Mousa Shaker A
Pharmaceutical Research Institute, Albany College of Pharmacy, Albany, New York, USA.
Timely Top Med Cardiovasc Dis. 2006 Aug 1;10:E19.
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. Fondaparinux, 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 VIIa complex leading to downregulation of procoagulant state, pro-angiogenesis, and proinflammatory factors induced by tissue factor/factor VIIa. Furthermore, a number of orally active direct antithrombin and anti-factor Xa are in advanced clinical development for various thromboembolic disorders.
自特鲁索首次描述癌症患者的游走性血栓性静脉炎以来的近130年里，血栓栓塞已成为一种公认的癌症表现体征和并发症。癌症会激活凝血系统，而化疗、放疗或手术治疗会进一步加剧这种激活。几乎所有癌症类型都会出现高凝状态，尽管发生率不同，高凝状态是癌症患者的第二大死亡原因。凝血激活与致癌作用之间的关系支持了癌症是一种高凝状态的观点，并对血栓形成的发展、肿瘤生长的增强以及不良临床结局的风险具有重要意义。虽然人们已经充分认识到癌症可激活凝血级联反应，但凝血系统的激活也可能支持肿瘤进展这一点却鲜为人知。此外，癌症患者的血小板激活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切的问题。本综述探讨了癌症中凝血和血小板激活的机制及临床意义。还将通过回顾关键临床研究的数据来讨论癌症患者静脉血栓栓塞的预防和治疗。最后，将探讨低分子量肝素作为一种抗肿瘤药物的新作用。华法林和普通肝素已临床应用50多年。两者都是有效的抗凝剂，但它们的使用存在一些障碍，包括需要进行密集的凝血监测、剂量反应关系差异很大、多种药物相互作用（华法林的情况）以及严重的免疫介导性血小板减少症（肝素的情况）。低分子量肝素的引入通过提高疗效和消除密集凝血监测的需求，推动了抗凝治疗的发展。磺达肝癸钠，第一种选择性Xa因子抑制剂，代表了抗凝治疗的又一进步。通过与抗凝血酶迅速而强烈地结合，抗凝血酶是其在血浆中的唯一生理靶点，磺达肝癸钠特异性地催化Xa因子的抑制，这导致对凝血酶生成的有效且呈线性剂量依赖性的抑制。此外，对Xa因子活性的有效抑制会损害组织因子/ VIIa因子复合物的激活，从而导致由组织因子/ VIIa因子诱导的促凝状态、促血管生成和促炎因子的下调。此外，一些口服活性直接抗凝血酶和抗Xa因子药物正处于针对各种血栓栓塞性疾病的晚期临床开发阶段。
