Prospective analysis of risk factors and distribution of venous thromboembolism in the population-based Malmö Thrombophilia Study (MATS)

doi:10.1016/j.thromres.2009.04.022

Thrombosis Research

Volume 124, Issue 6, December 2009, Pages 663-666

https://doi.org/10.1016/j.thromres.2009.04.022 Get rights and content

Abstract

Background

Despite venous thromboembolism (VTE) being a major cause of morbidity and mortality, there is still limited information on its prevalence and incidence in the general population.

Objective

To evaluate risk factors, distribution and epidemiology of VTE in the Malmö area with 280 000 inhabitants.

Methods

Patients diagnosed with VTE at Malmö University Hospital in 1998–2006 were invited to a prospective population-based study. Blood sampling and a questionnaire study could be performed in 70% of patients. Remaining 30% were excluded due to language problems, dementia, other severe disease, or unwillingness to participate.

Results

During 1998–2006 1140 VTE patients (559 men [49%, age 62 ± 16 years] and 581 women [51%, age 61 ± 20 years]) were included. Deep venous thrombosis (DVT) occurred in 882 (77%), pulmonary embolism (PE) in 330 (29%), and both DVT and PE in 72 (6%). The most common acquired risk factors among VTE patients were hormone therapy (24% of female DVT patients and 19% of female PE patients), immobilisation (17% of DVT patients and 18% of PE patients), previous surgery (13% of DVT patients and 19% of PE patients), and concomitant malignant disease (12% of DVT patients and 11% of PE patients). A positive family history for VTE was obtained from 25% of DVT patients and 22% of PE patients.

Yearly incidences of VTE, DVT and PE in Malmö were 66, 51, and 19/100.000, respectively.

Conclusion

Hormone therapy, immobilisation, previous surgery and concomitant malignancy were the most common acquired risk factors among VTE patients in this population-based study. The VTE-incidence was lower than in earlier epidemiological studies.

Section snippets

Background

Despite the fact that venous thromboembolism (VTE) is an important cause of morbidity and mortality in western countries there is still insufficient information available on risk factor patterns and patient characteristics in total materials of VTE patients derived from the general population. Many of previous studies have focused on VTE in defined patients groups, such as in patients with malignancies [1], [2], patients undergoing orthopaedic [3], gynaecologic laparoscopy [4] procedures, in

Patients

The Malmö Thrombophilia Study (MATS) is a prospective population-based study at Malmö University Hospital with a primary catchment area of 280 000 inhabitants. This is the only hospital in the area treating VTE patients. The study recruited patients between March 1998 and December 2006. During this period 1140 patients with VTE were included.

The criteria for inclusion in MATS were: patient age > 18 years, possibility to communicate in Swedish, and an objective diagnosis of DVT or PE made with

Results

A total of 1140 consecutive patients with VTE, 559 men (49%, age range 62 ± 16 years), and 581 women (51%, age range 61 ± 20 years) were included in the study between March 1998 and December 2006. Eight hundred eighty two (77%) patients had DVT, 330 (29%) patients had PE and 72 (6%) patients had both DVT and PE. Patient characteristics are shown in Table 1. Of 882 DVT patients, 499 (56%) patients hade left leg DVT, 116 (13%) had iliaca DVT, 465 (53%) had DVT involving femoropopliteal veins, 246

Discussion

Many previous studies focusing on the epidemiology of VTE have been of retrospective design and included patients from defined subgroups of the general population [15], [16], [17], [18], [19], [20], [21], whereas we as some previous investigators [13], [22] prospectively determined and clarified the distribution and incidences of VTE occurring both as DVT and PE in a population based study. We included both out-patients presenting at our hospital because of suspected VTE symptoms and

Conflict of interest statement

Nazim Isma, Peter J Svensson, Anders Gottsäter, and Bengt Lindblad have no conflicts of interest to declare.

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Air pollution is a major contributor to the global burden of disease and has been linked to several diseases and conditions, including cardiovascular disease. The biological mechanisms are related to inflammation and increased coagulability, factors that play an important role in the pathogenesis of venous thromboembolism (VTE, i.e., deep vein thrombosis or pulmonary embolism). This study investigates if long-term exposure to air pollution is associated with increased VTE incidence. The study followed 29 408 participants from the Malmö Diet and Cancer (MDC) cohort, which consists of adults aged 44–74 recruited in Malmö, Sweden between 1991 and 1996. For each participant, annual mean residential exposures to particulate matter <2.5 μg (PM_2.5) and <10 μg (PM₁₀), nitrogen oxides (NO_x) and black carbon (BC) from 1990 up to 2016 were calculated. Associations with VTE were analysed using Cox proportional hazard models for air pollution in the year of the VTE event (lag0) and the mean of the prior 1–10 years (lag1-10). Annual air pollution exposures for the full follow-up period had the following means: 10.8 μg/m³ for PM_2.5, 15.8 μg/m³ for PM₁₀, 27.7 μg/m³ for NO_x, and 0.96 μg/m³ for BC. The mean follow-up period was 19.5 years, with 1418 incident VTE events recorded during this period. Exposure to lag1-10 PM_2.5 was associated with an increased risk of VTE (HR 1.17 (95%CI 1.01–1.37)) per interquartile range (IQR) of 1.2 μg/m³ increase in PM_2.5 exposure. No significant associations were found between other pollutants or lag0 PM_2.5 and incident VTE. When VTE was divided into specific diagnoses, associations with lag1-10 PM_2.5 exposure were similarly positive for deep vein thrombosis but not for pulmonary embolism. Results persisted in sensitivity analyses and in multi-pollutant models. Long-term exposure to moderate concentrations of ambient PM_2.5 was associated with increased risks of VTE in the general population in Sweden.
MicroRNAs as prognostic biomarkers for (cancer–associated) venous thromboembolism
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MicroRNAs (miRNAs) are small noncoding RNAs with gene regulatory functions and are commonly dysregulated in disease states. As miRNAs are relatively stable, easily measured, and accessible from plasma or other body fluids, they are promising biomarkers for the diagnosis and prediction of cancer and cardiovascular diseases. Venous thromboembolism (VTE) is the third most common cardiovascular disease worldwide with high morbidity and mortality. The suggested roles of miRNAs in regulating the pathophysiology of VTE and as VTE biomarkers are nowadays more evidenced. Patients with cancer are at increased risk of developing VTE compared to the general population. However, current risk prediction models for cancer–associated thrombosis (CAT) perform suboptimally, and novel biomarkers are therefore urgently needed to identify which patients may benefit the most from thromboprophylaxis. This review will first discuss how miRNAs mechanistically contribute to the pathophysiology of VTE. Next, the potential use of miRNAs as predictive biomarkers for VTE in subjects without cancer is reviewed, followed by an in-depth focus on CAT. Several of the identified miRNAs in CAT were found to be differentially regulated in VTE as well, giving clues on the pathophysiology of CAT. We propose that subsequent studies should be adequately sized to determine which panel of miRNAs best predicts VTE and CAT. Thereafter, validation studies using comparable patient populations are required to ultimately unveil whether miRNAs—as standalone or incorporated into existing risk models—are promising valuable VTE and CAT biomarkers.
Thrombomodulin (THBD) gene variants and thrombotic risk in a population-based cohort study
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The protein C anticoagulant system plays a key role in maintaining the hemostatic balance. Although several studies have identified thrombomodulin gene (THBD) variants among venous thromboembolism (VTE) patients, the role of THBD in relation to VTE in humans remains to be clarified.
This study aimed to determine the thrombotic risk of rare and common THBD variants in a large population‐based cohort of middle‐aged and older adults.
The exome sequence of THBD was analyzed for qualifying variants in 28,794 subjects (born 1923–1950, 60% women), who participated in the Malmö Diet and Cancer study (1991–1996). Patients were followed from baseline until the first event of VTE, death, or 2018. Qualifying variants were defined as loss‐of‐function or non‐benign (PolyPhen‐2) missense variants with minor allele frequency <0.1%.
The single common coding variant rs1042579 was not associated with incident VTE. Sixteen rare variants were classified as qualifying and included in collapsing analysis. Seven individuals with VTE compared to 24 individuals without VTE carried one qualifying variant. Cox multivariate regression analysis adjusted for age, sex, body mass index, systolic blood pressure, smoking and alcohol consumption, rs6025, rs1799963, and the top two eigenvectors from a principal components analysis showed a hazard ratio of 3.0 (95% confidence interval 1.4–6.3) for the rare qualifying variants. The distributions of qualifying variants in THBD showed a difference for individuals with and without incident VTE indicating a possible position effect.
Rare qualifying THBD variants were associated with VTE, suggesting that rare variants in THBD contribute to development of VTE.
Alpha 2-macroglobulin 5 bp insertion/deletion polymorphism increases the risk of recurrent venous thromboembolism
2018, Gene Reports
Alpha 2-macroglobulin (A2M) is a protease inhibitor that has been reported to neutralize thrombin, which may decrease the risk of thrombosis. A 5-base pairs (bp) insertion/deletion polymorphism (rs3832852) at the splice acceptor site of exon 18 has been shown to affect the binding of A2M with proteases. However, the role of this important variant in A2M in recurrent VTE is unknown. We investigated the role of 5 bp insertion/deletion polymorphism in VTE recurrence in a follow up study. A2M 5 bp insertion/deletion polymorphism was genotyped in Malmö Thrombophilia Study (MATS, n = 1465, with follow up of ~10 years) by TaqMan Allelic Discrimination assay. Univariate Cox regression analysis showed that A2M polymorphism was significantly associated with higher risk of VTE recurrence (hazard ratio [HR] = 2.61, 95% confidence interval [CI] = 1.06–6.45, P = 0.037). This association remained significant (HR = 2.61, 95% CI = 1.06–6.47, P = 0.038) even after adjusting for sex, family history of VTE, thrombophilia and acquired risk factors for VTE. In conclusion, our results indicate that patients with A2M 5 bp insertion/deletion polymorphism are at significantly higher risk of VTE recurrence and this may predict VTE recurrence.
Fat mass and obesity-associated gene rs9939609 polymorphism is a potential biomarker of recurrent venous thromboembolism in male but not in female patients
2018, Gene
Multiple genetic variations have been identified in FTO (fat mass and obesity-associated) gene. Among them, FTO rs9939609 polymorphism is shown to be associated with the risk of primary venous thromboembolism (VTE). However, its role in recurrent VTE is not known. The aim of our study was to investigate the association between FTO rs9939609 polymorphism and the risk of VTE recurrence in a prospective follow-up study in both male and female patients. FTO rs9939609 polymorphism (T/A) was analyzed in the Malmö thrombophilia study (MATS, followed for ~10 years) by using TaqMan PCR. MATS patients (n = 1050) were followed from the discontinuation of anticoagulant treatment until diagnosis of VTE recurrence or the end of follow-up. A total of 126 patients (12%) had VTE recurrence during follow-up. Cox regression analyses showed that sex modified the potential effect of FTO rs9939609 polymorphism on VTE recurrence. Male patients with the AA genotype for the FTO rs9939609 polymorphism had significantly higher risk of VTE recurrence as compared to the TT or AT genotypes (univariate hazard ratio [HR] = 2.05, 95% confidence interval [CI] = 1.2–3.5, P = 0.009 and adjusted HR = 2.03, 95% CI 1.2–3.6, P = 0.013). There was no association between FTO rs9939609 polymorphism and VTE recurrence in female patients. In conclusion, our results show that FTO rs9939609 polymorphism in recurrent VTE may differ according to gender and FTO polymorphism may predict VTE recurrence in male patients.
A sibling based design to quantify genetic and shared environmental effects of venous thromboembolism in Sweden
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Totally 881,206 FS pairs and 95,198 HS pairs were included. The full model predicted heritability for VTE with 47% for males and 40% for females. Environmental factors shared by siblings contributed to 0% of the variance in liability for both sexes, and unique environment (E) components accounted for 53% in males and 60% in females.
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Subject codes: Genetics, epidemiology, thrombosis, cardiovascular disease, embolism

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Regular ArticleProspective analysis of risk factors and distribution of venous thromboembolism in the population-based Malmö Thrombophilia Study (MATS)

Abstract

Background

Objective

Methods

Results

Conclusion

Section snippets

Background

Patients

Results

Discussion

Conflict of interest statement

J Thromb Haemost

Lancet

J Vasc Surg

J Thromb Haemost

J Thromb Haemost

J Heart Lung Transplant

Chest

Blood

Am J Med

Am J Med

J Thromb Haemost

J Thromb Haemost

Chest

Venous thromboembolism in patients with colorectal cancer: incidence and effect on survival

J Clin Oncol

Incidence of venous thromboembolism and the impact on survival in breast cancer patients

J Clin Oncol

Low incidence of deep vein thrombosis after knee arthroscopy without thromboprophylaxis: a prospective cohort study of 335 patients

Acta Orthop

Risk factors for venous thrombotic disease

Thromb Haemost

Risk factors for venous thromboembolism

Circulation

A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study

Arch Intern Med

Regular Article
Prospective analysis of risk factors and distribution of venous thromboembolism in the population-based Malmö Thrombophilia Study (MATS)