The Tissue Factor Pathway in Disseminated Intravascular Coagulation

Abstract

In most instances, tissue factor (TF) exposed to the circulation is the sole culprit underlying the initiation of disseminated intravascular coagulation (DIC), although notable exceptions because of a more direct activation of the coagulation system, by snake venoms, for example, do occur. Peripheral monocytes and subendothelial structures are the potential sources of such TF; in the former, TF emerges on the cell surface on synthesis induction and in the latter it becomes available subsequent to permeability changes or damage to the endothelium. Subendothelial TF is constitutively present in fibroblasts, pericytes, and macrophages and at a higher than normal level in tumor-associated macrophages. This scenario of coagulation activation probably describes the principal events underlying emerging acute DIC states under pathophysiological conditions such as abruptio placentae, septic abortion, amniotic fluid embolization, and pregnancy toxemia. Under disease conditions associated with DIC, the continuous exposure to excess TF typically exhausts the available tissue factor pathway inhibitor (TFPI), leading to rampant thrombin generation, persistent feedback activation of factor XI (FXI) by the generated thrombin, and hence virtually uncheckable ongoing fibrin generation (DIC). Recently, it was shown that patients subject to meningococcal sepsis had comparatively large amounts of mainly monocyte-derived circulating TF-containing microparticles. Because phosphatidylserine (PS) is exposed on such particles, in addition to TF, they probably contribute crucially to DIC during meningococcal sepsis. Although endothelial cells (EC) have been shown to express large amounts of TF in vitro, this observation hardly relates to the situation in vivo, where, in contrast, synthesis and exposure of EC TF is very limited and not likely to be of any significance in emerging and ongoing DIC.

Combined Inhibition of Complement (C5) and CD14 Markedly Attenuates Inflammation, Thrombogenicity, and Hemodynamic Changes in Porcine Sepsis

“…Recently it was shown that E. coli-induced TF expression on human monocytes and TF activity in plasma microparticles was C5a-dependent (39). This may be of great importance, as the formation of microparticles seems to reflect the severity of DIC (40,41). There is evidence that expression of TF is also dependent on TLR4/MD-2 signal transduction (42).…”

Thrombin Rapidly Induces Protein Kinase D Phosphorylation, and Protein Kinase C δ Mediates the Activation

“…Thrombin also exerts direct effects on cells to regulate platelet aggregation, endothelial cell activation, and smooth muscle cell (SMC) 1 proliferation via interactions with members of the protease-activated receptor (PAR) family, such as PAR1, PAR2, PAR3, and PAR4, known as G-protein-coupled receptors (2,3). However, the intracellular signaling cascades downstream from the thrombin receptors are surprisingly complex and are still not well understood.…”

“…Thrombin belongs to the multifunctional serine protease family and plays an important role in the blood coagulation cascade through the cleavage of fibrinogen to fibrin (1,2). Thrombin also exerts direct effects on cells to regulate platelet aggregation, endothelial cell activation, and smooth muscle cell (SMC) 1 proliferation via interactions with members of the protease-activated receptor (PAR) family, such as PAR1, PAR2, PAR3, and PAR4, known as G-protein-coupled receptors (2,3).…”

Stress repair mechanism activity explains inflammation and apoptosis

“…Insoluble fibrin generation also closes the capillary gate and disrupts perfusion and oxygenation in organs and tissues (see "Capillary Gate Component" below). This causes stroke [195,196], mental disturbances [197,198], myocardial infarction [195,[199][200][201][202] …”