Microparticle-associated tissue factor activity in cancer patients with and without thrombosis

Tesselaar, Margot E.T.; Romijn, Fred P.H.T.M.; Linden, I K van der; Bertina, Rogier M.; Osanto, Susanne

doi:10.1111/j.1538-7836.2009.03504.x

Cited by 143 publications

(117 citation statements)

References 7 publications

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“…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.…”

Section: Introductionmentioning

confidence: 99%

“…[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.…”

mentioning

confidence: 99%

“…5,7,8 Moreover, levels of MP TF activity are predictive of VTE in pancreatic cancer patients, and VTE patients with elevated levels of MP TF activity have decreased survival, which may reflect the presence of more aggressive tumors. 6,20,43 These results suggest that MP TF may be a good biomarker with which to identify those pancreatic cancer patients at risk for VTE.…”

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confidence: 99%

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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

180

167

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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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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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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

180

167

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“…Several studies have quantified circulating TF during the acute phase of cancer-associated VTE and compared levels to those of an appropriately matched control population (62)(63)(64)(65)(66). Although highly suggestive for a pathophysiological role of circulating TF in Trousseau's syndrome, these studies, by demonstrating a temporal association, provide only circumstantial evidence for its causative involvement.…”

Section: Time Pointmentioning

confidence: 99%

“…There is a convincing body of independent evidence in the literature to suggest that levels of MP-associated TF are increased in patients with cancer and correlate with both markers of systemic coagulation activation (i. e. plasma D-dimer) and clinically overt clotting disorders such as VTE or decompensated DIC (62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73)(74). However, hardly any data is available on how the magnitude of MP-associated TF compares to the magnitude of TF expressed on circulating monocytes or tumour cells.…”

Section: Compartmentmentioning

confidence: 99%

Crosstalk between cancer and haemostasis

Bokemeyer¹

2012

Hamostaseologie

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SummaryCancer is characterized by bidirectional interrelations between tumour progression, coagulation activation, and inflammation. Tissue factor (TF), the principal initiator of the coagulation protease cascade, is centrally positioned in this complex triangular network due to its pleiotropic effects in haemostasis, angiogenesis, and haematogenous metastasis. While formation of macroscopic thrombi is the correlate of cancer-associated venous thromboembolism (VTE), a major healthcare burden in clinical haematology and oncology, microvascular thrombosis appears to be critically important to blood-borne tumour cell dissemination. In this regard, expression of TF in malignant tissues as well as shedding of TFbearing microparticles into the circulation are thought to be regulated by defined genetic events relevant to pathological cancer progression, thus directly linking Trousseau’s syndrome to molecular tumourigenesis.Because pharmacological inhibition of the TF pathway in selective tumour types and patient subgroups would be in line with the modern concept of individualized, targeted anti-cancer therapy, this review will focus on the role of TF in tumour biology and cancer-associated VTE.

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Microparticle analysis in disorders of hemostasis and thrombosis

2015

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Microparticles (MPs) are submicron vesicles released from the plasma membrane of eukaryotic cells in response to activation or apoptosis. MPs are known to be involved in numerous biologic processes, including inflammation, the immune response, cancer metastasis, and angiogenesis. Their earliest recognized and most widely accepted role, however, is the ability to promote and support the process of blood coagulation. Consequently, there is ongoing interest in studying MPs in disorders of hemostasis and thrombosis. Both phosphatidylserine (PS) exposure and the presence of tissue factor (TF) in the MP membrane may account for their procoagulant properties, and elevated numbers of MPs in plasma have been reported in numerous prothrombotic conditions. To date, however, there are few data on true causality linking MPs to the genesis of thrombosis. A variety of methodologies have been employed to characterize and quantify MPs, although detection is challenging due to their submicron size. Flow cytometry (FCM) remains the most frequently utilized strategy for MP detection; however, it is associated with significant technological limitations. Additionally, pre-analytical and analytical variables can influence the detection of MPs by FCM, rendering data interpretation difficult. Lack of methodologic standardization in MP analysis by FCM confounds the issue further, although efforts are currently underway to address this limitation. Moving forward, it will be important to address these technical challenges as a scientific community if we are to better understand the role that MPs play in disorders of hemostasis and thrombosis.

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Microparticle-associated tissue factor activity in cancer patients with and without thrombosis

Cited by 143 publications

References 7 publications

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

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

Crosstalk between cancer and haemostasis

Microparticle analysis in disorders of hemostasis and thrombosis

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