Contact activation products are new potential biomarkers to evaluate the risk of thrombotic events in systemic lupus erythematosus

Abstract

IntroductionPatients with systemic lupus erythematosus (SLE) have persistent platelet activation and an increased risk of thrombotic events, which cannot be accounted for by traditional cardiovascular risk factors. Factor (F)XII has a potentially important role in thrombus formation and is triggered by activated platelets. We therefore asked whether the contact system is involved in inflammation and vascular disease (VD) in SLE.MethodsFibrin clots were incubated with purified FXII or whole blood, and the activation and regulation of FXII were studied. Plasma from SLE patients with (n = 31) or without (n = 38) previous VD and from matched healthy controls (n = 68) were analyzed for the presence of complexes formed between contact system enzymes and antithrombin (AT) or C1 inhibitor (C1INH) and evaluated with regard to clinical data and laboratory parameters.ResultsFibrin clots elicited FXII activation and acted as co-factors for AT. In clotting plasma, the levels of FXIIa-AT increased, and FXIIa-C1INH decreased. A similar reciprocal relationship existed in SLE patients. FXIIa-AT was elevated in the SLE patients with a history of VD, while the corresponding levels of factor FXIIa-C1INH were significantly decreased. FXIIa-AT correlated strongly with platelet parameters. The odds ratio for VD among the SLE patients was 8.9 if they had low levels of FXIIa-C1INH, 6.1 for those with high levels of FXIIa-AT, and increased to 23.4 for those with both decreased levels of FXIIa-C1INH and increased levels of FXIIa-AT.ConclusionsActivation of FXII is elicited by fibrin during thrombotic reactions in vitro and in vivo, and fibrin acts as a heparin-like co-factor and regulates AT. Patients with SLE had altered levels of FXIIa-serpin complexes, supporting that the contact system is involved in this disease. FXIIa-serpin complexes are strongly associated with previous VD in SLE patients, suggesting that these complexes are potential biomarkers for monitoring and assessing the risk of thrombotic events in SLE.

TiO 2 nanoparticles tested in a novel screening whole human blood model of toxicity trigger adverse activation of the kallikrein system at low concentrations

“…This rapid clotting was reflected in increased levels of TAT and FXIIa-AT. TAT reflects the formation of thrombin from prothrombin, while FXIIa-AT mirrors activation of FXII triggered by the production of fibrin and thus reflects fibrin formation [42]. These two parameters monitor the essential steps in fibrinogen activation.…”

C1 inhibitor-mediated myocardial protection from chronic intermittent hypoxia-induced injury

“…It has been considered as a major inhibitor of complement system activation. C1INH is an acute phase protein that has a mean plasma level of ~250 mg/l and can be markedly upregulated up to 2.5-fold during the inflammation process (19). Previous data indicate that C1INH exerts an anti-apoptotic effect on vascular endothelial cell injury induced by gram-negative lipopolysaccharide (5).…”

The role and regulation of complement activation as part of the thromboinflammation elicited in cell therapies

“…Leukocytes and EC are also activated by bradykinin, produced by the contact system, and platelets are activated by thrombin, the major activation product of the contact/coagulation systems. Examples of crosstalk are: activated platelets triggering complement activation by chondroitin sulfate (Hamad et al, 2008); soluble C5b-9 activating platelets via immune complexes, for example (Sims and Wiedmer, 1991); C5a up-regulating tissue factor (TF) on monocytes and PMNs (Osterud and Bjorklid, 2012;Ritis et al, 2006); and platelets eliciting contact system activation by activating FXII via fibrin formation (Back et al, 2009(Back et al, , 2010(Back et al, , 2013 and the coagulation system via the LP (Gulla et al, 2010). In summary, one can state that thromboinflammation Fig.…”