Nitrated fibrinogen is a biomarker of oxidative stress in venous thromboembolism

Abstract

The pathogenesis of venous thromboembolism (VTE) is linked to inflammation and oxidant production, although specific markers for these pathways with pathological relevance to VTE have not been explored. The coagulant protein fibrinogen is post-translationally modified by nitric oxide-derived oxidants to nitrated fibrinogen in both acute and chronic inflammatory states. Therefore, nitrated fibrinogen may serve as a marker of inflammation and oxidative stress in VTE. To test this hypothesis we enrolled subjects (n=251) presenting with suspected VTE at the Hospital of the University of Pennsylvania emergency department, 50 (19.9 %) of whom were positive by imaging or 90-day follow-up. Mean nitrated fibrinogen was elevated in VTE positive (62.7 nM, 95 % CI 56.6–68.8) compared to VTE negative patients (54.2 nM, 95 % CI 51.4–57.1; P < 0.01). Patients in the highest quartile of nitrated fibrinogen had an increased risk of VTE compared with patients in the lowest quartile (OR 3.30; 95 % CI 1.25–8.68; P<0.05). This risk persisted after univariate adjustment for age, active cancer, and recent surgery, but not after multivariate adjustment. Mean fibrinogen levels measured either by the Clauss assay or by ELISA were not different between VTE negative and positive patients. These data indicate that nitrated fibrinogen is an oxidative risk marker in VTE, providing a novel mechanistic link between oxidant production, inflammation, and VTE.

Enhanced lysis and accelerated establishment of viscoelastic properties of fibrin clots are associated with pulmonary embolism

“…Before initiation of anticoagulant therapy, blood was drawn from subjects in 3.2% sodium citrate (BD Vacutainer, Franklin Lakes, NJ), and platelet-poor plasma was prepared as described previously (12) and stored at Ϫ80°C in 0.1-ml aliquots for single use. The target sample size was calculated based on preliminary clot formation and lysis time assays in initial DVT and PE subjects collected.…”

“…The target sample size was calculated based on preliminary clot formation and lysis time assays in initial DVT and PE subjects collected. However, due to use of these samples in another study (12), there were some limitations on sample volume and thus not every patient sample could be included in every assay. Because functional properties may provide insights about embolization, fibrinogen concentration, clot formation and lysis time assays and viscoelastic properties were given priority for sample analysis, respectively.…”

Inflammation in venous thromboembolism: Cause or consequence?

“…As an example, the levels of nitrated fibrinogen were significantly elevated in patients with VTE compared to those without VTE [78]. On the other side, both protein concentrations and mRNA expressions of endothelial nitric oxide synthase were significantly reduced in rat pulmonary tissues after PTE, which could be treated by L-arginine [74].…”

Asthma and risk of pulmonary thromboembolism

“…The pathogenesis of venous thromboembolism is also linked to oxidative stress [3]. Therefore, the involvement of oxidative stress may potentiate the increased risk of pulmonary thromboembolism in asthmatic patients.…”

“…The answer is well known: we do not know the right values of the carbon monoxide and nitric oxide conductance of haemoglobin (specific conductance (h)), which are necessary to the calculation of Vc and Dm. However, although we thought in 1987 that the conductance for nitric oxide could be taken as infinite [3], we have since changed our minds, as, at that time, we used the recommended carbon monoxide specific conductance of ROUGHTON and FORSTER [4], which was incorrect, as explained later by FORSTER [5]. The work of BORLAND et al…”