Factor VIIa interaction with EPCR modulates the hemostatic effect of rFVIIa in hemophilia therapy: mode of its action
Factor VIIa interaction with EPCR modulates the hemostatic effect of rFVIIa in hemophilia therapy: mode of its action
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DOI：
10.1182/bloodadvances.2016004143
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发表时间：
2017-06-01
期刊：
影响因子：
7.5
通讯作者：
Rao, L. Vijaya Mohan
中科院分区：
文献类型：
--
作者：
Keshava, Shiva;Sundaram, Jagan;Rao, L. Vijaya Mohan
最近的研究表明，凝血因子VIIa（FVIIa）结合内皮细胞蛋白C受体（EPCR）。据推测，FVIIa与EPCR的相互作用可能增强重组FVIIa（rFVIIa）在治疗条件下的止血作用。本研究旨在研究FVIIa与EPCR相互作用促进rFVIIa在血友病治疗中止血作用的机制。活性位点抑制的FVIIa能够与EPCR结合，但不能激活因子X，降低了纠正小鼠血友病模型系统中隐静脉损伤后出血所需的rFVIIa浓度。与表达正常水平EPCR的血友病小鼠相比，EPCR过度表达的血友病小鼠需要更高剂量的rFVIIa来恢复止血。在EPCR缺陷小鼠中，FVIII抗体给药仅诱导轻度血友病性出血，低剂量rFVIIa可完全纠正。给予治疗浓度的rFVIIa可增加EPCR过表达小鼠的血浆蛋白C水平，表明rFVIIa可取代EPCR中的蛋白C。EPCR水平未显著改变血浆中rFVIIa的生物利用度。总体而言，我们的数据表明EPCR水平影响rFVIIa治疗血友病的止血效果。我们目前的研究结果表明，FVIIa置换EPCR中的抗凝蛋白C，导致活化蛋白C生成下调，而不是EPCR-FVIIa对因子X活化的直接影响，是FVIIa与EPCR相互作用促进rFVIIa在血友病治疗中止血作用的机制。
Recent studies established that clotting factor VIIa (FVIIa) binds endothelial cell protein C receptor (EPCR). It has been speculated that FVIIa interaction with EPCR might augment the hemostatic effect of recombinant FVIIa (rFVIIa) in therapeutic conditions. The present study is carried out to investigate the mechanism by which FVIIa interaction with EPCR contributes to the hemostatic effect of rFVIIa in hemophilia therapy. Active-site inhibited FVIIa, which is capable of binding to EPCR but has no ability to activate factor X, reduced the concentration of rFVIIa required to correct the bleeding following the saphenous vein injury in mouse hemophilia model systems. Higher doses of rFVIIa were required to restore hemostasis in EPCR-overexpressing hemophilia mice compared with hemophilia mice expressing normal levels of EPCR. Administration of FVIII antibody induced only mild hemophilic bleeding in EPCR-deficient mice, which was corrected completely with a low dose of rFVIIa. Administration of therapeutic concentrations of rFVIIa increased plasma protein C levels in EPCR-overexpressing mice, indicating the displacement of protein C from EPCR by rFVIIa. EPCR levels did not significantly alter the bioavailability of rFVIIa in plasma. Overall, our data indicate that EPCR levels influence the hemostatic effect of rFVIIa in treating hemophilia. Our present findings suggest that FVIIa displacement of anticoagulant protein C from EPCR that results in downregulation of activated protein C generation and not the direct effect of EPCR-FVIIa on factor X activation is the mechanism by which FVIIa interaction with EPCR contributes to the hemostatic effect of rFVIIa in hemophilia therapy.