Antimetastatic Agents. I. Role of Cellular Procoagulants in the Pathogenesis of Fibrin Deposition in Cancer and the Use of Anticoagulants and/or Antiplatelet Drugs in Cancer Treatment

Rickles, Frederick R.; Hancock, Wayne W.; Edwards, R. Lawrence; Zacharski, Leo R.

doi:10.1055/s-2007-1002760

Cited by 48 publications

(24 citation statements)

References 26 publications

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“…In spite of the known increased risk for thrombosis in cancer patients receiving outpatient chemotherapy, at present there is no proven safe and effective method for primary prophylaxis. In a pilot study of patients in VA CSP # 75 who were receiving warfarin as adjunctive therapy for cancer [3], we demonstrated that chronic, therapeutic anticoagulation with warfarin was successful in significantly lowering FPA levels (p < 0.005) in 14/18 subjects (Fig. 2), suggesting that the potential for clotting events in these subjects might have been reduced.…”

Section: Cancer Patients Undergoing Chemotherapymentioning

confidence: 89%

“…The two principle tumor cell PCAs are tissue factor (TF), a factor VII-dependent, lipid-dependent cofactor for the activation of factor X, and cancer procoagulant (CP), a direct factor X activator, which functions in the absence of factor VII. The potential importance of these two interesting tumor-associated procoagulants are discussed elsewhere in this issue of Cancer and Metastasis Reviews, and have been reviewed recently [2,3]. In addition, the contribution of inflammatory leukocytes to thrombogenesis has also been assessed recently [2,33].…”

Section: Pathogenesis Of Thromboembolic Compfications Of Cancermentioning

confidence: 99%

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Hemostatic alterations in cancer patients

1992

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Nearly all patients with cancer manifest laboratory evidence of hypercoagulability and some develop clinical thromboembolic disease (TED). Routine laboratory studies of blood coagulation have been performed in several large, prospective trials of the use of anticoagulant drugs in cancer treatment. The results of these studies, as well as data from several smaller studies of more sensitive tests of hypercoagulability [e.g. fibrinopeptide A (FPA); thrombin-antithrombin (TAT) complexes; prothrombin fragment F1 + 2)], indicate that the levels of some clotting proteins parallel disease activity. However, no studies of sound methodologic design have yet been performed to indicate that any of these tests of blood coagulation can serve as adequate predictors of TED in patients with cancer. In addition to the important role played by tumor-related procoagulants, several other mechanisms may be involved in the pathogenesis of thromboembolic events in patients with cancer, including stasis and endothelial damage. Considerable variability in the relative importance of these mechanisms in the pathogenesis of TED may exist among patients with different types of cancer. The risk for TED associated with surgical procedures in cancer patients is substantial and prophylactic antithrombotic therapy should be considered for most of these patients. Chemotherapy and hormonal therapy of cancer probably increases the likelihood of TED, particularly in those subjects with indwelling venous catheters. This risk has been particularly well-studied in patients with breast cancer treated with tamoxifen plus cytotoxic drugs. The pathogenic mechanisms may be complex but vascular injury is likely as a proximate cause of venous access catheter thrombosis and can be prevented with low dose coumadin therapy. The utility of low dose coumadin anticoagulation in reducing the risk for TED during breast cancer treatment is unknown but is currently being tested in a large, multiinstitutional study. Since chronic coumadin anticoagulation of cancer patients, and single pulse dose heparin prior to intravenous chemotherapy, both prevent thrombin generation, these agents may be of use in reducing the risk of chemotherapy-associated thrombosis. Prophylactic anticoagulation should be considered for high risk patients.

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Section: Cancer Patients Undergoing Chemotherapymentioning

confidence: 89%

Section: Pathogenesis Of Thromboembolic Compfications Of Cancermentioning

confidence: 99%

Hemostatic alterations in cancer patients

1992

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“…Lack of inhibition by added CSA, CSB, and CSC in contrast to CSE strongly suggests a direct role of 4,6-di-Osulfated N-acetylgalactosamine GAG structures in the inhibition of intrinsic pathway protease. These findings also suggest potential pharmacologic use of CSE as specific anticoagulant in the management of prothrombotic states mediated by intrinsic pathway coagulation reactions.Mononuclear phagocytes constitute one of the major components in the cellular infiltrates that characterize atherosclerotic, neoplastic, and chronic inflammatory lesions (Ross, 1993;McGee et al, 1978;Rickles et al, 1988). These lesions are also associated with localized blood coagulation reactions and both qualitative and quantitative changes in GAGs 1 content (Wagner and Salisbury, 1989;McGee et al, 1990;Wilcox et al, 1989;Dietrich et al, 1993).…”

mentioning

confidence: 99%

“…Mononuclear phagocytes constitute one of the major components in the cellular infiltrates that characterize atherosclerotic, neoplastic, and chronic inflammatory lesions (Ross, 1993;McGee et al, 1978;Rickles et al, 1988). These lesions are also associated with localized blood coagulation reactions and both qualitative and quantitative changes in GAGs 1 content (Wagner and Salisbury, 1989;McGee et al, 1990;Wilcox et al, 1989;Dietrich et al, 1993).…”

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confidence: 99%

Specific Regulation of Procoagulant Activity on Monocytes

McGee

Teuschler

Parthasarathy

et al. 1995

Journal of Biological Chemistry

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Hypercoagulability of blood, monocytic infiltration, and changes in pericellular and extracellular matrix glycosaminoglycans (GAGs) 1 are observed in atherosclerosis, inflammation, and neoplasia. In the present studies, monocyte procoagulants and different GAGs including chondroitin sulfate (CS) A, CSB, CSC, CSD, CSE, and heparan sulfate, were tested either in clotting assays with whole plasma or in chromogenic assays with purified coagulation proteases. Procoagulant activity in plasma was inhibited by three of the seven GAGs, including heparan sulfate, CSE, and CSB. In contrast, activity of purified coagulation protease was inhibited only by CSE, and the inhibition was observed with intrinsic (factor VIIIa/IXa) but not extrinsic (tissue factor/ factor VII) components. Reciprocal titration experiments with enzyme and substrate and Scatchard type analyses were consistent with concentration-dependent inhibitory interactions between CSE and sites on both factor VIIIa and IXa. On purified phospholipids, CSE concentration resulting in half-maximal inhibition (K i ) was 5 ng/ml for interaction with factor IXa and >500 ng/ml for interaction with factor VIIIa. The K i values were lower for reactions on purified lipid than for reactions on monocyte surfaces and for reactions on resting than on endotoxin-stimulated monocytes. Experiments with CSE oligosaccharides of defined size indicated that the smallest CSE fragment capable of inhibitory activity was composed of 12-18 monosaccharide units. Collectively, these results indicate that factor X-activating reactions are inhibited by GAGs expressed on monocyte membranes. Inhibition is specific with respect to the structure of both the GAG and the activating protease. Lack of inhibition by added CSA, CSB, and CSC in contrast to CSE strongly suggests a direct role of 4,6-di-Osulfated N-acetylgalactosamine GAG structures in the inhibition of intrinsic pathway protease. These findings also suggest potential pharmacologic use of CSE as specific anticoagulant in the management of prothrombotic states mediated by intrinsic pathway coagulation reactions.Mononuclear phagocytes constitute one of the major components in the cellular infiltrates that characterize atherosclerotic, neoplastic, and chronic inflammatory lesions (Ross, 1993;McGee et al., 1978;Rickles et al., 1988). These lesions are also associated with localized blood coagulation reactions and both qualitative and quantitative changes in GAGs 1 content (Wagner and Salisbury, 1989;McGee et al., 1990;Wilcox et al., 1989;Dietrich et al., 1993).Monocytes and macrophages can accelerate membrane-dependent coagulation reactions via expression of TF (tissue factor) and membrane assembly sites for coagulation protease complexes. Membrane TF interacts with plasma factor VII with high affinity (K d , approximately 10 Ϫ9 M), forming functional protease complexes that cleave plasma coagulation factors IX and X and generate the serine esterases, factors IXa and Xa (Bach et al., 1986). Factor IXa in turn assembles on acidic phospholipids...

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“…They have shown that some tumor express TF on their cell surface while in other tumors, the procoagulants are localized to tumor associated macrophages [117]. The necessary coagulation factors, including factors VII, V, X, Xa, XIII, II and fibrinogen, are present within the intercellular space in some tu-275 mor tissue [102,118], but not others, including colon carcinoma [119], mesothelioma [120] and melanoma [121]. Radiolabeled fibrinogen and immunodetection of fibrin to show that fibrin is deposited on tumor cells.…”

Section: The Net Effect Of Prothrombogenesismentioning

confidence: 99%