Etanercept and venous thromboembolism: a case series

<p>Abstract</p> <p>Introduction</p> <p>The treatment with antitumor necrosis factor agents has often been associated with the induction of autoantibodies (antinuclear antibodies, anti-double stranded DNA antibodies and antiphospholipid antibodies). The clinical significance of these antibodies remains unclear, but they may predispose to antiphospholipid syndrome with thromboembolic complications. The association of etanercept with thromboembolic events has not been reported previously in the literature.</p> <p>Case presentation</p> <p>We describe the cases of three patients with rheumatoid arthritis, psoriatic arthritis and seronegative inflammatory arthritis who were treated with etanercept. They developed deep vein thrombosis and/or pulmonary embolism one to three years after the initiation of etanercept therapy. All three patients had a prolonged activated partial thromboplastin time with a positive lupus anticoagulant that persisted even after 12 weeks.</p> <p>Conclusion</p> <p>Although the clinical significance of antiphospholipid antibodies during treatment with antitumor necrosis factor agents remains unclear, they may predispose patients to develop antiphospholipid syndrome when associated with prolonged activated partial thromboplastin time, lupus anticoagulant positivity, or the presence of anti-β2 glycoprotein I. Clinicians must keep this in mind during therapy with antitumor necrosis factor agents in order to prevent, detect and treat potential consequences such as deep vein thrombosis and pulmonary embolism.</p

Canalization effect in the coagulation cascade and the interindividual variability of oral anticoagulant response. a simulation Study

<p>Abstract</p> <p>Background</p> <p>Increasing the predictability and reducing the rate of side effects of oral anticoagulant treatment (OAT) requires further clarification of the cause of about 50% of the interindividual variability of OAT response that is currently unaccounted for. We explore numerically the hypothesis that the effect of the interindividual expression variability of coagulation proteins, which does not usually result in a variability of the coagulation times in untreated subjects, is unmasked by OAT.</p> <p>Results</p> <p>We developed a stochastic variant of the Hockin-Mann model of the tissue factor coagulation pathway, using literature data for the variability of coagulation protein levels in the blood of normal subjects. We simulated <it>in vitro </it>coagulation and estimated the Prothrombin Time and the INR across a model population. In a model of untreated subjects a "canalization effect" can be observed in that a coefficient of variation of up to 33% of each protein level results in a simulated INR of 1 with a clinically irrelevant dispersion of 0.12. When the mean and the standard deviation of vitamin-K dependent protein levels were reduced by 80%, corresponding to the usual Warfarin treatment intensity, the simulated INR was 2.98 ± 0.48, a clinically relevant dispersion, corresponding to a reduction of the canalization effect.</p> <p>Then we combined the Hockin-Mann stochastic model with our previously published model of population response to Warfarin, that takes into account the genetical and the phenotypical variability of Warfarin pharmacokinetics and pharmacodynamics. We used the combined model to evaluate the coagulation protein variability effect on the variability of the Warfarin dose required to reach an INR target of 2.5. The dose variance when removing the coagulation protein variability was 30% lower. The dose was mostly related to the pretreatment levels of factors VII, X, and the tissue factor pathway inhibitor (TFPI).</p> <p>Conclusions</p> <p>It may be worth exploring in experimental studies whether the pretreatment levels of coagulation proteins, in particular VII, X and TFPI, are predictors of the individual warfarin dose, even though, maybe due to a canalization-type effect, their effect on the INR variance in untreated subjects appears low.</p

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Circadian clock and vascular disease.

Cardiovascular functions, including blood pressure and vascular functions, show diurnal oscillation. Circadian variations have been clearly shown in the occurrence of cardiovascular events such as acute myocardial infarction. Circadian rhythm strongly influences human biology and pathology. The identification and characterization of mammalian clock genes revealed that they are expressed almost everywhere throughout the body in a circadian manner. In contrast to the central clock in the suprachiasmatic nucleus (SCN), the clock in each tissue or cell is designated as a peripheral clock. It is now accepted that peripheral clocks have their own roles specific to each peripheral organ by regulating the expression of clock-controlled genes (CCGs), although the oscillation mechanisms of the peripheral clock are similar to that of the SCN. However, little was known about how the peripheral clock in the vasculature contributes to the process of cardiovascular disorders. The biological clock allows each organ or cell to anticipate and prepare for changes in external stimuli. Recent evidence obtained using genetically engineered mice with disrupted circadian rhythm showed a novel function of the internal clock in the pathogenesis of endothelial dysfunction, hypertension and hemostasis. Loss of synchronization between the central and peripheral clock also contributes to the pathogenesis of cardiovascular diseases, as restoration of clock homeostasis could prevent disease progression. Identification of CCGs in each organ, as well as discovery of tools to manipulate the phase of each biological clock, will be of great help in establishing a novel chronotherapeutic approach to the prevention and treatment of cardiovascular disorders

Synthesis of Tissue Factor Pathway Inhibitor in Human Synovial Cells and Chondrocytes Makes Joints the Predilected Site of Bleeding in Haemophiliacs

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