Context Venous thrombosis is a common complication in patients with cancer, leading to additional morbidity and compromising quality of life. Objective To identify individuals with cancer with an increased thrombotic risk, evaluating different tumor sites, the presence of distant metastases, and carrier status of prothrombotic mutations. Design, Setting, and Patients A large population-based, case-control (Multiple Environmental and Genetic Assessment [MEGA] of risk factors for venous thrombosis) study of 3220 consecutive patients aged 18 to 70 years, with a first deep venous thrombosis of the leg or pulmonary embolism, between March 1, 1999, and May 31, 2002, at 6 anticoagulation clinics in the Netherlands, and separate 2131 control participants (partners of the patients) reported via a questionnaire on acquired risk factors for venous thrombosis. Three months after discontinuation of the anticoagulant therapy, all patients and controls were interviewed, a blood sample was taken, and DNA was isolated to ascertain the factor V Leiden and prothrombin 20210A mutations. Main Outcome Measure Risk of venous thrombosis. Results The overall risk of venous thrombosis was increased 7-fold in patients with a malignancy (odds ratio [OR], 6.7; 95% confidence interval [CI], 5.2-8.6) vs persons without malignancy. Patients with hematological malignancies had the highest risk of venous thrombosis, adjusted for age and sex (adjusted OR, 28.0; 95% CI, 4.0-199.7), followed by lung cancer and gastrointestinal cancer. The risk of venous thrombosis was highest in the first few months after the diagnosis of malignancy (adjusted OR, 53.5; 95% CI, 8.6-334.3). Patients with cancer with distant metastases had a higher risk vs patients without distant metastases (adjusted OR, 19.8; 95% CI, 2.6-149.1). Carriers of the factor V Leiden mutation who also had cancer had a 12-fold increased risk vs individuals without cancer and factor V Leiden (adjusted OR, 12.1; 95% CI, 1.6-88.1). Similar results were indirectly calculated for the prothrombin 20210A mutation in patients with cancer. Conclusions Patients with cancer have a highly increased risk of venous thrombosis especially in the first few months after diagnosis and in the presence of distant metastases. Carriers of the factor V Leiden and prothrombin 20210A mutations appear to have an even higher risk.

See also H. T. Sørensen. Cancer and subsequent risk of venous thromboembolism. This issue, pp 527-8. Summary. Background: The incidence of venous thrombosis (VT) for cancer patients is increased compared with patients without cancer, but estimations of the incidence for different types of cancer have rarely been made because of the low incidence of various types of cancer. Large registries offer an opportunity to study the risk of VT in large cohorts of cancer patients, which is essential in decisions on prophylactic anti-coagulant treatment. Methods: This cohort study estimates the incidence of VT in cancer patients by using record linkage of a Cancer Registry and an Anticoagulation Clinic database in the Netherlands. Cumulative incidences in patients with different types of malignancies were estimated. We calculated relative risks (RRs) in relation to the presence of distant metastases and treatment. Results: Tumors of the bone, ovary, brain, and pancreas are associated with the highest incidence of VT (37.7, 32.6, 32.1, and 22.7/1000/0.5 year). Patients with distant metastases had a 1.9-fold increased risk [RR adj : 1.9; 95% confidence interval (CI): 1.6-2.3]. Chemotherapy leads to a 2.2-fold increased risk (RR adj : 2.2; 95% CI: 1.8-2.7) and hormonal therapy leads to a 1.6-fold increased risk (RR adj : 1.6; 95% CI: 1.3-2.1) compared with patients not using these treatment modalities. Patients with radiotherapy or surgery did not have an increased risk. Conclusions: We compared the overall incidences of VT in the first half year in our study to the risk of major bleeding as described in the literature. For patients with distant metastases, for several types of cancer, prophylactic anti-thrombotic treatment could be beneficial.

To cite this article: Tesselaar MET, Romijn FPHTM, van der Linden IK, Prins FA, Bertina RM, Osanto S. Microparticle-associated tissue factor activity: a link between cancer and thrombosis? J Thromb Haemost 2007; 5: 520-7.Summary. Background: Cancer, in particular mucinous adenocarcinoma, is associated with venous thromboembolism (VTE). Tissue factor (TF), initiator of coagulation, plays a central role in the paradigm that clotting and tumor growth form a vicious circle, in which hypercoagulability facilitates the aggressive biology of cancer and vice versa. Expression of TF in tumors is associated with poor differentiation and poor prognosis. Patient/methods: We investigated the association between clinically manifest VTE and procoagulant properties of circulating microparticles (MP) isolated from blood of unselected pancreatic and breast adenocarcinoma patients' consecutive subjects, who presented with ultrasound or CT-scan confirmed VTE, and healthy subjects. Results: Patients with disseminated breast and pancreatic cancer had significantly increased levels of MP-associated TF activity compared with healthy controls, subjects with idiopathic acute VTE and non-metastatic cancer patients. Patients with both high MP-associated TF-activity and MP-associated epithelial mucin (MUC1) had a lower survival rate at 3-9 months follow-up than those with low TFactivity and no MUC1 expression: the likelihood of survival was 0.42 (95% CI: 0.19-0.94) for an individual with these two predictor variables present, after adjustment for other factors (age cohort, type of cancer, VTE) in the Cox proportional hazards model. Conclusions: Our results suggest an important role for MP-associated TF and MUC1 in the pathogenesis of thrombosis in disseminated mucinous adenocarcinoma patients. Future studies should reveal the mechanism underlying the observed associations.

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It is now widely recognized that a strong correlation exists between cancer and aberrant hemostasis. Patients with various types of cancers, including pancreatic, colorectal, and gastric cancer, often develop thrombosis, a phenomenon commonly referred to as Trousseau syndrome. Reciprocally, components from the coagulation cascade also influence cancer progression. The primary initiator of coagulation, the transmembrane receptor tissue factor (TF), has gained considerable attention as a determinant of tumor progression. On complex formation with its ligand, coagulation factor VIIa, TF influences protease-activated receptor-dependent tumor cell behavior, and regulates integrin function, which facilitate tumor angiogenesis both in vitro and in mouse models. Furthermore, evidence exists that an alternatively spliced isoform of TF also affects tumor growth and tumor angiogenesis. In patient material, TF expression and TF cytoplasmic domain phosphorylation correlate with disease outcome in many, but not in all, cancer subtypes, suggesting that TFdependent signal transduction events are a potential target for therapeutic intervention in selected types of cancer. In this review, we summarize our current understanding of the role of TF in tumor growth and metastasis, and speculate on anticancer therapy by targeting TF. (Blood. 2012; 119(4):924-932) IntroductionAfter Trousseau's description of thrombophlebitis as a complication of pancreatic cancer in the 19th century, the notion that increased expression of tissue factor (TF) underlies the relation between coagulation and cancer has become generally accepted. Full-length TF (flTF) is a 47-kDa membrane-bound glycoprotein that is present on subendothelial cells. 1 In the classic concept of coagulation, it is thought that endothelial disruption leads to exposure of flTF to the bloodstream. Exposed flTF can bind to its natural ligand factor VII (FVII), which then becomes activated FVII (FVIIa). The thus formed flTF/FVIIa complex converts factor X (FX) to factor Xa (FXa), and FXa in turn activates prothrombin leading to formation of thrombin (factor IIa). Thrombin subsequently activates platelets and converts fibrinogen into fibrin, 2 essential components of a stable hemostatic plug. 1 The primary function of subendothelial flTF is to serve as a hemostatic envelope surrounding the vasculature. However, under certain conditions, the expression of flTF is induced in monocytes and endothelial cells. flTF is also often expressed on cancer cells and the tumor vasculature, 2 and flTF-bearing microparticles can become shed by these cells. 3 These flTF-bearing microparticles are important contributors to the thrombotic phenotype in cancer patients. 3 The flTF/FVIIa complex also influences pathways that do not lead to blood coagulation, but rather activate cell-bound proteaseactivated receptors (PARs) that are of importance during the inflammatory and angiogenic response to injury. 4 Furthermore, a soluble variant of flTF, known as alternatively spliced TF (asTF), stimulates angiogen...