Inactivation of factor XII active fragment in normal plasma. Predominant role of C-1-inhibitor.

Agostini, Ariane de; Lijnen, H.R.; Pixley, Robin A.; Colman, RW; Schapira, Marc

doi:10.1172/jci111360

Cited by 178 publications

(88 citation statements)

References 40 publications

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“…However, C1 inhibitor may share this latter role with α 2 macroglobulin (Ambrus et al, 2003). In the contact or kinin system, C1 inhibitor is the primary inhibitor of both plasma kallikrein and factor XIIa (de Agostini et al, 1984;Kaplan et al, 1985;Pixley et al, 1985). In this instance, α 2 macroglobulin clearly plays a lesser role than does C1 inhibitor.…”

Section: Introductionmentioning

confidence: 99%

C1 inhibitor: Biologic activities that are independent of protease inhibition

Davis

Cai

2007

Immunobiology

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C1 inhibitor therapy improves outcome in several animal models of inflammatory disease. These include sepsis and gram negative endotoxin shock, vascular leak syndromes, hyperacute transplant rejection, and ischemia-reperfusion injury. Furthermore, some data suggest a beneficial effect in human inflammatory disease. In many inflammatory conditions, complement system activation plays a role in pathogenesis. The contact system also very likely is involved in mediation of damage in inflammatory disease. Therefore, the beneficial effect of C1 inhibitor has been assumed to result from inhibition of one or both of these systems. Over the past several years, several other potential anti-inflammatory effects of C1 inhibitor have been described. These effects do not appear to require protease inhibition and depend on non-covalent interactions with other proteins, cell surfaces or lipids. In the first, C1 inhibitor binds to a variety of extracellular matrix components including type IV collagen, laminin, entactin and fibrinogen. The biologic role of these reactions is unclear, but they may serve to concentrate C1 inhibitor at extravascular inflammatory sites. The second is a noncovalent interaction with C3b that results in inhibition of formation of the alternative pathway C3 convertase, a function analogous to that of factor H. The third is an interaction with E and P selectins on endothelial cells that is mediated by the Lewis x tetrasaccharides that are expressed on C1 inhibitor. These interactions result in suppression of leukocyte rolling and transmigration. The fourth interaction is the binding of C1 inhibitor to gram negative bacterial endotoxin that results in suppression of endotoxin shock by interference with the interaction of endotoxin with its receptor complex on macrophages. Lastly, C1 inhibitor binds directly to gram negative bacteria, which leads to suppression of the development of sepsis, as demonstrated in the cecal ligation and puncture model. These observations suggest that C1 inhibitor is a multi-faceted anti-inflammatory protein that exerts its effects through a variety of mechanisms including both protease inhibition and several different non-covalent interactions that are unrelated to protease inhibition.

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Section: Introductionmentioning

confidence: 99%

C1 inhibitor: Biologic activities that are independent of protease inhibition

Davis

Cai

2007

Immunobiology

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“…Cl-Inh is the only known inhibitor in plasma of activated Clr and Cls, components of the classical pathway of complement (18), and the major inhibitor of activated Factor XII (Hageman factor) and kallikrein of the contact pathway of coagulation (19)(20)(21)(22). Inhibition of these so-called target proteinases by functional Cl-Inh comprises both proteolytic cleavage of a substrate-like peptide bond in the reactive center of the inhibitor and covalent linkage of the proteinase to the inhibitor: formation of bimolecular proteinase-C1-Inh complexes (18,20,(22)(23)(24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

Proteolytic inactivation of plasma C1- inhibitor in sepsis.

Nuijens¹,

Eerenberg-Belmer²,

Huijbregts³

et al. 1989

J. Clin. Invest.

137

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Activation of both the complement system and the contact system of intrinsic coagulation is implicated in the pathophysiology of sepsis. Because C1 inhibitor (Cl-Inh) (M, 110,000). Elevated iCl-Inh levels (_ 0.13 ,uM) were found in 81% of all patients, sometimes up to 1.6 MM. Levels of iCl-Inh on admission appeared to be of prognostic value: iCl-Inh was higher in 27 patients who died than in 21 patients who survived (P = 0.003). The mortality in 15 patients with iCl-Inh levels up to 0.2,uM was 27%, but in 12 patients with plasma iCl-Inh exceeding 0.44 gM, the mortality was 83%. The overall mortality in the patients with sepsis was 56%. We propose that the cleavage of Ci-Inh in patients with sepsis reflects processes that play a major role in the development of fatal complications during sepsis.

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“…El C1-inhibidor es la proteína inhibidora más importante de PK y del FXII (12) ; además, el inhibidor de la proteína de soya "corn tripsin inhibitor" (CTI) ha demostrado inhibir la vía de contacto in vitro (13) . En resumen, las consecuencias de la activación del FXII se observan en tres vías: coagulación, inflamación y complemento (Figura 2), produciendo fibrina, activación del C1qrs y liberación de bradikinina.…”

Section: Figura 1 Estructura Y Activación Del Fxiiunclassified

Tema 17-2014: La Vía De Contacto: ¿el Futuro De Los Anticoagulantes?

López¹

2014

RC_UCR-HSJD

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RESUMENDurante décadas el desarrollo de nuevos anticoagulantes se ha basado en la modificación de fármacos o moléculas previamente disponibles. La poca oferta ha ocasionado que actualmente sea aceptado no administrar anticoagulantes cuando existe una indicación clara de anticoagulación, incrementando así el riesgo de extensión del fenómeno trombótico, el síndrome postrombótico, la discapacidad a largo plazo y las recurrencias, que en conjunto causan más morbilidad y mortalidad que el sangrado secundario a sobreanticoagulación. Los nuevos anticoagulantes orales han ampliado la cantidad de pacientes potenciales, sin embargo existen más opciones viables a mediano plazo que pueden cambiar la anticoagulación tal y como la conocemos hoy en día. Se resume la evidencia disponible en cuanto a la utilización del Sistema de Contacto de la coagulación como modelo para el desarrollo de futuras opciones terapéuticas y sus implicaciones futuras. PALABRAS CLAVEAnticoagulación. Sistema de Contacto. Factor XII. ABSTRACTFor years, the development of new anticoagulant drugs has been based on modifications of previously available compounds. Currently, it is widely accepted to withhold the administration of anticoagulants even in the presence of an indication of anticoagulation, increasing the morbidity, long-term disability and relapses, which together account for more mortality than bleeding as a secondary effect. The novel oral anticoagulants have broadened the number of potential candidates; however, more options are foreseen in the future that can change clinical anticoagulation as it is prescribed today. We will summarize current knowledge on the coagulation Contact System and future therapeutic options.

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Inactivation of factor XII active fragment in normal plasma. Predominant role of C-1-inhibitor.

Cited by 178 publications

References 40 publications

C1 inhibitor: Biologic activities that are independent of protease inhibition

C1 inhibitor: Biologic activities that are independent of protease inhibition

Proteolytic inactivation of plasma C1- inhibitor in sepsis.

Tema 17-2014: La Vía De Contacto: ¿el Futuro De Los Anticoagulantes?

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