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

Welcome to the second issue of Seminars in Thrombosis and Hemostasis devoted to “Coagulopathies and Thrombosis: Usual and Unusual Causes and Associations.”[1] Venous thromboembolism (VTE), comprising both deep vein thrombosis (DVT) and pulmonary embolism (PE), is a leading health problem worldwide. According to the historical report of Silverstein et al,[2] the overall average age- and sex-adjusted annual incidence of VTE in the United States has been estimated at 117 per 100,000 (DVT, 48 per 100,000; PE, 69 per 100,000), with higher age-adjusted rates among males than females (130 versus 110 per 100,000, respectively). Thirty percent of affected patients die within 30 days, and a fifth suffer sudden death due to PE.[3] Nevertheless, VTE is predominantly a disease of older age because the incidence increases markedly with aging in both sexes, mostly sustained by PE. Remarkably, the average annual age- and sex-adjusted incidence of in-hospital VTE is 960 per 10,000 person-years, >100 times greater than the incidence among a community population of outpatients.[4] Accordingly, factors associated with institutionalization independently account for >50% of all cases of VTE in the community population of outpatients.[5]

Understanding the complex pathogenesis of VTE is essential, in that the recognition of “predisposing,” “contributing,” and “triggering” factors would permit the identification of patients at major risk, and therefore who may benefit from appropriate prophylaxis and more aggressive therapy.[6] Nevertheless a preliminary and formal distinction between “predisposing,” “contributing,” and “triggering” factors is imperative, as in other medical disorders. Whereas the first term refers to “anything that produces a susceptibility or disposition to a condition without actually causing it,” the second defines “an important factor that helps to cause a condition,” and the third reflects “the factor that actually causes the condition to occur.” In the specific case of VTE, there is merely a temporal distinction between the three, with the first contributing to raise the baseline risk of the patient, and the second plus the third acting in synergy to propel him or her over an individual threshold from which the thrombosis develops. One quaint analogy is that of someone falling from the top of a tower, with “predisposing factors” comparable to the elevator that brings the person higher and higher up the tower, “contributing” factors those taking the person from the lift to the tower's edge, and “triggering” factors those that provide the final push from the brink (Fig. [1]).

Figure 1 Predisposing, contributing, and triggering factors interplay in the development of venous thrombosis.

Although major attention has focused over past decades on “predisposing” factors, both “triggering” and “contributing” factors also deserve scrutiny, in that they might play a significant role in the final event, that is, the onset of thrombosis. Therefore, one aim of this second issue of Seminars in Thrombosis and Hemostasis, devoted to coagulopathies and thrombosis, is to provide a synthetic overview on some of these contributing factors, in particular “unusual” causes that are frequently ignored or overlooked.

In line with this theme, the first article by Lippi et al is devoted to the concept of “unsuspected triggers of VTE—trivial or not so trivial.” Although there are some drawbacks in the current literature that make it difficult to ascertain the true contribution of such so-called trivial triggers to the etiology of VTE, there has been an increasing awareness over the last few years of less typical precipitating conditions and events, including sneezing and coughing attacks, eating, migraine, sexual intercourse, strenuous physical exercise, drug abuse, and defecation. As highlighted, all these “triggering” factors are relatively innocent when considered alone, and they do not cause thrombosis in nonpredisposed subjects. However, the concomitant presence of such trivial elements with one or more strong risk factors for VTE might precipitate an acute thrombotic episode. This is the typical case, for example, of toilet activities (defecation and micturition) because up to 50% of hospitalized patients who are already at increased risk develop acute PE during such activities, with a remarkably high mortality rate (up to 33%).

In the second article, “Hemostatic and Fibrinolytic Abnormalities in Endocrine Diseases: A Narrative Review,” Targher et al summarize the current knowledge on hemostatic abnormalities in patients with a variety of endocrine disorders, including polycystic ovary syndrome, Cushing's syndrome, thyrotoxicosis, hypothyroidism, primary hyperparathyroidism, acromegaly, hypopituitarism, and growth hormone deficiency. Although the putative biological mechanisms are not fully understood, it seems reasonable to conclude that these endocrine diseases may increase the risk of thrombosis, especially atherothrombosis. The hemostatic unbalance observed in patients suffering from these endocrine pathologies usually range from mild to moderate but occasionally might yield meaningful laboratory findings reflective of clinical abnormalities (e.g., bleeding diathesis in overt hypothyroidism mainly due to an acquired von Willebrand's syndrome type 1), which are reversible after pharmacologic treatment of the hormonal dysfunction. They are therefore of limited consequence in the clinical practice if appropriately identified and managed. Nevertheless, as the authors conclude, the caveat for limiting adverse clinical consequences is the prompt recognition of these otherwise potentially severe disorders of hemostasis and thus their proper clinical management.

Polycystic ovary syndrome is a common but generally underrecognized endocrine disorder associated with multiple comorbidities such as diabetes, dyslipidemia, hypertension, and metabolic syndrome, all of which predispose women with polycystic ovary syndrome to early atherosclerosis. Therefore, the article by Mak and Dokras specifically deals with polycystic ovarian syndrome and the risk of cardiovascular disease and thrombosis, highlighting that women suffering from this condition experience a higher prevalence of subclinical atherosclerosis, as reflected in dysregulation of endothelial function, increased carotid intima media thickness, and the presence of coronary artery calcification. They also report preliminary data on abnormalities of serum biomarkers of cardiovascular disease (namely high sensitivity C-reactive protein, homocysteine, and adiponectin) in women with polycystic ovary syndrome, concluding that no definitive answers can be drawn regarding the dysregulation of both the coagulation and fibrinolytic systems in these conditions because of the limited data available. The risk of VTE is also unclear in this population, and further studies are needed to address whether oral contraceptives should reflect the first-line treatment.

Systemic lupus erythematosus (SLE) is a rare but potentially fatal multiorgan inflammatory disease, primarily affecting females. Due to the heterogeneity of clinical manifestations and lack of laboratory tests that are both specific and sensitive for the disease, the diagnosis of SLE can often be difficult. Although the precise etiology remains to be fully elucidated, Palatinus and Adams provide a comprehensive analysis on probable environmental, genetic, and hormonal factors that might contribute to the development of the disease. They also highlight that patients with SLE have an increased risk for premature thrombosis and/or atherosclerosis, with up to half experiencing a thrombotic event, antiphospholipid antibodies playing a key role by affecting various hemostatic protein interactions with phospholipids and cell surfaces, as well as platelet function. Antiphospholipid antibodies are also a key feature of the antiphospholipid syndrome (APS),[7] [8] and many individuals with SLE may also have APS. Despite recent advances in knowledge related to the factors that contribute to the pathophysiology of SLE, numerous challenges related to earlier diagnosis, as well as the prediction and prevention of thrombotic events, are covered in this article.

The hemostatic system plays a pivotal role for establishment and maintenance of pregnancy. Placental circulation develops by structural modifications of the spiral arteries and a pregnancy-induced hypercoagulable state, which is usually characterized by an increase of procoagulant factors and a decrease of natural anticoagulant factors and fibrinolysis. Therefore, it is conceivable that the inherent hypercoagulable state that characterizes pregnancy might be worsened by inherited or acquired thrombophilic conditions, which can propel the patient over the threshold for developing thrombosis. In line with this hypothesis, Grandone et al provide some valuable updates on the role of thrombophilia in adverse obstetric outcomes (namely preeclampsia, abruption placentae, fetal loss, and fetal growth restriction) and their prevention using antithrombotic therapy. Despite the huge number of studies available, there is still a gap in our knowledge regarding how thrombophilia and pregnancy might interplay, and many pathogenetic aspects of the obstetric complications remain incompletely understood. Nevertheless, the thrombophilic risk factors most strongly associated with adverse pregnancy outcome include the factor V Leiden and factor II 20210A gene polymorphisms, hyperhomocysteinemia, deficiencies of natural anticoagulants, and antiphospholipid antibodies. The authors also assess the relative clinical and cost effectiveness of different thromboprophylaxis regimens for VTE and recurrent pregnancy outcome, concluding both safety and efficacy of low molecular weight heparin as a promising approach to the prevention of pregnancy complications, although more research is still needed for definitive conclusions.

Because much has been said and written on the bidirectional relationship between cancer and hemostasis and the potential role of anticoagulant therapy in moderating thrombosis and cancer spread, Franchini et al provides a synopsis of the most valuable studies. It is now definitely established that malignancies influence the hemostatic system, with both elements interplaying in a “vicious cycle” of sorts, characterized by overexpression of procoagulant factors (especially thrombin), which in turn promote tumor growth, invasion, and spread. This explains why VTE, especially idiopathic venous thrombosis, occurs frequently as a paraneoplastic phenomenon, and in turn emphasizes that several components of primary and secondary hemostasis (namely platelets, tissue factor, and thrombin) play an important role in primary tumor growth and metastasis. These findings have led to the development of several clinical trials with anticoagulants in cancer patients. A biological rationale, along with preliminary clinical outcomes, suggests that anticoagulants, especially heparinoids, may hold promise not only for prevention of thrombotic complications but also for interfering with the mechanisms that affect cancer growth, downregulating tumor invasion and spread, and thus prolonging overall survival in cancer patients.

Continuing the association between thrombosis and cancer, the next article by Lippi et al addresses the intriguing association between prostate-specific antigen (PSA), prostate cancer, and disorders of hemostasis. Prostate cancer represents the leading form of malignancy in men and is the third leading cause of cancer deaths worldwide. A variety of hemostatic disorders (disseminated intravascular coagulation, VTE, acute coronary syndrome, and postsurgical bleeding) may develop in patients with prostate cancer, and these substantially contribute to the mortality and morbidity of this malignancy. The leading mechanisms underlying prostate cancer–related coagulopathies are similar to those of other malignancies (e.g., hyperexpression of tissue factor, cancer procoagulant and platelet-activating factor, and release of large amounts of both prothrombotic and profibrinolytic substances). Several lines of evidence also suggest that PSA, which is currently used as the pivotal biomarker in prostate cancer diagnostics, may possess some tumor-suppressing activities. Despite several structural homologies with other members of the vast kallikrein family, which actively interplays with the coagulation cascade, the role of PSA in the pathogenesis of hemostatic disorders remains circumstantial and speculative at best. However, observations that this enzyme tend to correlate positively with several markers of thrombin generation, postsurgical bleeding, as well as with coronary atherosclerosis and negative outcomes of myocardial infarction, raise intriguing hypotheses regarding the pathophysiological role of this serine protease in several hemostatic disorders.

Analogous to the relationship between cancer and thrombosis, a large amount of clinical and experimental evidence now supports the role of particulate air pollution in increasing cardiovascular risk. Franchini and Mannucci guide us on a journey toward understanding the complex interrelationship between the leading cause of mortality and morbidity worldwide (cardiovascular disease) and the foremost political and health-care problem (air pollution). Acute and chronic exposure to particulate matter has been shown to be associated (and even trigger) acute cardiac events, as well as promote the chronic development of cardiovascular disorders. A variety of biological mechanisms have been proposed, although the precise pathways are not fully understood. The literature data on the short-term and long-term cardiovascular effects of particulate air pollutants are discussed in this review, both from a clinical and mechanistic point of view.

In the next article, Girelli and colleagues offer a comprehensive and updated overview on the much-debated topic of the genetics of coronary artery disease (CAD). Although CAD and myocardial infarction (MI), its most severe complication, have been historically considered as diseases that “run in families” and thereby are characterized by a strong inherited background, they still represent the prototype of complex and multifactorial disorders, where a variety of environmental, lifestyle, and genetic factors interplay to trigger the adverse outcome. A myriad of genetic studies have been conducted over the past decade to assess for relationships between polymorphic variants into genes known to be involved in pathways and atherothrombosis, but results have generally been of questionable value because most of the genetic variants that could be identified were proven to be only modestly predictive, thereby explaining only a small fraction of the genetic risk and conferring only a small risk of disease. A limited knowledge regarding the exact role of these variants in the pathophysiology of CAD, and the ability to so far identify only loci and not the genes themselves are also highlighted as additional caveats. Nevertheless, some Genome-Wide Association Studies (GWAS), based on microchips to scan the whole genome in search of associations with complex phenotypes, have already identified promising loci associated with CAD, including 9p21.3, 1p13.1, 12q24, 10q11.21, 21q22, 6p24, 2q33, 1q41, 19p13, 1p32, and 3q22.3. Throughout their article, Girelli and colleagues review clinical evidences and provide valuable biological explanations linking these loci with CAD, concluding however that further studies are needed to provide biological insights into these loci that, at the end of a long journey from bench to bedside, might provide a better prevention and/or management of CAD/MI patients.

Inherited thrombophilia, which is usually defined as a “genetically determined tendency to develop VTE,” strongly contributes to the pathogenesis, inasmuch as nearly 40% of VTE episodes have a genetic background and 50% of carriers of inherited thrombophilic traits develop VTE. Accordingly, the spasmodic research for thrombophilia markers has been and still is an ongoing intriguing issue. In the article by Coppola et al, relatively rare inherited abnormalities (i.e., natural anticoagulant deficiencies, homozygous factor V Leiden, and combined defects) are reviewed, concluding that they result in more severe thrombophilic phenotypes, characterized by early-onset events, more frequent recurrence, and positive family history. Other more common polymorphisms such as heterozygous factor V Leiden and prothrombin G20210A are also reassessed in view of recent clinical evidences, which raise the conviction that they might be associated with a much lower VTE risk, mostly dependent on the presence of stronger triggering factors. At the end of their article, the authors conclude thereby that the clinical implications of inherited thrombophilia should be assessed in the framework of coexisting and/or circumstantial risk factors involved in the multifactorial pathogenesis of VTE.

The final chapter in this issue, by Favaloro et al, covers the aspect of laboratory investigation into thrombophilia. Although this subject has been previously covered by several recent articles in Seminars in Thrombosis and Hemostasis,[9] [10] [11] the current one takes a slightly different angle and examines how several elements interplay to compromise the utility of such testing. Thus, although testing for various thrombophilia markers has been widely initiated by clinicians following recent reports that current testing can help explain upward of 40 to 50% of familial recurrent thrombotic events, inappropriate sampling of individuals while on anticoagulant therapy, or just after the acute event, as well as nonfocused patient investigations, can lead to a high likelihood of false-positive findings, which has the potential for adverse clinical management as well as negative psychological impact on those investigated individuals. Coupled with consideration of the limited clinical usefulness of thrombophilia testing, given that such knowledge rarely changes clinical management for the individual patient, therefore begs the question of whether the current global trends for thrombophilia testing are doing our patients more harm than good.

Although several advances have been made in the diagnosis, treatment, and prevention of VTE, some questions remain unresolved, especially those concerning pathogenesis and risk factors. Owing to the huge global economical crisis, which is also dramatically affecting resources available to health-care systems worldwide, randomized controlled trials and cost-effective analyses are needed (more than ever), to establish whether the ongoing and ever-increasing significant expenditures for identifying inherited risk factors and preventing pathologies can be fully justified. Thus the identification of strong predisposing factors might be advisable because this might help prevent the inherent costs of treating otherwise preventable pathologies, whereas the assessment of minor predisposing risk factors might only have a narrow benefit, in that such knowledge would help prevent a very limited number of events while consuming valuable economical resources that might be much better redistributed. Although the contribution of inherited deficiencies of antithrombin, protein C and S, factor V, and prothrombin 20210A gene polymorphisms in determining a high VTE risk has been more clearly established,[6] the role of more frequent but less hazardous prothrombotic conditions, including other genetic polymorphisms (i.e., α-fibrinogen Thr312Ala, plasminogen-activator inhibitor 1 4G/5G, α-fibrinogen Thr312Ala, β-fibrinogen 455 G/A, factor XIII Val34Leu), is still a matter of debate. Therefore, it seems reasonable to conclude that to avoid resource waste on assessing questionable inherited conditions for establishing thrombotic risk, major focus could instead be placed on those “contributing” and “triggering” clinical factors that do not require expensive and labor-intensive laboratory investigations but still can help prevent VTE in the community (Fig. [1]). This is one goal of this issue of Seminars in Thrombosis and Hemostasis. We sincerely hope that you enjoy the collation of articles in this issue, and as always we thank all the authors for their most interesting contributions.

REFERENCES

• 1 Franchini M, Lippi G, Favaloro E J. Coagulopathies and thrombosis: usual and unusual causes and associations, part I.  Semin Thromb Hemost. 2009;  35(3) 257-259
• 2 Silverstein M D, Heit J A, Mohr D N, Petterson T M, O'Fallon W M, Melton III L J. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study.  Arch Intern Med. 1998;  158(6) 585-593
• 3 Heit J A, Silverstein M D, Mohr D N et al.. The epidemiology of venous thromboembolism in the community.  Thromb Haemost. 2001;  86(1) 452-463
• 4 Heit J A, Melton III L J, Lohse C M et al.. Incidence of venous thromboembolism in hospitalized patients vs community residents.  Mayo Clin Proc. 2001;  76(11) 1102-1110
• 5 Heit J A, O'Fallon W M, Petterson T M et al.. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study.  Arch Intern Med. 2002;  162(11) 1245-1248
• 6 Lippi G, Franchini M. Pathogenesis of venous thromboembolism: when the cup runneth over.  Semin Thromb Hemost. 2008;  34(8) 747-761
• 7 Wong R CW, Favaloro E J. Clinical features, diagnosis, and management of the antiphospholipid syndrome.  Semin Thromb Hemost. 2008;  34(3) 295-304
• 8 Favaloro E J, Wong R CW. Laboratory testing and identification of antiphospholipid antibodies and the antiphospholipid syndrome: a potpourri of problems, a compilation of possible solutions.  Semin Thromb Hemost. 2008;  34(4) 389-410
• 9 Varga E A, Kerlin B A, Wurster M W. Social and ethical controversies in thrombophilia testing and update on genetic risk factors for venous thromboembolism.  Semin Thromb Hemost. 2008;  34(6) 549-561
• 10 Cohn D M, Roshani S, Middeldorp S. Thrombophilia and venous thromboembolism: implications for testing.  Semin Thromb Hemost. 2007;  33(6) 573-581
• 11 Middeldorp S, Levi M. Thrombophilia: an update.  Semin Thromb Hemost. 2007;  33(6) 563-572