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Zn2+ interacts with a variety of haemostatic proteins in the bloodstream including fibrinogen, histidine-rich glycoprotein (HRG) and high molecular weight kininogen (HMWK) to regulate haemostasis. The availability of Zn2+ to bind such proteins is controlled by human serum albumin (HSA), which binds 70\u201385% of plasma Zn2+ under basal conditions. HSA also binds and transports non-esterified fatty acids (NEFAs). Upon NEFA binding, there is a change in the structure of HSA which leads to a reduction in its affinity for Zn2+. This enables other plasma proteins to better compete for binding of Zn2+. In diseases where elevated plasma NEFA concentrations are a feature, such as obesity and diabetes, there is a concurrent increase in hypercoagulability. Evidence indicates that NEFA-induced perturbation of Zn2+-binding by HSA may contribute to the thrombotic complications frequently observed in these pathophysiological conditions. This review highlights potential interventions, both pharmaceutical and non-pharmaceutical that may be employed to combat this dysregulation. Lifestyle and dietary changes have been shown to reduce plasma NEFA concentrations. Furthermore, drugs that influence NEFA levels such as statins and fibrates may be useful in this context. In severely obese patients, more invasive therapies such as bariatric surgery may be useful. Finally, other potential treatments such as chelation therapies, use of cholesteryl transfer protein (CETP) inhibitors, lipase inhibitors, fatty acid inhibitors and other treatments are highlighted, which with additional research and appropriate clinical trials, could prove useful in the treatment and management of thrombotic disease through amelioration of plasma Zn2+ dysregulation in high-risk individuals.<\/jats:p>","DOI":"10.3390\/ijms231810302","type":"journal-article","created":{"date-parts":[[2022,9,7]],"date-time":"2022-09-07T20:52:03Z","timestamp":1662583923000},"page":"10302","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Strategies for Therapeutic Amelioration of Aberrant Plasma Zn2+ Handling in Thrombotic Disease: Targeting Fatty Acid\/Serum Albumin-Mediated Effects"],"prefix":"10.3390","volume":"23","author":[{"given":"Spencer","family":"Regan-Smith","sequence":"first","affiliation":[{"name":"School of Medicine, University of St Andrews, St Andrews KY16 9TF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3457-8364","authenticated-orcid":false,"given":"Remi","family":"Fritzen","sequence":"additional","affiliation":[{"name":"School of Medicine, University of St Andrews, St Andrews KY16 9TF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen J.","family":"Hierons","sequence":"additional","affiliation":[{"name":"School of Medicine, University of St Andrews, St Andrews KY16 9TF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramzi A.","family":"Ajjan","sequence":"additional","affiliation":[{"name":"Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9JT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8396-9332","authenticated-orcid":false,"given":"Claudia A.","family":"Blindauer","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4580-1840","authenticated-orcid":false,"given":"Alan J.","family":"Stewart","sequence":"additional","affiliation":[{"name":"School of Medicine, University of St Andrews, St Andrews KY16 9TF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1111\/j.1749-6632.1972.tb16285.x","article-title":"Adhesion of platelets to subendothelium","volume":"201","author":"Baumgartner","year":"1972","journal-title":"Ann. 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