Role of current and emerging antithrombotics in thrombosis and cancer
Role of current and emerging antithrombotics in thrombosis and cancer
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DOI：
10.1358/dot.2006.42.5.973580
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发表时间：
2006-05-01
期刊：
影响因子：
1.8
通讯作者：
Mousa, Shaker A.
中科院分区：
文献类型：
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作者：
Mousa, Shaker A.
自Trousseau首次描述癌症患者的游走性血栓性静脉炎以来，近130年来，血栓栓塞已成为癌症的公认表现和并发症。凝血系统在癌症中被激活，并通过化疗、放疗或手术治疗进一步放大。高凝状态在几乎所有的癌症类型中都有记载，尽管发生率不同，并且是癌症患者死亡的第二大原因。凝血激活和癌变之间的关系支持癌症是一种高凝状态的观点，并对血栓形成的发展、肿瘤生长的增强和不良临床结局的风险具有影响。虽然癌症可以激活凝血级联反应是公认的，但凝血系统的激活也可能支持肿瘤进展，这一点鲜为人知。此外，癌症患者的血小板活化及其对肿瘤进展和转移的影响进一步扩大了止血系统在恶性肿瘤中的作用。转移性疾病患者的血栓形成问题是临床医生严重关注的问题。本文综述了凝血和血小板活化在癌症中的作用机制及其临床意义。癌症静脉血栓栓塞的预防和治疗也将通过回顾关键临床研究的数据进行讨论。最后，将探讨低分子量肝素作为抗凝血剂的新作用。华法林和普通肝素已经在临床上使用了50多年。两者都是有效的抗凝剂，但它们的使用与许多障碍有关，包括需要加强凝血监测，剂量-反应关系的广泛变化，多种药物相互作用（华法林）和严重的免疫介导的血小板减少症（肝素）。低分子量肝素的引入通过提高疗效和消除对强化凝血监测的需要来推进抗凝治疗。Fonclaparinux是第一种选择性Xa因子抑制剂，代表了抗凝治疗的又一进步。磺达肝癸钠通过与抗凝血酶（血浆中唯一的生理靶点）快速且强烈结合，特异性催化Xa因子的抑制，从而对凝血酶生成产生有效且呈线性剂量依赖性的抑制。此外，因子Xa活性的有效抑制损害了组织因子/因子Vila复合物的活化，导致由组织因子/因子Vila诱导的促凝血状态、促血管生成和促炎因子的下调。此外，许多口服活性的直接抗凝血酶和抗Xa因子正处于各种血栓栓塞性疾病的高级临床开发中。(c)2006年，《科学》杂志。All rights reserved.
In the nearly 130 years since Trousseau first described migratory thrombophlebitis in cancer patients, thromboembolism has become a well-established presenting sign and complication of cancer. The coagulation system is activated in cancer and is further amplified by treatment with chemotherapy, radiation or surgery. Hypercoagulation is documented in virtually all cancer types, albeit at different rates, and is the second leading cause of death in cancer patients. The relationship between clotting activation and carcinogenesis supports the view of cancer as a hypercoagulable state and holds implications for the development of thrombosis, enhancement of tumor growth and risk of poor clinical outcomes. Although it is well recognized that cancer can activate the coagulation cascade, it is less well known that activation of the coagulation system may also support tumor progression. Additionally, platelet activation in cancer patients and its impact on tumor progression and metastasis further expand the role of the hemostatic system in malignancy.The problem of thrombosis in patients with metastatic diseases is a serious concern for clinicians. This review explores the mechanisms and clinical implications of coagulation and platelet activation in cancer. The prevention and treatment of venous thromboembolism in cancer will also be discussed by reviewing data from key clinical investigations. Finally, the emerging role of low-molecular-weight heparin as an antineoplastic agent will be explored. Warfarin and unfractionated heparin have been in clinical use for more than 50 years. Both are effective anticoagulants, but their use is associated with a number of impediments, including the need for intensive coagulation monitoring, wide variation in dose-response relationships, multiple drug interactions (in the case of warfarin), and serious immune-mediated thrombocytopenia (in the case of heparin). The introduction of low-molecular weight heparin advanced anticoagulation therapy by enhancing efficacy and eliminating the need for intensive coagulation monitoring. Fonclaparinux, the first selective factor Xa inhibitor, represents yet another improvement in anticoagulation therapy. By binding rapidly and strongly to antithrombin, its sole physiologic target in plasma, fondaparinux catalyzes specifically the inhibition of factor Xa, which results in effective and linear dose-dependent inhibition of thrombin generation. Additionally, efficient inhibition of factor Xa activity impairs the activation of tissue factor/factor Vila complex leading to downregulation of procoagulant state, proangiogenesis, and proinflammatory factors induced by tissue factor/factor Vila. Furthermore, a number of orally active direct antithrombin and anti-factor Xa are in advanced clinical development for various thromboembolic disorders. (c) 2006 Prous Science. All rights reserved.