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Role of current and emerging antithrombotics in thrombosis and cancer.

机译：当前和新兴抗血栓药在血栓形成和癌症中的作用。

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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 roleof 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.
机译：自Trousseau首次在癌症患者中描述迁徙性血栓性静脉炎以来，近130年来，血栓栓塞已成为公认的癌症表现和并发症。凝血系统在癌症中被激活，并通过化学疗法，放射疗法或外科手术进一步放大。几乎在所有类型的癌症中都记录有高凝现象，尽管发生率不同，并且是癌症患者第二大死亡原因。凝血激活与癌变之间的关系支持将癌症视为高凝状态，并对血栓形成的发展，肿瘤生长的增强和不良临床结果的风险具有影响。尽管众所周知癌症可以激活凝血级联反应，但鲜为人知的是，凝血系统的激活也可以支持肿瘤的进展。另外，癌症患者中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。转移性疾病患者中的血栓形成问题是临床医生严重关注的问题。这篇综述探讨了癌症中凝血和血小板活化的机制及其临床意义。癌症中静脉血栓栓塞的预防和治疗也将通过回顾来自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肿瘤药的新兴作用。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，但是它们的使用存在许多障碍，包括需要加强凝结监测，剂量反应关系的广泛差异，多种药物相互作用（对于华法林而言）以及严重的免疫介导的血小板减少症（如果是肝素）。低分子量肝素的引入通过增强疗效并消除了对强化凝血监测的需求，进行了先进的抗凝治疗。第一种选择性Xa抑制剂Fondaparinux代表了抗凝疗法的又一进步。通过与血浆中唯一的生理指标抗凝血酶快速而牢固地结合，磺达肝素可特异性催化Xa因子的抑制，从而有效，线性地剂量依赖性地抑制凝血酶的产生。另外，对因子Xa活性的有效抑制削弱了组织因子/因子VIIa复合物的激活，从而导致由组织因子/因子VIIa诱导的促凝状态，促血管生成和促炎因子的下调。此外，针对各种血栓栓塞性疾病，许多口服活性直接抗凝血酶和抗凝血因子Xa处于先进的临床开发中。

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