Pharmacological concentrations of recombinant factor VIIa restore hemostasis independent of tissue factor in antibody-induced hemophilia mice.
Pharmacological concentrations of recombinant factor VIIa restore hemostasis independent of tissue factor in antibody-induced hemophilia mice.
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DOI：
10.1111/jth.13244
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发表时间：
2016-03
期刊：
影响因子：
--
通讯作者：
Rao LV
中科院分区：
文献类型：
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作者：
Keshava S;Sundaram J;Rajulapati A;Pendurthi UR;Rao LV
重组因子 VIIa (rFVIIa) 已广泛用于治疗具有针对因子 VIII 或 IX 的抑制性自身抗体的血友病患者。其作用机制尚不完全清楚。大多数体外研究表明，rFVIIa 的药理学浓度以磷脂依赖性机制恢复血友病的止血，与组织因子 (TF) 无关。然而，一些研究表明，TF 依赖性机制在 rFVIIa 纠正血友病患者出血中起主要作用。在这里，我们采用 TF 转基因小鼠中 FVIII 抗体诱导的血友病模型系统研究了 TF 在 rFVIIa 诱导的血友病止血中的潜在贡献。对表达低水平人TF的小鼠（LTF小鼠）、相对高水平人TF（HTF小鼠）或野生型小鼠（WT小鼠）施用中和性抗FVIII抗体以在这些小鼠中诱导血友病。然后用不同浓度的rFVIIa处理小鼠。用隐静脉出血模型评估rFVIIa诱导的止血。 FVIII 抑制性抗体的施用诱导了所有三种基因型的血友病出血表型。 rFVIIa 给药挽救了所有三种基因型的出血表型。在给予 FVIII 抗体的 LTF 和 HTF 小鼠中，rFVIIa 诱导的出血纠正没有观察到显着差异。我们的结果提供了强有力的证据支持rFVIIa药理剂量的止血作用源于不依赖于TF的机制。
Recombinant factor VIIa (rFVIIa) has been used widely for treating hemophilia patients with inhibitory autoantibodies against factor VIII or IX. Its mechanism of action is not entirely known. A majority of in vitro studies suggested that pharmacological concentrations of rFVIIa restore hemostasis in hemophilia in a phospholipid-dependent mechanism, independent of tissue factor (TF). However, a few studies suggested that a TF-dependent mechanism plays a primary role in rFVIIa correction of bleeding in hemophilia patients. Here, we investigated the potential contribution of TF in rFVIIa-induced hemostasis in hemophilia employing a model system of FVIII antibody-induced hemophilia in TF transgenic mice. Mice expressing low levels of human TF (LTF mice), relatively high levels of human TF (HTF mice) or wild-type mice (WT mice) were administered with neutralizing anti-FVIII antibodies to induce hemophilia in these mice. The mice were then treated with varying concentrations of rFVIIa. rFVIIa-induced hemostasis was evaluated with the saphenous vein bleeding model. Administration of FVIII inhibitory antibodies induced the hemophilic bleeding phenotype in all three genotypes. rFVIIa administration rescued the bleeding phenotype in all three genotypes. No significant differences were observed in rFVIIa-induced correction in the bleeding of LTF and HTF mice administered with FVIII antibodies. Our results provide strong evidence supporting that the hemostatic effect of pharmacological doses of rFVIIa stems from a TF-independent mechanism.