Coagulopathies and Thrombosis: Usual and Unusual Causes and Associations, Part I

Welcome to another issue of Seminars in Thrombosis and Hemostasis. This is the first of a series of issues broadly focused on coagulation abnormalities and thrombosis. In particular, our aim is to collect reviews from experts on multifaceted interactions between acquired and genetic factors that interconnect and modulate the clinical phenotype of hemostatic disorders. For the current issue, we have focused on the multifactorial nature of prothrombotic disorders with particular attention on some less well known associations with thrombosis. These articles therefore represent a sector of thrombosis and hemostasis that is only partially understood but where research is progressing and leading to fascinating findings. In addition, this issue serves as a dedication to another recently lost friend of this journal, Rodger Bick. Although physical inactivity is widely regarded as a major, independent risk factor for cardiovascular disease, the role of physical inactivity, or of an opposing state of exercise, in the pathophysiology of venous thromboembolism is currently disputed. Therefore, the first article, by Adams and colleagues, discusses the role of physical activity in lowering the thrombotic risk, both in the general population and in patients with chronic disorders such as cardiovascular and kidney diseases. Although the authors acknowledge several limitations in assessing the data from the available studies (heterogeneous for age, body composition, fitness level, underlying disease and treatment, as well as exercise intensity, frequency, duration, and energy expenditure) and the considered need for large prospective trials, the analysis of the literature suggest that exercise, on balance, exerts a beneficial antithrombotic effect in both younger individuals and those with chronic disorders. In older individuals, the risk of adverse events related to strenuous exercise can be contrasted with the positive effects of milder exercise regimes that incorporate resistance training. The second article, by Lippi and Maffulli, is a logical continuum of the former and explores the influences of physical exercise on hemostatic and fibrinolytic systems. As previously mentioned, the result of the different studies on this topic are strongly biased by several confounding variables, including the subjects investigated, the type, intensity, and duration of the exercise, and the methods used for hemostatic evaluation. However, after synthesizing the available data, the authors conclude that acute and strenuous exercise is associated with a transient hypercoagulability state, particularly in untrained individuals, as represented by increased thrombin generation, platelet hyperreactivity, and increased activity of several coagulation factors, especially factor VIII and von Willebrand factor. Interestingly, exercise is also associated with an increased fibrinolytic activity. These adaptive changes, although apparently reversible, might exert a beneficial long-term effect, offering some sort of protection against the risk of thrombosis and adverse cardiovascular events in physically active individuals. Nonalcoholic fatty liver disease (NAFLD), which encompasses a broad spectrum of conditions from simple steatosis to steatohepatitis (NASH) and cirrhosis, appears to be the most frequent hepatic disorder in developed countries and is increasingly regarded as the liver manifestation of the metabolic syndrome. The third article in this issue of Seminars in Thrombosis and Hemostasis, by Targher and colleagues, addresses the contribution of NAFLD and NASH to the prothrombotic state seen in the metabolic syndrome. Interestingly, on the basis of the available data, the authors conclude that NAFLD/NASH, especially in its necro-inflammatory form, might be associated with a systemic proinflammatory/prothrombotic state, independent from mutual metabolic risk factors. Accordingly, these clinical entities might not be simply markers of the proinflammatory/ prothrombotic state in the metabolic syndrome but rather actively involved in its pathogenesis through the systemic release of proinflammatory and procoagulant factors (C-reactive protein, plasminogen activator inhibitor-1, interleukin-6, fibrinogen, and other proinflammatory cytokines). The next article, by Franchini and colleagues, is focused on the controversial association between thyroid dysfunction and hemostatic abnormalities. In this