Therapeutic roles of heparin anticoagulants in cancer and related disorders.

Cancer represents a major cause of overall mortality, second to cardiovascular disorders. Cancer patients frequently encounter hypercoagulable states, with recurrent thromboembolic events due to the impact of cancer cells and chemotherapy/radiotherapy on the coagulation cascade. The expression of highly procoagulant proteins have been implicated to involve in tumor cell-induced thrombin generation, leading to platelet activation and fibrin clot formation. These include binding of heparin to angiogenic growth factors (e.g., basic fibroblast growth factor and vascular endothelial growth factor); modulation of tissue factor (TF); and enhanced TF-pathway-inhibitor release, and inhibition of matrix-degrading enzymes. The classical anticoagulant (unfractionated heparin; UFH), and its derived low-molecular-weight heparins (LMWH) are polypharmacologic agents. These anticoagulants are composed of oligosccharides with structural/molecular heterogeneity. Heparins bind to wide range of molecules via electrostatic interactions with the glycosaminoglycan chains, and hence possess numerous therapeutic properties beyond their anticoagulant effects, including anti-cancer potentials. Recent studies demonstrate that UFH and LMWH fractions interfere with various cellular/inflammatory processes and reduce mortality/morbidity in malignancy-associated thrombosis and vascular disorders. There are certain weaknesses of heparins, particularly when patients receiving prolonged therapy, including bleeding complications. Paradoxically, many individuals receiving heparin anticoagulants develop antibodies against the complex formed between heparin and platelet factor 4 because of massive platelet/cellular activation and hypercoagulable state, resulting in clinical manifestation referred to as heparin-induced thrombocytopenia (HIT) syndrome. Increased risk of venous thromboembolic events are likely in individuals with malignancy-associated thrombosis coupled with underlying HIT pathogenesis. This article will review the existing knowledge about the experimental/clinical anti-cancer properties of heparin anticoagulants and provide a rationale for future research.