Pro-Coagulant and Pro-Thrombotic Effects of Paclitaxel Mediated by Red Blood Cells

Abstract

Background Paclitaxel is one of the most widely used anti-cancer drugs, but numerous case reports of thrombotic events in the cancer patients using paclitaxel raise concern over its pro-thrombotic risk. Materials and Methods We investigated whether paclitaxel can elicit pro-thrombotic properties in red blood cells (RBCs) through phosphatidylserine (PS) exposure and microvesicle (MV) release. Results In freshly isolated human RBCs, paclitaxel induced thrombin generation through PS exposure and MV release, whereas either coagulation factors or platelets were unaffected. Paclitaxel-induced PS exposure in RBC was mediated by scramblase activation which was induced by calcium-independent protein kinase C (PKC)ζ activation. Paclitaxel also increased RBC-endothelial cell adhesion and RBC aggregate formation which can also contribute to thrombosis. Indeed, intravenous administration of paclitaxel to rats induced PS exposure and PKCζ activation in RBCs in vivo which ultimately promoted venous thrombus formation. Conclusion These results demonstrated that paclitaxel may elicit pro-thrombotic properties in RBCs through PS exposure and MV release, which can ultimately promote thrombus formation.

Incidence and risk factors of symptomatic thrombosis related to peripherally inserted central catheter in patients with lung cancer

“…A previous study (Chung et al., 2007) demonstrated that paclitaxel could induce pro‐coagulant activity in red blood cells through phosphatidylserine exposure and micro‐vesicle release, which could ultimately increase the thrombotic risk. In addition to increasing thrombin generation, paclitaxel could also promote adhesion between red blood cells and endothelial cells as well as aggregation of red blood cells (Kim et al., 2018). As docetaxel has a similar mechanism of action to paclitaxel, it may contribute to thrombosis via the above mechanisms.…”

Phospholipid Scramblases: Role in Cancer Progression and Anticancer Therapeutics

“…Paclitaxel, an established anticancer drug increases PS exposure in RBC that leads to blood coagulation and thrombosis. However, if it leads to over expression of any specific scramblase, remains to be determined ( Kim et al, 2018 ). Synthetic enzyme made from eight DNA strands induces scrambling of ∼ 10 7 lipids in biological membranes.…”

“…Paclitaxel,an alkaloid from Pacific yew tree ( Taxus brevifolia ) stimulates PS exposure in RBCs that leads to blood coagulation and thrombosis ( Kim et al, 2018 ). Paclitaxel induced 60% increase in apoptosis and G2/M phase cell-cycle arrest in Canine mammary cancer cells by down regulating Bcl-2 and up regulating Bax ( Ren et al, 2018 ).…”

Discovery of a Natural Syk Inhibitor from Chinese Medicine through a Docking-Based Virtual Screening and Biological Assay Study

“…Traditional Chinese medicine (TCM), with an over 2000 year history in the treatment of diseases, is a valuable source for drug leads and candidates in the process of drug discovery. Many popular natural compounds, such as artemisinin, berberine, ginkgolide, and paclitaxel, extracted from TCMs, play an important role in disease treatments [10,11,12,13]. In this work, a combined approach involving docking-based virtual screening and bioassay-based validation was performed to identify natural Syk small molecule inhibitors from TCMs.…”