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 (r(2)=0.33, P<0.0001), residual ß-band intensity (r(2)=0.07, P<0.01), and fibrinogen clotting ability (r(2)=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.

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.

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.

Pharmacological prevention of venous thromboembolism in orthopaedic surgery.

The prophylaxis of venous thromboembolism (VTE) with anticoagulant drugs is a long-established practice in hip and knee replacement surgery, as well as in the treatment of femoral neck fractures, while there are few data regarding the prevention of VTE in other fields of orthopaedic surgery and traumatology. In order to provide practical recommendations for daily management of VTE prophylaxis in orthopaedic patients, recently the Italian Societies of Thrombosis and Haemostasis, Orthopaedics and Traumatology and Anaesthesia have drawn up a first Intersociety Consensus on antithrombotic prophylaxis in total hip and knee replacement surgery, and in the treatment of femoral neck fracture, then updated in 2013, and a subsequent Intersocietary Consensus, in cooperation also with the Society of general practitioners, concerning antithrombotic prophylaxis in other types of orthopaedic surgery and traumatology. Before starting any prophylactic treatment it is of crucial importance the assessment of both thrombotic and bleeding risk of patients undergoing surgery. Thromboembolic prophylaxis is recommended with low molecular weight heparins (LMWH), fondaparinux (FON) or with the new oral anticoagulants (NOA) in patients undergoing hip and knee replacement surgery while patients undergoing treatment of femoral neck fracture should be treated with LMWH or FON. Regarding the non-prosthetic orthopaedic surgery and traumatology, it is recommended prophylaxis with LMWH or FON in situations of high thromboembolic risk or in the case of interventions or trauma involving pelvis, acetabulum or knee.

Thromboembolic burden, prognostic assessment and outcomes of females compared to males in acute pulmonary embolism.

BACKGROUND: Literature lacks on sex differences in acute pulmonary embolism (PE). Therefore, the aim of our study was to provide information about sex difference in thromboembolic burden, prognostic assessment and outcomes of PE. MATERIALS AND METHODS: We analyzed and compared differences between females and males retrieving data of a multicenter, observational, retrospective, cohort study aimed to analyze characteristics of PE patients admitted in Internal Medicine wards of Tuscany, Italy. RESULTS: 272 (60.1%) of 452 patients enrolled in the study were females. Females were older than males (76.6 ± 12.0 vs. 73.5 ± 13.4 years, p = 0.0005). Mean length of hospital stay was longer in females (11.3 vs. 9.5 days, p = 0053). Reduced mobility was more frequent in females (46.3% vs. 35.5%, p = 0.0322), whereas COPD and active cancer were in males (20% vs. 9.9%, p = 0.0034, and 39.4% vs. 23.8%, p = 0.0004, respectively). Incidental diagnosis of PE was performed more often in males compared to females (19.3% vs. 11.4%, p = 0.0289). No sex difference was found in diagnostic approach, despite females underwent more often to legs ultrasonography compared to males (90.7% vs. 79.4%, p = 0.0008). Both all cause and PE-related mortality were higher in males (12.2 and 8.3% vs. 7.7 and 5.1%, respectively), despite difference was not significant. Females were found to have more likely central PE and distal deep vein thrombosis compared to males (57.7% vs. 43.8%, p = 0.0039, and 22.9% vs. 13.9%, p = 0.0206, respectively). None difference was found in shock index and median simplified PESI score between females and males, whereas according to 2008 ESC prognostic model females were more likely to be categorized at high or intermediate risk than in males (81.5% vs. 71.5%, p = 0.0159). Echocardiographic right heart dysfunction was found more often in females than in males (56.5% vs. 44%, p = 0.0124). No sex difference was found neither on acute treatment nor in prescription of vitamin K antagonists at hospital discharge. Bleeding events were significantly higher in females compared to males (4.7% vs. 0.5%, p = 0.0189). CONCLUSION: Understanding the difference between females and males is of utmost importance for physicians who manage acute PE in clinical practice. Females present major pulmonary thromboembolic burden, more frequently right heart dysfunction and treatment-related bleedings but lower in-hospital mortality than males. Our study could implicate that management of acute PE should be tailored according to sex. Prospective studies are warranted to better clarify this topic.

Novel oral anticoagulants in atrial fibrillation: which novel oral anticoagulant for which patient?

Atrial fibrillation is the most common rhythm disorder and represents a major public health problem because it carries an increased risk of arterial thromboembolism and ischemic stroke. Current european society of cardiology guidelines recommend to stratify atrial fibrillation patients according to the CHA2DS2-VASc score and to administer anticoagulation, preferably with novel oral anticoagulants, that is, dabigatran, rivaroxaban, or apixaban, if the CHA2DS2-VASc score is at least 1. All novel anticoagulants have shown the same, if not greater, efficacy and safety as warfarin, with some advantages. The choice among the novel oral anticoagulants depends on their different pharmacokinetic profile, patients' stroke and bleeding risk, comorbidities, drug tolerability and costs and, finally, patients' preferences.

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.

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.

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.