Increased microparticle tissue factor activity in cancer patients with Venous Thromboembolism

Manly, David A.; Wang, Jianguo; Glover, Sam L.; Kasthuri, Raj S.; Liebman, Howard A.; Key, Nigel S.; Mackman, Nigel

doi:10.1016/j.thromres.2009.09.019

Cited by 185 publications

(163 citation statements)

References 18 publications

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“…Strikingly, no MP-associated TF activity was found in non-cancer patients who had suffered from acute VTE. Also Manly et al detected higher MP-associated TF activity levels in 53 cancer patients with different tumour types and acute VTE than in 13 cancer patients without VTE [42]. Furthermore, Zwicker et al applied a newly developed method, the impedance flow cytometry, and showed elevated numbers of TF-positive MPs in 60% of cancer patients with acute VTE compared to 27% of cancer patients without VTE [10].In contrast to the above-mentioned studies, in our large prospective study we measured baseline MP levels of cancer patients and followed them over a 2-year period or until occurrence of VTE or death or loss of follow-up, in order to find parameters that might be predictive of cancer-associated VTE.…”

Section: Discussionmentioning

confidence: 96%

“…Nevertheless, this prothrombinase assay is a well established method that had previously been used in several different clinical studies for the assessment of circulating procoagulant MPs in patients with a variety of diseases, such as sepsis [39], HIV [26], type 1 and type 2 diabetes [40], acute coronary syndrome [41], VTE [14,42], and preeclampsia [43]. Yet, up to date there are no studies applying this functional prothrombinase assay in a solid phase in cancer.…”

Section: Discussionmentioning

confidence: 99%

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Circulating procoagulant microparticles in cancer patients

Thaler

Weinstabl

et al. 2010

Ann Hematol

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Accumulating evidence indicates that microparticles (MPs) are important mediators of the interaction between cancer and the hemostatic system. We conducted a large prospective cohort study to determine whether the number of circulating procoagulant MPs is elevated in cancer patients and whether the elevated MP levels are predictive of occurrence of venous thrombembolism (VTE). We analyzed plasma samples of 728 cancer patients from the ongoing prospective observational Vienna Cancer and Thrombosis Study (CATS). Study endpoint was the occurrence of symptomatic VTE. Sixty-five age-and sex-matched healthy controls were recruited for defining the cut-off point for elevated MPs (4.62 nanomolar phosphatidylserine nM PS ), which was set at the 95th percentile of MP levels in healthy controls. The measurement of MPs was performed after capture onto immobilized annexin-V, and determination of their procoagulant activity was quantified with a prothrombinase assay. During a median observation period of 710 days 53 patients developed VTE. MP levels (nM PS) were significantly higher in cancer patients than in healthy controls (median 25th-75th percentile : 3.95 1.74-7.96 vs. 1.19 0.81-1.67 , p<0.001). Multivariate analysis including age, sex, surgery, chemo-and radiotherapy showed no statistically significant association of the hazard ratio of elevated MPs with VTE (0.95 [95% CI: 0.55-1.64], p=0.856). In conclusion, MP levels were elevated in cancer patients compared to healthy individuals in this study. However, elevated MP levels were not predictive of VTE.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Circulating procoagulant microparticles in cancer patients

Thaler

Weinstabl

et al. 2010

Ann Hematol

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“…[14][15][16][17][18][19] In some patients with pancreatic cancer, high levels of TF-positive MPs are found in the circulation and, in a small pilot study, were predictive of VTE. [5][6][7]9,20 In a mouse model of human colorectal tumors, human TF protein is released into the circulation. 21 In nude mice bearing orthotopic human pancreatic tumors (L3.6pl) plasma levels of human TF protein were correlated with the levels of thrombin-antithrombin (TAT) complex, a marker of the activation of coagulation.…”

Section: Introductionmentioning

confidence: 99%

“…4 Another potential circulating biomarker of VTE risk in pancreatic cancer patients is microparticle (MP) tissue factor (TF). [5][6][7][8][9] Full-length TF (flTF) is a transmembrane protein that activates the coagulation cascade. 10 In addition, an alternatively spliced form of TF (asTF) has been identified that lacks a membrane anchor and therefore can be released as a soluble protein.…”

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confidence: 99%

Tumor-derived tissue factor activates coagulation and enhances thrombosis in a mouse xenograft model of human pancreatic cancer

Wang

Geddings

Aleman

et al. 2012

Blood

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179

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IntroductionThe link between cancer and venous thromboembolism (VTE) is referred to as Trousseau syndrome. Interestingly, different cancer types are associated with different rates of VTE, with pancreatic cancer having one of the highest rates. 1,2 A VTE risk-scoring model has been developed that stratifies ambulatory cancer patients undergoing chemotherapy into 3 VTE risk categories based on 5 parameters: (1) the site of the primary tumor, (2) prechemotherapy leukocyte count, (3) platelet count, (4) hemoglobin level, and (5) body mass index. 3 Recently, this model was expanded to include the biomarkers D-dimer and soluble P-selectin. 4 Another potential circulating biomarker of VTE risk in pancreatic cancer patients is microparticle (MP) tissue factor (TF). [5][6][7][8][9] Full-length TF (flTF) is a transmembrane protein that activates the coagulation cascade. 10 In addition, an alternatively spliced form of TF (asTF) has been identified that lacks a membrane anchor and therefore can be released as a soluble protein. 11 Increased TF expression is correlated with poor prognosis in pancreatic cancer. [12][13][14] Cultured human pancreatic tumor lines express variable levels of both flTF and asTF and release TF-positive MPs containing flTF into the culture medium. [14][15][16][17][18][19] In some patients with pancreatic cancer, high levels of TF-positive MPs are found in the circulation and, in a small pilot study, were predictive of VTE. [5][6][7]9,20 In a mouse model of human colorectal tumors, human TF protein is released into the circulation. 21 In nude mice bearing orthotopic human pancreatic tumors (L3.6pl) plasma levels of human TF protein were correlated with the levels of thrombin-antithrombin (TAT) complex, a marker of the activation of coagulation. 22 Further, plasma from these tumor-bearing mice was found to enhance thrombin generation in vitro in a human TF-dependent manner. 22 Another study found that human (SOJ-4) and mouse (PANC02) pancreatic cell lines expressed TF, and the investigators observed an accumulation of tumor-derived MPs at the site of thrombosis and increased thrombosis in a microvascular model. 18 The objective of the present study was to determine the role of tumor-derived TF in the activation of coagulation and thrombosis in a xenograft mouse model of human pancreatic tumors. We found that only TF-positive tumors activated coagulation and that this activation was abolished by inhibition of human TF. Two TF-positive pancreatic tumor cell lines activated coagulation, but only one had detectable levels of circulating TF-positive MPs, which suggested that activation of coagulation was due to TF expression by the tumor itself rather than to TF on the MPs. Mice with elevated levels of TF-positive MPs exhibited increased thrombosis in a saphenous vein model, but not in an inferior vena cava (IVC) stenosis model. Methods Cell linesHuman pancreatic (MIAPaCa-2 [CRL-1420] Abs and proteinsPE-labeled mouse IgG control (#555574), mouse anti-human TF (#550312) and FITC-conjugated anti-human MUC...

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“…These patients' serum TF level was about 67% higher than normal (Kakkar and DeRuvo, 1995). The increase in the TF level in circulated blood is responsible for the formation of malignant tumor patients' hypercoagulable state and is an important reason for phlebothrombosis (Manly et al, 2010).…”

Section: Discussionmentioning

confidence: 84%

Effect of Tissue Factor on Invasion Inhibition and Apoptosis Inducing Effect of Oxaliplatin in Human Gastric Cancer Cell

Li²,

Hou³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Objective: Tissue factor (TF) is expressed abnormally in certain types of tumor cells, closely related to invasion and metastasis. The aim of this study was to construct a human gastric cancer cell line SGC7901 stably-transfected with human TF, and observe effects on oxaliplatin-dependent inhibition of invasion and the apoptosis induction. Methods: The target gene TF was obtained from human placenta by nested PCR and introduced into the human gastric cell line SGC7901 through transfection mediated by lipofectamine. Stably-transfected cells were screened using G418. Examples successfully transfected with TF-pcDNA3 recombinant (experimental group), and empty vector pcDNA3 (control group) were incubated with oxaliplatin. Transwell chambers were used to show change in invasive ability. Caspase-3 activity was detected using a colorimetric method and annexin-V/PI doublestaining was applied to detect apoptosis. Results: We generated the human gastric cancer cell line SGC7901/TF successfully, expressing TF stably and efficiently. Compared with the control group, invasion increased, whereas caspase-3 activity and apoptosis rate were decreased in the experimental group. Conclusion: TF can enhance the invasive capacity of gastric cancer cells in vitro. Its increased expression may reduce invasion inhibition and apoptosis-inducing effects of oxaliplatin and therefore may warrant targeting for improved chemotherapy.

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Increased microparticle tissue factor activity in cancer patients with Venous Thromboembolism

Cited by 185 publications

References 18 publications

Circulating procoagulant microparticles in cancer patients

Circulating procoagulant microparticles in cancer patients

Tumor-derived tissue factor activates coagulation and enhances thrombosis in a mouse xenograft model of human pancreatic cancer

Effect of Tissue Factor on Invasion Inhibition and Apoptosis Inducing Effect of Oxaliplatin in Human Gastric Cancer Cell

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