Pulmonary Embolism
Pulmonary embolism (PE) is a serious medical condition characterized by the blockage of one or more arteries in the lungs. This obstruction typically occurs when a blood clot, known as an embolus, travels from another part of the body, most commonly the deep veins of the legs (a condition known as deep vein thrombosis or DVT), and lodges in the pulmonary vasculature. The severity of PE can range from mild symptoms to sudden, life-threatening cardiovascular collapse.
The biological basis of pulmonary embolism involves a complex interplay of factors that promote blood clot formation (thrombosis) and its subsequent migration to the lungs. Once a clot obstructs a pulmonary artery, it impedes blood flow to a portion of the lung, leading to impaired gas exchange and increased pressure within the pulmonary arteries. Genetic predisposition plays a significant role in an individual’s susceptibility to developing blood clots. Research, including genome-wide association studies, has identified genetic loci associated with general thrombosis, which is the underlying cause of PE[1].
Clinically, PE presents with varied symptoms such as sudden shortness of breath, chest pain, coughing, and dizziness. Prompt diagnosis is crucial and often involves imaging techniques like CT pulmonary angiography. Treatment typically focuses on preventing further clot formation and growth with anticoagulant medications, and in severe cases, may involve clot-dissolving drugs (thrombolytics) or surgical removal of the clot. Early intervention is critical for improving patient outcomes and reducing mortality.
Pulmonary embolism holds significant social importance as a major public health concern worldwide. It is a leading cause of cardiovascular mortality and contributes substantially to healthcare burden due to its high incidence and potential for severe morbidity. Understanding the genetic factors that influence susceptibility to PE is vital for identifying at-risk individuals, guiding preventive strategies, and developing more targeted and effective therapies.
Limitations
Section titled “Limitations”Research into the genetic underpinnings of pulmonary embolism, particularly through genome-wide association studies (GWAS), has made significant strides, yet several limitations warrant careful consideration when interpreting findings and planning future investigations. These limitations touch upon the methodologies employed, the diversity of populations studied, and the inherent complexity of genetic architecture.
Methodological and Statistical Considerations
Section titled “Methodological and Statistical Considerations”A primary limitation arises from the typical design of GWAS, which often focuses on identifying common single nucleotide polymorphisms (SNPs) with individual effects, applying stringent statistical thresholds to minimize false positives. While effective for initial discoveries, this approach may not fully capture the intricate genetic architecture of complex conditions like pulmonary embolism, potentially overlooking variants with more modest effect sizes or those involved in complex interactions[2]. The reliance on individually assessed common SNPs can limit the ability to identify genetic variation that accounts for significant proportions of phenotypic variation, suggesting a need for alternative analytic strategies [2].
Furthermore, the ascertainment of phenotypes can introduce limitations. For instance, studies that utilize self-reported events for diagnoses such as thrombosis, while enabling large-scale analyses, carry the potential for misclassification or recall bias, which can affect the accuracy and reliability of the phenotype data [1]. Such measurement concerns, coupled with the challenges of ensuring robust replication in independent cohorts, can impact the confidence in reported associations and the generalizability of findings, especially when initial effect sizes might be inflated due to smaller discovery sample sizes.
Population Diversity and Generalizability
Section titled “Population Diversity and Generalizability”A significant constraint in current genetic research on pulmonary embolism, as with many complex traits, is the disproportionate representation of populations of European descent in many large-scale GWAS[3]. This demographic imbalance can restrict the generalizability of identified genetic associations to diverse global populations, as allele frequencies, linkage disequilibrium patterns, and environmental exposures vary considerably across different ancestries. Consequently, genetic markers and risk prediction models derived from predominantly European cohorts may not be directly transferable or accurately predictive in non-European groups. This limitation underscores the critical need for more ethnically diverse cohorts to ensure that genetic discoveries are broadly applicable and contribute equitably to global health.
Complex Genetic Architecture and Missing Heritability
Section titled “Complex Genetic Architecture and Missing Heritability”Despite the success of GWAS in identifying numerous genetic loci, a substantial proportion of the heritability for complex conditions like pulmonary embolism often remains unexplained by the identified common variants[2]. This phenomenon, known as “missing heritability,” suggests that current genetic models, which primarily assess the effects of individual common SNPs, may not fully reflect the true genetic architecture. It implies that unmeasured factors, such as rare variants, structural variations, or complex epistatic interactions between genes, might play a more significant role than currently understood [2].
Moreover, the interplay between genetic predispositions and environmental factors, including lifestyle, comorbidities, and specific exposures, presents a complex web of interactions that is often not fully elucidated. While some research endeavors to explore gene-environment interactions[4], comprehensively accounting for these confounders and their combined impact on pulmonary embolism risk represents a significant ongoing challenge. Addressing this missing heritability and unraveling the intricate gene-environment interactions are crucial steps to fully understand the etiology of pulmonary embolism and to develop more precise risk prediction and prevention strategies.
Variants
Section titled “Variants”Genetic variations play a significant role in an individual’s susceptibility to pulmonary embolism by influencing various aspects of the coagulation cascade and related biological pathways. Several genes encoding key clotting factors and regulatory proteins have common variants associated with altered thrombosis risk. These genetic predispositions can affect the balance between clot formation and dissolution, leading to an increased likelihood of venous thromboembolism (VTE), which includes pulmonary embolism.
Variations in core coagulation factors, such as Factor V and Factor II (prothrombin), are well-established contributors to thrombosis risk. The F5 gene, encoding Factor V, is particularly notable for the rs6025 variant, commonly known as Factor V Leiden, which leads to activated protein C (APC) resistance, thereby increasing the risk of abnormal clot formation and is a “widely known” locus for VTE. Thrombosis itself refers to the formation of a blood clot that can obstruct blood flow, and genetic research has identified loci associated with this process[1]. Relatedly, pulmonary arterial hypertension (PAH) is another condition affecting the pulmonary vasculature, for which susceptibility loci have been identified through genome-wide association studies[5]. The interplay between these conditions highlights the complex nature of pulmonary vascular health.
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs6025 | F5 | venous thromboembolism pulmonary embolism inflammatory bowel disease peripheral arterial disease peripheral vascular disease |
| rs1894692 | SLC19A2 - F5 | pneumonia blood protein amount atrial fibrillation tissue factor pathway inhibitor amount endometriosis |
| rs115478735 rs529565 rs9411377 | ABO | atrial fibrillation low density lipoprotein cholesterol measurement, lipid measurement low density lipoprotein cholesterol measurement low density lipoprotein cholesterol measurement, phospholipid amount cholesteryl ester measurement, intermediate density lipoprotein measurement |
| rs3756011 rs4253417 | F11 | protein measurement blood protein amount factor XI measurement, venous thromboembolism Thromboembolism pulmonary embolism |
| rs4444878 | F11-AS1 | pulmonary embolism cardioembolic stroke drug use measurement, deep vein thrombosis deep vein thrombosis heart disease |
| rs2066865 | FGA - FGG | venous thromboembolism pulmonary embolism heart disease encounter with health service Thromboembolism |
| rs1799963 | F2 | venous thromboembolism pulmonary embolism prothrombin amount deep vein thrombosis venous thromboembolism, factor VII measurement |
| rs17490626 rs78707713 | TSPAN15 | pulmonary embolism interleukin-17 receptor A measurement proheparin-binding EGF-like growth factor amount platelet volume deep vein thrombosis |
| rs7654093 | FGG - LRAT | pulmonary embolism thrombophilia deep vein thrombosis drug use measurement, deep vein thrombosis |
| rs56010410 | FGB - FGA | pulmonary embolism |
Classification within Thromboembolic Disorders and Research Criteria
Section titled “Classification within Thromboembolic Disorders and Research Criteria”From a classificatory perspective, pulmonary embolism is considered a significant component of venous thromboembolism, a class of conditions whose incidence and mortality have been rigorously studied at a population level[1]. While specific clinical classification systems or severity gradations for pulmonary embolism are not detailed, the research framework often categorizes individuals based on the occurrence of thrombotic events, including self-reported incidents[1]. These self-reported events serve as operational definitions or diagnostic criteria within large-scale genetic association studies, enabling the identification of genetic loci linked to thrombosis [1]. This categorical approach is crucial for understanding genetic predispositions to such vascular events.
Terminology and Measurement Approaches in Genetic Studies
Section titled “Terminology and Measurement Approaches in Genetic Studies”The terminology surrounding pulmonary embolism is intrinsically linked to concepts like thrombosis and venous thromboembolism, which are key terms in cardiovascular and pulmonary health[1]. In the context of genetic research, the trait definition for conditions like thrombosis can involve “self-reported events,” which represent a measurement approach for phenotype ascertainment in large cohorts [1]. This method allows for the large-scale investigation of genetic susceptibility, such as the identification of specific single-nucleotide polymorphisms (SNPs) associated with thrombotic outcomes[1]. Such operational definitions are vital for the efficient and broad-based collection of data in genome-wide association studies.
Causes of Pulmonary Embolism
Section titled “Causes of Pulmonary Embolism”Pulmonary embolism (PE) arises from a complex interplay of genetic predispositions, environmental exposures, and coexisting medical conditions that collectively increase the risk of thrombus formation and subsequent migration to the pulmonary vasculature. Understanding these multifactorial causes is crucial for prevention and management.
Genetic Susceptibility to Thromboembolism
Section titled “Genetic Susceptibility to Thromboembolism”An individual’s genetic blueprint plays a significant role in determining their susceptibility to pulmonary embolism, primarily through inherited tendencies for blood clot formation. Genome-wide association studies (GWAS) have identified multiple genetic loci, including at least eight specific regions, that are significantly associated with an increased risk of thrombosis[1]. These inherited variants can influence various aspects of the coagulation cascade, fibrinolysis, and vascular endothelial function, thereby predisposing individuals to venous thromboembolism, which is the most common precursor to PE.
While Mendelian forms of hypercoagulability exist, the research primarily highlights polygenic influences, where multiple common genetic variations each contribute a small effect to overall risk. The cumulative effect of these polygenic risk factors means that individuals carrying several such variants may have a substantially elevated lifetime risk compared to the general population. Further research into gene-gene interactions among these identified loci could unveil more intricate mechanisms underlying thrombotic risk.
Environmental and Lifestyle Contributors
Section titled “Environmental and Lifestyle Contributors”Beyond inherent genetic factors, environmental exposures and lifestyle choices are critical determinants in the development of pulmonary embolism. Smoking, for instance, represents a notable environmental trigger that can interact with an individual’s genetic profile to impact pulmonary health[4]. Such gene-environment interactions can modify the expression or function of genes involved in inflammation, vascular integrity, and coagulation, potentially accelerating the process of thrombus formation.
Although specific details on diet, socioeconomic factors, or geographic influences on pulmonary embolism risk are not extensively detailed in the provided research, the broader concept of environmental factors modulating genetic predispositions is well-established in complex diseases. These external elements can act as critical modulators, either exacerbating or mitigating an individual’s inherent genetic risk, ultimately influencing the likelihood of developing a thrombotic event that leads to pulmonary embolism.
Comorbidities and Acquired Risk Factors
Section titled “Comorbidities and Acquired Risk Factors”Several acquired health conditions and physiological states significantly contribute to an elevated risk of pulmonary embolism by creating a pro-thrombotic environment or impairing blood flow. Various pulmonary diseases themselves, for which genetic susceptibility loci have been identified, can act as important comorbidities. For example, individuals with chronic obstructive pulmonary disease (COPD)[6] (Lancet Respir Med), [6](Nat Genet) or idiopathic pulmonary fibrosis (IPF)[7]may experience increased risk due to chronic inflammation, impaired mobility, or systemic effects on coagulation, all of which predispose to venous thromboembolism.
Beyond specific lung conditions, the broader physiological changes associated with certain health states contribute to PE risk. Genetic predispositions to conditions like pulmonary arterial hypertension (PAH)[5]underscore the complex nature of pulmonary vascular diseases, where underlying pathological changes can indirectly contribute to thromboembolic events. These comorbidities often create a state of venous stasis, endothelial damage, or hypercoagulability, which are fundamental components of Virchow’s triad, thereby increasing the propensity for thrombus formation and subsequent pulmonary embolism.
Biological Background
Section titled “Biological Background”Pulmonary embolism (PE) is a serious condition resulting from the obstruction of pulmonary arteries, most commonly by a blood clot (thrombus) that has traveled from another part of the body, often the deep veins of the legs. The biological underpinnings of PE involve a complex interplay of genetic predispositions, molecular signaling pathways, cellular functions, and pathophysiological responses within the cardiovascular and respiratory systems. Understanding these mechanisms is crucial for comprehending the risk factors, disease progression, and potential therapeutic targets for PE.
Genetic Susceptibility and Lung Function
Section titled “Genetic Susceptibility and Lung Function”Pulmonary embolism, while often acutely triggered, has underlying genetic predispositions that influence both vascular health and lung function, thereby impacting an individual’s susceptibility. Genome-wide association studies (GWAS) have identified numerous genetic loci associated with lung function, highlighting the polygenic nature of respiratory health[4]. For instance, specific genes like CHRNA5/3 and HTR4 have been linked to the development of airflow obstruction [8], and variants in IREB2 and GALCare associated with pulmonary artery enlargement in chronic obstructive pulmonary disease (COPD)[9]. These genetic factors can modulate the structural integrity and functional capacity of the lungs, potentially influencing susceptibility to, or the severity of, pulmonary vascular compromise and subsequent embolism [10]. Furthermore, research has identified 8 loci associated with thrombosis, the primary cause of emboli, indicating a direct genetic contribution to the risk of clot formation [1].
Molecular Mechanisms of Thrombogenesis
Section titled “Molecular Mechanisms of Thrombogenesis”The formation of a thrombus, the precursor to a pulmonary embolus, involves intricate molecular and cellular pathways within the circulatory system. This process, known as thrombogenesis, is a dysregulation of normal hemostasis, where key biomolecules such as coagulation factors, platelets, and endothelial cells interact to form a stable clot. Genetic variants can influence the expression or function of these critical proteins, enzymes, and receptors, leading to a prothrombotic state [1]. Regulatory networks governing platelet activation and the coagulation cascade can be disrupted, either by inherited genetic factors or acquired conditions, pushing the homeostatic balance towards excessive clot formation. Ultimately, an improperly formed or unstable thrombus, often originating in the deep veins, can detach and travel through the bloodstream to the pulmonary vasculature, initiating the embolic event.
Pathophysiology of Pulmonary Obstruction
Section titled “Pathophysiology of Pulmonary Obstruction”Once a pulmonary embolus lodges in the pulmonary arteries, it immediately disrupts normal physiological processes at the tissue and organ level. The physical obstruction leads to an increase in pulmonary vascular resistance, forcing the right ventricle of the heart to work harder, which can result in acute right ventricular strain and failure. This mechanical blockage also causes ventilation-perfusion mismatch, where areas of the lung are ventilated but not perfused with blood, impairing gas exchange and leading to hypoxemia. The affected lung tissue may also undergo compensatory responses, such as bronchoconstriction and vasoconstriction in the non-perfused areas, further exacerbating the mismatch and contributing to respiratory distress.
Systemic Consequences and Compensatory Responses
Section titled “Systemic Consequences and Compensatory Responses”The immediate pulmonary obstruction by an embolus triggers a cascade of systemic consequences and compensatory responses throughout the body. The impaired gas exchange in the lungs leads to reduced oxygen delivery to systemic tissues, potentially causing tissue hypoxia and organ dysfunction. The cardiovascular system attempts to compensate for the reduced cardiac output and increased pulmonary pressure, often through sympathetic nervous system activation, leading to tachycardia and systemic vasoconstriction. However, these compensatory mechanisms can be overwhelmed, especially in individuals with pre-existing cardiovascular or pulmonary conditions such as COPD or idiopathic pulmonary fibrosis, where underlying genetic variants may already predispose to compromised lung function or pulmonary artery enlargement[9]. The severity of these systemic effects depends on the size and number of emboli, the patient’s underlying health, and the efficacy of the body’s adaptive responses.
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Population Studies
Section titled “Population Studies”Understanding the population-level impact and risk factors for pulmonary embolism (PE) relies heavily on large-scale epidemiological investigations and genetic association studies. These studies employ diverse methodologies, from community-based incidence tracking to genome-wide analyses, to characterize the burden of disease, identify susceptible populations, and uncover underlying biological mechanisms.
Epidemiological Incidence and Demographic Patterns
Section titled “Epidemiological Incidence and Demographic Patterns”Population-based studies have been instrumental in establishing the incidence and mortality rates associated with venous thromboembolism (VTE), which encompasses pulmonary embolism. For instance, a community-based study conducted in Western France provided specific incidence rates for VTE within that region[11]. Further research, drawing from a broader population-based study, detailed the incidence and mortality patterns of venous thrombosis, offering crucial insights into its public health impact[12]. These epidemiological investigations often analyze demographic factors such as age, sex, and other baseline characteristics to understand their correlation with disease occurrence, contributing to a comprehensive picture of who is most affected and under what circumstances.
Genetic Susceptibility and Large-Scale Cohort Investigations
Section titled “Genetic Susceptibility and Large-Scale Cohort Investigations”Large-scale genetic studies, particularly genome-wide association studies (GWAS), have been employed to identify genetic loci associated with thrombosis, the underlying cause of pulmonary embolism. One such study involved a substantial cohort of 6,135 individuals with self-reported thrombotic events and a control group of 252,827 individuals, successfully identifying eight distinct genetic loci linked to thrombosis[1]. These comprehensive investigations leverage massive sample sizes and advanced statistical methods to pinpoint specific genetic variations that contribute to disease risk, offering a foundation for understanding inherited predispositions within general populations. Such large-scale efforts often involve participants drawn from broad customer bases, which can contribute to a diverse representation of the wider population.
Cross-Population Approaches and Methodological Considerations
Section titled “Cross-Population Approaches and Methodological Considerations”Population studies on pulmonary embolism and related conditions frequently involve extensive collaborations across different research centers and utilize diverse cohorts to enhance generalizability and statistical power. While specific cross-population comparisons for pulmonary embolism were not detailed, studies focusing on related respiratory conditions, such as chronic obstructive pulmonary disease (COPD) and lung function, exemplify the use of multi-ethnic cohorts[10]. These studies often combine data from various ancestries, including Hispanic populations, and utilize meta-analysis approaches to synthesize findings across multiple cohorts, thereby providing more robust insights into genetic and environmental factors [6]. Methodological considerations in these large-scale studies include the careful selection of study designs, ensuring representativeness of the sampled populations, and managing the vast amounts of genomic and phenotypic data, all of which are critical for drawing valid population-level implications.
Frequently Asked Questions About Pulmonary Embolism
Section titled “Frequently Asked Questions About Pulmonary Embolism”These questions address the most important and specific aspects of pulmonary embolism based on current genetic research.
1. My parent had a PE; am I at higher risk?
Section titled “1. My parent had a PE; am I at higher risk?”Yes, absolutely. Genetic predisposition plays a significant role in your susceptibility to developing blood clots, which lead to PE. If a close family member like a parent has had a PE, it suggests you might have inherited some of those genetic risk factors. This doesn’t mean you will get one, but your baseline risk is likely higher.
2. Does long travel increase my personal clot risk?
Section titled “2. Does long travel increase my personal clot risk?”Yes, long travel, especially with prolonged immobility, can increase your risk of blood clots. If you also have a genetic predisposition to form clots, this risk is compounded. Your genetics can make you more sensitive to environmental triggers like sitting still for hours, leading to a higher likelihood of developing DVT and potentially PE.
3. Does my family’s background change my clot risk?
Section titled “3. Does my family’s background change my clot risk?”Yes, your ethnic background can influence your genetic risk for blood clots. Much of the research on genetic factors has focused on populations of European descent, and different ethnic groups can have varying frequencies of genetic markers. This means that risk factors identified in one group might not apply equally to others, highlighting the need for diverse research.
4. Why do some people get clots easily, but I don’t?
Section titled “4. Why do some people get clots easily, but I don’t?”There’s a strong genetic component to how easily a person forms blood clots. Some individuals inherit variations in genes that affect their coagulation cascade, making them more prone to thrombosis. Others may have genetic profiles that provide more protection, explaining why people can have very different susceptibilities even with similar lifestyles.
5. Can exercise prevent clots even with family history?
Section titled “5. Can exercise prevent clots even with family history?”Exercise and an active lifestyle are definitely beneficial for overall cardiovascular health and can help reduce the general risk of blood clots. However, if you have a strong genetic predisposition, exercise alone might not completely eliminate your risk. It’s a crucial part of risk reduction, but genetic factors still play a significant underlying role that might require additional management or awareness.
6. Could a DNA test actually tell me my PE risk?
Section titled “6. Could a DNA test actually tell me my PE risk?”A DNA test can identify some known genetic variants associated with an increased risk of blood clots. For example, variations in genes like Factor V are known to increase risk. While these tests can provide insights into your genetic predisposition, they don’t give a definitive “yes” or “no” answer, as many complex genetic and environmental factors contribute to overall risk.
7. Is my PE risk only a concern when I’m older?
Section titled “7. Is my PE risk only a concern when I’m older?”Not necessarily. While the risk of PE can increase with age, genetic predispositions are present from birth and can influence your susceptibility throughout your life. These genetic factors mean that some individuals may be at a higher risk for clots even at a younger age, especially when combined with other risk factors.
8. My sibling had a clot, why am I different?
Section titled “8. My sibling had a clot, why am I different?”Even within the same family, genetic inheritance isn’t identical. You and your sibling each inherit a unique combination of genes from your parents. One sibling might inherit more of the genetic variants that increase clot risk, while the other might inherit fewer, explaining why your individual susceptibilities can differ.
9. If clots run in my family, what can I do?
Section titled “9. If clots run in my family, what can I do?”If blood clots are common in your family, it’s really important to be proactive. Talk to your doctor about your family history, stay active, avoid prolonged immobility, and be aware of symptoms. Understanding your genetic predisposition helps your doctor assess your personal risk and discuss potential preventive strategies, like specific medications or lifestyle changes.
10. Does sitting all day make me more prone to clots?
Section titled “10. Does sitting all day make me more prone to clots?”Yes, prolonged sitting or immobility can increase your risk of developing blood clots, especially in the legs. If you also have a genetic predisposition to form clots, this daily habit becomes an even greater concern. Your genetics can make you more susceptible to the effects of a sedentary lifestyle, making regular movement even more important.
This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.
Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.
References
Section titled “References”[1] Hinds, D. A., et al. “Genome-wide association analysis of self-reported events in 6135 individuals and 252 827 controls identifies 8 loci associated with thrombosis.” Hum Mol Genet, 2016, PMID: 26908601.
[2] Yao, T. C., et al. “Genome-wide association study of lung function phenotypes in a founder population.” J Allergy Clin Immunol, 2013, PMID: 23932459.
[3] Manichaikul, A. et al. “Genome-wide study of percent emphysema on computed tomography in the general population. The Multi-Ethnic Study of Atherosclerosis Lung/SNP Health Association Resource Study.”Am J Respir Crit Care Med.
[4] Hancock, D. B., et al. “Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function.” PLoS Genet, 2012, PMID: 23284291.
[5] Germain, Marine et al. “Genome-wide association analysis identifies a susceptibility locus for pulmonary arterial hypertension.”Nat Genet, vol. 45, no. 4, 2013, pp. 433-438. PMID: 23502781.
[6] Cho, M. H., et al. “Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis.”Lancet Respir Med, vol. 2, no. 3, 2014, pp. 214-225.
[7] Noth, I., et al. “Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome-wide association study.”Lancet Respir Med, vol. 2, no. 4, 2014, pp. 309-317.
[8] Wilk, J. B., et al. “Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction.” Am J Respir Crit Care Med, vol. 186, no. 6, 2012, pp. 511-518.
[9] Lee, J. H., et al. “IREB2 and GALC are associated with pulmonary artery enlargement in chronic obstructive pulmonary disease.”Am J Respir Cell Mol Biol, vol. 52, no. 3, 2015, pp. 384-393.
[10] Chen, W. et al. “A genome-wide association study of chronic obstructive pulmonary disease in Hispanics.”Ann Am Thorac Soc, vol. 12, no. 3, Mar. 2015, pp. 340–348.
[11] Oger, E. “Incidence of venous thromboembolism: a community-based study in Western France. EPI-GETBP Study Group. Groupe d’Etude de la Thrombose de Bretagne Occidentale.”Thromb. Haemost., vol. 83, 2000, pp. 657–660.
[12] Naess, I.A. et al. “Incidence and mortality of venous thrombosis: a population-based study.”J. Thromb. Haemost., vol. 5, 2007, pp. 692–699.