title: Therapeutic implications of protein disulfide isomerase inhibition in thrombotic disease.
abstract: The study of thrombus formation has increasingly applied in vivo tools such as genetically modified mice and intravital microscopy to the evaluation of molecular and cellular mechanisms of thrombosis. Among several unexpected findings of this approach was the discovery that protein disulfide isomerase serves an essential role in thrombus formation at sites of vascular injury. The observation that the commonly ingested quercetin flavonoid, quercetin-3-rutinoside, inhibits protein disulfide isomerase and blocks thrombus formation in preclinical studies has set the stage for clinical trials using protein disulfide isomerase antagonists as antithrombotics. Although the mechanisms by which protein disulfide isomerase facilitates platelet activation and fibrin formation have yet to be elucidated, protein disulfide isomerase antagonists are currently being developed as antithrombotics. This review will consider what is known about the role of protein disulfide isomerase in platelet accumulation and fibrin generation with a focus on pharmacological strategies for blocking protein disulfide isomerase activity in the context of thrombus formation. Potential indications and clinical trial design for testing the efficacy of protein disulfide isomerase inhibition to reduce the incidence of thrombosis will be considered.
authors.affiliation: From the Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. rflaumen@bidmc.harvard.edu.
authors.forename: Robert
authors.initials: R
authors.lastname: Flaumenhaft
authors.affiliation: From the Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Furie
authors.affiliation: From the Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Zwicker
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005337:Fibrin / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006801:Humans; D015539:Platelet Activation / Q000187:drug effects; D019704:Protein Disulfide-Isomerases / Q000037:antagonists & inhibitors* / Q000097:blood; D013927:Thrombosis / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D005343:Fibrinolytic Agents; D005337:Fibrin; D019704:Protein Disulfide-Isomerases
keywords: blood platelet; platelet inhibitors; thrombosis
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