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Keywords:

  • atherosclerosis;
  • deep vein thrombosis;
  • prospective study;
  • pulmonary embolus

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References

Summary. Background: Whether atherosclerotic disease predisposes to venous thrombosis is uncertain. Objective: To determine whether subclinical atherosclerosis, manifested as increased carotid intima-media thickness (IMT) or presence of carotid plaque, is associated with increased incidence of venous thromboembolism (VTE). Patients and methods: The Atherosclerosis Risk in Communities study is a prospective cohort of adults aged 45–64 years, examined at baseline (1987–89) and followed for cardiovascular events. Bilateral carotid ultrasound for IMT measurements was done at baseline for portions of the common and internal carotid arteries, and carotid bifurcation and also to detect the presence of carotid plaque. Exclusion criteria included baseline anticoagulant use, history of coronary heart disease, stroke, or VTE, and incomplete data. First VTE during follow-up was validated using abstracted medical records. Results: Among 13 081 individuals followed for a mean of 12.5 years, 225 first VTE events were identified. Unadjusted hazard ratios (HR) (95% CI) of VTE across quartiles of baseline IMT were 1.0, 1.16 (0.77–1.75), 1.64 (1.12–2.40), and 1.52 (1.03–2.25). However, this association disappeared after adjustment for age, sex, and ethnicity (HRs: 1.0, 1.06, 1.40, and 1.18). Further adjustment for body mass index and diabetes weakened the relative risks even further. Presence of carotid plaque at baseline also was not associated with VTE occurrence; adjusted HR = 0.97, 95% CI = 0.72–1.29. Conclusion: Increased carotid IMT or presence of carotid plaque was not associated with an increased incidence of VTE in this middle-aged cohort, suggesting subclinical atherosclerosis itself is not a VTE risk factor.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References

Venous thromboembolism (VTE), usually manifested clinically as deep vein thrombosis (DVT) or pulmonary embolism (PE), reflects a culmination of prothrombotic risk factors leading to thrombosis. There are many well-established risk factors for VTE that are considered acquired or inherited [1,2]. The acquired factors include such things as prolonged immobility, surgery, estrogen exposure (pregnancy, oral contraceptives, and hormone replacement therapy), trauma, malignancy, advancing age, and the lupus anticoagulant. Additionally, the factor (F) V Leiden mutation, prothrombin 20210A gene mutation, elevated levels of FVIII, activated protein C (PC) resistance, and deficiencies of antithrombin, PC, and protein S are all inherited factors proven to predispose to VTE.

A proportion of VTE events occur in patients who are not found to have any of the known inherited or acquired risk factors. These idiopathic cases make up to approximately 50% of VTE events in various investigations [3–5]. Not only do the known risk factors fail to account for all VTE cases, but in different individuals with the same risk factors, some develop VTE while the others do not, suggesting additional processes contribute to risk in those who develop VTE. Furthermore, it is unclear why age and obesity are independently associated with increased risk for VTE despite adjustment for other risk factors associated with these conditions (such as immobility, surgery, or concurrent morbidities) [5,6]. Atherosclerosis could plausibly contribute to the etiology of these cases, as atherosclerotic arteries display coagulation system activation by stimulation of platelets and hemostatic factors. Several studies have demonstrated hemostatic marker elevation in individuals who have or are prone to develop coronary heart disease (CHD). Fibrinogen, von Willebrand factor (VWF) antigen, tissue plasminogen activator antigen, D-dimer, and FVII activity were all elevated in subjects with a history of ischemic CHD, and fibrinogen and D-dimer independently predicted an increased risk of future cardiac and cerebral events [7–12]. Moreover, subjects with peripheral arterial disease had elevated fibrinogen and D-dimer levels in several investigations [13–15]; such patients also may have diminished venous flow due to compromised arterial flow.

It is possible that this coagulation system activation acts systemically to trigger clot formation in the venous circulation or that generalized coagulation system activation promotes both VTE and atherosclerotic diseases. The few studies exploring a possible association between atherosclerosis and venous thrombosis suggest a possible link. In a prospective study, Libertiny and Hands found that subjects suffering from symptomatic peripheral arterial disease with a decreased ankle-brachial index had an increased risk of venous thrombotic events [16]. In a case–control evaluation by Hong et al. [17] there was a higher prevalence of coronary artery calcification found in subjects with VTE compared to controls without VTE. A case–control study by Prandoni et al. [18] reported a higher prevalence of carotid plaques in patients with VTE compared with thrombosis-free controls. To prospectively evaluate this question, we evaluated the incidence of VTE in subjects with subclinical atherosclerosis [measured by carotid intima-media thickness (IMT) and presence of plaque]. Increased carotid IMT is a reliable marker of early and developing atherosclerosis and is associated with traditional cardiovascular disease (CVD) risk factors as well as CHD and stroke incidence [19,20].

Patients and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References

Participants

The Atherosclerosis Risk in Communities (ARIC) Study is a prospective, multi-center investigation of the natural history, etiology, and clinical manifestations of atherosclerotic disease in men and women from four communities: Forsyth County, NC; Jackson, MS; the northwest suburbs of Minneapolis, MN; and Washington County, MD [21]. The entire ARIC cohort consists of 15 792 subjects, aged 45–64 years, who were recruited between 1987 and 1989 for baseline examination that included studies to detect the presence of atherosclerosis and to evaluate atherosclerotic risk factors. Informed consent was obtained from each participant and the respective institutional review board approvals were obtained at each site. Subjects underwent up to three post-baseline examinations at 3 years intervals and continue to be followed for occurrence of cardiovascular and cerebrovascular events, including VTE.

Baseline assessments

High resolution B-mode ultrasound (Biosound 2000 II SA; Biosound, Indianapolis, IN, USA) was used to measure IMT bilaterally in the extracranial carotid arteries, in the areas of the common carotid artery (1 cm proximal to the dilatation of the carotid bulb), the carotid bifurcation (1 cm proximal to the flow divider), and the internal carotid artery (1 cm distal to the flow divider). Standardized protocols for scanning and reading were used based on a technique validated by Pignoli et al. [22]. To enhance the reproducibility of carotid artery measurements standardized interrogation angles were used. Centralized training, certification, and quality control programs were implemented for both the sonographers and the readers to ensure reliability and validity of these measurements. Detailed descriptions of the ultrasound scanning and reading techniques are described in ARIC Manual No. 6 [23]. The mean IMT values at the six carotid sites were combined to produce an overall mean IMT. In case of missing data at any of the six carotid sites, maximum likelihood techniques were used to estimate the mean carotid IMT. Correlations between scans at different visits 7–10 days apart, performed by different sonographers and read by different readers were 0.77, 0.73, and 0.70 for the bifurcation, internal and common carotid, respectively.

The presence of atherosclerotic plaque was recorded qualitatively by the ultrasound readers at any of the six segments during carotid B-mode ultrasound measurement. Plaques were defined as wall thickness in excess of 1.5 mm or the presence of lumen encroachment or irregular intimal surface and/or image characteristics indicative of structural heterogeneity of the arterial wall [24]. The reproducibility in identifying the presence or absence of a plaque in any of the six artery segments, measured by Cohen's kappa statistic on blinded rereading was 0.76 for intra-reader agreement and 0.56 for inter-reader agreement.

Body mass index (BMI; kg m−2) was computed from height and weight obtained at baseline. Diabetes was defined as fasting plasma glucose level greater than or equal to 7 mmol L−1 (126 mg dL−1), a non-fasting plasma glucose level greater than or equal to 11.1 mmol L−1 (200 mg dL−1), self-reported physician diagnosis of diabetes, or pharmacologic treatment of diabetes. Medication use was assessed by questionnaire. FVIII and VWF were measured as previously described [11].

VTE ascertainment

VTE events were identified through December 31, 2001. The ARIC cohort was followed at clinic visits every 3 years, annual telephone calls, and surveillance of community hospitals. Hospitalizations were identified by participant report and systematic search of local hospital discharges for cohort members. For all hospitalizations, International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) discharge codes were recorded and used to identify possible cases of thrombosis.

Information from hospital records and records from hospitalizations within 3 months of a potential admission for VTE were reviewed independently by two physicians; differences in VTE classification were resolved by discussion [5]. Clinical diagnoses without objective tests were not validated as cases. Definite DVT was defined as a positive duplex ultrasound or venogram or, in rare cases, by computed tomography. Probable DVT required a positive Doppler ultrasound or impedance plethysmography. PE was classified using results of ventilation/perfusion scans, angiography, computed tomography or, rarely, autopsy. Indeterminate scans without angiograms, and positive perfusion scans without ventilation scans, were not considered cases. VTEs were classified as idiopathic or secondary (occurring within 90 days of major trauma, surgery, or marked immobility, or associated with active cancer or chemotherapy), and first or recurrent.

Ascertainment of first arterial CVD events during follow-up

First CHD and stroke events were ascertained using standardized ARIC protocols [25,26]. CHD included fatal or non-fatal hospitalized myocardial infarction (MI), fatal CHD, silent MI identified by electrocardiography, or coronary revascularization. Stroke events were classified using hospital record information according to a computer algorithm, and an expert reviewer independently classified each eligible case using criteria adapted from the National Survey of Stroke [27]; disagreements were adjudicated by a second expert physician.

Data analysis

Statistical analysis  Of 15 792 participants, those with the following baseline characteristics were excluded: history of CHD (n = 1110) or stroke (n = 310), ethnicity other than African-American or white (n = 44), non-whites at the Minnesota or Maryland field centers (n = 49), history of VTE at baseline (n = 233), anticoagulant use (n = 28), and missing IMT data (n = 937). The remaining 13 081 participants used in the analysis contributed a total of 165 428 person-years of follow-up. Follow-up time started at the baseline examination and ceased when any of the following occurred: incident VTE, death, loss to follow-up, or else December 31, 2001.

Participant characteristics by carotid IMT quartiles were compared using analysis of variance. Proportional hazards regression models were used to calculate hazard rate ratios of VTE in the upper three quartiles of IMT using the lowest quartile of IMT as the reference. Variables found to be risk factors for VTE in LITE in a previous analysis (age, race, sex, BMI, diabetes, FVIII, and VWF) [28,29], and therefore likely to confound the association of IMT with VTE occurrence, were chosen as covariates. In addition, the same analyses were repeated with carotid plaque (present, absent) as the independent variable. Because our primary analysis investigated the association between subclinical atherosclerosis (rather than overt, symptomatic disease) and VTE, we considered in a subsequent model whether arterial CVD (CHD or stroke) occurring before VTE during follow-up was associated with VTE.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References

Thirty-three per cent of participants had a carotid plaque. Characteristics of participants in each carotid IMT quartile are given in Table 1. Compared to the other three quartiles, participants in the highest quartile of mean IMT were more likely to be male and have diabetes, and they had a higher mean BMI, FVIII and VWF concentrations. Participants in the highest IMT quartile also had more arterial CVD events during follow-up.

Table 1.   Characteristics of Atherosclerosis Risk in Communities (ARIC) subjects by quartiles of carotid intima-media thickness (IMT)*, ARIC Study
CharacteristicMean carotid IMT quartile
1 (0.372–0.619 mm)2 (0.619–0.700 mm)3 (0.700–0.806 mm)4 (0.806–2.284 mm)
  1. *All variables were measured at baseline except arterial cardiovascular disease (CVD) during follow-up. A test of overall difference in each characteristic among IMT quartiles was statistically significant (P < 0.01) for all characteristics.

n3270327032713270
Age (mean, years)51.653.254.556.6
Sex (% male)26.237.449.560.6
Race (% white)77.472.273.773.7
Body mass index (mean, kg m−2)26.227.328.028.0
Diabetes (%)5.68.411.515.6
Factor VIII (mean, %)128129131132
von Willebrand factor (mean, %)112115118121
Arterial CVD event during follow-up (%)3.77.19.916.2
Any carotid plaque (%)11.919.232.468.0

A first VTE occurred in 225 participants (95 idiopathic, 130 secondary). Across quartiles of IMT the age-adjusted incidence rate of VTE (per 1000 person-years) was 1.12, 1.20, 1.58, and 1.31. Table 2 presents crude and multivariate adjusted HR for VTE (95% CI) by quartiles of IMT. Compared with those in the lowest quartile of mean baseline carotid IMT, the crude HR for quartiles two through four of IMT were 1.16, 1.64, and 1.52. However this association disappeared after adjustment for age, sex, and ethnicity (Table 2). There still was no association between VTE and IMT with further adjustment for BMI and diabetes. This was true for men and women, separately, and for idiopathic VTE. Further adjustment for FVIII and VWF had no impact on the HR. Of note, in the multivariate model, age and BMI were associated with VTE, with VTE incidence increasing 7% per year of age and 7% per kg m−2 greater BMI.

Table 2.   Hazard ratios (95% CI) of venous thromboembolism by quartiles of carotid IMT and by presence or absence of carotid plaque, ARIC Study, 1987–2001
ModelHRs by quartile of mean IMTHRs by plaque status
1234No plaquePlaque
  1. *Adjusted for age (continuous), sex, race (Caucasian, African-American), BMI (continuous), diabetes (yes, no). Sex was not included as a covariate in sex-specific models. BMI, body mass index; HR, hazard ratios; IMT, intima media thickness, VWF, von Willebrand factor.

Crude1.001.16 (0.77–1.75)1.64 (1.12–2.40)1.52 (1.03–2.25)1.001.09 (0.82–1.43)
Adjusted for age, race, and sex1.001.06 (0.70–1.60)1.40 (0.95–2.08)1.18 (0.78–1.79)1.000.95 (0.72–1.26)
Adjusted for age, race, sex, diabetes, BMI1.000.98 (0.65–1.49)1.27 (0.85–1.88)1.00 (0.65–1.53)1.000.97 (0.72–1.29)
Also adjusted for factor VIII and VWF*1.001.01 (0.66–1.53)1.29 (0.87–1.91)1.06 (0.70–1.62)1.000.99 (0.74–1.32)
Idiopathic only*1.001.22 (0.61–2.43)1.63 (0.85–3.13)1.51 (0.77–2.98)1.000.85 (0.55–1.34)
Men only*1.000.94 (0.45–1.96)1.15 (0.59–2.25)0.81 (0.40–1.61)1.000.92 (0.60–1.41)
Women only*1.000.99 (0.59–1.65)1.30 (0.79–2.13)1.19 (0.69–2.04)1.001.02 (0.69–1.50)

We conducted a further analysis using greater IMT cutpoints. Adjusted for age, sex, ethnicity, BMI, and diabetes, the VTE hazards ratio for IMT greater than, vs. less than, the 90th percentile was 0.82 (95% CI 0.53–1.26) and for greater than, vs. less than, the 95th percentile was 1.14 (95% CI 0.87–1.88). Results based on carotid plaque status (Table 2) were similar: no association was found between the presence of carotid plaque and subsequent VTE development (multivariately adjusted HR = 0.97, 95% CI 0.72–1.29).

We next added to the multivariate model of IMT and VTE a variable indicating the occurrence of first CHD or stroke event during follow-up (yes, no). First arterial CVD event was significantly associated with development of subsequent VTE (HR = 1.51, 95% CI 1.01–2.25).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References

Our study did not find an association between subclinical carotid atherosclerosis, as reflected by increased carotid IMT and/or the presence of carotid plaque, and incidence of VTE. These results contrast with those from Prandoni et al. [17], who studied VTE in relation to carotid plaque detected by ultrasound. In that study, patients with unexplained VTE (n = 299) demonstrated a 2-fold higher prevalence of carotid plaque compared with patients who had secondary VTE and with non-VTE controls. That investigation was a cross-sectional analysis of non-fatal cases of VTE compared with hospital controls; risk factors were measured after hospitalization. In contrast, our prospective study associated potential baseline risk factors with first VTE, fatal or non-fatal. A limitation of a prospective study of VTE, like ours, is the inability to measure confounding factors associated with both VTE and arterial CVD that are variable and happen to occur shortly before a VTE event.

We did find a significant positive association between arterial CVD events during follow-up and VTE. Thus, atherosclerosis itself may not predict an increased risk for VTE development, but conditions resulting from atherosclerosis (e.g. MI or stroke) may predispose to VTE because of the potential for associated morbidity, hospitalizations, surgery, and immobility. In addition, the instability of the atherosclerotic plaque may be the important factor in VTE risk, a characteristic not measured by ultrasound imaging. Atherosclerosis that is progressive and unstable could lead to endothelial damage and coagulation system activation systemically thereby promoting thrombus formation in the veins.

In conclusion, the presence of subclinical atherosclerosis, indexed by ultrasonographically assessed carotid IMT and carotid plaque, was not associated with VTE incidence in this prospective cohort study.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References

The ARIC Study was funded by contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022 from the U.S. National Heart, Lung, and Blood Institute. Dr Reich was supported by training grant # HL-007062–27 from the National Heart, Lung, and Blood Institute. The authors thank the staff and participants in the ARIC Study for their important contributions to this work.

Disclosure of Conflict of Interests

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References

The authors state that they have no conflict of interest.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References
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