Blood coagulation factors as inflammatory mediators
Introduction
Blood coagulation and the inflammatory process are interrelated as part of the innate host defense mechanism. The importance of this interrelationship is highlighted by the major complications of sepsis: disseminated intravascular coagulation (DIC) and multiple organ failure. Thrombi formed during these complications are often accompanied by massive inflammation. The interaction between coagulation and inflammation is a bidirectional process of which inflammation-induced coagulation is well established and has therefore been extensively reviewed [1], [2], [3], [4], [5], [6]. Coagulation-induced inflammation, on the other hand, has only recently gained attention; inhibition of coagulation during Gram-negative sepsis might be an important target for therapeutic intervention [7], [8], [9], [10], [11]. The overall aim of this overview is to summarize our current understanding concerning coagulation factors and their role in inflammation.
Section snippets
Coagulation cascade
Upon vessel injury, platelets adhere to macromolecules in subendothelial tissues and aggregate to form a hemostatic plug. The platelets stimulate local activation of plasma coagulation factors, leading to generation of a fibrin clot that reinforces platelet aggregate. Current ideas about the mechanism(s) underlying blood coagulation are based on the waterfall or cascade model introduced in the early 1960s [12], [13]. Traditionally, coagulation was divided into an “intrinsic”, an “extrinsic”,
Inflammatory system
The inflammatory response is a local response to cellular injury that serves as a mechanism initiating the elimination of noxious agents (for example, bacteria or antigens) and of damaged tissue. The result of each inflammatory reaction may be beneficial (defend the body against agents deranging its homeostasis) or harmful (damage to surrounding tissues) for the involved tissue. Inflammation is characterized by redness, swelling, heat, pain, and deranged tissue function. These signs are mainly
TF/FVIIa-induced inflammation
FVII is a 50-kDa vitamin K-dependent gamma-carboxylated plasma glycoprotein, which in its activated form FVIIa activates FX to FXa and FIX to FIXa by limited proteolysis. FVIIa alone shows very little proteolytic activity and realizes its full enzymatic activity only when bound to TF. Although FVII is activated by the coagulation products FXa and thrombin, trace amounts of FVIIa appear present in plasma at all time [29]. TF is a 47-kDa, non-enzymatic, membrane-bound glycoprotein that is
FXa-induced inflammation
Active-site-inhibited FXa treatment of septic baboons or human volunteers showed no beneficial effects of FXa inhibition on inflammation while FXa-mediated coagulation was inhibited [64], [68]. Nevertheless, in vitro data strongly point to a role for FXa in inflammation via PAR-mediated intracellular signaling. As shown in Fig. 1, FXa cleaves PAR-1 and PAR-2, resulting in activation of the NF-κB pathway, MAP kinase phosphorylation, and expression of the angiogenesis-promoting genes Cyr61 and
Thrombin-induced inflammation
For more than 25 years, it is claimed that thrombin has pro-inflammatory properties. In 1977, it was shown that heparin is not suitable as an anticoagulant in ex vivo leukocyte migration tests, which are used to demonstrate the presence of migration inhibition factor (MIF) [76]. In the presence of heparin, the MIF effect disappears very rapidly. The change in response when using heparinized blood is not due to a direct effect of heparin, because heparin has no effect when added to defibrinated
Conclusion
Individual coagulation factors play an important role in inflammation induced by infectious agents. However, definite answers about the relative contribution of the individual coagulation factors remain elusive, since inhibition of one factor influences the expression of other factors as well. Inhibition of, for instance, TF results in decreased production of FXa and thrombin, while inhibition of thrombin results in lowered levels of FXIa, FVIIIa, FVa, and thus FXa and thrombin. Furthermore, in
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