The many faces of tissue factor

Tissue factor (TF) is a member of the cytokine receptor superfamily and binds FVII/VIIa. The TF:FVIIa complex has both procoagulant and signaling activities. It functions in many biological processes, including hemostasis, thrombosis, inflammation, angiogenesis and tumor growth. Importantly, TF is essential for hemostasis. However, increased TF expression within atherosclerotic plaques and elevated levels of circulating TF-positive micro particles promote thrombosis. TF increases inflammation by enhancing intravascular fibrin deposition, by increasing the formation of pro-inflammatory fragments of fibrin and by generating coagulation proteases, including FVIIa, FXa and thrombin, that activate protease-activated receptors (PARs). In endotoxemia and sepsis, TF-dependent thrombin generation and activation of PAR1 on dendritic cells enhance inflammation. Finally, the TF:FVIIa complex contributes to tumor growth by activating PAR2

Editorial Commentary: Tissue factor expression by the endothelium: Coagulation or inflammation?

In this issue of Trends in Cardiovascular Medicine, Witkowski et al. review studies proposing that tissue factor (TF) links coagulation and inflammation. Importantly, TF is a cofactor for the coagulation protease factor VIIa(FVIIa) and therefore it is theTF:FVIIa complex that initiates the coagulation cascade. Interestingly, it has structural homology to members of the class 2 cytokine receptor family. The primary role of the TF:FVIIa complex is to maintain hemostasis. Indeed, a complete deficiency of either TF or FVII is not compatible with life. Activation of the coagulation cascade by the TF:FVIIa complex generates a number of serine proteases that can activate cells and enhance inflammation by cleavage of protease activated receptors (PARs). For instance, FXa activates PAR2 and thrombin activates PAR1. Therefore, the TF:FVIIa complex has a secondary role as an enhancer of inflammation

Commentary: Tissue factor as a potential coagulative/vascular marker in relapsing-remitting multiple sclerosis

Koudriavtseva and colleagues measured levels of different biomarkers in healthy controls, patients with remitting multiple sclerosis (MS), and patients with relapsing MS. The Quantikine enzyme-linked immunosorbent assay (ELISA) (R&D Systems, Minneapolis,MN, Cat. No. DCF300) was used to measure plasma tissue factor (TF) (S. Lorenzano, personal communication). The authors found that patients with relapsing MS had lower levels of plasma TF compared to either patients with remitting MS or the control group. It was concluded that plasma TF is a promising biomarker and possible therapeutic target in relapsing-remitting MS

Letter to Editor response: Endothelial cell tissue factor and coagulation

Thank you for the opportunity to respond to the letter by Drs. Witkowski and Rauch about our editorial. It is very challenging moving from in vitro studies with cultured cells to in vivo studies that analyze gene expression. In the tissue factor(TF) field it is well accepted that cultured endothelial cells(EC) do not express TF under basal conditions but can be induced to express TF after stimulation with a variety of agonists. Witkowski and Rauch state that the induction of TF in culture ECs “makes itlikelythatTFderivedfromECs contributes to coagulation under pathological conditions”. However, the models they present in support of arole for ECTF in coagulation are not selective for TF. For instance, over-expression of an NFκB inhibitor or EC-specific knock-out of miR-126 will affect many genes in the endothelium. Interestingly, miR-126 also regulates TF expression in monocytes. Furthermore,blood vessels are surrounded by pericytes, smooth muscle cells and adventitial fibroblasts, all of which express TF. Therefore, it is very difficult to distinguish the contribution of TF expression induced in the endothelium from that exposed on perivascular cells due to disruption of the endothelialbarrier

Venous thrombosis and cancer: from mouse models to clinical trials

Cancer patients have a ~4 fold increased risk of venous thromboembolism (VTE) compared with the general population and this is associated with significant morbidity and mortality. This review summarizes our current knowledge of VTE and cancer from mouse models to clinical studies. Notably, risk of VTE varies depending on the type and stage of cancer. For instance, pancreatic and brain cancer patients have a higher risk of VTE than breast and prostate cancer patients. Moreover, patients with metastatic disease have a higher risk than those with localized tumors. Tumor-derived procoagulant factors and growth factors may directly and indirectly enhance VTE. For example, increased levels of circulating tumor-derived, tissue factor-positive microvesicles may trigger VTE. In a mouse model of ovarian cancer, tumor-derived IL-6 and hepatic thrombopoietin has been linked to increased platelet production and thrombosis. In addition, mouse models of mammary and lung cancer showed that tumor-derived granulocyte colony-stimulating factor causes neutrophilia and activation of neutrophils. Activated neutrophils can release neutrophil extracellular traps (NETs) that enhance thrombosis. Cell-free DNA in the blood derived from cancer cells, NETs and treatment with cytotoxic drugs can activate the clotting cascade. These studies suggest that there are multiple mechanisms for VTE in patients with different types of cancer. Preventing and treating VTE in cancer patients is challenging; the current recommendations are to use low molecular weight heparin. Understanding the underlying mechanisms may allow the development of new therapies to safely prevent VTE in cancer patients

Role of tissue factor in thrombosis in antiphospholipid antibody syndrome

Antiphospholipid syndrome (APS) is an acquired autoimmune disorder defined by the presence of an antiphospholipid antibody (aPL) and the occurrence of at least one associated clinical condition that includes venous thrombosis, arterial thrombosis or pregnancy morbidity. The aPL detected in APS have long been thought to have a direct prothrombotic effect in vivo. However, the pathophysiology underlying their coagulopathic effect has not been defined. Emerging data suggest a role for the procoagulant protein tissue factor (TF). In this review we provide an overview of TF, describe mouse models used in the evaluation of the role of TF in thrombosis, as well as summarize recent work on TF and APS

Tissue factor and oxidative stress

In this issue of Blood, Ebert et al conclude that endothelial cell (EC) tissue factor (TF) activity induces a prothrombotic state in mice that lack the antioxidant paraoxonase-2 (PON2)

Evaluation of the ability of commercial enzyme-linked immunosorbent assays to measure mouse tissue factor

Background: Tissue factor (TF) is the primary cellular initiator of the blood coagulation cascade. Increased levels of TF expression on circulating monocytes or on extracellular vesicles (EVs) are associated with thrombosis in a variety of diseases, including sepsis and COVID-19. Objectives: Here, we aimed to evaluate the ability of 4 commercial TF enzyme-linked immunosorbent assays (ELISAs) to measure mouse TF in cells and plasma. Methods: We used 4 commercial mouse TF ELISAs (SimpleStep, R&D Systems, MyBioSource [sandwich], and MyBioSource [competitive]). We used recombinant mouse TF (rmTF; 16-1000 pg/mL), cell lysates from a TF-expressing mouse pancreatic cancer cell line, and plasma and EVs isolated from plasma from mice injected with vehicle or bacterial lipopolysaccharide (LPS). Results: The 2 MyBioSource kits failed to detect rmTF or TF in cell lysates. The SimpleStep and R&D kits detected rmTF in buffer or spiked into plasma in a concentration-dependent manner. These kits also detected TF in cell lysates from a mouse pancreatic cancer cell line. A higher signal was observed with the SimpleStep kit compared to the R&D kit. However, the SimpleStep and R&D kits failed to detect TF in plasma or EVs from LPS-treated mice. Conclusion: Our results indicate that some commercial ELISAs can be used to measure mouse TF levels in cell lysates but they cannot detect TF in plasma or EVs from endotoxemic mice

Venous Thromboembolism: Risk Factors, Biomarkers, and Treatment

Articles in this series: •Zhu T, Martinez I, Emmerich J. Venous thromboembolism: risk factors for recurrence. Arterioscler Thromb Vasc Biol. 2009;29:298–310. •Jang MJ, Choi W, Bang SM, Lee T, Yeo-Kyeoung K, Ageno W, Doyeun Oh. Metabolic syndrome is associated with venous thromboembolism in the Korean population. Arterioscler Thromb Vasc Biol. 2009;29:311–315. •Sousou T, Khorana AA. New insights into cancer-associated thrombosis. Arterioscler Thromb Vasc Biol. 2009;29:316–320. •Farmer-Boatwright MK, Roubey RAS. Venous thrombosis in the antiphospholipid syndrome. Arterioscler Thromb Vasc Biol. 2009;29:321–325. •James AH. Venous thromboembolism in pregnancy. Arterioscler Thromb Vasc Biol. 2009;29:326–331. •Pabinger I, Ay C. Biomarkers and venous thromboembolism. Arterioscler Thromb Vasc Biol. 2009;29:332–336. In 2005, the U.S. Senate declared March as deep vein thrombosis (DVT) awareness month. This is the second year in which we have highlighted this event with a collection of 6 articles in Arteriosclerosis, Thrombosis, and Vascular Biology focused on DVT. It is estimated that 2 million Americans per year develop DVT, which is associated with life-threatening pulmonary embolism (PE). DVT and PE are collectively termed venous thromboembolism (VTE). Despite the large number of cases, a survey conducted by the American Public Health Association in 2002 found that 74% of Americans were unaware of venous thrombosis.1 The risk of VTE increases with thrombophilias, age, pregnancy, and comorbidities, including cancer and antiphospholipid syndrome (APS). It has not yet been determined whether similar mechanisms lead to VTE in each of these disorders. The articles in this issue describe current research into disorders associated with increased VTE risk, including potential pathophysiologic mechanisms, treatment of these clinical situations, and a review on biomarkers for the detection and prevention of VTE.