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The assessment and monitoring of liver fibrosis (LF) is a key issue in the management and definition of prognosis of patients with chronic hepatitis C (CHC). In this respect, despite recognized limitations (invasive nature, sampling errors, interobserver variability, nondynamic evaluation of LF), liver biopsy is traditionally considered the reference standard. These limitations stimulated the search for noninvasive approaches for the assessment of LF, particularly attractive in patients with hemophilia and other congenital bleeding disorders (CBD). In patients with congenital bleeding disorders (CBD), who often suffer from CHC because of the past use of nonvirally inactivated plasma-derived products, the risk of bleeding hamper to routinely obtain histological data for LF staging. A variety of methods have been proposed and, in some cases, validated in patients with CHC and other liver diseases, including biomarkers directly or indirectly associated with LF, often combined in scores or algorithms, and the more recently developed physical approaches, evaluating the properties of the liver parenchyma with instrumental techniques studying the propagation of specific signals, that is, transient elastography (TE), acoustic radiation force impulse imaging elastography, and magnetic resonance elastography. This review will describe the available strategies for noninvasive assessment of LF, with more details on the latter promising instrumental approaches. Moreover, although lacking of validation against liver biopsy, recent studies extending the use of noninvasive methods (particularly TE) in the setting of patients with CBD will be discussed., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Pathogenesis of atherosclerosis involves multiple mechanisms, including imbalanced lipid metabolism, disturbed equilibrium of the immune response, and chronic inflammation of the artery wall. Several reports have shown a relationship between the development of atherosclerosis and the presence of infectious diseases, widely occurring in the general population, often chronic and/or asymptomatic. Beyond Chlamydia pneumoniae, a large number of infectious agents have been linked with an increased risk of vascular disease, with variable strength of supporting data: Porphyromonas gingivalis, Helicobacter pylori, influenza A virus, herpes virus, hepatitis C virus, cytomegalovirus, and human immunodeficiency virus. Infections may contribute to atherosclerosis either via direct infection of vascular cells or via the indirect effects of cytokines or acute phase proteins induced by infection at "nonvascular" sites. More recently, investigators reported that the aggregate burden ("infectious burden") of these chronic infections, rather than the effects of a single organism, might contribute to atherosclerosis and its thrombotic complications. However, the role of infection, as a proinflammatory cause of atherosclerosis, is still debated in the literature. This article will review available data suggesting a relationship between different infective pathogens and atherothrombosis, the hypothesized mechanisms, and the potential role for antimicrobial treatment., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Recurrent joint bleeding leading to progressive musculoskeletal damage (hemophilic arthropathy), in spite of on-demand replacement with deficient factor concentrates, is the clinical hallmark of severe hemophilia A and B (i.e., the congenital deficiencies of coagulation factors VIII and IX with circulating levels <1 IU/dL). Fifty years of clinical experience, which began in Northern Europe and then initiated in other European countries and in North America, up to the recent randomized clinical trials, have provided definitive evidence that preventing bleeding from an early age through long-term regular prophylactic concentrate infusions limits the adverse clinical consequences of arthropathy and its complications in the quality of life of hemophilic children. Primary prophylaxis started after the first joint bleed and/or before the age of 2 is now the evidence-based, first-choice treatment in severe hemophilia. Interestingly, recent data also suggest a role for early prophylaxis in preventing inhibitor development, the most serious complication of hemophilia therapy. Secondary prophylaxis is aimed to avoid (or delay) the progression of arthropathy. The earlier the treatment is started, the better the outcomes in joint status and quality of life. Although prophylaxis has radically transformed the natural history of severe hemophilia, relevant barriers to its implementation and diffusion remain. Beyond the obvious economic constraints and problems with venous access and long-term adherence, uncertainties regarding the optimal prophylaxis regimen require further evaluation in prospective studies to optimize approaches based on definite outcome measures and cost-effectiveness/cost-utility analyses. Scientific evidence, current clinical strategies, and open issues of prophylaxis in children with hemophilia will be addressed in this review., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

The prompt and accurate diagnosis of pulmonary embolism (PE) greatly influences patient outcomes. However, diagnosing PE is one of the most difficult challenges confronting physicians, even more so when the clinical suspicion is addressed in children, during pregnancy, or in elderly patients. In these patient groups, symptoms and signs from concomitant conditions or diseases may mimic PE and make difficult defining clinical probability categories for PE as usually applied to general adult patients. Moreover, the diagnostic techniques show wider, specific limitations in these settings. PE is considered rare in children. The diagnostic management of a child with suspected PE is largely extrapolated from the knowledge achieved in adult patients. An increased risk of venous thromboembolism is reported in all trimesters of pregnancy and in the puerperium. An accurate diagnosis of PE in pregnancy has important implications, including the need for prolonged anticoagulation, delivery planning, and prophylaxis during future pregnancies, as well as concerns about future oral contraceptive use and estrogen therapy. Although incidence, morbidity, and mortality increase steadily with age, PE remains an underdiagnosed disease in elderly patients. About 40% of PE found at necropsy were not suspected antemortem. In the present article, challenges in diagnosing PE in children, during pregnancy, and in the elderly will be discussed, reviewing the available clinical, laboratory, and instrumental diagnostic strategies., (© Thieme Medical Publishers.)

A variety of disease- and treatment-related factors affect the coagulation system and the risk of bleeding and thrombotic complications in patients with multiple myeloma (MM) and related plasma cell disorders (PCD). As commonly observed in other cancer settings, the malignant clone induces a cytokine environment responsible for a hypercoagulable state. The increase of blood viscosity and impairment of platelet and coagulation function due to circulating monoclonal proteins are considered key mechanisms in the hemostatic abnormalities frequently detected in patients with PCD. However, clinically significant bleeding is relatively rare and poorly correlated with these abnormalities. Management is often challenging because of the multifactorial pathogenesis and underestimation or misdiagnosis of acquired bleeding disorders, particularly acquired von Willebrand syndrome. In recent years, growing interest in thromboembolic risk has emerged after the introduction of novel and more effective antimyeloma agents (thalidomide and lenalidomide), which was associated with increased risk of venous thromboembolism, particularly when associated with dexamethasone and multiagent chemotherapy in newly diagnosed patients. The clinical impact of bleeding and thrombotic complications in patients with PCD, with emphasis on MM, will be discussed in this review, reporting the current knowledge about pathophysiologic mechanisms and implications for management., (© Thieme Medical Publishers.)