Inhibitors of Hemostatic System in Cancer: Basic and Clinical Aspects

The first notion about the association of hemostatic system dysfunction with malignant disease was published more than 100 years ago. Since then, numerous experimental studies have been performed revealing underlying pathophysiologic mechanisms of this phenomenon. It is widely known that coagulation and fibrinolytic system components not only play a role in thromboembolic and hemorrhagic complications of the disease but also contribute to cancer progression. The current issue of Seminars in Thrombosis and Hemostasis focuses on the role of inhibitors of the hemostatic system in cancer. This issue contains articles that review in detail the results of experimental studies on the biological role of the inhibitors and articles that deal with clinical aspects of current achievements in the field.

The first article summarizes available information on the role of the majority of hemostatic endogenous inhibitors in cancer and on the activity of pharmacological compounds that resemble the activity of the naturally occurring inhibitors or interfere with tumor growth and metastatic spread. The influence of coagulation and fibrinolytic inhibitor deregulation on pathophysiology of thromboembolic and bleeding complications in patients with malignancy is described. Moreover, the article describes the biological function of the inhibitors, which in numerous pathologic processes is independent of their role in hemostasis. Interestingly, hemostatic system inhibitors contribute to both the natural course of cancer and to complications of anticancer treatment (e.g., after radiation therapy). The article points to the possibilities of introducing the inhibitors or agents interfering with them as novel, adjunct forms of anticancer therapy.

In the next article, Amirkhosravi and colleagues comprehensively discuss the role of tissue factor pathway inhibitor (TFPI) in cancer. There is growing evidence that this inhibitor reduces metastases formation and interferes with angiogenesis, a rate-limiting process in tumor growth and dissemination. This activity opens the possibility of introducing the inhibitor to the panel of anticancer compounds. Releasing TFPI from the endothelial cell pool is one of the multiple activities of heparin, commonly instituted in patients with malignancy. Of interest are recent results of a study on the effect of a novel non-anticoagulant low-molecular-weight heparin (LMWH) that retains TFPI releasing function. It was proved that in cancer patients, the antimetastatic effect of LMWH is independent of coagulation inhibition.

The next article summarizes information on the expression and activity of TFPI-2 in cancer patients. This inhibitor is thought to serve as a maintenance factor for normal tissue, whereas its expression gradually decreases during cancer progression. Its role in apoptosis and angiogenesis is also reviewed. Several mechanisms leading to downregulation of TFPI-2 expression in cancer tissue are described. Restoration of TFPI-2 expression in experimental models of tumor tissue inhibits invasion, tumor growth, and metastasis, which creates a novel possibility of cancer patient treatment.

O'Reilly introduces readers to the issue of antiangiogenic antithrombin. It is widely known that cancer cannot grow beyond a few cubic millimeters without formation of a new blood vessel network supplying proliferating tumor cells. Hemostatic system components strongly contribute to the process of angiogenesis. Moreover, there are hidden angiogenesis inhibitors among the proteins of the coagulation and fibrinolysis components. One of these inhibitors is antiangiogenic antithrombin, which derives from the antithrombin molecule. Recently, antiangiogenic agents were successfully introduced to the clinic. Thus, searching for new inhibitors of angiogenesis is of particular interest.

Recently, attention has been given to the function of activated protein C (APC) and its inhibitor, protein C inhibitor (PCI), in tumor biology. The proteins were demonstrated to play various roles not only in the regulation of hemostasis but also in inflammation, proliferation, apoptosis, tumor cell migration, and invasion and metastasis. Suzuki and Hayashi summarize the role of APC and PCI in the malignancy.

The article by Hanly and Winter describes the results of studies on thrombomodulin in cancer biology. This natural endothelial anticoagulant, apart from its role in inflammation and thrombosis, is a cytoprotectant in many types of cancer, and as such, increased thrombomodulin expression serves as a positive predictive and prognostic factor.

The role of protease activated receptor (PAR) is widely recognized. Of interest, the activity of the receptor plays an essential role also in cancer growth and metastatic dissemination. PAR serves as a receptor for thrombin; however, other factors, such as tissue factor (TF) and factors VII and X, are documented to induce PAR downstream signaling as well. All the above-mentioned coagulation factors contribute to cancer progression. Thus, blocking the activity of PAR is a possible option for repealing this biological effect. Tsopanoglou and Maragoudakis performed experimental studies in which they elegantly demonstrated that small molecules blocking the activity of PAR-1 receptor inhibit angiogenesis. The review outlines the data obtained.

Numerous clinical studies performed in cancer patients undergoing heparin treatment due to thromboembolic complications suggested that the role of heparin exceeds its solely anticoagulant effect as the patients enjoyed longer overall survival. The review compiled by Falanga and Marchetti deals with mechanisms of heparin activity and presents the rationale for its administration in anticancer treatment.

A role of oral anticoagulants in cancer is discussed in the article by Weitz and Leibman. Observation of activation of the coagulation system in malignancy led clinicians to a hypothesis that administration of vitamin K antagonists would be a beneficial option for anticancer treatment. Unfortunately, oral anticoagulants did not fulfill the expectations. However, none of the studies on vitamin K antagonists in humans with cancer were adequately designed or sufficiently powered to definitively exclude an effect on cancer patient survival.

The next two articles focus on current clinical issues of anticoagulant administration in cancer patients. Thromboembolic episodes are frequent in this population of patients. They may be the only symptom of so-called occult malignancy and complicate the natural course of cancer or its treatment. They may be diagnosed at any stage of malignancy; however, their highest incidence is predominately observed at an advanced stage of the disease. Thromboembolic episodes are one of the most frequent causes of cancer patient death. Thus, appropriate prophylaxis and treatment of the complication is required. Lee comprehensively presents the updated guidelines for prevention of thromboembolic complications in cancer patients.

In turn, Petralia and Kakkar extensively discuss current recommendations for management of cancer-related thromboembolism and secondary prophylaxis. They also provide evidence-based analysis of clinical data regarding the impact of LMWH administration on survival of cancer patients who have thromboembolic disease.

For many years, much experimental data provided extensive evidence that platelets contribute to the metastatic process. Recent developments also pointed to their influence on angiogenesis and proteolytic events during cancer progression. The final article presents a pathophysiologic rationale for employment of antiplatelet modalities, such as antibodies against glycoprotein (GP)IIb-IIIa, direct thrombin inhibitors, PAR-1 targeted therapy, as well as cyclooxygenase (COX) and lipoxygenase (LOX) inhibitors, in anticancer therapy. Interestingly, despite convincing experimental data, none of the new specific antiplatelet agents have yet been tested in clinical trials in cancer patients.

We would like to thank all the authors for their valuable contributions. We hope that this issue of Seminars in Thrombosis and Hemostasis will provide hematologists and oncologists as well as basic scientists with a better understanding of the problem of hemostatic abnormalities in cancer and be useful in their everyday practices.