{"id":4764,"date":"2025-07-22T08:39:57","date_gmt":"2025-07-22T08:39:57","guid":{"rendered":"https:\/\/medical.biomarin.com\/en-us\/?page_id=4764"},"modified":"2026-01-07T19:45:45","modified_gmt":"2026-01-07T19:45:45","slug":"thromboembolism","status":"publish","type":"page","link":"https:\/\/medical.biomarin.com\/en-us\/hemophilia-a\/valoctocogene-roxaparvovec-safety\/thromboembolism\/","title":{"rendered":"Thromboembolism"},"content":{"rendered":"<div id=\"acf-block-645511272e5db\" class=\"hero hero-no-overlay hero-small-title\">\n            <div class=\"hero-background-image hero-background-image-desktop\" style=\"background-image: url(https:\/\/medical.biomarin.com\/en-us\/wp-content\/uploads\/sites\/2\/2025\/10\/Program-banner-drop.png?v=1.20);\"><\/div>\n\t    <div class=\"hero-background-image hero-background-image-mobile\" style=\"background-image: url(https:\/\/medical.biomarin.com\/en-us\/wp-content\/uploads\/sites\/2\/2025\/10\/Program-banner-drop-Mobile.png?v=1.20);\"><\/div>\n    \t<div class=\"overlay\"><\/div>\n\t<div class=\"wrapper\">\n\t\t<div class=\"inner-wrapper\">\n\t\t\t<div class=\"hero-content\">\n\t\t\t    \t\t\t        <ul class=\"breadcrumb\">\n\t\t\t            \t\t\t                                                                        <li><a href=\"https:\/\/medical.biomarin.com\/en-us\/hemophilia-a\/\">Hemophilia A<\/a><\/li>\n                            \t\t\t                                                                        <li><a href=\"https:\/\/medical.biomarin.com\/en-us\/hemophilia-a\/valoctocogene-roxaparvovec-safety\/\">Valoctocogene roxaparvovec safety<\/a><\/li>\n                            \t\t\t                                                                        <li>Thromboembolism<\/li>\n                            \t\t\t            \t\t\t        <\/ul>\n\t\t\t    \t\t\t\t\t\t\t\t\t\t\t\t    <h1>Thromboembolism\n<\/h1>\n\t\t\t\t\t\t\t\t\t\t\t\t\n                <p class=\"inline-buttons\">\n                                                        <\/p>\n\t\t\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t<\/div>\n<\/div>\n\n\n<div id=\"acf-block-645512ae5ba05\" class=\"block wrapped-content bg-band bg-band-primary block-zero-top block-tight-bottom\">\n    <div class=\"wrapper\">\n        <div class=\"inner-wrapper\">\n                \n<div id=\"acf-block-645512ae5bb64\" class=\"block-wysiwyg\">\n            <h2>State of Knowledge Summary<\/h2>\n<ul>\n<li>An increase in factor VIII (FVIII) activity may contribute to a patient&#x2019;s individual, multifactorial risk for venous and arterial thrombotic events.<sup>1,2 <\/sup><\/li>\n<li>Patients with histories of arterial or venous thromboembolic events and known inherited or acquired thrombophilia, including conditions associated with increased thromboembolic risk (e.g., atrial fibrillation), were excluded from clinical trials.<sup>3<\/sup><\/li>\n<li>In clinical trials some patients experienced elevations of FVIII activity to levels greater than the upper limit of normal (ULN).<sup>3,4 <\/sup><\/li>\n<li>No thromboembolic events have been reported in patients treated with&#xA0;valoctocogene roxaparvovec, even when factor VIII (FVIII) levels exceeded 150 IU\/dL.<sup>3-5<\/sup><\/li>\n<\/ul>\n    <\/div>\n        <\/div>\n    <\/div>\n<\/div>\n\n<div id=\"acf-block-645514ad0bc61\" class=\"block wrapped-content block-tight-top block-tight-bottom\">\n    <div class=\"wrapper\">\n        <div class=\"inner-wrapper\">\n                \n<div id=\"acf-block-645514ad0d39d\" class=\"block-wysiwyg\">\n            <ul>\n<li>FVIII activity levels above ULN were observed in GENEr8-1 and Study 270-201.<sup>3,4<\/sup><\/li>\n<li>Four patients in Study 270-201 receiving 6 x 10<sup>13<\/sup> vg\/kg exhibited FVIII levels above 150 IU\/dL as measured by the one-stage assay (range 201&#x2013;349 IU\/dL) during the first year; no thromboembolic events were reported, and all patients had normal platelet counts, prothrombin time, and activated partial-thromboplastin time.<sup>4<\/sup><\/li>\n<li>To date, no patients in GENEr8-1 have experienced a thromboembolic event, including patients with FVIII activity levels &gt;150 IU\/dL. <sup>3,7,8<\/sup>&nbsp;Patients who experienced FVIII activity levels &gt;150 IU\/dL had no adverse outcomes related to thromboembolic events.\n<ul>\n<li>One patient experienced noncardiac chest pain concurrent with an elevated FVIII activity level &gt;300 IU\/dL on study day 139 and, per investigator discretion, was initiated on aspirin and enoxaparin.<sup>3<\/sup><\/li>\n<li>No other patients with FVIII activity levels &gt;150 IU\/dL, including 2 with transient FVIII activity levels &gt;300 IU\/dL, required intervention.<sup>3<\/sup> All results were reviewed by the independent Data Monitoring Committee.<\/li>\n<\/ul>\n<\/li>\n<li>In GENEr8-1, coagulation parameters were evaluated following the November 2020 data cut as part of laboratory safety assessments.<sup>3<\/sup> In the intent-to-treat (ITT) population, 5.2% (7\/134) of patients reported hematology laboratory abnormalities. FVIII increased and fibrin D-dimer increased were reported in 2 (1.5%) patients; activated partial thromboplastin time (aPTT) prolonged, aPTT shortened, coagulation test abnormal, hematocrit decreased, hemoglobin decreased, neutrophil count decreased, prothrombin time shortened, thrombin time prolonged, and von Willebrand&rsquo;s factor (vWF) antigen decreased were each reported in 1 (0.7%) patient. All adverse events were Grade 1 or 2. Thrombin generation assays were also performed regularly, and results were compared for samples with FVIII activity between 40 and 150 IU\/dL (n=349) and with FVIII activity &gt;150 IU\/dL (n=47). While samples with FVIII activity &gt;150 IU\/dL had slightly lower lag time and time to peak thrombin, they had similar peak height and endogenous thrombin potential as samples with FVIII activity of 40&ndash;150 IU\/dL.<sup>3<\/sup><\/li>\n<\/ul>\n<h3>Factor VIII Activity Levels Above ULN<sup>a<\/sup><\/h3>\n    <\/div>\n\n<figure id=\"acf-block-64873b592ce96\">\n    <div class=\"image image-rounded image-align-left\">\n                    <img decoding=\"async\" class=\"\" src=\"https:\/\/medical.biomarin.com\/en-us\/wp-content\/uploads\/sites\/2\/2025\/11\/FVIII-Activity-Levels-Above-ULN-Table-_DEC2024_Revised.jpg?v=1.20\" alt=\"Image of FVIII-Activity-Levels table\"\/>            <\/div>\n            <figcaption><p><sup>a<\/sup>ULN of &gt;150 IU\/dl for OSA and ULN of &gt;170 IU\/dl for CSA.<\/p>\n<\/figcaption>\n    <\/figure>\n        <\/div>\n    <\/div>\n<\/div>\n\n<div id=\"acf-block-6488291730e8c\" class=\"block next-previous\">\n    <div class=\"wrapper\">\n\t\t<div class=\"inner-wrapper\">\n            <div class=\"link link-prev\">\n                                    <p><a class=\"button button-text button-arrow button-arrow-left\" href=\"https:\/\/medical.biomarin.com\/en-us\/valoctocogene-roxaparvovec-safety\/malignancy-vector-integration\/\" target=\"_self\">Malignancy (vector integration)<\/a><\/p>\n                            <\/div>\n            <div class=\"link link-next\">\n                                    <p><a class=\"button button-text button-arrow\" href=\"https:\/\/medical.biomarin.com\/en-us\/valoctocogene-roxaparvovec-safety\/fviii-inhibitor-development-summary\/\" target=\"_self\">FVIII Inhibitor Development Summary<\/a><\/p>\n                            <\/div>\n\t\t<\/div>\n\t<\/div>\n<\/div>\n\n<div id=\"acf-block-6481afaff0fe9\" class=\"block references\">\n    <div class=\"wrapper\">\n\t\t<div class=\"inner-wrapper\">\n\t\t    \t\t\t    <h4>References:\n<\/h4>\n\t\t\t\t\t\t                <ol>\n                                                                                                                        <li><span>Jenkins PV, Rawley O, Smith OP, et al. Elevated factor VIII levels and risk of venous thrombosis. Br J Haematol. 2012;157(6):653-663.\n<\/span><\/li>\n                                                                                                                                                <li><span>Algahtani FH, Stuckey R. High factor VIII levels and arterial thrombosis: illustrative case and literature review. Ther Adv Hematol. 2019;10:2040620719886685. \n<\/span><\/li>\n                                                                                                                                                <li><span>Ozelo MC, Mahlangu J, Pasi KJ, et al. Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A. N Engl J Med. 2022;386(11):1013-1025.\n<\/span><\/li>\n                                                                                                                                                <li><span>Rangarajan S, Walsh L, Lester W, et al. AAV5-Factor VIII Gene Transfer in Severe Hemophilia A. N Engl J Med. 2017;377(26):2519-2530.\n<\/span><\/li>\n                                                                                                                                                <li><span>Mahlangu J, Kaczmarek R, von Drygalski A, et al. Two-Year Outcomes of Valoctocogene Roxaparvovec Therapy for Hemophilia A. N Engl J Med. 2023;388(8):694-705.\n<\/span><\/li>\n                                                                                                                                                <li><span>EU ROCTAVIAN SmPC\n<\/span><\/li>\n                                                                                                                                                <li><span>Leavitt AD, Mahlangu J, Raheja P, et al. Efficacy and safety of valoctocogene roxaparvovec 4 years after gene transfer in GENEr8-1 [presentation]. Presented at the International Society on Thrombosis and Haemostasis (ISTH) Congress. June 22-26, 2024; Bangkok, Thailand.\n<\/span><\/li>\n                                                                                                                                                <li><span>Leavitt AD, Mahlangu J, Raheja P, et al. Efficacy, safety, and quality of life 4 years after valoctocogene roxaparvovec gene transfer for severe hemophilia A in the phase 3 GENEr8-1 trial. Res Pract Thromb Haemost. 2024;8(8):102615.\n<\/span><\/li>\n                                                            <\/ol>\n\t\t\t\t\t<\/div>\n\t<\/div>\n<\/div>","protected":false},"excerpt":{"rendered":"","protected":false},"author":2,"featured_media":0,"parent":4754,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":{"_acf_changed":false,"inline_featured_image":false,"footnotes":""},"class_list":["post-4764","page","type-page","status-publish","hentry"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.1.1 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Thromboembolism | BioMarin Medical<\/title>\n<meta name=\"description\" content=\"Learn more about Thromboembolism\" \/>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" 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