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Keywords:

  • atherosclerosis;
  • family history;
  • risk factors;
  • venous thrombosis

Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Disclosure of Conflict of Interests
  8. References

Summary. Background: Recent studies indicate that arterial cardiovascular diseases and venous thromboembolism (VTE) share common risk factors. A family history of myocardial infarction (MI) is a strong and independent risk factor for future MI. Objectives: The purpose of the present study was to determine the impact of cardiovascular risk factors, including family history of MI, on the incidence of VTE in a prospective, population-based study. Patients and methods: Traditional cardiovascular risk factors and family history of MI were registered in 21 330 subjects, aged 25–96 years, enrolled in the Tromsø study in 1994–95. First-lifetime VTE events during follow-up were registered up to 1 September 2007. Results: There were 327 VTE events (1.40 per 1000 person-years), 138 (42%) unprovoked, during a mean of 10.9 years of follow-up. In age- and gender-adjusted analysis, age [hazard ratio (HR) per decade, 1.97; 95% confidence interval (CI), 1.82–2.12], gender (men vs. women; HR, 1.25; 95% CI, 1.01–1.55), body mass index (BMI; HR per 3 kg m−2, 1.21; 95% CI, 1.13–1.31), and family history of MI (HR, 1.31; 95% CI, 1.04–1.65) were significantly associated with VTE. Family history of MI remained a significant risk factor for total VTE (HR, 1.27; 95% CI, 1.01–1.60) and unprovoked VTE (HR, 1.46; 95% CI, 1.03–2.07) in multivariable analysis. Blood pressure, total cholesterol, HDL-cholesterol, triglycerides, and smoking were not independently associated with total VTE. Conclusions: Family history of MI is a risk factor for both MI and VTE, and provides further evidence of a link between venous and arterial thrombosis.

Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common disease, with serious short- and long-term complications, and a potential fatal outcome [1]. It affects 1–3 per 1000 adults each year [1,2], and is the third most common cardiovascular disease [3]. Although surgery, trauma, hospitalization, malignancy, immobilization, pregnancy, use of oestrogens, and inherited thrombophilia are associated with VTE [1,4], approximately 30–50% of the events occur in the absence of obvious predisposing factors [5].

The concept that VTE and atherosclerotic cardiovascular diseases are two distinct disease entities has recently been challenged. A higher frequency of carotid plaques in patients with idiopathic VTE has been reported [6]. The long-term incidence of cardiovascular disease is reported to be substantially increased in patients with VTE, compared to population controls [7]. A recent meta-analysis, based on selected prospective studies and case–control studies with verified endpoints, concluded that cardiovascular risk factors were associated with VTE [8]. However, prospective studies on the relation between traditional cardiovascular risk factors and VTE show diverging results. In the Nurses’ Health Study, obesity, cigarette smoking, and hypertension, but not diabetes or elevated cholesterol, were independent predictors for PE [9]. In the Physicians’ Health Study [3], only body mass index (BMI) and height were identified as independent risk factors for VTE, whereas smoking and abdominal obesity were predictors for VTE in another study on middle-aged men [10]. In the LITE-study, obesity and diabetes, but not cigarette smoking, hypertension, and dyslipidemia, showed independent association to VTE [11]. In the Copenhagen City Heart Study, total cholesterol, HDL-cholesterol (inverse), diabetes, and smoking were associated with VTE [12]. These studies suggest that VTE and cardiovascular disorders may share some common risk factors, and that VTE may occur as the first cardiovascular event in some patients at risk for atherosclerosis.

A family history of myocardial infarction (MI) is a strong and independent risk factor for future MI [13] and death from cardiovascular disease [14]. Family history of MI had synergistic interactions on risk for cardiovascular disease, together with smoking and dyslipidemia [15,16]. To the best of our knowledge, no study has investigated family history of MI as a risk factor for VTE. To address this question, we performed a prospective, population-based study and assessed the impact of traditional cardiovascular risk factors, including family history of MI, on the incidence of VTE.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Disclosure of Conflict of Interests
  8. References

Study population

Participants were recruited from the fourth survey of the Tromsø study (conducted in 1994–95), a single-centre prospective, population-based study, with repeated health surveys of inhabitants in Tromsø, Norway. All inhabitants aged >24 years were invited, and 27 158 (77% of the eligible population) participated. The study was approved by the regional committee for research ethics, and all participants gave their informed written consent to participate. Subjects who did not consent to medical research (n = 300), and subjects not officially registered inhabitants of the municipality of Tromsø at baseline (n = 43), were excluded from the study. Furthermore, subjects with a known history of VTE (n = 46), and subjects with missing values for blood pressure, BMI, triglycerides, total cholesterol, HDL-cholesterol, smoking, self-reported diabetes (n = 264), or family history of MI (n = 5175), were excluded. Thus, a total of 21 330 subjects were included in the study, and followed from the date of enrolment in 1994–95 through the end of the study period, 1 September 2007.

Cardiovascular risk factors

Baseline information on cardiovascular risk factors was collected by physical examinations, blood samples, and self-administered questionnaires. Blood pressure was recorded with an automatic device (Dinamap Vital Signs Monitor, 1846, Critikon Inc., Tampa, FL, USA), by specially trained personnel. Participants rested for 2 min in a sitting position, and then three readings were taken on the upper right arm, separated by 2-min intervals. The average of the two last readings was used in the analysis. Height and weight were measured with subjects wearing light clothing and no shoes. The BMI was calculated as weight in kilograms, divided by the square of height in meters (kg m−2). Non-fasting blood samples were collected from an antecubital vein, serum prepared by centrifugation after 1 h respite at room temperature, and further analyzed at the Department of Clinical Chemistry, University Hospital of North Norway. Serum total cholesterol and triglycerides were analyzed by enzymatic, colorimetric methods, and commercially available kits (CHOD-PAP for cholesterol, and GPO-PAP for triglycerides: Boeringer Mannheim, Mannheim, Germany). Serum HDL-cholesterol was measured after precipitation of lower-density lipoproteins with heparin and manganese chloride. Information on self-reported diabetes, current smoking, and family history of MI was collected from a self-administered questionnaire. To identify family history of MI, subjects were asked to report whether their mother, father, sister, brother, child, or none in the family had a history of MI before the age of 60 years. Positive family history was regarded as one or more first degree relatives with a history of MI before the age of 60 years.

Outcome assessment

All first-lifetime events of VTE during follow-up were identified by searching the computerized index of medical diagnoses, the autopsy register, and the radiology procedure register at the University Hospital of North Norway. The University Hospital of North Norway is the only hospital in the region, and all hospital care and relevant diagnostic radiology in the Tromsø community are provided exclusively by this hospital. The relevant discharge codes were ICD-9 codes 325, 415.1, 451, 452, 453, 671.3, 671.4, 671.9, for the period 1994–98, and ICD-10 codes I26, I80, I81, I82, I67.6, O22.3, O22.5, O87.1, O87.3 for the period 1999–2007. The index of medical diagnoses included diagnoses from outpatient clinic visits and hospitalizations. An additional search through the computerized index of autopsy diagnoses was conducted, and cases diagnosed with VTE, either as a cause of death (part one of the death certificate), or as a significant condition (part two of the death certificate), were identified. We also searched the radiology database to identify potential cases of objectively confirmed VTE that may have been missed because of coding errors in the index of medical diagnoses. All relevant diagnostic procedures performed at the Department of Radiology, to diagnose VTE during the 13-year period, were systematically reviewed by trained personnel, and cases with objectively confirmed VTE were identified.

The medical records for each potential VTE case, derived from the medical diagnostic index, the autopsy register, or the radiology procedure register, were reviewed by trained personnel. The personnel were blinded to the baseline variables, including family history of MI. For subjects derived from the medical diagnostic index and the radiology procedure register, an episode of VTE was verified and recorded as a validated outcome when all four of the following criteria were fulfilled: (i) objectively confirmed by diagnostic procedures (compression ultrasonography, venography, spiral-CT, perfusion-ventilation scan, pulmonary angiography or autopsy); (ii) the medical record indicated that a physician had made a diagnosis of DVT or PE; (iii) signs and symptoms consistent with DVT or PE were present; (iv) the patient underwent therapy with anticoagulants (heparin, warfarin, or a similar agent) thrombolytics, or vascular surgery. For subjects derived from the autopsy registry, a VTE event was recorded as an outcome when the autopsy record indicated VTE as cause of death or as a significant condition.

A VTE event was further classified as unprovoked or provoked, based on the presence of provoking factors at the time of diagnosis. A VTE occurring without any provoking factor was defined as unprovoked, and a VTE occurring in the presence of one or more provoking factors was defined as provoked. The following were regarded as provoking factors: recent surgery or trauma (within eight weeks before the event), acute medical condition (acute MI, acute ischemic stroke, major infectious disease), cancer, marked immobilization (bed rest > 3 days, wheelchair patients, long distance travel ≥4 h within the last 14 days), or other potential provoking factor, described by a physician in the medical record (e.g. intravascular catheter).

Statistical analyses

For each participant, person-years of follow-up were accrued from the date of enrolment in the Tromsø study (1994–95), to the date a VTE event was first diagnosed, the date the participant died or moved from the municipality of Tromsø, or to the end of the study period (1 September 2007). During the study period, 3086 subjects moved from the municipality of Tromsø, and 1736 subjects died.

Statistical analysis was carried out using SPSS version 15.0 (SPSS Inc., Chicago, IL, USA). The significance level was 0.05. Incidence rates with 95% confidence interval (CI) were calculated for various levels of the potential risk factors. Age and BMI were categorized into three intervals (age: <50, 50–69, and ≥70 years; BMI: <25, 25–29, and ≥30 kg m−2). Blood pressure, total cholesterol, triglycerides, and HDL-cholesterol were categorized into quartiles. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) for VTE by the level of each risk factor. A multivariable Cox model was used to identify factors independently associated with total VTE (unprovoked + provoked) and unprovoked VTE. The proportional hazard assumption was verified, by evaluating the parallelism between the curves of the log–log survivor function for different categories of the variables.

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Disclosure of Conflict of Interests
  8. References

Mean age was 45 ± 14 years, and 11 212 (52.6%) were women. There were 327 validated, first VTE events during 233 089 person-years of follow-up (mean 10.9 years). The overall crude incidence rate of VTE was 1.40 per 1000 person-years. The incidence rate increased markedly with age, and there were no major differences between men and women in subjects younger than 60 years. In subjects aged 60–69 years, the incidence was higher in men than in women (P = 0.05; Fig. 1). Subject characteristics are shown in Table 1.

image

Figure 1.  Line graph showing the incidence of venous thromboembolism (VTE) in men and women with increasing age: the Tromsø study 1994–2007.

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Table 1.   Baseline characteristics of subjects enrolled in the Tromsø study (1994–95)
  1. Values are means ± 1 standard deviation, or percentage with numbers in brackets.

Age (years)45 ± 14
Gender (% women)52.6 (11 212)
Body mass index (kg m−2)25.1 ± 3.8
Systolic blood pressure (mmHg)133 ± 20
Diastolic blood pressure (mmHg)78 ± 12
Triglycerides (mmol L−1)1.52 ± 1.00
Total cholesterol (mmol L−1)5.99 ± 1.29
HDL-cholesterol (mmol L−1)1.50 ± 0.41
Smoking (%)36.3 (7735)
Self-reported diabetes (%)1.4 (305)
Family history of myocardial infarction (%)24.9 (5312)

Characteristics of the VTE events are shown in Table 2. Among the subjects with incident VTE, 64.5% had DVT and 35.5% had PE, with or without concurrent DVT (Table 2). A total of 138 events (42.2%) were unprovoked (Table 2). Cancer was the most common provoking factor, and 22% of the patients with VTE had active cancer at the time of diagnosis (Table 2).

Table 2.   Characteristics of venous thromboembolism (VTE) events (n = 327): the Tromsø study (1994–2007)
 % (n)
  1. *Family history of VTE (in first degree relative before 60 years of age). †Other diseases within the previous year (myocardial infarction, ischemic stroke, heart failure, inflammatory bowel disease, chronic infections, chronic obstructive pulmonary disease, or myeloproliferative disorders). ‡Other provoking factors described by a physician in the medical record (e.g. intravascular catheter).

Deep vein thrombosis64.5 (211)
Pulmonary embolism35.5 (116)
Unprovoked42.2 (138)
Clinical risk factors
 Estrogens (HRT, oral contraceptives)7.0 (23)
 Heredity*2.8 (9)
 Pregnancy0.6 (2)
 Other medical conditions†19.3 (63)
Provoking factors
 Surgery18.3 (60)
 Trauma7.3 (24)
 Acute medical conditions15.6 (51)
 Cancer22.0 (72)
 Immobilization (bed rest > 3 days, wheelchair)16.8 (55)
 Other‡4.6 (15)

Table 3 summarizes crude incidence rates and age- and gender-adjusted HRs for VTE by various levels of cardiovascular risk factors. Age was significantly associated with increased risk of VTE. Subjects 70 years or older had an elevenfold higher risk of VTE (HR, 11.33; 95% CI, 8.32–15.42), compared to those younger than 50 years of age. Men had a significantly higher risk of VTE than women (HR, 1.25; 95% CI, 1.01–1.55). The incidence rate of VTE increased linearly from 0.9 to 2.7 over the three categories of BMI, and obese individuals (BMI ≥ 30 kg m−2) had an almost 2-fold increased risk of VTE (HR, 1.92; 95% CI, 1.41–2.63) compared to those with BMI lower than 25 kg m−2 (Table 3). Neither systolic nor diastolic blood pressure was associated with increased risk of VTE. Test for trends in HRs were borderline significant for quartiles of triglycerides (P = 0.08) and total cholesterol (P = 0.08), whereas HDL-cholesterol showed no association with VTE (P = 0.9; Table 3). Smoking was not associated with VTE (HR, 1.04; 95% CI, 0.82–1.33). The incidence rate of VTE in subjects with self-reported diabetes was 3.71 compared to 1.37 in subjects without diabetes, and the risk of VTE by diabetes was non-significantly 1.4-fold increased (HR, 1.37; 95% CI, 0.74–2.47).

Table 3.   Incidence rates (events per 1000 person-years) of venous thromboembolism (VTE) by risk factor status, and age- and gender-adjusted hazard ratios for VTE: the Tromsø study
 VTE eventsPerson-yearsIncidence rate (95% confidence interval) Hazard ratio (95% confidence interval)
Age (years)
 <5084154 7810.54 (0.44–0.67)1.00
 50–6916464 4492.54 (2.18–2.97)4.69 (3.61–6.10)
 ≥707913 8595.70 (4.57–7.11)11.33 (8.32–15.42)
Gender
 Female161123 3671.31 (1.12–1.53)1.00
 Male166109 7221.51 (1.30–1.76)1.25 (1.01–1.55)
Body mass index (kg m−2)
 <25113125 0300.90 (0.75–1.09)1.00
 25–2915184 8051.78 (1.52–2.09)1.44 (1.13–1.85)
 ≥306323 2542.71 (2.12–3.47)1.92 (1.41–2.63)
Systolic blood pressure (mmHg)
 <1204455 7240.79 (0.59–1.06)1.00
 120–1305463 6660.85 (0.65–1.11)0.87 (0.58–1.30)
 131–1427955 8321.41 (1.13–1.76)1.11 (0.76–1.62)
 ≥14315057 8682.59 (2.21–3.04)1.02 (0.71–1.48)
Diastolic blood pressure (mmHg)
 <705460 6710.89 (0.68–1.16)1.00
 70–765256 9360.91 (0.69–1.19)0.77 (0.53–1.14)
 77–848257 1401.44 (1.16–1.79)0.93 (0.66–1.33)
 ≥8513958 3422.38 (2.02–2.81)1.08 (0.78–1.51)
Triglycerides (mmol L−1)
 <0.875558 7050.94 (0.72–1.22)1.00
 0.87–1.246957 2551.21 (0.96–1.53)1.01 (0.71–1.45)
 1.25–1.879358 7671.58 (1.29–1.94)1.15 (0.82–1.61)
 ≥1.8711058 3621.88 (1.56–2.27)1.28 (0.92–1.78)
Total cholesterol (mmol L−1)
 <5.063856 9390.67 (0.49–0.92)1.00
 5.06–5.855758 1320.98 (0.76–1.27)0.99 (0.66–1.50)
 5.86–6.818958 9291.51 (1.23–1.86)1.10 (0.75 1.63)
 ≥6.8214359 0892.42 (2.05–2.85)1.29 (0.89–1.88)
HDL-cholesterol (mmol L−1)
 <1.218656 3871.53 (1.23–1.88)1.00
 1.21–1.447158 3911.22 (0.96–1.53)0.80 (0.59–1.10)
 1.45–1.749159 8521.52 (1.24–1.87)0.98 (0.73–1.33)
 ≥1.757958 4591.35 (1.08–1.69)0.80 (0.58–1.10)
Smoking
 No227147 8761.53 (1.34–1.74)1.00
 Yes10085 2131.17 (0.96–1.42)1.04 (0.82–1.33)
Self-reported diabetes
 No316230 1241.37 (1.23–1.53)1.00
 Yes1129653.71 (2.05–6.70)1.35 (0.74–2.47)
Family history of myocardial infarction
 No211174 8451.21 (1.06–1.38)1.00
 Yes11658 2441.99 (1.66–2.39)1.31 (1.04–1.65)

The incidence rate of VTE in subjects with family history of MI was 1.91 (95% CI, 1.66–2.39) per 1000 person-years compared to 1.21 (95% CI, 1.06–1.38) in those without family history of MI. Subjects with family history of MI had a significant 1.3-fold increased risk of VTE (HR, 1.31; 95% CI, 1.04–1.65; Table 3).

Table 4 shows multivariable HRs for total and unprovoked VTE. Family history of MI remained significant as a risk factor for both total VTE (HR, 1.27; 95% CI, 1.01–1.60) and unprovoked VTE (HR, 1.46; 95% CI, 1.03–2.07) after adjustments for all the other traditional cardiovascular risk factors (Table 4). The risk of unprovoked VTE increased with increasing number of affected relatives, and subjects with family history of MI in ≥2 first degree relatives had a 1.75-fold increased risk of unprovoked VTE compared to subjects without family history of MI (HR, 1.75; 95% CI, 0.90–3.41). Age (HR per decade, 1.90; 95% CI, 1.74–2.07), male gender (HR, 1.36; 95% CI, 1.08–1.73), and BMI (HR per 3 kg m−2, 1.24; 95% CI, 1.15–1.35) were also significantly associated with VTE in the multivariable model, whereas blood pressure, blood lipids, and smoking showed no association with VTE (Table 4).

Table 4.   Multivariable hazard ratios (HRs) with 95% confidence interval (CI) for venous thromboembolism (VTE): the Tromsø study (1994–2007)
 Total VTEUnprovoked VTE
HR (95% CI)HR (95% CI)
Family history of myocardial infarction (yes/no)1.27 (1.01–1.60)1.46 (1.03–2.07)
Age (decade)1.90 (1.74–2.07)1.80 (1.59–2.06)
Gender (male)1.36 (1.08–1.73)1.44 (1.00–2.07)
Body mass index (3 kg m−2)1.24 (1.15–1.35)1.30 (1.16–1.47)
Smoking (yes/no)1.14 (0.89–1.46)0.95 (0.64–1.40)
Self-reported diabetes (yes/no)1.24 (0.67–2.29)1.08 (0.39–2.96)
HDL-cholesterol (0.5 mmol L−1)1.02 (0.87–1.20)1.26 (1.00–1.60)
Total cholesterol (1 mmol L−1)1.07 (0.97–1.18)1.01 (0.87–1.18)
Triglycerides (1 mmol L−1)0.90 (0.78–1.03)0.95 (0.77–1.17)
Diastolic blood pressure (10 mmHg)0.98 (0.85–1.12)0.89 (0.72–1.10)

Surprisingly, HDL-cholesterol was associated with an increased risk of unprovoked VTE (HR, 1.26; 95% CI, 1.00–1.60; Table 4). Age- and gender-stratified analysis revealed that the increased risk of unprovoked VTE by HDL-cholesterol was highest in women below 50 years of age (data not shown). The increased risk of VTE by HDL-cholesterol in young women was not explained by estrogenic supplementation or menopausal status, as adjustment for these variables did not attenuate the HR.

Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Disclosure of Conflict of Interests
  8. References

Recent studies have suggested that atherosclerotic cardiovascular diseases and VTE share common risk factors [6,8–12,17]. In this study, age, male gender, BMI, and family history of MI were identified as independent risk factors for VTE. Other traditional cardiovascular risk factors, including blood pressure, total cholesterol, and triglycerides were not independent predictors for VTE. Surprisingly, HDL-cholesterol was significantly associated with increased risk of unprovoked VTE in multivariable analysis.

Familial aggregation of coronary heart disease is a strong and independent risk factor for arterial cardiovascular events [13,14]. To the best of our knowledge, we have for the first time identified an association between family history of MI and VTE. The risk of unprovoked VTE in our study was of similar magnitude to arterial cardiovascular events in familial aggregates of cardiovascular diseases [13,14].

A family history of cardiovascular disease has previously been identified as a predictor for subclinical carotid atherosclerosis [18], and as an independent predictor for coronary calcification in young subjects [19]. A higher frequency of carotid plaques [6] and coronary calcification [20] has been reported in patients with VTE. However, the impact of subclinical atherosclerosis as a risk factor for VTE is controversial. A recent prospective study showed a significant association between carotid intima media thickness (IMT) and first episode of VTE, but the association disappeared after adjusting for cardiovascular risk factors [17], whereas no association was observed in subjects above 65 years of age [21]. Atherosclerosis is associated with endothelial dysfunction, coagulation activation, and platelet activation [22], with a subsequent increase in risk of arterial thrombosis [23,24]. Thus, it may be speculated, that underlying endothelial dysfunction, coagulation, and platelet activation are a plausible link between arterial and venous thrombosis by appearing in the slow-flowing venous system. The latter assumption is supported by a prospective study, showing that a first arterial cardiovascular event is associated with subsequent development of VTE [17].

Prospective studies in elderly [21] and middle-aged [17] subjects have failed to confirm subclinical atherosclerosis, as an independent risk factor for VTE. Cardiovascular risk factors, such as smoking and dyslipidemia, had synergistic interactions with family history on the risk for cardiovascular disease [15,16]. In our study, traditional cardiovascular risk factors, including blood pressure, blood lipids, and smoking, were not independent risk factors for VTE, and did not influence family history of MI as a risk factor for VTE in multivariable analysis. These findings indicate that other factors than the atherosclerotic process itself may also contribute to the link between arterial and venous thrombosis. In addition, the sequence of thrombotic events is not predetermined. Patients who have suffered a VTE event are reported to have increased risk of an arterial thromboembolic event during long-term follow-up [7]. Lack of associations with other traditional cardiovascular risk factors, and undetermined sequence of thrombotic events, suggest that increased risk of VTE in subjects with family history of MI is probably a result of genetic and environmental determinants that exert their impact by as yet unknown mechanism(s).

Another possible link between arterial thromboembolism and VTE could be the metabolic syndrome, a cluster of cardiovascular risk factors associated with risk of cardiovascular disease and overall mortality [25,26]. Recent case–control studies have reported a 2-fold higher prevalence of the metabolic syndrome in subjects with idiopathic VTE [27] and recurrent VTE [28] compared to controls. However, this association has not yet been confirmed in prospective studies of general populations.

Some studies [12,29,30] have shown decreased HDL-cholesterol in patients with VTE, suggesting a protective role of HDL-cholesterol on the risk of VTE, a concept supported by the antithrombotic properties of HDL [31]. Other studies [11,32,33], however, were unable to establish any association between HDL-cholesterol and risk of VTE. In contrast to previous studies, HDL-cholesterol was associated with increased risk of unprovoked VTE, and apparently the risk was highest in young women. The finding was not explained by estrogenic supplementation or menopausal status, as adjustments for these variables did not attenuate the HR. The association of HDL-cholesterol and increased risk of unprovoked VTE could possibly be explained by chance, or by unrecognized confounders.

Most previous prospective studies may have limited implications to the general population, as they were carried out in specific population cohorts, such as male physicians, female nurses, middle-aged or elderly [3,9–11], or because no risk assessment for cardiovascular risk factors was performed [12]. Our prospective, population-based cohort study included both male and female subjects above 24 years of age. In agreement with previous studies [9–12], we confirmed that age and BMI were strong and independent risk factors for both total and unprovoked VTE. Obese individuals (BMI ≥ 30 kg m−2) had a 2-fold increased risk of VTE, and subjects above 70 years of age had an elevenfold increased risk of VTE compared to subjects below 50 years of age.

In our study, subjects with self-reported diabetes had a 2.5-fold higher incidence rate of VTE, and a non-significantly 1.4-fold increased risk of VTE. Previous reports from prospective studies are conflicting, with regard to the impact of diabetes on risk of VTE [3,11]. The apparent inconsistency between studies may to some extent rely on different diagnostic criteria for diabetes.

The main strengths of our study are its prospective design, long-term follow-up, and large number of participants and validated VTE events. The study cohort represents a general population, with a wide age structure, because of the high rate of attendance among people in the Tromsø community. All hospital care in the region is exclusively provided by a single hospital, which enhances the possibility of a complete VTE register. However, the study has some limitations. Analyses were restricted to subjects who had provided information on family history of MI. However, the HRs for VTE by the traditional cardiovascular risk factors were essentially identical, when analyzing the complete cohort (data not shown), implying that the selected cohort was representative for the total population. Another possible limitation of the study regards misclassification of family history of MI among those who reported family history. Both under-reporting and over-reporting of affected relatives are possible. In a previous validation study on the reliability of reported family history of MI, Kee et al. [34] demonstrated a high specificity (97%) and a lower sensitivity (68%) of a positive family history of MI. Thus, underestimation of the risk associated with family history of MI is more likely. In our study, several risk factors were modifiable. In general, modifiable risk factors are a potential limitation of cohort studies, especially when the time between exposure and disease manifestation is very long. This type of non-differential misclassification generally leads to underestimation of the true associations. Furthermore, information on concomitant treatment was not available in our study, and thus could not be taken into consideration.

In conclusion, family history of MI as an independent risk factor for VTE provides further evidence for the concept of a link between arterial and venous thrombosis. Traditional cardiovascular risk factors did not seem to be underlying determinants for this association, suggesting that family members share yet unknown genetic or environmental risk factors.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Disclosure of Conflict of Interests
  8. References

CART is supported by an independent grant from Pfizer AS.

Disclosure of Conflict of Interests

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Disclosure of Conflict of Interests
  8. References

The authors state that they have no conflict of interest.

References

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Disclosure of Conflict of Interests
  8. References
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