Preface

This issue of Seminars in Thrombosis and Hemostasis, guest edited by Professor Leo R. Zacharski, M.D., discusses the regulation of tumor growth by coagulation-reactive drugs. The close relationship between the hemostasis system and malignancies has long been recognized, especially from the viewpoint of thromboembolic complications. Cancer is one of the well-known risk factors for thromboembolism, especially venous, and there is substantial evidence that malignancies activate the hemostasis system. Equally important, however, is the impact that the hemostasis system has on tumor growth and metastasis. Many components of the hemostasis system, such as platelets, tissue factor, fibrinogen, fibrin, thrombin, fibrinolytic components, and many others, are involved in these complex processes that involve surface adhesion molecules and a variety of hemostasis-unrelated enzyme systems. These complex mechanisms are expertly dissected, and important concepts are developed where the growth and dissemination of malignant cells could be interrupted by already existing, mostly anticoagulantly active medications or where new compounds need to be developed and explored for their efficacy.

In the first article, Zacharski and coworkers review data on how an activation of the fibrinolytic system affects the management of cancers. The fibrinolytic system is intimately involved in tumor growth and dissemination and the course of malignancy can be altered by either inhibition or activation of the fibrinolytic system, depending on specific circumstances. In animal models the generation of plasmin by streptokinase or urokinase retarded growth of certain tumors and extension of metastases. The injection of plasmin had similar effects, especially when coadministered with chemotherapeutic modalities. Some data suggest that plasmin has a direct toxic effect on tumor cells. The authors also review the data available on treating cancer patients with activators of the fibrinolytic system. Although extensive double-blind trials are still missing, the available data suggest a positive impact. The observed variability in results is explained by the findings that different activators of plasminogen act differently on certain types of tumors. There is enough information, however, to initiate appropriate multicenter trials with fibrinolytic activators alone or in combination with chemotherapeutic agents.

The next contribution by Ornstein et al reviews the impact of the coagulation system on the treatment of human gliomas. Patients with these tumors have an activated hemostasis system that may not only lead to venous thromboembolism but also stimulate tumor growth and invasion. Tissue factor (TF) released from these tumors and the subsequent generation of thrombin play a major role. There is evidence that the amount of TF liberated correlates with the extent of the gliomas. TF not only activates the clotting system but also affects tumor cell adhesion and migration. The use of anticoagulants in these patients might, therefore, not only prevent the development of thromboses but also potentially reduce tumor proliferation. Suitable anticoagulants might be low-molecular-weight heparins (LMWHs), a newly developed pentasaccharide, direct thrombin inhibitors, and a variety of compounds that interfere with TF expression. It is suggested that large clinical trials be initiated to optimize treatment of patients with gliomas.

Francis and Amirkhosravi next describe the effects of antihemostatic agents on experimental tumor dissemination. The hypercoagulability associated with malignancies is well known and most patients have clinically overt, compensated disseminated intravascular coagulation. In addition, there is a close relationship between the hemostasis system and cancer dissemination. For this reason, anticoagulant therapy of cancer patients has been advocated. Tissue factor, fibrinogen, fibrin, and platelet adhesion and aggregation play important roles in these events. The authors describe their experimental studies in which the effects of various anticoagulants were examined in animals injected with blood-borne tumor cells. Heparin and oral anticoagulants were found to inhibit metastasis formation. Tumor cells apparently form complexes with platelets and fibrin, which fosters tumor cell adhesion to the vessel wall. Also, administration of platelet function inhibitors impaired tumor cell dissemination. Inhibition of tissue factor by antibodies or by administering tissue factor pathway inhibitor (TFPI) also affected tumor cell adhesion to the vascular wall. The data strongly suggest that tissue factor expression is of major importance in tumor metastasis. It is suggested that major clinical trials with already existing anticoagulants be initiated and that newly developed agents also be studied.

In the following contribution, Trikha and Nakada review the relationship between platelets and malignancies. It is reiterated that platelets play an important role in tumor cell metastasis and that the glycoprotein (Gp) receptors IIb/IIIa are intimately involved. Certain tumor cells induce platelet aggregation, and this correlates with their metastatic potential. In animal experiments blockade of GpIIb/IIIa inhibited dissemination of tumor cells. Platelets also participate in growth and angiogenesis of primary and disseminated tumors. They provide a large supply of angiogenic and mitogenic factors and thus foster growth and angiogenesis. Again, GpIIb/IIIa receptors appear to be involved and blockade of these receptors by, for example, abciximab also inhibits this platelet involvement. There appears to be enough basic information on the role of platelets in tumor dissemination, growth, and angiogenesis that clinical trials with platelet function antagonists should be initiated.

Mousa reviews the information available on the use of anticoagulants in cancer patients. Patients with cancer not only are at risk for developing venous thromboembolism but also frequently present with a thrombotic event before the malignancy is diagnosed. Prevention of thromboembolism can be attempted by administration of unfractionated heparin (UFH) or LMWHs. For long-term treatment, again LMWH as well as oral vitamin K antagonists are the choices. Because angiogenesis, tumor growth, and dissemination are also linked to the hemostasis system, studies are under way to attempt to inhibit these processes by anticoagulants as well. LMWH, TFPI, oral anticoagulants, and a variety of other, newer anticoagulants are being tested, either alone or in combination. Encouraging results on antiangiogenesis are presented.

In the next article Varki and Varki review the status of heparin use in patients with malignancies. Heparin not only is a potent antithrombotic agent and anticoagulant but also was shown to inhibit tumor metastasis. Cancer progression and metastasis are associated with overexpression of sialylated fucosylated mucins, which are similar in structure to selectins, that is, vascular adhesion molecules. Heparin also potently blocks P-selectin, which leads to inhibition of platelet-mucin interactions. Because mucins are vital to survival of circulating cancer cells, heparin reduces cancerous tumor cell survival. In view of this new knowledge, the use of UFH in treating cancer patients should be revisited. Little is yet known about whether LMWHs have the same effects as UFH and, if so, whether different LMWHs have different properties. The authors propose a protocol in which UFH is administered specifically during the interval from initial visualization of a primary cancer until after its surgical removal.

Next, Liu and associates discuss the dynamic regulation of tumor growth and metastasis by heparan sulfate glycosaminoglycans. This review summarizes the views and concepts related to cell surface/extracellular heparan sulfate-like glycosaminoglycans in tumor biology. These complex molecules are intimately involved in tumor initiation, progression, and metastasis. They participate in the regulation of coagulation, growth factor signaling, cell adhesion, proliferation, and mobility. They can either promote or inhibit tumorigenic processes. Although a fair amount of information is known about these heparan sulfate-like glycosaminoglycans, many details have still to be learned. Newer technologies will undoubtedly aid in the exploration of these complex and fascinating molecules.

In the next article, Crosgrove and coworkers review the available evidence on the effects of heparins, especially LMWH, on cancer mortality. Several case studies and meta-analyses seem to suggest that UFH and LMWH improve overall mortality in cancer patients. This improvement is not solely due to reduced thromboembolic risks. There is also evidence to suggest that LMWHs have a better effect than UFH. As described by previous authors in this issue, heparin's antitumor effects are most likely due to alterations of enzyme systems (above and beyond the coagulation-related enzymes), angiogenesis, cellular growth, and tumor dissemination. It is suggested that the present knowledge on the benefits of heparins, especially LMWHs, be expanded by appropriate clinical trials that make use of the presently already available LMWHs. Through these studies, if successful, many lives of cancer patients can potentially be saved.

The last article, by Kommareddy and coworkers, was independently submitted and is placed in this issue because of its relationship to cancer. Very little is described about upper extremity deep venous thrombosis, probably because in most patients it is clinically asymptomatic. This comprehensive review, which discusses this subject from anatomical aspects to pathophysiology, clinical recognition, diagnostic options, and therapy, stresses that upper extremity deep venous thrombosis is a complication of many underlying disease processes, including malignancies, and that catheter placement is probably the most common cause.

I wish to thank all the authors of this issue for their outstanding contributions. My special appreciation goes to Professor Leo R. Zacharski, M.D., for his own contributions and for bringing together such an illustrious group of experts to address this important issue of linking hemostasis with cancer. It is hoped that the complexity of the issues is clearly and understandably presented, and that this work will indeed trigger clinical trials in which a number of existing and newer anticoagulant therapeutics are used as an adjunct to treating cancer patients.