Coagulopathies and Thrombosis: Usual and Unusual Causes and Associations. Part V.

Welcome to the fifth issue of Seminars in Thrombosis & Hemostasis devoted to the topic “Coagulopathies and Thrombosis: Usual and Unusual Causes and Associations.” In our previous issues, we provided several insights into the life-threatening pathologies represented by venous and arterial thrombosis, reviewing common as well as less appreciated relationships between physiological/pathological conditions and the pathogenesis, prevention, diagnosis, and managed care.[1] [2] [3] [4] In this fifth issue, we supply additional material related primarily to the pathogenesis and management of arterial and venous thrombosis.

In the first article,[5] the guest editors with Lippi as lead author have investigated the concept of “holiday thrombosis.” This is perhaps a fitting time to present the data in this review, given that this is the last issue of Seminars in Thrombosis & Hemostasis for 2011, and thus leads toward the Christmas holiday period for many of our readers. There is now much reliable evidence that acute thromboses (both venous thromboembolism [VTE] and acute coronary syndrome) follow a typical seasonal pattern and display characteristic spikes during the holiday periods. Overindulgence as well as abrupt changes in several lifestyle habits have been proposed to be potential precipitating factors during such periods. Long travels, unhealthy diet, excessive or binge drinking and eating, changed (either decreased or increased) physical activity, heightened emotional and psychological stress, might all variably contribute to trigger an acute thrombotic event. Although the true causes of the prothrombotic “holiday phenomenon” largely remain speculative, there is a widespread perception that most represent preventable events. Although drastic and unrealistic measures, such as canceling holiday periods from our calendar or leaving for vacations without our beloved partner may seem unreasonable, some risk-avoidance strategies might be advisable for individuals considered to be at highest risk for the ill effects of “holiday excesses.” The article in part extends a previous exploration by these authors into otherwise “unexpected” triggers of thrombosis.[6]

In the second article of this issue, Di Minno and colleagues[7] explore the relationship between alcohol and coronary heart disease. Contrary to the serious and adverse consequences of heavy, irregular, or binge alcohol drinking, in part reflecting a potential trigger to “holiday thrombosis” as explored earlier, light/moderate alcohol consumption appears to be associated with protection from vascular and all-cause mortality, ischemic stroke, peripheral arterial disease, congestive heart failure, and recurrence of ischemic events. The article can therefore be considered an extension of a previous related review in Seminars in Thrombosis & Hemostasis.[8] After reviewing the information with respect to major aspects of cardiovascular pathophysiology, to potential confounders, and to underlying mechanisms, several concepts emerge according to Di Minno and colleagues.[7] First, the recommended amounts of “safe alcohol drinking” in healthy individuals are up to two standard drinks (∼20 g/d) for a man and up to one drink (10 g/d) for a nonpregnant woman. The overall balance for young premenopausal women, but not for older women, would be unfavorable for drinking. The risk of cancer would not outweigh potential benefits of alcohol on heart disease. Second, within the frame of a balanced pattern of dietary energy intake, patients with cardiovascular disease who drink alcohol should not exceed one or two standard drinks per day for women or up to two or three drinks per day for men. Third, the low rates of coronary heart disease among the Mediterranean people may be related to their pattern of drinking wine, especially red wine, almost every day during meals. Regular drinking is associated with better outcomes than occasional (binge)/weekly drinking. Fourth, wine (ethanol with antioxidants) exhibits significantly higher anti-inflammatory effects than gin (ethanol without polyphenols), and thus in general wine should be preferred to liquor or beer.

Lijfering et al then explore the relationship between venous and arterial thrombosis from a causal perspective.[9] Venous and arterial thrombosis are traditionally regarded as two different diseases with respect to pathophysiology, epidemiology, clinics, as well as preventive and treatment strategies. Research findings of the past few years suggest that this categorical distinction may instead be misleading. However, whether the described relationship between venous and arterial thrombosis is real or a result of other factors such as confounding, chance, or bias is still unclear. In this review, the authors review the current literature to better understand potential causal relations between cardiovascular risk factors, atherosclerosis, arterial thrombosis, and venous thrombosis. Furthermore, they propose future study designs to further elucidate the causal link between venous and arterial thrombosis. They also comment on the effect of statins on the occurrence of both arterial and venous thrombosis, and discuss the possible clinical implications of these findings. It is worth noting that this contribution represents that of an Eberhard F. Mammen Young Investigator awardee (Dr. Lijfering).[10] [11] Accordingly, the guest editors hope that readers of this journal will find this article of particular interest.

The concepts explored by Lijfering et al[9] are in part continued in the next article by Poredos and Jezovnik,[12] who review the relationship between dyslipidemia, statins, and VTE. Although the major risk factors of VTE are well recognized, the pathology often develops in subjects without any obvious precipitating factor. As explored previously, recent evidence suggests a link between arterial and venous thrombosis, particularly in patients with idiopathic venous thrombosis. Therefore, similar or identical risk factors may play a role or even interplay in the development of both diseases. A positive association between classical risk factors of atherosclerosis, including dyslipidemia, and VTE has been reported. Recent studies have also demonstrated an association between hypercholesterolemia and objectively verified VTE. Circulating lipids have been shown to exert both prothrombotic and endothelium-deteriorating properties. Hyperlipidemic blood also generates a greater amount of thrombin, and expresses a higher level of platelet activity and markers of endothelial dysfunction. The authors propose that statins may protect against VTE by impeding or counteracting these mechanisms. Some observational, controlled studies and two meta-analyses have shown that statins significantly reduced VTE risk, most likely in a process independent from cholesterol lowering, through mechanisms related to the pleiotropic effects of these drugs. However, there are also opposing findings about the efficacy of statins in prevention of VTE, and the use of statins is not without adverse effects. Therefore, the use of statins for prophylaxis of VTE cannot be recommended and further studies are needed to clarify their use, if any, for prevention of VTE.

The next article by Allman-Farinelli[13] continues the theme of venous thrombosis, but this time from the perspective of obesity, defined as a body mass index of 30 kg/m² or greater. The world appears to be experiencing an obesity pandemic, with rates of obesity rising for more than two decades. Of particular concern are the risks that millions of obese people are likely to develop chronic disease, even at ages earlier than their parents might have. There is now undeniable evidence of a strong association between obesity and reduced life expectancy, as well as with a variety of chronic disorders such as coronary artery disease, diabetes, breathing difficulties during sleep, certain types of cancer, and osteoarthritis. Nevertheless, as obesity also increases the risk of venous thrombosis, the incidence of this pathology is also expected to rise significantly. Plausible mechanisms exist to explain this relationship, including the physical effects of body fat limiting venous return and a proinflammatory, prothrombotic, and hypofibrinolytic milieu. Loss of body weight has been shown to reduce the concentrations of coagulation factors and plasminogen activator inhibitor-1 toward the normal range. Whether weight loss would prevent secondary occurrence of VTE in the absence of anticoagulant therapy is, however, as yet unknown.

The next article by Tufano et al[14] discusses the challenge of diagnosing pulmonary embolism (PE) in selected patient cohorts in the light of available clinical, laboratory, and instrumental diagnostic strategies. Although the prompt and accurate diagnosis of PE greatly influences patients' outcomes, this is one of the most difficult challenges confronting physicians, especially 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 challenge the application of clinical probability categories usually applied to general adult patients. Moreover, the diagnostic techniques (namely D-dimer testing) show wider, specific limitations in these settings. PE is considered rare in children, and the diagnostic management of a child with suspected PE is thus largely extrapolated from the knowledge achieved in adult patients. An increased risk of VTE is reported in all trimesters of pregnancy and in the puerperium. An accurate diagnosis of PE in pregnancy is important in terms of 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, with ∼40% of PE found at necropsy not suspected antemortem.

Humans have for long sought to enhance their “athletic” performance to enhance body weight, aggressiveness, mental concentration, and physical strength, reducing at the same time fatigue, pain, and thereby improving recovery. Although regular training is a cornerstone for achieving these objectives, the auxiliary use of ergogenic aids has become commonplace in all elite and competitive sports. The demarcation between ergogenic aids and doping substances or practices is continuously challenging and mostly based on perceptions regarding the corruption of the fairness of competition and the potential side effects or adverse events arising from the use of otherwise unnecessary potentiating substances. A kaleidoscope of side effects has been associated with the use of doping agents, including behavioral, skeletal, endocrinologic, metabolic, hemodynamic, and cardiovascular imbalances. As reviewed by Lippi and Banfi,[15] the most striking association with thrombotic complications among the various doping substances has been reported for androgenic anabolic steroids (i.e., cardiomyopathy, fatal and nonfatal arrhythmias, myocardial infarction, intracardiac thrombosis, stroke, VTE, limb arterial thrombosis, branch retinal vein occlusion, cerebral venous sinus thrombosis) and blood boosting (i.e., VTE and myocardial infarction, especially for epoetin and analogs). The potential thrombotic complication arising from misuse of other doping agents such as the administration of cortisol, growth hormone, prolactin, cocaine, and platelet-derived preparations is instead speculative or anecdotal at best. This article provides an overview on the epidemiological association as well as the underlying biochemical and biological mechanisms linking the practice of doping in sports with the development of thrombosis.

As subsequently reviewed by Coppola and colleagues,[16] 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 and related plasma cell disorders. 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 the impairment of platelet and coagulation function due to circulating M proteins are considered key mechanisms in the hemostatic abnormalities frequently detected in patients with plasma cell disorders. However, clinically significant bleeding is relatively rare and poorly correlates 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 VTE, particularly when associated with dexamethasone and multiagent chemotherapy in newly diagnosed patients. This article can be seen as an extension of another recent related review on this topic in this journal.[17]

According to the most recent statistics of the United States Renal Data System, as many as 527,283 U.S. residents were under treatment for end-stage renal disease in the year 2007, primarily due to diabetes, hypertension, glomerulonephritis, cystic kidney, and urologic disease. Considering that the burden of end-stage renal disease is dramatically high and continues to rise exponentially due to the increasing prevalence of the underlying disorders, Montagnana and colleagues[18] review the relationship between hemodialysis and thrombosis, describing the epidemiology and pathogenesis of thrombosis of dialysis vascular access and discussing the application of therapeutic interventions in prevention and treatment of this clinical problem. Patients undergoing chronic hemodialysis have a high risk of arterial thrombotic events as well as vascular access thrombosis. The latter complication, which is dramatic in term of life expectancy and quality, has been consistently associated with inherited (i.e., the prothrombin 20210 polymorphism, and polymorphisms in the genes encoding for transforming growth factor-β1, nitric oxide synthase, plasminogen activator inhibitor-1, angiotensin converting enzyme, and methylene tetrahydrofolate reductase) and acquired thrombotic risk factors (i.e., diabetes, obesity, atrial fibrillation, hypertension, hyperhomocysteinemia, hyperlipoproteinemia(a), low serum albumin, antiphospholipid antibodies, autoantibodies against protein C and S, erythropoietin administration, malnutrition, and cytomegalovirus infection). The three main factors involved in the pathogenesis of vascular access thrombosis overlap those of venous thrombosis and include endothelial cell injury, blood stasis, and hypercoagulability. These changes are characteristic of patients affected by end-stage renal disease and might be further aggravated during and after hemodialysis.

In severe infection and sepsis, activation of coagulation frequently occurs and this will contribute to the development of multiple organ dysfunction.[19] Factor V Leiden is a relatively common mutation resulting in a mild procoagulant state and consequently an increased tendency to develop thrombosis. Hypothetically, then, patients with factor V Leiden may therefore suffer from more severe coagulopathy during or subsequent to severe infection or sepsis. Aggravation of the procoagulant state in sepsis may in turn result in more severe organ dysfunction and an increased risk of death. Levi and colleagues[20] therefore review the experimental and clinical evidence regarding the relationship between the presence of a factor V Leiden mutation and the incidence and outcome of sepsis. Unfortunately, both experimental and clinical studies show inconsistent results and have failed to as yet resolve this issue. Accordingly, additional analyses in larger cohorts of septic patients or long-term prospective studies in patients with a known factor V Leiden mutation will be required to enable clarification. Although it is biologically plausible that the factor V Leiden mutation and the ensuing activated protein C resistance would aggravate the response to sepsis, the opposite may also be true, as it has been speculated that a balanced and moderate increase in thrombin generation, as may result from a heterozygous factor V Leiden mutation, could instead be protective during severe infection and sepsis by means of generating slightly more activated protein C.

The final article in this issue of Seminars in Thrombosis & Hemostasis represents a slight change in focus for this issue, and also for that largely representative of the previous related issues.[1] [2] [3] [4] Much of our understanding of the pathogenesis of thrombosis has long been based on observations made on large blood vessels, as typically represented by venous and arterial thrombosis. Nevertheless, there has been a recent shift in attention to the microvasculature and to how microcirculatory occlusion affects function of various organs in diseases. The article by Kwaan[21] therefore fittingly provides an overview of microthrombosis in small blood vessels, with discussion of the progressive stages of its development. The initial event is triggered by a variety of diseases, followed by a second phase when multiple contributory factors amplify the process with the final phase of microvascular occlusion and microvascular thrombosis. The final result is either recovery or injury to the affected organ. If the process is generalized, it is often associated with catastrophic and fatal outcomes. Current knowledge of the leading role of contributory factors has led to a new paradigm shift. A therapeutic approach limited to a single target of the underlying disorder, such as the use of anticoagulants, is insufficient and too often unsuccessful when applied to microthrombosis in small blood vessels. Accordingly, simultaneous management of all contributory factors needs to be considered to ensure more successful outcomes.

The guest editors of this issue of Seminars in Thrombosis & Hemostasis would like to sincerely thank all the authors for their interesting contributions, and we hope that our readers enjoy the collation of articles and the fifth issue of this series related to “Coagulopathies and Thrombosis: Usual and Unusual Causes and Associations.”

REFERENCES

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• 2 Lippi G, Franchini M, Favaloro E J. Coagulopathies and thrombosis: usual and unusual causes and associations, part II.  Semin Thromb Hemost. 2009;  35 (7) 591-595
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• 6 Lippi G, Franchini M, Favaloro E J. Unsuspected triggers of venous thromboembolism—trivial or not so trivial?.  Semin Thromb Hemost. 2009;  35 (7) 597-604
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• 11 Eberhard F. Mammen Young Investigator Award Winners. Available at: http://www.thieme.com/index.php?option=com_content&view=article&id=249&catid=70
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• 13 Allman-Farinelli M. Obesity and venous thrombosis – a review.  Semin Thromb Hemost. 2011;  37 (8) 903-907
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• 16 Coppola A, Tufano A, Di Capua M, Franchini M. Bleeding and thrombosis in multiple myeloma and related plasma cell disorders.  Semin Thromb Hemost. 2011;  37 (8) 929-945
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• 19 Hofstra J J, Schouten M, Levi M. Thrombophilia and outcome in severe infection and sepsis.  Semin Thromb Hemost. 2007;  33 (6) 604-609
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