From the Guidelines
Inflammation increases tissue factor expression primarily through the activation of inflammatory signaling pathways, as evidenced by the most recent study 1.
Key Mechanisms
- Inflammatory mediators, such as pro-inflammatory cytokines (e.g., TNF-α, IL-1) and bacterial endotoxins (e.g., LPS), stimulate cells like monocytes, macrophages, and endothelial cells.
- These stimuli activate transcription factors, particularly nuclear factor kappa B (NF-κB), which binds to the tissue factor gene promoter and enhances its transcription.
- Inflammation causes endothelial cell damage, exposing subendothelial tissue factor to circulating blood.
- Inflammatory mediators also increase the shedding of tissue factor-containing microparticles from various cells, further amplifying coagulation potential.
Clinical Significance
- The upregulation of tissue factor serves as a protective mechanism to limit bleeding during injury but can become pathological in conditions of excessive inflammation.
- This can lead to thrombotic complications like disseminated intravascular coagulation (DIC), deep vein thrombosis, or arterial thrombosis.
- The tissue factor pathway is the primary initiator of the coagulation cascade, making its inflammatory regulation clinically significant in managing thrombotic risk in inflammatory diseases, as supported by studies 1.
Evidence Summary
The most recent and highest quality study 1 provides evidence for the interaction between coagulation and inflammation, highlighting the role of tissue factor in the coagulation cascade. While other studies 1 provide additional insights into the relationship between inflammation and cardiovascular disease, the primary mechanism of inflammation increasing tissue factor expression is well-established in the most recent study 1.
From the Research
Inflammation and Tissue Factor Expression
- Inflammation increases tissue factor expression, which plays a crucial role in the initiation of the extrinsic blood coagulation pathway 2.
- The upregulation of tissue factor (TF) resulting from its enhanced exposure to clotting factor FVII/FVIIa often manifests not only a hypercoagulable but also an inflammatory state 3.
- Proinflammatory cytokines, chemokines, adhesion molecules, and tissue factor expression are involved in the complex interactions between inflammation and hemostasis 4.
Mechanisms of Inflammation-Induced Tissue Factor Expression
- Inflammation induces the expression of tissue factor by vascular cells, and systemic Gram-negative infection induces expression of TF by vascular cells 2.
- Coagulant mediators (FVIIa, FXa, and FIIa) are proinflammatory, which are largely transmitted by protease-activated receptors (PAR) to elicit inflammation, including the expression of tissue necrosis factor, interleukins, adhesion molecules, and growth factors 3.
- Fibrin, and its fragments, are also able to promote inflammation, and the inflammatory consequence could be enormous in the event of TF hypercoagulability accompanied by the elevations in clotting signals, including fibrin overproduction 3.
Relationship Between Inflammation and Coagulation
- There is a complex crosstalk between inflammation and hemostasis, involving proinflammatory cytokines, chemokines, adhesion molecules, tissue factor expression, platelet and endothelial activation, and microparticles 4.
- Coagulation also augments inflammation, causing a vicious cycle, mainly achieved by means of thrombin-induced secretion of proinflammatory cytokines and growth factors 4.
- The challenge for the future will be to identify a pharmacologic agent that will arrest the inflammatory cascade and thus prevent further amplification and resultant host injury 5.