Sitting at the apex of the clotting cascade, the tissue factor (TF) : factor VIIa (FVIIa) complex is essential for hemostasis and contributes to thrombosis. In addition to its hemostatic role, TF:FVIIa-dependent cleavage and activation of protease-activated receptor 2 (PAR2) is involved in tumor growth, angiogenesis and inflammation. This supplement explores new aspects of TF:VIIa biology in seventeen reviews divided into seven sections.
I. Factor VIIa
How FVIIa interacts with cell surfaces is explored in two reviews. In the first, Drs. Rao and Pendurthi discuss the possible significance of the recent finding that the endothelial protein C receptor (EPCR) actually binds both FVIIa and protein C with approximately equal affinities. They suggest that EPCR may play a role in FVIIa clearance in vivo and also speculate that pharmacologic doses of FVIIa could indirectly downregulate protein C function. In the second review, Dr. Monroe reports on in vitro experiments exploring the mechanisms by which FVIIa (especially bound to platelets) may function to restore hemostasis in patients with dilutional coagulopathy.
II. Tissue distribution and cell biology of tissue factor:factor VIIa complex in health and disease
Cell signaling via the TF:VIIa complex, and mechanisms of TF encryption/decryption, are the topic of three lively reviews in this section. Dr. Petersen discusses microarray experiments showing that the repertoire of genes induced by TF:FVIIa activation of PAR2 differs from that induced via thrombin activation of PAR1. Drs. Pendurthi and Rao provide evidence that colocalization of TF:VIIa and PAR2 in lipids rafts is essential for FVIIa signaling. They also tackle the recent proposal that protein disulfide isomerase (PDI) converts TF between encrypted and decrypted forms, summarizing negative evidence from their recent studies. On the other hand, Dr. Engelmann and colleagues argue that PDI-induced activation of cell-surface TF (via catalyzing the formation of a specific disulfide bond) represents the initial step that permits triggering of the clotting cascade.
III. The tissue factor:factor VIIa microenvironment
Two reviews in this section focus on the role of the membrane surface in controlling blood clotting reactions. Dr. Morrissey and colleagues have employed a novel supported bilayer system to investigate, at the nanometer scale, how protein–phospholipid interactions control TF:VIIa activity. They also describe detailed molecular dynamics simulations of the FVIIa Gla domain bound to phospholipid membrane to explain, with atomic resolution, which Ca2+ ions play structural roles and which play phospholipid-binding roles in the assembly of the TF:VIIa complex on cell surfaces. Dr. Imagilov and coworkers describe the use of an ingenious microfluidic approach to investigate the spatiotemporal dynamics of blood coagulation, revealing that both the size and shape of surfaces presenting TF – in addition to TF concentration – control when and where blood clotting is triggered.
IV. Platelet tissue factor
Three reviews focus on platelet TF, a topic that is not without controversy. This may be, in part, due to the very low levels of TF associated with platelets. Dr. Mezzano and colleagues describe the storage, synthesis and function of TF in platelets. Recently, his group showed that platelets synthesize TF and he proposes a new model in which platelets not only mediate “primary hemostasis” but also provide TF to initiate “secondary hemostasis”. In the second review Dr. Escolar and coworkers describe the uptake of TF-positive microparticles by platelets. Lastly, Drs. Butenas, Orfeo and Mann failed to detect TF activity in platelets and propose an alternative view on the role of TF in the propagation phase of coagulation. Their data indicate that TF is required for the initiation of blood coagulation but is not required for later thrombin generation. Clearly, further studies are needed to investigate the role of TF in the propagation of a thrombus in vivo and the contribution of platelet TF to hemostasis and thrombosis.
V. Microparticles and tissue factor in disease
Two reviews describe the role of TF-positive microparticles in disease. Summarizing work on circulating TF-positive microparticles, Drs. Lechner and Weltermann assess different approaches that have been used to detect and quantify TF expression on microparticles, and emphasize the need for assay standardization – important because the development of a simple and reliable assay that accurately measures levels of circulating TF-positive microparticles may help determine whether this can be used as a biomarker of a prothrombotic state. In the second review Dr. Dignat-George provides a broad overview of microparticles, including their formation, composition, and function in a variety of vascular diseases.
VI. Tissue factor pathway inhibitor
Dr. Rosing and colleagues summarize recent data demonstrating that protein S is a cofactor for tissue factor pathway inhibitor (TFPI), and argue that a deficiency of protein S diminishes the anticoagulant activity of both activated protein C and TFPI.
VII. Animal models of hemostasis and thrombosis
Finally, four reviews focus on animal models of hemostasis and thrombosis. Dr. Whinna provides an overview of mouse models of thrombosis. Dr. Margaritis discusses his work on viral-mediated delivery of FVIIa to correct the hemostatic defects in hemophilia B mice, and the phenotype of transgenic mice overexpressing FVIIa. Dr. Hoffman’s review focuses on her recent work on TF expression in a mouse model of wound healing, noting that TF expression around blood vessels near the cutaneous punch is transiently downregulated. The last review, by Dr. Taubman and coworkers, describes work on mice having a selective reduction of TF expression in smooth muscle cells. These studies demonstrate that, in a model of carotid artery injury, smooth muscle cell TF drives thrombosis, and also contributes to intimal hyperplasia in a model of femoral artery injury.
Summary
Many recent studies indicate that the TF:FVIIa complex may play unexpected roles in a variety of biological processes. A better understanding of this key complex may lead to the development of improved hemostatic agents and therapeutics for treating thrombosis and other diseases.
Footnotes
Conflict of interest statement
Dr. Mackman is a member of the Scientific Advisory Board of Thrombotargets Group and Othera Pharmacueticals. Dr. Morrissey reports no relevant conflicts.
Contributor Information
James Morrissey, Email: jhmorris@uiuc.edu, Department of Biochemistry, College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA
Nigel Mackman, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.