Systemic thrombin generation in cancer patients is correlated with extrinsic pathway activation

Costantini, Vincenzo; Monte, Paola De; Cazzato, Alessia; Stabile, Anna Maria; Deveglia, R.; Frezzato, E.; Paolucci, M.

doi:10.1097/00001721-199801000-00010

Cited by 23 publications

(10 citation statements)

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“…This is a better reflection of the in vivo situation [17]. The absence of elevated levels of factor VII a also indicates that in this cancer patient group there is no extrinsic pathway activation, as previously observed [18,19].…”

Section: Discussionsupporting

confidence: 68%

Increased D-dimer levels correlate with binding of activated protein C, but not tissue factor expression, on peripheral blood monocytes in cancer patients

et al. 2000

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Monocyte tissue factor expression is supposed to play an important role in the hypercoagulability of blood in cancer patients. The relation between coagulation parameters and the expression of monocyte membrane proteins involved in hemostasis or monocyte activation was studied in 21 patients with a disseminated malignancy and 21 age- and sex-matched healthy controls. In the cancer patient group no increase of monocyte tissue factor expression was found (8. 4% vs. 7.8%; P = 0.83), but a significant increase of monocyte-bound activated protein C (APC) (28.8% vs. 13.4%; P = 0.009) and monocyte CD16 expression (34.5% vs. 27.0%; P = 0.007) was observed. There was also a significant increase of D-dimers (2.0 vs. 0.2 microg/ml; P = 0.001), a decrease of antithrombin (83.5% vs. 102.0%; P = 0.004), but no increase of TAT complexes (1.7 vs. 1.5 microg/l; P = 0.38) or factor VII(a) (68.5% vs. 75.0%; P = 0.52). The increase of D-dimers was significantly correlated with the monocyte APC (R = 0.60; P = 0. 005), but not with monocyte tissue factor levels (R = -0.22; P = 0. 35) or TAT complexes (R = 0.12; P = 0.60). These results reflect a local rather than systemic thrombin and fibrin formation. It is suggested that the APC formed locally enters the circulation and binds to peripheral blood monocytes. APC bound on monocytes is known to inhibit monocyte cytokine production and might therefore be involved in regulatory responses of monocytes in cancer patients.

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Section: Discussionsupporting

confidence: 68%

Increased D-dimer levels correlate with binding of activated protein C, but not tissue factor expression, on peripheral blood monocytes in cancer patients

et al. 2000

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“…Moreover miR-10b levels are higher in cancer patient serum (48). Thrombin, which is frequently present in excess in cancer patient serum (49), also increases the miR-10b expression level. However, the anti-angiogenic effect of heparin on HMEC-1 cells was reversed after stable transfection with miR-10b (Fig.…”

Section: Discussionmentioning

confidence: 96%

Heparin Impairs Angiogenesis through Inhibition of MicroRNA-10b

Shen

Fang

et al. 2011

Journal of Biological Chemistry

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Heparin, which has been used as an anticoagulant drug for decades, inhibits angiogenesis, whereas thrombin promotes tumor-associated angiogenesis. However, the mechanisms underlying the regulation of angiogenesis by heparin and thrombin are not well understood. Here, we show that microRNA-10b (miR-10b) is down-regulated by heparin and up-regulated by thrombin in human microvascular endothelial cells (HMEC-1). Overexpression of miR-10b induces HMEC-1 cell migration, tube formation, and angiogenesis, and downregulates homeobox D10 (HoxD10) expression via direct binding of miR-10b to the putative 3 UTR of HoxD10. In addition, HMEC-1 cell migration and tube formation are induced by HoxD10 knockdown, whereas angiogenesis is arrested when HoxD10 expression is increased after anti-miR-10b or heparin treatments. Furthermore, expression of miR-10b and its transcription factor Twist are up-regulated by thrombin, whereas HoxD10 expression is impaired by thrombin. Using quartz crystal microbalance analysis, we show that heparin binds to thrombin, thereby inhibiting thrombin-induced expression of Twist and miR-10b. However, the expression of miR-10b is not attenuated by heparin any more after thrombin expression is silenced by its siRNA. Interestingly, we find that heparin attenuates miR10b expression and induces HoxD10 expression in vivo to inhibit angiogenesis and impair the growth of MDA-MB-231 tumor xenografts. These results provide insight into the molecular mechanism by which heparin and thrombin regulate angiogenesis.Thrombosis is considered an early clinical indication and frequent complication of cancer (1, 2). Malignant tumors often exhibit increased expression of tissue factor and cancer procoagulant, which can be followed by activation of cell surface protease receptors and fibrin generation (3). In addition, tumor cells can interact with blood cells, particularly monocytes, macrophages, and platelets, leading to the generation of thrombin and thrombosis through the clotting cascade or platelet activation (4). Moreover, aggressive antitumor therapies such as chemotherapy, radiation, and surgery also increase the risk of thrombosis.Positive feedback signaling loops exist between tumor tissue and the coagulation system (5, 6). For instance, it is widely accepted that elements of the coagulation and fibrinolytic system may aid in cancer cell survival, proliferation, invasion, and metastasis, as well as tumor angiogenesis (7). Therefore, inhibition of the activation of coagulation could be a useful antitumor strategy. A number of studies have shown that anticoagulant drugs can extend survival in patients with certain types of cancer (8), and studies are currently ongoing to confirm the effects of anticoagulant therapy in a range of tumor types. However, the molecular mechanisms involved in the action of anticoagulants in this process are not well understood.Heparins, in particular those of low molecular weight, are effective in the prevention and treatment of thromboembolic events in cancer patients (9, 10). As early...

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“…Routine blood tests on cancer patients reveal that up to 90% have abnormal levels of haemostatic markers (clotting factors V, VII, IX and XI) and approximately 15% of these patients will exhibit clinically significant symptoms such as venous thromboembolic episodes, post‐operative venous thrombosis and disseminated intravascular coagulation (Gouin‐Thibault & Samama, 1999). Constantini et al (1998) reported elevated plasma levels of FVIIa, as well as increased thrombin generation, in patients with various types of cancer compared with healthy controls. Gabazza et al (1994) also reported higher levels of haemostatic activation markers and a lower fibrinolytic activity in the plasmas of 25 lung cancer patients during multidrug combination chemotherapy compared with pretreatment values.…”

Section: Discussionmentioning

confidence: 99%

The effects of chemotherapeutic agents on the regulation of thrombin on cell surfaces

Paredes¹,

Xu²,

Berry³

et al. 2003

Br J Haematol

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Summary. Thromboembolic disorders are common in cancer patients. Two major contributing factors are central venous catheters for drug delivery and the use of l-aparaginase, which decreases the plasma antithrombin level, but the causes of the hypercoagulable state in these patients are not fully understood. In this study, the T24/83 cell line was used as a model to investigate the effects of chemotherapeutic agents on cell surface thrombin regulation. Plasma thrombin generation and prothrombin consumption was increased in most of the treated cells, particularly vincristine-and adriamycin-treated cells (P < 0AE05), compared with controls. However, no free thrombin generation or prothrombin consumption was observed in factor VII (FVII)-depleted plasma. No significant differences in the levels of thrombin-a 2 -macroglobulin (IIa-a 2 M) and thrombin-antithrombin (TAT) were observed between controls and any of the treatments, except for vincristine-and adriamycintreated cells, which showed a significant difference in TAT production (P < 0AE05). Also, there was an upregulation in tissue factor (TF) mRNA expression in etoposide-, methotrexate-and vincristine-treated monolayers compared with controls, as well as an upregulation in TF protein production in vincristine-treated cells. The data suggests that thrombin generation occurs via the extrinsic (TF-dependent) coagulation pathway on cell surfaces and that some chemotherapeutic agents are able to upregulate TF mRNA and protein expression in T24/83 cells.

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Systemic thrombin generation in cancer patients is correlated with extrinsic pathway activation

Cited by 23 publications

References 0 publications

Increased D-dimer levels correlate with binding of activated protein C, but not tissue factor expression, on peripheral blood monocytes in cancer patients

Increased D-dimer levels correlate with binding of activated protein C, but not tissue factor expression, on peripheral blood monocytes in cancer patients

Heparin Impairs Angiogenesis through Inhibition of MicroRNA-10b

The effects of chemotherapeutic agents on the regulation of thrombin on cell surfaces

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