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.