title: Heparin-associated anti-Xa activity and platelet-derived prothrombotic and proinflammatory biomarkers in moderate to high-risk patients with acute coronary syndrome.
abstract: Heparin compounds, to include fractionated and unfractionated preparations, exert both antithrombotic and antiinflammatory effects through combined inhibition of factor Xa and thrombin. The contribution of modulated platelet activity in vivo is less clearly defined. The SYNERGY library was a prospectively designed repository for candidate clinical, hemostatic, platelet, and molecular biomarkers from patients participating in SYNERGY--a large-scale, randomized clinical trial evaluating the comparative benefits of unfractionated heparin (UFH) and enoxaparin in high-risk patients with acute coronary syndrome (ACS). Samples were collected from 201 patients enrolled at 26 experienced, participating sites and shipped to established core laboratories for analysis of platelet, endothelium-derived, inflammatory and coagulation activity biomarkers. Tissue factor pathway inhibitor (TFPI)--a vascular endothelial cell-derived factor Xa regulatory protein-correlated directly with plasma anti-Xa activity (unadjusted: r = 0.23, P < 0.0001; adjusted: β = 0.10; P = 0.001), as did TFPI-fXa complexes (unadjusted: r = 0.34, P < 0.0001; adjusted: β = 0.38; P = < 0.0001). In contrast, there was a direct and inverse relationship between anti-Xa activity and two platelet-derived biomarkers-plasminogen activator inhibitor-1 (unadjusted: r = -0.18, P = 0.0012; adjusted: β = -0.10; P = 0.021) and soluble CD40 ligand (unadjusted: r = -0.11, P = 0.05; adjusted: β = -0.13; P = 0.049). All measured analyte relationships persisted after adjustment for age, creatinine clearance, weight, sex, and duration of treatment. Differences in biomarkers between patients receiving UFH and those randomized to enoxaparin were not observed. The ability of heparin compounds to affect the prothrombotic and proinflammatory states which characterize ACS may involve factor Xa-related modulation of platelet activation and expression. Whether this potentially beneficial effect is direct or indirect and achieved, at least in part, through the release of endothelial cell-derived coagulation regulatory proteins will require further investigation.
authors.affiliation: Division of Cardiology Medicine, Duke University Medical Center, Duke Clinical Research Institute, Durham, NC 27715, USA. richard.becker@duke.edu
authors.forename: Richard C
authors.initials: RC
authors.lastname: Becker
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Mahaffey
authors.forename: Hongqiu
authors.initials: H
authors.lastname: Yang
authors.forename: A J
authors.initials: AJ
authors.lastname: Marian
authors.forename: Mark I
authors.initials: MI
authors.lastname: Furman
authors.forename: A
authors.initials: A
authors.lastname: Michael Lincoff
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
authors.forename: John L
authors.initials: JL
authors.lastname: Petersen
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Reist
authors.forename: Neal S
authors.initials: NS
authors.lastname: Kleiman
mesh_terms: D054058:Acute Coronary Syndrome / Q000097:blood / Q000188:drug therapy; D000368:Aged; D015415:Biomarkers / Q000097:blood; D019774:Blood Coagulation Factor Inhibitors / Q000097:blood*; D001792:Blood Platelets / Q000378:metabolism; D023201:CD40 Ligand / Q000097:blood; D017984:Enoxaparin / Q000008:administration & dosage*; D015951:Factor Xa / Q000032:analysis; D065427:Factor Xa Inhibitors; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage*; D006801:Humans; D008074:Lipoproteins / Q000097:blood*; D008297:Male; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D015539:Platelet Activation / Q000187:drug effects; D012307:Risk Factors
chemical_list: D015415:Biomarkers; D019774:Blood Coagulation Factor Inhibitors; D017984:Enoxaparin; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D008074:Lipoproteins; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; C051928:lipoprotein-associated coagulation inhibitor; D023201:CD40 Ligand; D015951:Factor Xa