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

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

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)

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

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.

Novel mouse hemostasis model for real-time determination of bleeding time and hemostatic plug composition

Hemostasis is a rapid response by the body to stop bleeding at sites of vessel injury. Both platelets and fibrin are important for the formation of a hemostatic plug. Mice have been used to uncover the molecular mechanisms that regulate the activation of platelets and coagulation under physiologic conditions. However, measurements of hemostasis in mice are quite variable, and current methods do not quantify platelet adhesion or fibrin formation at the site of injury

Tissue factor expression, extracellular vesicles, and thrombosis after infection with the respiratory viruses influenza A virus and coronavirus

Tissue factor (TF) is induced in a variety of cell types during viral infection, which likely contributes to disseminated intravascular coagulation and thrombosis. TF-expressing cells also release TF-positive extracellular vesicles (EVs) into the circulation that can be measured using an EVTF activity assay. This review summarizes studies that analyze TF expression, TF-positive EVs, activation of coagulation, and thrombosis after infection with influenza A virus (IAV) and coronaviruses (CoVs), including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), SARS-CoV, and Middle East respiratory syndrome CoV (MERS-CoV). The current pandemic of coronavirus disease 2019 (COVID-19) is caused by infection with SARS-CoV-2. Infection of mice with IAV increased TF expression in lung epithelial cells as well as increased EVTF activity and activation of coagulation in the bronchoalveolar lavage fluid (BALF). Infection of mice with MERS-CoV, SARS-CoV, and SARS-CoV-2 also increased lung TF expression. Single-cell RNA sequencing analysis on the BALF from severe COVID-19 patients revealed increased TF mRNA expression in epithelial cells. TF expression was observed in peripheral blood mononuclear cells infected with SARS-CoV. TF was also expressed by peripheral blood mononuclear cells, monocytes in platelet-monocyte aggregates, and neutrophils isolated from COVID-19 patients. Elevated circulating EVTF activity was observed in severe IAV and COVID-19 patients. Importantly, EVTF activity was associated with mortality in severe IAV patients and with plasma D-dimer, severity, thrombosis, and mortality in COVID-19 patients. These studies strongly suggest that increased TF expression in patients infected with IAV and pathogenic CoVs contributes to thrombosis