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Semin Thromb Hemost 2010; 36(1): 001-005
DOI: 10.1055/s-0030-1248719
PREFACE

© Thieme Medical Publishers

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

Emmanuel J. Favaloro1 , Giuseppe Lippi2 , Massimo Franchini3
  • 1Department of Haematology, ICPMR, Westmead Hospital, Westmead, NSW Australia
  • 2Sezione di Chimica Clinica, Università di Verona, Verona, Italy
  • 3Immunohematology and Transfusion Center, Department of Pathology and Laboratory Medicine, University Hospital of Parma, Parma, Italy
Further Information

Publication History

Publication Date:
13 April 2010 (online)

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Welcome to the third issue of Seminars in Thrombosis and Hemostasis devoted to usual and unusual causes and associations of coagulopathies and thrombosis.[1] [2] 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 age- and 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).[3] 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.[3] [4]

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.[5] 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.[6]

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 α2 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.[7] In contrast, the involvement of FXIII in thrombotic disorders and its association with the risk of such diseases is less clear. This review gives an account of the data accumulated mainly in the last decade on the association of FXIII with atherothrombotic diseases, presents conclusions and hypotheses drawn from these data, and exposes the limitations of the published studies and current knowledge on this topic. The involvement of FXIII in atherogenesis and its role in coronary artery disease, atherothrombotic ischemic stroke, and peripheral artery disease are discussed, with particular reference to the association of FXIII levels and polymorphisms with the risk of these diseases.

We now change focus a little and consider coagulopathies associated with pathologies involving two major organs, the kidney and the liver. In the third article of this issue, Jalal and colleagues consider the concept of hemostasis disorders associated with chronic kidney disease. Importantly, chronic kidney disease, like VTE, is an important global health problem, and its prevalence is also expected to grow substantially given that the leading causes are not effectively delineated (e.g., diabetes). Chronic kidney disease is typically associated with a prothrombotic tendency in the early stages of disease, whereas in its more advanced stage, or end-stage renal disease, patients suffer from a prothrombotic tendency and, in many cases, a bleeding diathesis. The precise etiology behind the coexistence of these paradoxical and conflicting hemostatic disorders is still poorly understood. This review critically appraises studies examining abnormalities in the hemostasis pathway in patients with chronic kidney disease, as well as the therapeutic options that are currently available to treat them.

The next article by Targher and coworkers evaluates the association between hemostatic disorders and abdominal obesity, and in particular the emerging role of fatty liver disease in these pathological processes. Abdominal obesity represents a major public health concern because it has already reached epidemic proportions worldwide. Its prevalence is believed to be on the rise, and it is associated with an increased risk of cardiovascular morbidity and mortality as well as other pathological conditions. A large body of evidence suggests that abdominal obesity is associated with a prothrombotic tendency, which may, at least in part, contribute to the increased risk of atherothrombosis in affected individuals. This review briefly summarizes the evidence of direct and indirect effects of the accumulation of excess lipid in visceral adipose tissue on coagulation and fibrinolysis. Moreover, it critically appraises the rapidly expanding body of experimental and clinical data that support a potential direct contribution of the accumulation of excess lipid in the liver (nonalcoholic fatty liver disease, a very frequent pathological condition in subjects with abdominal obesity) in the pathogenesis of the obesity-induced hemostatic disorder.

Swine flu is known to be mostly caused by influenza A subtypes, especially H1N1, H1N2, H2N3, H3N1, and H3N2. In pigs, three influenza A virus subtypes (H1N1, H1N2, and H3N2) are the most common strains worldwide.[8] Although swine influenza virus (SIV) or S-OIV (swine-origin influenza virus) is endemic in pigs, zoonosis in humans has been only occasionally reported, very rarely achieving a widespread distribution. In early 2009, however, the World Health Organization declared a “public health emergency of international concern” when the first two cases of the 2009 H1N1 S-OIV were reported in the United States, followed by hundreds of cases in Mexico. The current transmission of this virus among humans appears much higher than that traditionally observed with seasonal influenza, causing several outbreaks of febrile respiratory infection ranging in severity from self-limited to severe and even life-threatening disease. Notably, this virus continues to spread globally and already counts 702,086 cases and 11,073 deaths (death rate of infected cases: 1577 per 100,000). The regional death rate per 100,000 inhabitants has been identified as 1.31 in the United States, 0.86 in Australia, 0.30 in the United Kingdom, and 0.17 in France, Belgium, and Italy.[8]

The following article, by Lippi et al, continues the theme of global impact to evaluate the potential association of influenza and cardiovascular disease, in particular associated with potential pandemics of the S-OIV 2009. Influenza infection has become an important focus of both public and medical attention because of high-level perceived clinical and public health effects, enormously amplified by the current and ongoing 2009 H1N1 flu pandemic. Reliable biological and clinical evidence support a significant association between influenza infection and cardiovascular disorders, so S-IOV might also be regarded as a potential multifaceted bioweapon able to affect the function of the cardiovascular system through a kaleidoscope of humoral, biological, and biochemical mechanisms. In acute coronary ischemic episodes, it seems reasonable to consider any acute influenza virus infection as a precipitating prothrombotic factor, or a final event propelling predisposed individuals (e.g., those with preexisting coronary artery disease or other strong risk factors) beyond a threshold to precipitate the development of infarction in synergy with other well-known triggers.[9] However, influenza virus–induced endothelial dysfunction, modification of lipoprotein metabolism, atherosclerotic plaque outgrowth, and inflammation additionally support the role of influenza infection as a strong cardiovascular risk factor. Relevant information regarding the 2009 H1N1 infection remains understandably limited, so definitive conclusions are not yet possible. Nevertheless, current recorded mortality data would lead us to conclude that this new virus might represent a sinister threat to humankind, with cardiovascular mortality risk highlighting an additional crucial role for further increasing the alert against this menace. These authors also support calls for vaccination against these viruses, both the seasonal and the new S-OIV, because this might represent a feasible strategy for short- and long-term prevention of virus-associated cardiovascular disease.

Changing tack, these authors consider a much more pleasant association: moderate red wine consumption and reduced cardiovascular disease risk. The term French paradox was coined in 1992 to describe the relatively low incidence of cardiovascular disease in the French population, despite a relatively high dietary intake of saturated fats, and potentially attributable to the consumption of red wine. After nearly 20 years, several studies have investigated the fascinating, overwhelmingly positive biological and clinical associations of red wine consumption with cardiovascular disease and mortality. Light to moderate intake of red wine produces a kaleidoscope of potentially beneficial effects that target all phases of the atherosclerotic process, from atherogenesis (early plaque development and growth) to vessel occlusion (flow-mediated dilatation, thrombosis). Such beneficial effects involve cellular signaling mechanisms, interactions at the genomic level, and biochemical modifications of cellular and plasma components. Red wine components, especially alcohol and other polyphenolic compounds, may decrease oxidative stress, enhance cholesterol efflux from vessel walls (mainly by increasing levels of high-density lipoprotein cholesterol), and inhibit lipoproteins oxidation, macrophage cholesterol accumulation, and foam-cell formation. These components may also increase nitric oxide bioavailability and thereby antagonize the development of endothelial dysfunction, decrease blood viscosity, improve insulin sensitivity, counteract platelet hyperactivity, inhibit platelet adhesion to fibrinogen-coated surfaces, and decrease plasma levels of von Willebrand factor (VWF), fibrinogen, and coagulation factor VII. Light to moderate red wine consumption is also associated with a favorable genetic modulation of fibrinolytic proteins, ultimately increasing the surface-localized endothelial cell fibrinolysis. Overall, therefore, the French paradox may have its basis within a milieu containing several key molecules, so that favorable cardiovascular benefits might be primarily attributable to combined, additive, or perhaps synergistic effects of alcohol and other components of wine on atherogenesis, coagulation, and fibrinolysis. Conversely, chronic heavy alcohol consumption and binge drinking are associated with an increased risk of cardiovascular events. These authors conclude by advising that although mounting evidence strongly supports the beneficial cardiovascular effects of moderate red wine consumption (one to two drinks per day; 10–30 g alcohol) in most populations, clinical advice to abstainers to initiate daily alcohol consumption has not yet been substantiated in the literature and must be considered with caution on an individual basis.

The next two articles in this issue cover a less common but still largely topical issue, thrombotic thrombocytopenic purpura (TTP). In the first one, Zhou and colleagues evaluate the clinical and basic research into TTP. For a rare disease with <80 years of history, this research has been significantly accelerated since the identification of unusually large vWF multimers and ADAMTS-13 (a disintegrin and metalloproteinase with thrombospondin-1-like domains) deficiency as the potential cause. The VWF-cleaving metalloprotease ADAMTS-13 has since been extensively characterized and its biological action tested both in vitro and in vivo. There have also been considerable efforts to understand the interaction between ADAMTS-13 and its substrate VWF, as well as its biological regulation. This review focuses on recent advances in the understanding of the biology of VWF cleavage by ADAMTS-13 and how this newly gained knowledge will eventually help the clinical management of patients with TTP. The article also discusses the potential of ADAMTS-13 as a therapeutic drug for thrombotic conditions other than TTP.

The second article on this topic is by Sarah Just, who reviews the methodologies and clinical utility of ADAMTS-13 activity testing. The VWF cleaving protease ADAMTS-13 was first identified in 1987. Congenital and acquired deficiency of ADAMTS-13 is not only associated with TTP but also a variety of other thrombotic microangiopathies (TMAs).[10] Assays for measurement of ADAMTS-13 were developed in the late 1990s, and significant improvements have occurred in related testing protocols, hence permitting their performance in routine hemostasis laboratories. This article reviews the original ADAMTS-13 activity assays as well as those currently available. It also discusses the consistency of results among various methods and the clinical utility of ADAMTS-13 testing in TTP, TMA, and other disease conditions.

The final three articles in this issue are related to patient management. The first one, by Coppola and coworkers, considers the management of cardiovascular diseases in patients with hemophilia, again reflecting a balance between bleeding and thrombotic risk. These authors first consider that morbidity and mortality for cardiovascular disease are likely to be lower in patients with hemophilia than in the general male population. However, the clinical impact of these diseases is increasing in hemophilia patients in parallel with their increased life expectancy due to modern safe replacement treatments and improvements in comprehensive care. Although no rigorous trial concerning treatment of ischemic coronary disease is currently available, and because such studies are probably not feasible in this setting, the analysis of case reports describing management of coronary artery disease and cardiac surgery in hemophilic patients provides the major pieces of information. These suggest, given the lack of evidence-based guidelines, that treatment strategies should be similar to those used in nonhemophilic subjects, provided that control of bleeding risk (e.g., an adequate concentrate replacement) is also established. On the whole, treatment should be tailored to balance the actual thrombotic risk and the preexisting bleeding tendency, enhanced by the use of antithrombotic agents. The available information is discussed, together with the recent suggestions of experts developed to provide more uniform approaches and collection of data. Treatment of cardiovascular disease reflects the evolving scenario in which clinicians who treat hemophilia will have to extend their interactions with other specialists to confront the new challenges of the comprehensive care of aging hemophilic patients, especially in developing countries.[11]

The next article by Vande Vusse et al is largely a commentary piece that reflects on the rise and fall of aprotinin as a prohemostatic therapy. Aprotinin, also known as bovine pancreatic trypsin inhibitor, has been used clinically to enhance hemostasis for decades and was approved in the United States in 1993 for reduction of bleeding during complex procedures such as liver and coronary artery bypass surgery. The marketing of aprotinin ceased recently (in 2008) when observational studies and a randomized clinical trial reported an apparent increased cardiovascular toxicity in patients receiving the drug. The importance of prohemostatic therapy is reviewed in light of new information on the long-term deleterious effects of blood transfusion, including increased risk of cardiovascular disease, malignancy, and infection possibly attributable to delivery of a load of red cell–derived redox-active iron. These major adverse outcomes from transfusion, along with weaknesses in the design of clinical trials that failed to control adequately for alternative mechanisms of toxicity, complicate the interpretation of risks versus benefits in clinical trials of aprotinin given to reduce transfusion requirements in the acute surgical setting. The authors believe that the positive properties and applications of aprotinin may not have received sufficient attention in the decision to remove this drug from the therapeutic armamentarium, and accordingly they are also reviewed. Potential application of prohemostatic drugs including aprotinin to special populations at risk of operative blood loss requiring transfusion is also illustrated with a description of nine patients with coagulopathies whose operative bleeding was managed effectively with this pharmacological agent. As such, these authors propose that this drug may remain safe and effective in special populations of patients at risk for bleeding with surgery, with additional beneficial effects seemingly unrelated to its prohemostatic properties, especially its apparent striking antineoplastic effects, warranting further study.

The final article in this issue by Homar and colleagues discusses the effective long-term prevention of thromboembolism through the application of novel oral anticoagulant drug delivery systems (DDSs). Despite intensive research in the field of oral anticoagulants over the last decade,[12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] simple and effective long-term prevention of thromboembolism is still an unmet need. In addition to drug discovery approaches, the development of novel oral DDSs of clinically well-established anticoagulants therefore presents an intriguing means of improving anticoagulant therapy. All relevant clinical trials with anticoagulants formulated in the oral DDSs are reviewed, and selected preclinical examples of promising novel anticoagulant DDSs are also described. For greater understanding, a background on DDSs and drug absorption from the gastrointestinal tract is also provided. Three leading approaches for the oral anticoagulant DDS are currently being investigated in clinical settings, all relying on coadministration of anticoagulants with specific carriers. In contrast to the clinical setting, a diverse range of possibilities for oral delivery of anticoagulant are being investigated in preclinical trials (e.g., nanotechnology), and these authors therefore propose that an examination of their performance in clinical trials would be of considerable interest.

We conclude this issue of Seminars in Thrombosis and Hemostasis with some correspondence. Letters to the editor are accepted at the discretion of the editors, providing they relate to the current or a previous issue of the journal. Accordingly, Girolami and colleagues raise two issues related to a previous review by Mariani and Bernardi on FVII deficiency,[23] the role of tissue thromboplastins of different origin in the initial characterization of FVII defects as well as the role of the FVIIa assay in the investigation of these individuals, which is notably identified as a cumbersome and poorly standardized functional assay.[24] Bernardi and colleagues provide a reply to these issues.

As always, we hope you enjoy the collection of articles in this issue, and we thank all the authors for their most interesting contributions.

REFERENCES