Key result
Heparin linked to ~40% lower 28-day mortality in moderate-to-severe sepsis risk subgroups.
Why the study?
The influence of heparin on tissue factor and plasminogen activator inhibitor type 2 expression in stimulated human monocytes and its effects on gene expression were not fully understood.
Cohort (n=12,408)
Yes
Heparin-associated mortality reduction in moderate-severe sepsis risk should not yet change practice; leaves open targeted anticoagulation for prospective trials.
Stimulated monocytes are involved in blood clotting and fibrin dissolution by synthesizing tissue factor (TF) and fibrinolytic components such as plasminogen activator inhibitor type 2 (PAI-2). Heparin interacts with smooth muscle cells, platelets, and endothelial cells and specifically binds to human monocytes. In endothelial and smooth muscle cells, heparin selectively inhibits collagenase and tissue plasminogen activator gene expression. To investigate (1) heparin's influence on the hemostatic system by its interactions with plasma factors and cellular elements and (2) to determine its effects on gene expression in blood circulating cells, we studied the effect of heparin on TF and PAI-2 protein and mRNA in human lipopolysaccharide (LPS)- or interferon-gamma (IFN-gamma)-stimulated monocytes. TF and PAI-2 proteins were investigated by ELISA and by assaying procoagulant activity. The mRNA study was carried out by an initial PCR screening followed by a Northern blot semiquantitative analysis. Heparin (0.5 U/mL) inhibited both TF and PAI-2 production and gene expression. The contemporaneous protein and mRNA decrease (TF and PAI-2 protein 22 and 42%, respectively; suggests that this action is, at least partially, at the transcriptional level. The effect is not specific for heparin and is not demonstrated by other glycosaminoglycans (chondroitin-4-sulfate or dermatan sulfate). This action may be relevant for the antithrombotic activity of heparin in cell-mediated blood clotting activation.
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Pepe et al. (1997) conducted a cohort in Sepsis (n=12,408). Heparin (anticoagulant treatment) vs. No anticoagulant treatment was evaluated on 28-day mortality (moderate risk level subgroup) (HR 0.60, 95% CI 0.48-0.75, p=<0.005). In a retrospective cohort of sepsis patients, anticoagulant treatment with heparin significantly reduced 28-day mortality in patients with moderate (HR 0.60) and severe (HR 0.57) risk levels, but not in those with mild or dangerous risk levels.
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