{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T19:21:30Z","timestamp":1788808890361,"version":"build-2803163510"},"reference-count":29,"publisher":"Georg Thieme Verlag KG","issue":"03","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Semin Thromb Hemost"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Intravenous direct thrombin inhibitors (DTIs) are used for thromboembolic disorders. This systematic review aims to characterize intravenous DTI agents, dosing, monitoring strategies (or use), bleeding, and mortality, in pediatric patients with acute venous thromboembolism (VTE) or heparin-induced thrombocytopenia with thrombosis (HITT). MEDLINE, Embase, and Cochrane's CENTRAL were searched from inception through July 2023. Case series, retrospective studies, and prospective studies providing per-patient or summary data for patients\u2009&lt;\u200918 years of age with VTE or HITT treated with an intravenous DTI were included. Selection and data extraction were conducted independently by two reviewers. Sixteen studies (7 case reports, 1 case series, 5 retrospective studies, 3 prospective studies) with 85 patients were included. Target conditions included acute VTE in 54 (64%) and HITT in 31 (36%) patients. Bivalirudin, argatroban, and lepirudin were used in 52 (61%), 27 (32%), and 6 (7%) patients, respectively. Fifty-two (61%) patients received a bolus dose, and weighted mean infusion rates for bivalirudin, argatroban, and lepirudin were 0.2\u2009mg\/kg\/hr, 1.2 mcg\/kg\/min, and 0.15\u2009mg\/kg\/hr, respectively. The activated partial thromboplastin time was utilized for monitoring in 82 (96%) patients. Complete or partial thrombus resolution was reported in 53 (62%) patients, mortality in 6 (7%) patients, and bleeding complications in 14 (16%) patients. In this systematic review involving 85 pediatric patients treated with an intravenous DTI for acute VTE or HITT, bivalirudin was the most commonly utilized agent, with a rate of resolution over 60% despite a high acuity in the population studied. Prospective collaborative studies are warranted to establish optimal dosing and further characterize VTE and bleeding outcomes.<\/jats:p>","DOI":"10.1055\/s-0044-1791534","type":"journal-article","created":{"date-parts":[[2024,10,7]],"date-time":"2024-10-07T23:08:11Z","timestamp":1728342491000},"page":"329-334","source":"Crossref","is-referenced-by-count":7,"title":["Intravenous Direct Thrombin Inhibitors for Acute Venous Thromboembolism or Heparin-Induced Thrombocytopenia with Thrombosis in Children: A Systematic Review of the Literature"],"prefix":"10.1055","volume":"51","author":[{"given":"Amy L.","family":"Kiskaddon","sequence":"additional","affiliation":[{"name":"Divisions of Cardiology and Hematology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland"},{"name":"Johns Hopkins All Children's Institute for Clinical and Translational Research, St. Petersburg, Florida"},{"name":"Heart Institute, Johns Hopkins All Children's Hospital, St. Petersburg, Florida"},{"name":"Department of Pharmacy, Johns Hopkins All Children's Hospital, St. Petersburg, Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josh","family":"Branstetter","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Children's Healthcare of Atlanta, Atlanta, Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pam","family":"Williams","sequence":"additional","affiliation":[{"name":"Medical Library, Johns Hopkins All Children's Hospital, St. Petersburg, Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera","family":"Ignjatovic","sequence":"additional","affiliation":[{"name":"Johns Hopkins All Children's Institute for Clinical and Translational Research, St. Petersburg, Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Memken","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Johns Hopkins All Children's Hospital, St. Petersburg, Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristopher","family":"Wilhoit","sequence":"additional","affiliation":[{"name":"University of South Florida, Tampa, Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil A.","family":"Goldenberg","sequence":"additional","affiliation":[{"name":"Johns Hopkins All Children's Institute for Clinical and Translational Research, St. Petersburg, Florida"},{"name":"Division of Hematology, Departments of Medicine and Pediatrics, Johns Hopkins School of Medicine, Baltimore, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"194","published-online":{"date-parts":[[2024,10,7]]},"reference":[{"issue":"03","key":"ref1","doi-asserted-by":"crossref","first-page":"e2021054649","DOI":"10.1542\/peds.2021-054649","article-title":"The continued rise of venous thromboembolism across US children's hospitals","volume":"149","author":"S H O'Brien","year":"2022","journal-title":"Pediatrics"},{"key":"ref2","first-page":"e737S","article-title":"Antithrombotic therapy in neonates and children: antithrombotic therapy and prevention of thrombosis, 9th ed.:","volume":"141","author":"P Monagle","year":"2012"},{"issue":"11","key":"ref3","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1007\/s40262-013-0094-1","article-title":"Pharmacokinetics and pharmacodynamics of anticoagulants in paediatric patients","volume":"52","author":"D L Yee","year":"2013","journal-title":"Clin Pharmacokinet"},{"issue":"01","key":"ref4","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.thromres.2007.09.007","article-title":"Utility of aPTT in monitoring unfractionated heparin in children","volume":"122","author":"A K Chan","year":"2008","journal-title":"Thromb Res"},{"issue":"03","key":"ref5","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.thromres.2006.10.006","article-title":"Monitoring unfractionated 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