Laboratoire de Recherches sur la Croissance Cellulaire, la Réparation et la Régénération Tissulaires UMR CNRS 7149, Université Paris Val de Marne, Avenue du Général de Gaulle, 94010, Créteil cedex, France.
Cancer Chemother Pharmacol. 2011 Oct;68(4):847-54. doi: 10.1007/s00280-010-1553-0. Epub 2011 Jan 13.
Bexarotene, (LGD1069, Targretin), is an antitumoral agent used as chemotherapy in the treatment of cutaneous T-cell lymphoma. Therapy with bexarotene is accompanied by adverse events, such as, bleeding, hemorrhage, and coagulopathy
In order to design applications for bexarotene, it was very important to gain an understanding of how bexarotene inhibits blood clotting
We investigated the interaction between bexarotene or vehicle alone, and coagulation factors or blood cells. We used both in vitro and in vivo assays. Anticoagulant activity of bexarotene or vehicle was assessed by clotting time tests (TT, RT, APTT, and PT). Coagulation factors activity was measured by adding diluted test plasma to artificially prepared factor-deficient plasma. Direct interactions between bexarotene and factor Xa were studied by chromogenic substrate assay. A mouse model was used to investigate in vivo effects of the drug on blood system and for evaluation of clinical hematology and organ pathology.
Increases in clotting times (prothrombin time and activated thromboplastin time) occurred with bexarotene in in vitro and in vivo experiments. We detected no significant influence of bexarotene on factors II, V, VII, VIII, XI and XII, while factor IX and factors X were affected. Bexarotene exerts anticoagulant effects and acts mainly as a direct factor IX and factor X inhibitor. On the contrary, the vehicle is remarkably inert toward the coagulation system. The number of blood cells was unaffected in mice treated with bexarotene or with the vehicle.
Monitoring of the coagulation factors profile should be considered in cancer patients receiving bexarotene, particularly those with a known diagnosis of coagulation factors deficient.
贝沙罗汀（LGD1069，他扎罗汀）是一种抗肿瘤药物，用于治疗皮肤 T 细胞淋巴瘤的化疗。贝沙罗汀治疗伴随着不良反应，如出血、出血和凝血障碍。
为了设计贝沙罗汀的应用，了解贝沙罗汀如何抑制血液凝固非常重要。
我们研究了贝沙罗汀或单独载体与凝血因子或血细胞之间的相互作用。我们使用了体外和体内试验。通过凝血时间试验（TT、RT、APTT 和 PT）评估贝沙罗汀或载体的抗凝活性。通过将稀释的测试血浆加入人工制备的因子缺乏血浆中测量凝血因子活性。通过显色底物测定法研究贝沙罗汀与因子 Xa 之间的直接相互作用。使用小鼠模型研究药物对血液系统的体内影响，并评估临床血液学和器官病理学。
在体外和体内实验中，贝沙罗汀增加了凝血时间（凝血酶原时间和活化部分凝血活酶时间）。我们没有检测到贝沙罗汀对因子 II、V、VII、VIII、XI 和 XII 有显著影响，而因子 IX 和因子 X 受到影响。贝沙罗汀具有抗凝作用，主要作为直接因子 IX 和因子 X 抑制剂。相反，载体对凝血系统的活性明显惰性。用贝沙罗汀或载体处理的小鼠的血细胞数量没有变化。
接受贝沙罗汀治疗的癌症患者，特别是已知存在凝血因子缺乏症的患者，应考虑监测凝血因子谱。
