Thromb Haemostasis
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Randomized Controlled Trial Clinical Trial
Drotrecogin alfa (activated) (recombinant human activated protein C) reduces host coagulopathy response in patients with severe sepsis.
Drotrecogin alfa (activated) improved survival in patients with severe sepsis in PROWESS, a double-blind, study of 1690 adult patients randomized to drotrecogin alfa (activated) at 24 microg/kg/h (N=850) or placebo (N=840) infused for 96 hours. Pharmacodynamic effects of drotrecogin alfa (activated) were assessed with 15 prospectively defined systemic biomarkers of hemostasis, inflammation and endothelial injury. The last-observation-carried-forward (LOCF) method of imputation for missing observations was the prospectively defined statistical method. ⋯ However, the present results using different statistical methods do not provide a strong basis for systemic anti-inflammatory or pro-fibrinolytic effects. These latter two effects may occur at the local or cellular level. The systemic biomarkers reported here might not be the most appropriate approach to demonstrate these potential effects of drotrecogin alfa (activated).
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Platelets and leukocytes can form heterotypic aggregates. We studied how shear stress influences platelet-leukocyte aggregation (PLA). Shear stress was applied to hirudinized blood, using a cone-and-plate(let) analyzer. ⋯ In conclusion, shear stress per se enhances PLA formation. With agonist stimulation, shear stress enhances PLA formation primarily mediated by integrins, but attenuates PLA formation primarily mediated by P-selectin. The present results indicate that P-selectin-mediated bridging is essential for the initiation of PLA formation, while integrin-bridgings contribute importantly to the stability of heterotypic conjugates under high shear stress.