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

Welcome to the third issue of Seminars in Thrombosis and Hemostasis devoted to usual and unusual causes and associations of coagulopathies and thrombosis. This current issue follows the theme of the previous two but also considers slightly different aspects, including the paradoxical associations of various pathologies with both thrombosis and bleeding and some growing worldwide issues and concerns, including obesity, chronic kidney disease, and swine influenza pandemics. Venous thromboembolism (VTE) comprises deep vein thrombosis (DVT) and pulmonary embolism (PE), which essentially represent two epiphenomena of the same clinical pathological process. VTE is a leading health problem worldwide, as testified by the overall average ageand sex-adjusted annual incidence in the United States of 117 per 100,000 people (DVT, 48 per 100,000; PE, 69 per 100,000), with higher age-adjusted rates among men than women (130 versus 110 per 100,000, respectively). A fifth of these patients suffer sudden death due to PE, 30% die within 30 days, and the incidence increases markedly with aging in both sexes, mostly sustained by PE. In line with this theme, we begin this issue by considering the role of two coagulation factors in blood clotting and thrombosis: factor (F) I (i.e., fibrinogen) and FXIII. It is noteworthy that these reflect the first and last named coagulation factors according to the classical Roman numeral terminology. Naturally, we now recognize that the historically defined sequential naming order does not really mirror the true series of sequential steps involved in secondary hemostasis. Rather, although fibrinogen is recruited early in the process of hemostasis and provides the major source of clottable protein to enable formation of the thrombus, it also provides the final end product of coagulation, namely fibrin. Also notable is that FXIII is intricately involved in this process, permitting the stabilization of the fibrin clot. Thus the first article in this issue, by de Moerloose and colleagues, discusses how fibrinogen may contribute to thrombosis risk in several different ways. For example, various mutations in the fibrinogen genes predispose to thrombosis, and high levels of fibrinogen are also associated with an increased thrombotic risk. Although the underlying causative mechanisms are not clear, the role of associated inflammatory and hypercoagulable states are implicated. Particular attention has recently focused on polymorphisms of fibrinogen genes involved in increased levels in, or qualitative changes to, fibrinogen. The association between dysfibrinogenemia and risk of thrombosis is also well known, and some mechanisms have been clearly identified. Paradoxically, some patients with hypofibrinogenemia or afibrinogenemia may also suffer from severe thromboembolic complications. The management of these patients is particularly challenging because they are paradoxically at risk of both bleeding and thrombosis. In summary, this review discusses the various quantitative and qualitative defects of fibrinogen associated with thrombosis, the tests that may predict the thrombotic risk, as well as some preventive or therapeutic approaches. This article is a logical supplementary review to one previously published by these authors in Seminars in Thrombosis and Hemostasis related to fibrinogen deficiencies as defects within the context of rare bleeding disorders. In the second article, Muszbek and coworkers discuss the role of FXIII in the development of various atherothrombotic diseases. FXIII is a protransglutaminase that after activation cross-links fibrin chains and several plasma proteins, most importantly a2 plasmin inhibitor, to fibrin. FXIII strengthens the fibrin clot by covalent bonds and protects fibrin from elimination by the fibrinolytic system. In short, FXIII has emerged as a key regulator of fibrinolysis during the last two decades. FXIII is also present in platelets, monocytes, and macrophages, but this cellular form does not contribute significantly to maintaining hemostasis. FXIII deficiency is a life-threatening bleeding diathesis with well-studied clinical consequences. FXIII deficiency was reviewed by these authors in a previous issue of Seminars in Thrombosis and Hemostasis. In contrast, the involvement of