Role of Tissue Factor in Vascular Failure

The term ‘vascular failure’ has been proposed as a highly integrated concept that includes a broad spectrum of vascular diseases, based on vascular endothelial dysfunction, smooth muscle dysfunction, and metabolic abnormalities of the vessel wall, including inflammation, oxidative stress and alterations of neurohormonal balance. Vascular failure encompasses a broad spectrum of pathophysiology from subclinical to end-stage atherosclerosis.¹ Subclinical atherosclerosis is represented by risk factors such as hypertension, diabetes, dyslipidemia, smoking habit, metabolic syndrome (MetS), chronic kidney disease, and so on. On the other hand, end-stage atherosclerosis includes acute coronary syndrome (ACS). In the light of early intervention to reduce risk factors and prevent disease progression, we need to clinically detect ‘vascular failure’ in its early stage even in the absence of anatomic vascular abnormalities.

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In this issue of the journal, Kohashi et al² demonstrate that smoking causes upregulation of monocyte tissue factor (TF) activity, which may be associated with advancement of carotid atherosclerosis, as estimated by carotid intima-media thickness (IMT), and the risk of atherothrombotic events in patients with MetS. Prior to these observations, their group previously found that monocyte TF activity is significantly upregulated in MetS patients in comparison with normal subjects, and the upregulation was independently associated with carotid IMT.^3,4 TF is the transmembrane receptor for factor VII/VIIa (FVII/FVIIa). The TF-FVIIa complex is the major cellular initiator of the extrinsic coagulation cascade leading to thrombin generation, fibrin deposition and platelet activation.⁵ To maintain steady-state conditions, several inhibitory pathways may be activated to counteract the activity of the coagulation system. The serine protease inhibitor TF pathway inhibitor undergoes a quaternary complex with factor Xa, thus inhibiting the TF-FVIIa-complex.⁶

In the vessel wall, TF is constitutively expressed in subendothelial cells such as vascular smooth muscle cells, leading to rapid initiation of coagulation when the vessel is damaged (Figure). In contrast, endothelial cells and leukocytes do not express TF under physiological conditions, and consequently there is no appreciable contact of cellular TF with the circulating blood. In response to various stimuli, however, TF expression and activity can be induced in endothelial cells as well as in leukocytes such as monocytes/macrophages and granulocytes.⁷ TF plays a significant role in thrombus formation in ACS. Mach et al identified a cell surface-based signaling system, CD154 (CD40 ligand), binding to its receptor CD40 on leukocytes,⁸ which can induce TF expression.⁹ Because several cell types in atheroma bear CD154, this pathway probably contributes to macrophage TF expression in human atheromas. We recently observed using immunohistochemistry that myeloid-related protein (MRP)-8/14, identified as one of the ST-elevation myocardial infarction-related genes, was expressed in aspirated thrombi and colocalized with activated Mac-1 (CBRM1/5)-positive leukocytes in patients with ACS. That result suggests that MRP-8/14 activates Mac-1 (CD11b/CD18) and accelerates Mac-1-mediated inflammatory process in the pathophysiology of ACS. In addition, we also observed in an in-vitro experiment that recombinant human MRP-8/14 could be stimulated to increase TF concentration in the supernatant of cultured human umbilical vein endothelial cells. The result suggests that leukocyte-derived MRP-8/14, which stimulates endothelial cells to release TF, may contribute to the pro-thrombotic milieu in ACS (i.e., end-stage vascular failure [Figure]).¹⁰

Figure.

Possible pathophysiological role of tissue factor (TF) in the atherothrombosis of acute coronary syndrome. In the vascular wall, TF is constitutively expressed in smooth muscle cells, leading to rapid thrombus formation at the site of vascular injury such as ruptured plaques. In the inflammatory process in acute coronary syndrome, platelet-leukocyte interactions are promoted via the action of adhesion molecules. Leukocyte-derived and/or platelet-derived MRP-8/14, which acts as a regulator of these cell-to-cell interactions, is secreted into blood stream and may stimulate endothelial cells to release TF, possibly also contributing to thrombus formation. Microparticles containing TF may be associated with thrombus propagation.

Several studies have provided evidence for the presence of detectable circulating TF activity in healthy subjects¹¹ and for increased levels of circulating TF antigen in patients with ACS.¹² In those studies, the circulating TF level was measured as its plasma concentration using an enzyme-linked immunosorbent assay, which can detect the activity of TF and TF-FVIIa complex. Blood monocytes are considered to represent the predominant source of TF in the circulation. Similar to vascular endothelial cells, however, monocytes constitutively express only a little TF under basal conditions, but its expression is further enhanced by specific stimuli. Thus, the measurement of monocyte TF activity may be more rational to evaluate its functional role in pro-thrombotic activity, compared with the plasma TF concentration. In this respect, the results of a series of studies by Kohashi et al^2–4 provide important evidence that patients with subclinical vascular failure such as MetS have a potential risk for atherothrombotic events and that smoking still further enhances this risk.

Circulating TF is also located in microparticles, which are small membrane vesicles that are released from many different cell types by exocytic budding of the plasma membrane in response to cellular activation or apoptosis. The microparticles have procoagulant activity by themselves, because they express phospholipids. The TF-containing microparticles are submicrometric fragments released from activated or apoptotic eukaryotic cells. Depending on their origin, they differ in antigen and phospholipid composition. The microparticles need to be distinguished from exosomes, which originate from intracellular compartments. The main source of circulating microparticles are monocytes and platelets, but other vascular cells such as endothelial cells can also release TF-containing microparticles.¹³ The levels of TF-containing microparticles, measured using flow cytometry, are elevated in patients with cardiovascular risk factors such as hypertension, diabetes, dyslipidemia, and obesity, but their specific role is still debated. In addition, in-vitro thrombin generation induced by TF-containing microparticles has been confirmed.¹⁴ The microparticles are considered to play a role in thrombus propagation (Figure). In fact, a growing thrombus separates TF produced at the vessel wall from circulating coagulation factors. Under these conditions, TF-containing microparticles in the blood stream may still bind to activated platelets.¹⁵

TF may play a pivotal role in thrombogenesis at various stages of vascular failure, from subclinical to end-stage. Measurement of circulating TF holds promise as an evaluation of the pathophysiology of vascular failure. As a biomarker, circulating TF is measured by its plasma concentration, flow cytometry-based microparticles and its activity in monocytes. It will be a future task to clarify how to distinguish these measurements based on the difference in clinical significance of each measurement.

Disclosure

T.I. has received honorariums from Mochida, research grants from Shionogi, Daiichi Sankyo, Takeda, Mitsubishi Tanabe, Teijin, Boehringer Ingelheim, Bayer, Abbott Vascular, Kaatsu Japan, Goodman, Clinico, St. Jude Medical, Public Health Research Center, Boston Scientific, Union Tool, and Research Institute for Production Development. M.S. and S.T. declare no conflicts of interest. K.N. has received honorariums from Boehringer Ingelheim, Daiichi Sankyo, Astellas, MSD, Takeda, Mitsubishi Tanabe, and Sanofi, as well as research grants from Sanwa Kagaku Kenkyusho, Astellas, Takeda, Boehringer Ingelheim, Bayer, Teijin, and Mitsubishi Tanabe.

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