Coagulation in Vertebrates with a Focus on Evolution and Inflammation

Doolittle, Russell F.

doi:10.1159/000321005

Cited by 56 publications

(52 citation statements)

References 66 publications

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“…Indeed, the contact system is highly conserved among mammalian species. 23 Thrombus formation in FXII heterozygous mice (having 50% of normal FXII plasma levels) was similar to wild-type animals (having 100%), indicating that half of normal plasma concentration is sufficient for vessel-occlusive clot formation. Modulating FXII expression levels by antisense nucleotides showed that reduction of more than 75% FXII antigen plasma levels is required to produce thrombo-protection in a model of stasisinduced venous thrombosis.…”

mentioning

confidence: 83%

In vivo roles of factor XII

Renné

Schmaier

Nickel

et al. 2012

Blood

297

216

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Coagulation factor XII (FXII, Hageman factor, EC ‫؍‬ 3.4.21.38) is the zymogen of the serine protease, factor XIIa (FXIIa). FXII is converted to FXIIa through autoactivation induced by "contact" to charged surfaces. FXIIa is of crucial importance for fibrin formation in vitro, but deficiency in the protease is not associated with excessive bleeding. For decades, FXII was considered to have no function for coagulation in vivo. Our laboratory developed the first murine knockout model of FXII. Consistent with their human counterparts, FXII ؊/؊ mice have a normal hemostatic capacity. However, thrombus formation in FXII ؊/؊ mice is largely defective, and the animals are protected from experimental cerebral ischemia and pulmonary embolism. This murine model has created new interest in FXII because it raises the possibility for safe anticoagulation, which targets thrombosis without influence on hemostasis. We recently have identified platelet polyphosphate (an inorganic polymer) and mast cell heparin as in vivo FXII activators with implications on the initiation of thrombosis and edema during hypersensitivity reactions. Independent of its protease activity, FXII exerts mitogenic activity with implications for angiogenesis. The goal of this review is to summarize the in vivo functions of FXII, with special focus to its functions in thrombosis and vascular biology. (Blood. 2012;120(22):4296-4303)The factor XII-driven plasma contact system Fibrin formation may be initiated by 2 distinct pathways, either triggered by exposure of blood to a damaged vessel wall (extrinsic) or to blood-borne (intrinsic) factors. The intrinsic pathway of coagulation is initiated by factor XII (FXII, Hageman factor), in a reaction involving high molecular weight kininogen (HK) and plasma kallikrein (PK). These factors are collectively referred to as the plasma contact system. [1][2][3][4][5][6] Contact with negatively charged surfaces induces a conformational change in zymogen FXII resulting in a small amount of active FXII (FXIIa). 7 FXIIa cleaves PK to generate active PK, which in turn reciprocally activates FXII. 8 FXIIa triggers fibrin formation through activation of factor XI (FXI) and also liberates the inflammatory mediator bradykinin (BK) from HK through cleavage by PK. 3 Binding of BK to the kinin B2 receptor (B2R) activates proinflammatory signaling pathways that dilate vessels, induce chemotaxis of neutrophils, and increase vascular permeability. 9 Thus, the FXIIa-driven contact system has proinflammatory and procoagulant activities via the kallikrein kinin-system and the intrinsic coagulation pathway, respectively ( Figure 1). The serpin C1 esterase inhibitor (C1INH) is the major plasma inhibitor of FXIIa and PK and controls proteolytic activity of the contact system. 10 Besides C1INH, antithrombin III (ATIII) and PAI-1 also have FXIIa-blocking activity. 11 In vitro, FXIIa triggers activation of the classic complement pathway and initiates the fibrinolytic system via PK-mediated urokinase activation. 5 Whether FXIIa has the capacity...

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mentioning

confidence: 83%

In vivo roles of factor XII

Renné

Schmaier

Nickel

et al. 2012

Blood

297

216

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“…Whereas the complement system has been considered to be part of the innate immune system for Ͼ 30 years, it has only recently been determined that coagulation also partakes in inflammation and the early immune defense. 7,8 In the latter studies, a major focus has been on the ability of the clotting cascade to trigger pro-and anti-inflammatory reactions, such as the release of cytokines and the activation of protease-activated receptors. However, it is unknown to what extent coagulation can actively contribute to the elimination of an invading microorganism.…”

Section: Introductionmentioning

confidence: 99%

Coagulation, an ancestral serine protease cascade, exerts a novel function in early immune defense

Loof

Mörgelin

Johansson

et al. 2011

Blood

162

132

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Phylogenetically conserved serine protease cascades play an important role in invertebrate and vertebrate immunity. The mammalian coagulation system can be traced back some 400 million years and shares homology with ancestral serine proteinase cascades that are involved in, for example, Toll receptor signaling in insects and release of antimicrobial peptides during hemolymph clotting. In the present study, we show that the induction of coagulation by bacteria leads to immobilization and killing of Streptococcus pyogenes bacteria inside the clot. The entrapment is mediated via cross-linking of bacteria to fibrin fibers by the action of coagulation factor XIII (fXIII), an evolutionarily conserved transglutaminase. In a streptococcal skin infection model, fXIII ؊/؊ mice developed severe signs of pathologic inflammation at the local site of infection, and fXIII treatment of wild-type animals dampened bacterial dissemination during early infection. Bacterial killing and cross-linking to fibrin networks was also detected in tissue biopsies from patients with streptococcal necrotizing fasciitis, supporting the concept that coagulation is part of the early innate immune system. (Blood. 2011;118(9):2589-2598)

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“…The recent discovery that C-terminal peptides of human thrombin, a key enzyme in the coagulation cascade, constitute a novel class of HDPs with bactericidal and anti-inflammatory properties, has defined new HDPs and expanded the field of innate immunity to thrombin and the coagulation system [9] . From an evolutionary perspective, this additional role of thrombin is logical, since injury and infection both represent situations necessitating an optimized innate immune system [10,11] . Structurally, analyses show that the major thrombin-derived C-terminal peptide of 96 amino acids represents a novel structural entity, which is related to other cysteine-linked HDPs, including defensins, containing the ␥ -core motif [9,12] .…”

Section: Introductionmentioning

confidence: 99%

The C-Terminal Sequence of Several Human Serine Proteases Encodes Host Defense Functions

et al. 2011

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Serine proteases of the S1 family have maintained a common structure over an evolutionary span of more than one billion years, and evolved a variety of substrate specificities and diverse biological roles, involving digestion and degradation, blood clotting, fibrinolysis and epithelial homeostasis. We here show that a wide range of C-terminal peptide sequences of serine proteases, particularly from the coagulation and kallikrein systems, share characteristics common with classical antimicrobial peptides of innate immunity. Under physiological conditions, these peptides exert antimicrobial effects as well as immunomodulatory functions by inhibiting macrophage responses to bacterial lipopolysaccharide. In mice, selected peptides are protective against lipopolysaccharide-induced shock. Moreover, these S1-derived host defense peptides exhibit helical structures upon binding to lipopolysaccharide and also permeabilize liposomes. The results uncover new and fundamental aspects on host defense functions of serine proteases present particularly in blood and epithelia, and provide tools for the identification of host defense molecules of therapeutic interest.

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Coagulation in Vertebrates with a Focus on Evolution and Inflammation

Cited by 56 publications

References 66 publications

In vivo roles of factor XII

In vivo roles of factor XII

Coagulation, an ancestral serine protease cascade, exerts a novel function in early immune defense

The C-Terminal Sequence of Several Human Serine Proteases Encodes Host Defense Functions

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