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.