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.[1] [2] 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.[3] [4]

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.[5]

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).[6]

The next article, by Franchini and colleagues, is focused on the controversial association between thyroid dysfunction and hemostatic abnormalities. In this review, the authors analyze the hemostatic system (i.e., primary hemostasis, secondary hemostasis, and fibrinolysis) in different thyroid disorders and conclude that patients with hyperthyroidism or subclinical hypothyroidism appear to have an increased thrombotic risk, whereas patients with overt hypothyroidism frequently experience a bleeding tendency. However, as the authors and other investigators have reported in previous reviews on this topic,[7] [8] [9] [10] most studies performed on the hemostatic profile of patients with thyroid diseases have significant drawbacks, such as the small study size, the lack of a control group, and the heterogeneity of the thyroid disorders included, which would make comparisons between different studies difficult to interpret conclusively. A clear answer to the degree and type of hemostatic abnormalities in patients with thyroid diseases will only arise when prospective clinical trials on large series of patients become available.

In the next article, Zuern and colleagues review the existing literature data on gender-specific differences in platelet function and response to aspirin. On the basis that women < 65 years of age do not benefit from aspirin therapy in primary prevention of coronary artery disease and that the overall mortality after myocardial infarction is higher in women than in men, it can be hypothesized that “platelet biology” might differ between genders. In support of such a concept, gender differences in platelet reactivity and “aspirin resistance” have been reported, and several studies have also shown increased platelet reactivity at baseline and less effective inhibition of platelet aggregation by aspirin in women. Although the definitive mechanisms underlying these gender-specific differences remain to be elucidated, results from animal models and clinical studies suggest that platelets in females are in general more prone to trigger and participate in the thrombotic process than are platelets in males. This article also assesses the sex-related effects on other hemostatic tests including the platelet function analyzer (PFA-100)[11] and the role of gender-specific antithrombotic therapy in women with atherosclerosis.[12]

Franchini and colleagues undertake a review of current knowledge related to the modulation of the clinical phenotype of severe hemophilia by prothrombotic genetic risk factors in the next article. Although the few published studies seem to indicate an association between the presence of factor V Leiden and cases with milder clinical phenotype, the results from the available literature on this topic are controversial, and the real impact of inherited thrombophilic markers on the clinical course of severe hemophilia needs to be established.[13] [14] It is therefore possible that this interaction could be part of a multifactorial process where several other factors also play a role in ameliorating the clinical severity in hemophilia patients.[15] Furthermore, a clarification of the role of genetic thrombophilia in the modulation of clinical phenotype in such patients will arise only from multicenter, large-scale studies.[16]

Psoriasis is a chronic inflammatory, immune-mediated skin disease affecting up to 3% of the general population and is associated with a significant impairment of the quality of life. In the next article of this issue of Seminars in Thrombosis and Hemostasis, Gisondi and Girolomoni review a most interesting association: the biological and clinical link between psoriasis and atherothrombosis. The authors identify a variety of concomitant disease-related (i.e., hyperhomocysteinemia, elevated C-reactive protein, elevated blood inflammatory cytokines, and platelet hyperreactivity) and non–disease-related (i.e., insulin resistance/diabetes, obesity, dyslipidemia, hypertension, metabolic syndrome, and habitual tobacco smoking) cardiovascular risk factors in patients with psoriasis.[17] [18] The authors also report on the interactions between the different comorbidities and on the impact of the treatment of psoriasis and associated risk factors in reducing the risk of developing atherothrombotic events.

Depressive disorders, which basically include major depression and dysthymia, represent the second leading cause of disability worldwide. Major focus has recently been placed on the multifaceted and bidirectional relationship between cardiovascular disease and mental depression. Indeed, patients affected by a variety of mental disorders are at an increased risk for cardiac morbidity and mortality, whereas the presence of depressive symptoms is also associated with an increased risk for cardiac events, even when a diagnosis of major depression is lacking. Hence, in the next article, by Lippi and colleagues, the multifaceted nature of thrombosis is further supported by reviewing the intriguing relationship between cardiovascular disease and mental depression. Thus, although depressed patients are at significantly higher risk for cardiac morbidity and mortality, mental depression is also nearly 3 times more frequent in patients after an acute myocardial infarction and contributes to a worse prognosis.[19] [20] The authors also discuss the current knowledge on the not yet fully understood pathways underlying the interplay between depression and cardiovascular disorders, focusing in particular on hemostatic abnormalities that occur in the setting of mental disorders.

The final article of this issue has been prepared by Kannan and colleagues as a tribute to the memory of Rodger Bick and is on the topic of heparin-induced thrombocytopenia, a topic of great interest to Bick.[21] Heparin is the second most widely used anticoagulant/antithrombotic agent besides warfarin and is commonly used for various purposes such as treatment and surgical indications. A significant adverse effect of heparin treatment can occur with the formation of heparin/platelet factor 4 antibodies, which in turn leads to platelet/endothelial cell activation followed by heparin-induced thrombocytopenia (HIT). These authors report on some methodological variations in the diagnosis of HIT antibodies and also highlight the association of HIT positivity in patients with the FcγRIIa polymorphism. Very recent studies have also shown that heparin contaminants may lead to an increase in HIT-related antibody production, and this is also discussed in this article.

The guest editors hope that you enjoy reading the collection of article in this issue of Seminars in Thrombosis and Hemostasis, and we sincerely thank the authors of these articles for their interesting and timely contributions.

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