Sassi Mouna, Chakroun Taher, Mbemba Elisabeth, Van Dreden Patrick, Elalamy Ismail, Larsen Annette K, Gerotziafas Grigoris T
1 Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, Institut National de la Santé et de la Recherche Médicale (INSERM) U938, Sorbonne Universities, Université Pierre et Marie Curie (UPMC), Paris, France.
2 Laboratoire de Biologie, Centre de Maternité et de Néonatologie, Hôpital Fattouma Bourguiba, Monastir, Tunisia.
Clin Appl Thromb Hemost. 2017 Mar;23(2):155-163. doi: 10.1177/1076029616665922. Epub 2016 Sep 24.
A documented relationship between ovarian cancer and thrombosis does exist. Low-molecular-weight heparins (LMWHs) are cornerstone drugs in the primary prevention and treatment of venous thromboembolic events in patients with cancer. However, cancer cells may alter the efficiency of these antithrombotic agents.
We aimed to characterize the procoagulant phenotype of human epithelial ovarian adenocarcinoma cells, IGROV1, and to compare the capacity of tinzaparin and enoxaparin to inhibit thrombin generation triggered by these cells.
Thrombin generation induced by different concentrations of IGROV1 cells on platelet poor plasma (PPP) was assessed by the calibrated automated thrombogram assay. Tissue factor (TF) expression was studied using Western blot analysis. Then, the experimental model of thrombin generation was used to compare the inhibitory effect of clinically relevant concentrations of both tinzaparin and enoxaparin. The inhibitory concentration 50 (IC50) of the mean rate index and the endogenous thrombin potential and the 2-fold increase in lag time were analyzed on the basis of the anti-Xa and anti-IIa activities of the LMWHs.
IGROV1 cells suspended into PPP resulted in a significant increase in thrombin generation in the absence of any exogenous source of TF and phospholipids. Tissue factor was expressed by IGROV1 cells. Tinzaparin was a more potent inhibitor of thrombin generation than enoxaparin. The inhibition of thrombin generation induced by IGROV1 cancer cells depended mainly on the anti-Xa activity of the LMWHs.
This experimental study in ovarian cancer cells demonstrates that the antithrombotic activity of LMWHs is not completely predicted by the anti-Xa or anti-IIa activities measured in PPP.
卵巢癌与血栓形成之间确实存在已被证实的关联。低分子量肝素（LMWHs）是癌症患者静脉血栓栓塞事件一级预防和治疗的基础药物。然而，癌细胞可能会改变这些抗血栓药物的疗效。
我们旨在描述人上皮性卵巢腺癌细胞IGROV1的促凝表型，并比较替扎肝素和依诺肝素抑制这些细胞引发凝血酶生成的能力。
通过校准自动血栓图分析法评估不同浓度的IGROV1细胞在乏血小板血浆（PPP）上诱导的凝血酶生成情况。使用蛋白质印迹分析研究组织因子（TF）的表达。然后，利用凝血酶生成实验模型比较临床相关浓度的替扎肝素和依诺肝素的抑制作用。根据低分子量肝素的抗Xa和抗IIa活性分析平均速率指数、内源性凝血酶潜力的半数抑制浓度（IC50）以及滞后时间增加2倍的情况。
悬浮于PPP中的IGROV1细胞在没有任何外源性TF和磷脂来源的情况下导致凝血酶生成显著增加。IGROV1细胞表达组织因子。替扎肝素比依诺肝素更有效地抑制凝血酶生成。IGROV1癌细胞诱导的凝血酶生成抑制主要取决于低分子量肝素的抗Xa活性。
这项在卵巢癌细胞中的实验研究表明，低分子量肝素的抗血栓活性不能完全通过在PPP中测得的抗Xa或抗IIa活性来预测。
