title: Acylcarnitines are anticoagulants that inhibit factor Xa and are reduced in venous thrombosis, based on metabolomics data.
abstract: In many patients with deep vein thrombosis and pulmonary embolism (venous thromboembolism, VTE), biomarkers or genetic risk factors have not been identified. To discover novel plasma metabolites associated with VTE risk, we employed liquid chromatography-mass spectrometry-based untargeted metabolomics, which do not target any specific metabolites. Using the Scripps Venous Thrombosis Registry population for a case-control study, we discovered that 10:1 and 16:1 acylcarnitines were low in plasmas of the VTE patient group compared with matched controls, respectively. Data from targeted metabolomics studies showed that several long-chain acylcarnitines (10:1, 12:0, 12:2, 18:1, and 18:2) were lower in the VTE group. Clotting assays were used to evaluate a causal relationship for low acylcarnitines in patients with VTE. Various acylcarnitines inhibited factor Xa-initiated clotting. Inhibition of factor Xa by acylcarnitines was greater for longer acyl chains. Mechanistic studies showed that 16:0 acylcarnitine had anticoagulant activity in the absence of factor Va or phospholipids. Surface plasmon resonance investigations revealed that 16:0 acylcarnitine was bound to factor Xa and that binding did not require the γ-carboxy glutamic acid domain. In summary, our study identified low plasma levels of acylcarnitines in patients with VTE and showed that acylcarnitines have anticoagulant activity related to an ability to bind and inhibit factor Xa.
authors.affiliation: Department of Molecular and Experimental Medicine and.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Deguchi
authors.affiliation: Department of Molecular and Experimental Medicine and.
authors.forename: Yajnavalka
authors.initials: Y
authors.lastname: Banerjee
authors.affiliation: Center for Metabolomics and Mass Spectrometry, The Scripps Research Institute, La Jolla, CA; and.
authors.forename: Sunia
authors.initials: S
authors.lastname: Trauger
authors.affiliation: Center for Metabolomics and Mass Spectrometry, The Scripps Research Institute, La Jolla, CA; and.
authors.forename: Gary
authors.initials: G
authors.lastname: Siuzdak
authors.affiliation: Center for Metabolomics and Mass Spectrometry, The Scripps Research Institute, La Jolla, CA; and.
authors.forename: Ewa
authors.initials: E
authors.lastname: Kalisiak
authors.affiliation: Department of Molecular and Experimental Medicine and.
authors.forename: José A
authors.initials: JA
authors.lastname: Fernández
authors.affiliation: Center for Metabolomics and Mass Spectrometry, The Scripps Research Institute, La Jolla, CA; and.
authors.forename: Linh
authors.initials: L
authors.lastname: Hoang
authors.affiliation: Center for Metabolomics and Mass Spectrometry, The Scripps Research Institute, La Jolla, CA; and.
authors.forename: Minerva
authors.initials: M
authors.lastname: Tran
authors.affiliation: Department of Molecular and Experimental Medicine and.
authors.forename: Subramanian
authors.initials: S
authors.lastname: Yegneswaran
authors.affiliation: Department of Molecular and Experimental Medicine and The Scripps Clinic, La Jolla, CA.
authors.forename: Darlene J
authors.initials: DJ
authors.lastname: Elias
authors.affiliation: Department of Molecular and Experimental Medicine and.
authors.forename: John H
authors.initials: JH
authors.lastname: Griffin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000627:therapeutic use; D002331:Carnitine / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000378:metabolism; D016022:Case-Control Studies; D015951:Factor Xa / Q000737:chemistry / Q000378:metabolism*; D065427:Factor Xa Inhibitors / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D055432:Metabolomics; D008875:Middle Aged; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012307:Risk Factors; D020246:Venous Thrombosis / Q000097:blood / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D014859:Warfarin / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; C116917:acylcarnitine; D014859:Warfarin; D015951:Factor Xa; D002331:Carnitine