Lucia Ciucciarelli

Behçet’s syndrome pathophysiology and potential therapeutic targets

Behçet syndrome is a systemic inflammatory disorder characterized by multiorgan involvement such as oral and genital ulcers, uveitis, skin lesions as well as by less frequent, but often more severe, central nervous system and vascular manifestations. The pathogenetic mechanisms are still incompletely known; however the interaction between a specific genetic background and environmental or infectious factors certainly contributes to the immune dysregulation that characterizes this disease. The discovery of new immunological pathways in Behçet syndrome pathogenesis may help us to set up new treatments. In this review, we will focus our attention on the possible mechanisms underlying Behçet syndrome pathogenesis and their potential role as novel therapeutic targets.

Neutrophil Activation Promotes Fibrinogen Oxidation and Thrombus Formation in Behçet Disease.

Background— Behçet disease (BD) is a systemic vasculitis with a broad range of organ involvement, characterized by a multisystemic, immune-inflammatory disorder involving vessels of all sizes and often complicated by thrombosis. Systemic redox imbalance and circulating neutrophil hyperactivation have been observed in BD patients and are thought to be responsible for impaired coagulation. We here focused on the pathogenetic mechanisms potentially linking immune cell activation and thrombosis, and specifically examined whether neutrophil activation can affect fibrinogen modifications and consequently elicit thrombosis. Methods and Results— Blood samples were collected from 98 consecutive BD patients attending our dedicated Center and from 70 age- and sex-matched healthy controls; in all patients fibrinogen function and structure, fibrin susceptibility to plasmin-lysis, plasma redox status, leukocyte oxidative stress markers, and possible reactive oxygen species sources were examined. Thrombin-catalyzed fibrin formation and fibrin susceptibility to plasmin-induced lysis were significantly impaired in BD patients (P<0.001). These findings were associated with increased plasma oxidative stress markers (P<0.001) and with a marked carbonylation of fibrinogen (P<0.001), whose secondary structure appeared deeply modified. Neutrophils displayed an enhanced NADPH oxidase activity and increased reactive oxygen species production (P<0.001), which significantly correlated with fibrinogen carbonylation level (r2=0.33, P<0.0001), residual &bgr;-band intensity (r2=0.07, P<0.01), and fibrinogen clotting ability (r2=0.073, P<0.01) Conclusions— In BD patients, altered fibrinogen structure and impaired fibrinogen function are associated with neutrophil activation and enhanced reactive oxygen species production whose primary source is represented by neutrophil NADPH oxidase.

Pathogenesis and potential therapeutic targets in systemic lupus erythematosus: from bench to bedside

Systemic lupus erythematosus (SLE) is considered an autoimmune disease with multiorgan involvement. Many advances have been made during the last decade regarding inflammatory pathways, genetic and epigenetic alterations, adaptive and innate immune system mechanisms specifically involved in SLE pathogenesis. Apoptosis has been proposed as an important player in SLE pathogenesis more than a decade ago. However, only recently new key apoptotic pathways have been investigated and the link between apoptotic debris containing autoantigens, innate immunity and ongoing inflammation has been further elucidated. Better understanding of cellular mechanisms and involved cytokines contributed to the development of new biological drugs specifically addressed for SLE therapy.

A new cytofluorimetric approach to evaluate the circulating microparticles in subjects with antiphospholipid antibodies

INTRODUCTION Growing evidence supports the idea that microparticles (MPs) could contribute to the pathogenesis of the thrombotic phenomena associated with antiphospholipid antibody syndrome (APS), inducing a hypercoagulable state. But, to date, different approaches to evaluate circulating MPs and conflicting results have been reported. MATERIALS AND METHODS We have characterized the different circulating subpopulations of MPs in APS patients, and in asymptomatic aPL-positive subjects (carriers) by examining the correlation between the amount and phenotype of MPs and the clinical parameters. Forty-eight subjects were enrolled: 16 with primary APS, 16 aPL-positive, but without clinical criteria for APS (carriers), and 16 healthy subjects. The levels of MPs were evaluated using a new cytofluorimetric approach based on BD Horizon Violet Proliferation dye (VPD) 450. RESULTS AND CONCLUSIONS Using a new detection cytofluorimetric approach, we demonstrated that the AnnV-negative MPs, underestimated/or excluded in the previous studies, are a large subset of circulating MPs. Also, the levels of MPs in the plasma of aPL positive subjects indicate a state of cellular activation, which is much more pronounced in patients with APS compared to aPL carriers. Moreover, the preliminary data of our pilot study suggest that the evaluation of circulating MPs, in particular PMPs and EMPs, could be used as a surrogate biomarker for platelet and vascular damage monitoring and, if confirmed in a more numerous cohort of patients, it could be used as a prognostic factor to identify aPL positive subjects at higher risk of developing thrombosis.

An Approach to Differential Diagnosis of Antiphospholipid Antibody Syndrome and Related Conditions

The antiphospholipid antibody syndrome is a systemic, acquired, immune-mediated disorder characterized by episodes of venous, arterial, or microcirculation thrombosis and/or pregnancy abnormalities, associated with the persistent presence of autoantibodies, confirmed at least in two occasions 12 weeks apart, directed to molecular complexes consisting of phospholipids and proteins. Antiphospholipid antibody syndrome should always be considered as a potential diagnosis especially for young patients presenting with a history of thrombotic events, in particular when they occur without any obvious external trigger or any inherited thrombophilic mutation (even if 2006 criteria do not exclude antiphospholipid antibody syndrome in patients with other inherited or acquired prothrombotic conditions), or for women with recurrent pregnancy losses or later fetal deaths. Many other disorders are able to mimic antiphospholipid antibody syndrome, so a broad range of alternative diagnoses should be investigated and ruled out during clinical workup.

Cardiovascular oncology: a new discipline inside internal medicine?

Cardiovascular disease and cancer incidence and prevalence have risen over the past few decades to become the leading causes of death. On the one hand, cancer patients will be treated with cardiotoxic chemotherapies; on the other, cardiovascular patients will receive a new diagnosis of cancer and will have to face treatments that may worsen their disease. Moreover, venous thromboembolism can commonly complicate the natural course of patients with cancer in an apparently spontaneous manner or can be triggered by a clinical event such as surgery, invasive procedures, a course of chemotherapy or radiotherapy and is known to be the second cause of death in these patients who also may need to be treated for pre-existing medical conditions or comorbidities. Thus, we introduce the concept of cardiovascular oncology (in the place of cardiooncology) to underline that the problems in this field are not limited to cardiotoxicity of chemotherapies and to the interaction between cardiologists and oncologists, and we focus on the role of the Internist, the only health care giver able to face the multiple problems that cancer patients may undergo.

Thrombosis in Autoimmune Diseases: A Role for Immunosuppressive Treatments?

Autoimmune diseases are not infrequently associated with arterial or venous thrombotic events. Chronic inflammation and immune system impairment are considered the main pathogenetic mechanisms. Some of the drugs used in the treatment of such diseases have been associated with an increased risk of thrombosis. On the contrary, their anti-inflammatory and immune modulator activity could correct some mechanisms leading to thrombosis. In this review, recent evidence available on this topic is examined. There is a lack of adequate studies, but available evidence suggests that glucocorticoids and high-dose immunoglobulins are associated with an increased incidence of venous thromboembolism. Although available data do not allow drawing definite conclusions and more data are needed from future studies and registries, physicians should be aware of these associations.

The predictive role of the Bova risk score in acute normotensive pulmonary embolism: A retrospective analysis on a real life cohort

Accurate prognostic stratification is of utmost importance for the optimal management of acute pulmonary embolism (PE). It has been shown that the combination of history, clinical parameters, echocardiographic and computer tomography pulmonary angiography patterns and cardiac biomarkers permits to stratify short-term PE prognosis [1]. Although many prognostic models have been proposed, it is still to be determined which one is to be preferred [2]. The Bova score is a new proposed risk assessment model aimed to stratify 30-day prognosis in normotensive patients suffering for acute PE [3]. Briefly, Bova risk score is composed of four variables, i.e. systolic blood pressure (SBP) 90–100 mm Hg (2 points), heart rate (HR) ≥ 110 beats per minute (bpm) (1 point), troponin elevation (2 points) and echocardiographic or computer tomographypulmonary angiography right heart dysfunction (RHD)(2 points). Therefore Bova score ranges from zero points (all variables absent) to seven points (all variables present). The Bova score categorizes three risk classes at low (≤2 points), intermediate (3–4 points) and high (≥5 points) risk of PE-related complications, defined as death from PE, hemodynamic collapse, or recurrent nonfatal PE [3]. The score was retrospectively evaluated in a large patient cohort from Spain, in which the increasing risk on PE-related adverse events among patients classified in the 3 risk classes was confirmed [4]. Patients with Bova risk score ≤ 2 (class I) had in-hospital 3.7% and 30-day 4%,, patients with Bova risk score 3–4 (class II) had in-hospital 15% and 30-day 18% and patients with Bova risk score ≥ 5 (class III) had in-hospital 37% and 30-day 42% of PE-related complications, respectively [4]. Morever inhospital and 30-day PE-related mortality were 2.5% and 3.1% in class I, 6.2% and 6.8% in class II and 8.8% and 10.5% in class III, respectively. The Area under receiver operating characteristics (ROC) curves (AUC) of the Bova score for the main endpoint in the validation cohort was 0.74 (95% CI: 0.68–0.80), whereas it was 0.60 (95% CI: 0.52–0.69) for in-hospital PE-related mortality [4]. The Bova score requires further evaluation and especially in real life cohorts before it may be recommended for use on clinical practice. Therefore we retrospectively calculated the Bova risk score and tested its predictive ability as prognosticator for all cause and PE-related inhospital mortality in normotensive PE patients admitted in twenty-

Atrial fibrillation and its influence on stroke risk

Atrial fibrillation (AF) is the most common cardiac arrhythmia in the clinical setting. AF increases both the risk and severity of stroke, and is associated with substantial morbidity and mortality. Decisions regarding appropriate stroke prevention in AF patients are crucial and require individual assessment of both thromboembolic and bleeding risk. This review will pro- vide an overview of recommended risk assessment tools and discuss other possible risk factors which could improve risk stratification in AF patients.