Substrates of Factor XIII-A: roles in thrombosis and wound healing.

FXIII (Factor XIII) is a Ca²+-dependent enzyme which forms covalent ϵ-(γ-glutamyl)lysine cross-links between the γ-carboxy-amine group of a glutamine residue and the ϵ-amino group of a lysine residue. FXIII was originally identified as a protein involved in fibrin clot stabilization; however, additional extracellular and intracellular roles for FXIII have been identified which influence thrombus resolution and tissue repair. The present review discusses the substrates of FXIIIa (activated FXIII) involved in thrombosis and wound healing with a particular focus on: (i) the influence of plasma FXIIIa on the formation of stable fibrin clots able to withstand mechanical and enzymatic breakdown through fibrin-fibrin cross-linking and cross-linking of fibrinolysis inhibitors, in particular α2-antiplasmin; (ii) the role of intracellular FXIIIa in clot retraction through cross-linking of platelet cytoskeleton proteins, including actin, myosin, filamin and vinculin; (iii) the role of intracellular FXIIIa in cross-linking the cytoplasmic tails of monocyte AT1Rs (angiotensin type 1 receptors) and potential effects on the development of atherosclerosis; and (iv) the role of FXIIIa on matrix deposition and tissue repair, including cross-linking of extracellular matrix proteins, such as fibronectin, collagen and von Willebrand factor, and the effects on matrix deposition and cell-matrix interactions. The review highlights the central role of FXIIIa in the regulation of thrombus stability, thrombus regulation, cell-matrix interactions and wound healing, which is supported by observations in FXIII-deficient humans and animals.

Complement and Cardiovascular Disease--The Missing Link in Haemodialysis Patients.

BACKGROUND: Patients on haemodialysis (HD) have high rates of cardiovascular (CV) disease and activation of the complement system. Despite evidence in non-renal patients that these may be linked, this association has received little attention in HD patients to date. In the setting of a randomised controlled trial we evaluated the relationships between baseline complement levels and subsequent CV events and mortality, in addition to the effects of HD with a vitamin E (VE)-coated dialysis membrane on circulating complement levels. METHODS: A total of 260 HD patients were randomised to dialysis with a VE-coated dialysis membrane or non-VE coated equivalent for 12 months. Blood samples were taken at baseline, 6 and 12 months for measurement of C3, factor D, factor H and SC5b-9 levels. Data were collected prospectively on deaths and CV events. RESULTS: Higher C3 levels at baseline were associated with subsequent CV events (hazard ratio 1.20 (1.01-1.42) per 0.1 mg/ml). Patients with intermediate SC5b-9 levels had significantly lower CV event rates and mortality than those with either high or low levels (p < 0.01). There were no effects of the VE-membranes on the complement components measured nor the clinical endpoints considered. CONCLUSIONS: The levels of C3 and SC5b-9 may have prognostic utility for predicting future CV events and/or mortality in HD patients - a relationship that requires further investigation. Dialysing prevalent HD patients with VE-bonded polysulfone membranes for a period of 12 months did not alter the circulating levels of the alternative complement pathway components considered here.

Adipose tissue inflammation: feeding the development of type 2 diabetes mellitus.

The global increase in obesity-induced type 2 diabetes (T2DM) represents a burden for healthcare systems worldwide. Of particular concern is the increased morbidity associated with T2DM, in particular cardiovascular disease (CVD), leading to premature death. Obesity initially leads to the development of insulin resistance in adipose and other tissues. Insulin resistance is initially compensated by increased insulin secretion but ultimately insufficient insulin is produced and this leads to the development of T2DM. Understanding the causal mechanisms underpinning the development of obesity-induced insulin resistance may be beneficial in improving quality of life and life expectancy, with the potential for a major global impact on healthcare systems. There is abundant evidence from animal, human studies and in vitro studies to support functional roles for a number of inflammatory factors in obesity-induced insulin resistance. In this review we provide an overview of the evidence supporting a fundamental role for the fluid phase (in particular the complement system) and the cellular components of the innate immune system in the pathogenesis of obesity-induced insulin resistance and ultimately development of T2DM.

Elevated properdin and enhanced complement activation in first-degree relatives of South Asian subjects with type 2 diabetes.

OBJECTIVE: Emerging data implicate activation of the complement cascade in the pathogenesis of type 2 diabetes. The objective of the current study was to evaluate the relationships between components of the complement system, metabolic risk factors, and family history of type 2 diabetes in healthy South Asians. RESEARCH DESIGN AND METHODS: We recruited 119 healthy, first-degree relatives of South Asian subjects with type 2 diabetes (SARs) and 119 age- and sex-matched, healthy South Asian control subjects (SACs). Fasting blood samples were taken for measurement of complement factors and standard metabolic risk factors. RESULTS: SARs were characterized by significantly higher properdin (mean concentration 12.6 [95% CI 12.2-13.1] mg/L vs. SACs 10.1 [9.7-10.5] mg/L, P < 0.0001), factor B (187.4 [180.1-195.0] mg/L vs. SACs 165.0 [158.0-172.2] mg/L, P < 0.0001), and SC5b-9 (92.0 [86.1-98.3] ng/mL vs. SACs 75.3 [71.9-78.9] ng/mL, P < 0.0001) and increased homeostasis model assessment of insulin resistance (2.86 [2.61-3.13] vs. SACs 2.31 [2.05-2.61], P = 0.007). C-reactive protein did not differ between SARs and SACs (P = 0.17). In subgroup analysis of 25 SARs and 25 SACs with normal oral glucose tolerance tests, properdin, factor B, and SC5b-9 remained significantly elevated in SARs. CONCLUSIONS: Increased properdin and complement activation are associated with a family history of type 2 diabetes in South Asians independent of insulin resistance, and predate the development of impaired fasting glucose and impaired glucose tolerance. Properdin and SC5b-9 may be novel biomarkers for future risk of type 2 diabetes in this high-risk population and warrant further investigation.

Complement C3 is a novel plasma clot component with anti-fibrinolytic properties.

BACKGROUND AND METHOD: Increased plasma clot density and prolonged lysis times are associated with cardiovascular disease. In this study, we employed a functional proteomics approach to identify novel clot components which may influence clot phenotypes. RESULTS: Analysis of perfused, solubilised plasma clots identified inflammatory proteins, including complement C3, as novel clot components. Analysis of paired plasma and serum samples confirmed concentration-dependent incorporation of C3 into clots. Surface plasmon resonance indicated high-affinity binding interactions between C3 and fibrinogen and fibrin. Turbidimetric clotting and lysis assays indicated C3 impaired fibrinolysis in a concentration-dependent manner, both in vitro and ex vivo. CONCLUSION: These data indicate functional interactions between complement C3 and fibrin leading to prolonged fibrinolysis. These interactions are physiologically relevant in the context of protection following injury and suggest a mechanistic link between increased plasma C3 concentration and acute cardiovascular thrombotic events.