Department of Pharmacology and Toxicology, CSL Behring GmbH, Marburg, Germany.
Department of Clinical Research and Development, CSL Behring GmbH, Marburg, Germany.
PLoS One. 2021 Oct 6;16(10):e0258192. doi: 10.1371/journal.pone.0258192. eCollection 2021.
Acquired coagulopathy may be associated with bleeding risk. Approaches to restore haemostasis include administration of coagulation factor concentrates, but there are concerns regarding potential prothrombotic risk. The present study assessed the prothrombotic potential of four-factor prothrombin complex concentrate (4F-PCC) versus activated PCC (aPCC) and recombinant factor VIIa (rFVIIa), using three preclinical animal models.
The first model was a modified Wessler model of venous stasis-induced thrombosis in rabbit, focusing on dilutional coagulopathy; the second model employed the same system but focused on direct oral anticoagulant reversal (i.e. edoxaban). The third model assessed the prothrombotic impact of 4F-PCC, aPCC and rFVIIa in a rat model of ferric chloride-induced arterial thrombosis.
In the first model, thrombi were observed at aPCC doses ≥10 IU/kg (therapeutic dose 100 IU/kg) and rFVIIa doses ≥50 μg/kg (therapeutic dose 90 μg/kg), but not 4F-PCC 50 IU/kg (therapeutic dose 50 IU/kg). The impact of 4F-PCC (up to 300 IU/kg) on thrombus formation was evident from 10 minutes post-administration, but not at 24 hours post-administration; this did not change with addition of tranexamic acid and/or fibrinogen concentrate. 4F-PCC-induced thrombus formation was lower after haemodilution versus non-haemodilution. In the second model, no prothrombotic effect was confirmed at 4F-PCC 50 IU/kg. The third model showed lower incidence of thrombus formation for 4F-PCC 50 IU/kg versus aPCC (50 U/kg) and rFVIIa (90 μg/kg).
These results suggest that 4F-PCC has a low thrombotic potential versus aPCC or rFVIIa, supporting the clinical use of 4F-PCC for the treatment of coagulopathy-mediated bleeding.
获得性凝血障碍可能与出血风险相关。恢复止血的方法包括输注凝血因子浓缩物，但存在潜在促血栓形成风险的担忧。本研究使用三种临床前动物模型评估了四因子凝血酶原复合物浓缩物（4F-PCC）与活化凝血酶原复合物（aPCC）和重组因子 VIIa（rFVIIa）的促血栓形成潜力。
第一个模型是改良的 Wessler 兔静脉淤滞性血栓形成模型，重点关注稀释性凝血障碍；第二个模型采用相同的系统，但侧重于直接口服抗凝剂逆转（即依达肝素）。第三个模型评估了 4F-PCC、aPCC 和 rFVIIa 在氯化铁诱导的大鼠动脉血栓形成模型中的促血栓形成作用。
在第一个模型中，在 aPCC 剂量≥10IU/kg（治疗剂量 100IU/kg）和 rFVIIa 剂量≥50μg/kg（治疗剂量 90μg/kg）时观察到血栓，但 4F-PCC 50IU/kg（治疗剂量 50IU/kg）时没有观察到。4F-PCC（高达 300IU/kg）对血栓形成的影响在给药后 10 分钟即可显现，但在给药后 24 小时则不然；与添加氨甲环酸和/或纤维蛋白原浓缩物一起，这种情况并没有改变。与非血液稀释相比，血液稀释后 4F-PCC 诱导的血栓形成减少。在第二个模型中，4F-PCC 50IU/kg 时未证实有促血栓形成作用。第三个模型显示，与 aPCC（50U/kg）和 rFVIIa（90μg/kg）相比，4F-PCC 50IU/kg 的血栓形成发生率较低。
这些结果表明，与 aPCC 或 rFVIIa 相比，4F-PCC 的血栓形成潜力较低，支持临床使用 4F-PCC 治疗凝血障碍性出血。
