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Recombinant human activated protein C as a therapy for pre-eclampsia Peng, Gang
INTRODUCTION: Pre-eclampsia remains one of the most common causes of maternal mortality in the developed world, and we still have no known effective prophylaxis and proven modifiers. The recent successful clinical trial of recombinant human activated protein C (rhAPC) in the management of SIRS (systemic inflammatory response syndrome) has drawn attention to the possible use of this medicine for other conditions. Pre-eclampsia, has remarkable similarity to SIRS and may be such a condition. METHODS: We established the safety and the efficacy of rhAPC in two scenarios: early-onset pre-eclampsia and severe postpartum pre-eclampsia. Twenty one women were enrolled in the trial; the rhAPC infusion ran at 24 μg/kg/h for up to 96h. For basic research, blood samples were drawn at 0.5 hr before rhAPC infusion, 4 hr, 28 hr, 52 hr and 76 hr of infusion, and 4 hr after infusion was stopped. The influence of rhAPC on haemostatic parameters were measured by Thromboelastography (R-time, etc.) and ELISA, the regulatory effects on the activities of circulating cytokines were detected by Luminex assay, the Mrna and protein levels of peripheral blood neutrophil components were tested by real-time RT-PCR and Western immunoblotting. RESULTS: R-time (clotting time) in postnatal patients was significantly delayed by rhAPC (p =0.0454, 28hr: 29.7%; 52hr and 72hr: 60.9%). The infusion also resulted in significant decreases in post-natal Fl+2 (4hr: 2.9%; 28hr: 22.4%; p =0.0218), PAI-1 (4hr: 23.6%; 28hr: 69.0%; p =0.0078), IL-6 (4hr: 18.8%; 28hr: 49.8%; p =0.0319) and IL-10 (4hr: 30.7%; 28hr: 36.6%; p =0.0317) concentration respectively. Moreover, rhAPC caused significant reduction in post-natal neutrophil TLR-2 (p =0.0002), TLR-4 (p≺0.0001) and cryopyrin (p≺0.0001) mRNA expression respectively. Significant up-regulation of caspase-3, at the same time, have been observed in antepartum patients (p =0.0323). CONCLUSIONS: rhAPC exhibits anticoagulant effect. It may also stimulate fibrinolysis by forming a complex with or degrading PAI-1. Its therapeutic mechanism partly depends on its inhibitory effect on the deleterious Thl type cytokines and pro-inflammatory cytokines. It may repress the activation of neutrophils in postnatal pre-eclampsia through TLR-2, -4 and cryopyrin signaling pathways and promote apoptosis of neutrophils via caspase-3.
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