf\/10.1160\/TH08-04-0242.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2018,3,21]],"date-time":"2018-03-21T07:19:42Z","timestamp":1521616782000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.thieme-connect.de\/DOI\/DOI?10.1160\/TH08-04-0242"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008]]},"references-count":0,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2017,11,23]]},"published-print":{"date-parts":[[2008]]}},"URL":"https:\/\/doi.org\/10.1160\/th08-04-0242","relation":{},"ISSN":["0340-6245","2567-689X"],"issn-type":[{"value":"0340-6245","type":"print"},{"value":"2567-689X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008]]}}}