Familial risk of venous thromboembolism: a nationwide ...

Journal of Thrombosis and Haemostasis, 9: 320–324 DOI: 10.1111/j.1538-7836.2010.04129.x

ORIGINAL ARTICLE

Familial risk of venous thromboembolism: a nationwide
cohort study

H . T . S Ø R E N S E N , * A . H . R I I S , * L . J . D I A Z ,   E . W . A N D E R S E N ,   J . A . B A R O N à § and P . K . A N D E R S E N  
*Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus N;  Department of Biostatistics, University of Copenhagen,
Copenhagen, Denmark; àDepartments of Medicine and Community and Family Medicine, Dartmouth Medical School, Hanover, NH; and
§Department of Medicine, University of North Carolina, Chapel Hill, NC, USA

To cite this article: Sørensen HT, Riis AH, Diaz LJ, Andersen EW, Baron JA, Andersen PK. Familial risk of venous thromboembolism: a nationwide
cohort study. J Thromb Haemost 2011; 9: 320–4.

Summary. Background: Venous thromboembolism has genetic occur in any venous system, but predominantly occurs in the
determinants, but population-based data on familial risks are vessels of the lower limbs. Causes of venous thromboembolism
limited. Objectives: To examine the familial risk of venous primarily involve disturbances in the pathways regulating
thromboembolism. Methods: We undertook a nationwide hemostatis: coagulation, anticoagulation and fibrinolysis [3,4].
study of a cohort of patients with deep venous thrombosis or Well-established clinical risk factors include recent surgery,
pulmonary embolism born after 1952. We used the Danish cancer, fractures, immobilization, recent pregnancy and use of
National Registry of Patients covering all Danish hospitals, for estrogens [3,4].
the years 1977 through 2009, to identify index cases of venous
thromboembolism, and assessed the incidence among their However, during the last decades, genetic factors contributing
siblings. We compared standardized incidence ratios (SIRs) of to the increased risk of venous thromboembolism have been
the observed and expected number of venous thromboembolism discovered [5]. Most of these factors are mutations and
cases among siblings, using population-specific, gender-specific polymorphisms in genes coding for coagulation proteins; the
and age-specific incidence rates. Results: We identified 30 179 first was described by Egeberg [6] in the mid-1960s in a family
siblings of 19 599 cases of venous thromboembolism. The with hereditary antithrombin deficiency. Inherited disorders
incidence among siblings was 2.2 cases per 1000 person-years, havebeendescribedfor protein Candprotein S,andinthe1990s
representing a relative risk of 3.08 (95% confidence interval resistance to protein C caused by a mutation in coagulation FV
[CI] 2.80–3.39) as compared with the general population. The Leiden was reported [7–9]. Subsequent epidemiologic studies
risk was higher for both men (SIR 3.36, 95% CI 2.96–3.82) and have shown that these mutations are risk factors for venous
women (SIR 2.81, 95% CI 2.45–3.23). The risk was similar thromboembolism, although not for recurrence [5,7,8,10].
among siblings of index cases with venous thrombosis and those
of index cases with pulmonary embolism. Conclusion: Venous A few studies have used familial aggregation of thrombosis
thromboembolism has a strong familial component. to measure the extent of genetic disposition [7,11–18]. These
found that first-degree relatives of venous thromboembolism
Keywords: cohort study, epidemiology, familial risk, venous cases are also at increased risk. However, some of the studies
thromboembolism. have been relatively small, covering a few hundred patients
with venous thromboembolism, and all relied on subject-
Introduction reported pedigree information and case reporting, data that are
subject to selection and recall biases, making quantitative
Deep vein thrombosis, with its complications such as pulmo- estimation inaccurate.
nary embolism and post-thrombotic syndrome, is a common
and serious disease, affecting approximately two per 1000 To clarify these issues, we used nationwide population-based
persons per year in Western populations [1,2]. Thrombosis can registries in Denmark to estimate the relative risk of venous
thromboembolism in siblings of patients with the disorder,
Correspondence: Henrik Toft Sørensen, Department of Clinical giving us the opportunity to avoid recall bias and obtain precise
Epidemiology, Aarhus University Hospital, Olof Palmes Alle 43-45, estimates of sibling relative risks.
8200 Aarhus N, Denmark.
Tel.: +45 8942 4827; fax: +45 8942 4801. Methods
E-mail: [email protected]
Study population and design
Received 26 July 2010, accepted 12 October 2010
We based this study on the entire Danish population (of
approximately 5.4 million) and obtained data from two
nationwide population-based registries. We identified all

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Familial risk and venous thromboembolism 321

patients with diagnoses of venous thromboembolism in the We compared the incidence of venous thromboembolism in
Danish National Registry of Patients [19,20], and identified siblings of thromboembolism cases with the incidence in the
their parents and siblings in the Danish Civil Registration general population. The population incidence rates were
System [21–23]. Information on essentially all discharges from computed as the total number of first diagnoses for venous
Danish acute-care hospitals has been recorded in the Danish thromboembolism in a particular year divided by the number
National Registry of Patients since 1977. The recorded data of Danish citizens at the beginning of that year.
include dates of admission and discharge, up to 20 discharge
diagnoses, hospital department codes and the surgical proce- Incidence rates were computed for gender, as well as age
dures performed. Discharge diagnoses were classified according group (0–100 in intervals of 5 years), calendar period (from
to the International Classification of Diseases (ICD), eighth 1975 to 2010, in 5-year periods) and time since diagnosis of the
revision, until the end of 1993, and the 10th revision from 1994 index case (as < 1 year, 1–2 years or ‡ 3 years). The incidence
to 2009. Outpatient and emergency room visits have been rates were multiplied by the corresponding person-years of
recorded in the registry since 1994. The 10-digit Civil Regis- observation to yield the expected numbers of cases. The
tration Number, which is permanent and unique to each number of cases among siblings was divided by the expected
Danish citizen, is also recorded, enabling the compilation of a numbers to give a standardized incidence ratio (SIR).
patientÕs specific discharge history. Data were retrieved for all
persons listed with a diagnosis of venous thrombosis or The person-years at risk and the events were counted for all
pulmonary embolism in the Danish National Registry of combinations of gender, age group, calendar period and time
Patients from 1 January 1977 to 31 December 2009. since index diagnosis, and the SIRs were estimated. We used
Poisson regression with robust (generalized estimating equa-
We defined ÔprovokedÕ venous thromboembolism cases as tions or ÔsandwichÕ) variance estimates, where the families were
those with a diagnosed malignancy before or within 90 days regarded as clusters [25]. If, for example, kgap is the rate of
after the thrombotic event in the Danish National Registry of disease in siblings of gender g, age group a and calendar period
Patients, and those with a diagnosis of fracture, surgery, p, and cgap is the rate of the disease in the general population
trauma or pregnancy within 90 days of hospitalization for for the same values of gender, age and period, then the Poisson
venous thromboembolism. The remaining thromboembolism model is
cohort members were classified as ÔunprovokedÕ [20,24].
kgap ¼ qcgap;
ICD codes for all diagnoses are provided in the Appendix.
Since 1 April 1968, all persons residing in Denmark have and the estimate of q, q^, is the SIR.
been registered with their civil registration number, date of We used the score test to compute P-values for the difference
birth, residency, date of immigration or emigration and date of
death in the Civil Registration System [22]. Parents are also in risk between groups. In a subanalysis, we restricted the study
recorded if the person lived with them in 1968 or later. The population to patients with unprovoked venous thromboem-
completeness of information and the parental civil registration bolism.
numbers increased from 10% from the cohorts born in 1950 to
43% in the 1952 cohort, 99% in the 1960 cohort and 100% for Results
cohorts born after 1970 [21,22]. Adopted children cannot be
identified as such in the registry, and are recorded under their We identified 147 232 persons with a first diagnosis of venous
adopted parents, but the magnitude of this misclassification is thromboembolism within the study period in the Danish
small [22]. For the purposes of our analyses, we defined siblings National Registry of Patients: 86 020 patients with venous
as individuals with the same mother. thrombosis and 61 212 with pulmonary embolism. Of these,
We retrieved data on vital status from the registry from the 22 820 were born after 1952, and for 19 599 (85.8%) we were
period 1 April 1968 to 31 December 2009 for members of the able to identify the mother in the Civil Registration System.
venous thromboembolism cohort, and identified siblings who The prevalence of provoked venous thromboembolism among
could be traced in the Civil Registration System. For each all venous thromboembolism cases was 0.39 before 1994 and
sibship, the person discharged with a diagnosis of venous decreased to 0.33 thereafter. We found a total of 30 179
thromboembolism on the earliest date was designated the index siblings followed for a total of 210 160 person-years. Table 1
case, and the sibling was subsequently followed for disease provides descriptive data of the study population.
occurrence as described below.
The overall incidence of venous thromboembolism in
Statistical analysis siblings of venous thromboembolism cases was 2.2 cases per
1000 person-years, and that in the general population was 0.7
Siblings living in Denmark on the dates of hospital diagnosis of cases per 1000 person-years. Siblings had a three-fold increased
the index cases were followed from those dates (or birth of the risk, with an age-adjusted and sex-adjusted SIR of 3.08 (95%
sibling if later) until a hospital diagnosis for venous thrombo- confidence interval [CI] 2.80–3.39) (Table 2) and an incidence
embolism, emigration, death or the end of the study period, difference of around 1.5 cases per 1000 person-years.
whichever came first.
The SIRs for siblings of male cases was 3.36 (95% CI
2.96–3.82), higher than that for siblings of female cases (2.81,
95% CI 2.45–3.23; P = 0.056). The relative risk differed with
the gender of the index case and of the sibling. For female index

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322 H. T. Sørensen et al

Table 1 Descriptive data for index patients with venous thromboembo- Table 3 Observed and expected numbers of cases of venous thrombo-
lism embolism among siblings of index cases, with standardized incidence ratios
and 95% confidence intervals (CIs), by time since the diagnosis of the
Cohort index case

Deep venous Pulmonary Overall Years Observed Expected Years of Standardized
thrombosis embolism (N = 19 152) since follow-up incidence ratio
(N = 13 765) (N = 5387) diagnosis (95% CI)

Variables N %N %N % < 1 66 15.4 24 936 4.28 (3.36–5.45)
1–2 76 27.9 43 235 2.73 (2.18–3.42)
Age (years) ‡ 3 314 104.6 141 989 3.00 (2.67–3.37)

< 25 2195 15.9 1013 18.8 3208 16.8

25–40 6510 47.3 2452 45.5 8962 46.8

> 40 5060 36.8 1922 35.7 6982 36.5 substantial variation in the incidence differences with age,
varying from 1.02 to 1.66 venous thrombosis cases per 100
Gender person-years. We found a tendency for the SIR to decrease
with increasing follow-up time (P for trend = 0.020) (Table 3).
Females 7309 53.1 2999 55.7 10 308 53.8 Within the first year of follow-up, we found an SIR of 4.28
(95% CI 3.36–5.45), which decreased to 3.00 (95% CI 2.67–
Males 6456 46.9 2388 44.3 8844 46.2 3.37) after more than 3 years of follow-up. Restricting the
analysis to unprovoked cases increased SIRs slightly (data not
Recent malignancy (before or up to 90 days after venous shown).

thromboembolism/index date) The risk did not differ substantially between venous
thrombosis and pulmonary embolism as the clinical presenta-
Yes 661 4.8 338 6.3 999 5.2 tion for index cases or siblings (Table 4). The SIR for femoral
venous thrombosis was 2.12 (95% CI 1.21–3.70) and that for
No 13 104 95.2 5049 93.7 18 153 94.8 distal venous thrombosis was 2.83 (95% CI 1.98–4.06).

Recent pregnancy (within 90 days before venous thromboembolism/

index date)

Yes 702 5.1 250 4.6 952 5.0

No 13 063 94.9 5137 95.4 18 200 95.0

Recent surgery or trauma (within 90 days before venous

thromboembolism/index date)

Yes 4007 29.1 1624 30.1 5631 29.4

No 9758 70.9 3763 69.9 13 521 70.6

Table 2 The observed and expected numbers of cases of venous Discussion
thromboembolism among siblings, and standardized incidence ratios
and 95% confidence intervals (CIs) In this large nationwide study, we found that siblings of
patients with venous thromboembolism were at a two-fold to
Observed Expected Years of Standardized three-fold increased risk of venous thromboembolism as
follow-up incidence ratio compared with the general population. The association was
(95% CI) strongest for siblings of young cases, and was most pro-
nounced in the 3 months after the diagnosis of the index case.
Total 456 147.9 210 160 3.08 (2.80–3.39) Moreover, male siblings of male index cases had the highest
109 875 3.36 (2.96–3.82) risk, which is consistent with evidence obtained from twin
Male index 246 73.2 registry data [26].
100 285 2.81 (2.45–3.23)
case Our results are largely consistent with a population-based
case–control study from The Netherlands, in which 31.5% of
Female 210 74.7 venous thromboembolism cases and 17.3% of controls
reported having one or more first-degree relatives with a
index case history of venous thrombosis [11]. The relative risk estimates
varied from 2.2 up to 4, depending on the number of relatives
Age of the index case (years) affected. An interesting finding was that a family history was
poorly associated with known genetic factors, but the increased
0–19 14 1.2 12 507 11.42 (6.76–19.28) risk was particularly high if both a family history and known
14 672 7.76 (5.36–11.24) genetic factors were present. With our cohort design, we were
20–24 28 3.6 23 464 4.60 (3.35–6.32) able to estimate the incidence rate of venous thromboembolism
32 958 4.28 (3.37–5.42) among siblings and avoid reliance on potentially biased subject
25–29 38 8.3 40 033 3.54 (2.87–4.38) reports of relativesÕ involvement.
40 826 2.89 (2.37–3.52)
30–34 70 16.4 29 360 2.08 (1.63–2.64) The sibling relative risks that we observed are similar to
16 340 1.85 (1.39–2.46) those for many diseases [27]. A family history represents the
35–39 91 25.7 integration of risk within a family from shared genetic
susceptibilities and family clustering of environmental expo-
40–44 100 34.6 sures, lifestyles and behaviours [28]. However, an environmental
factor must be very strong (carrying a relative risk at least 10) to
45–49 68 32.7

‡ 50 47 25.4

cases, the SIRs were 2.97 (95% CI 2.47–3.57) for venous
thromboembolism in a female sibling and 2.63 (95% CI 2.17–
3.17) for that in a male sibling (P = 0.37). For male index
cases, the SIRs for venous thromboembolism among female
and male siblings were 2.59 (95% CI 2.13–3.15) and 3.99
(95% CI 3.39–4.17), respectively (P = 0.001).

The SIRs decreased with the age of the index case, from
11.42 (95% CI 6.76–19.28) for index cases below the age of
19 years to 1.85 (95% CI 1.39–2.46) for index cases aged more
than 50 years (P for trend < 0.001). However, there was no

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Familial risk and venous thromboembolism 323

Table 4 Observed and expected numbers of cases of venous thromboembolism according to the clinical manifestation of the index case, with standardized
incidence ratios and 95% confidence intervals (CIs)

Observed Expected Years of Standardized incidence
follow-up ratio (95% CI)

Clinical manifestation of the index case – deep venous thrombosis

Sibling risk of deep venous thrombosis 257 77.0 148 592 3.34 (2.94–3.78)
28.8 148 592 2.64 (2.08–3.34)
Sibling risk of pulmonary embolism 76
30.6 61 568 2.74 (2.21–3.41)
Clinical manifestation of the index case – pulmonary embolism 11.5 61 568 3.40 (2.49–4.65)

Sibling risk of deep vein thrombosis 84

Sibling risk of pulmonary embolism 39

explain the sibling SIRs that we observed [29]. If a single genetic result of substantial confounding by referral and diagnostic
variant were to explain the familial risks seen here, it would bias. On the other hand, we only had data on major risk
probably have a dominant mode of action, be relatively factors associated with provoked venous thromboembolism,
uncommon (allele frequency of at most 5%) and confer a and lacked information on lifestyle factors. Obesity is an
relative risk of at least 10 [30,31]. Indeed, there is strong evidence established risk factor for venous thromboembolism that has
that there are genetic risk factors for venous thromboembolism a weak familial component, and so may explain a part of the
[5]. Several of the strong genetic risk factors (e.g. deficiencies of association [3,34]. Smoking also exhibits a familial tendency,
antithrombin and protein C) have a prevalence of less than 1% but is only a weak risk factor for venous thromboembolism
of the population [5], which could conceivably underlie the sort [24]. The particularly high SIRs in the few months after the
of associations that we observed. In contrast, moderate genetic index diagnosis suggest either heightened surveillance after the
risk factors such as FV Leiden, blood groups and prothrombin index case, or the sharing of time-limited environmental
20210A are much more common. These risk factors are factors such as prolonged travel and acute illnesses. A
associated with relative risks of two to five [5], which would potential weakness is that our data on venous thrombo-
not explain the sibling SIRs that we observed. embolism were obtained from registry diagnoses, which may
not be entirely accurate. About 10–26% of the patients listed
Several small studies have assessed the risk of venous in the hospital registries with an inpatient department might
thrombosis in family members with FV Leiden and other not fulfill strict criteria for the disease [35–37]. We only had
mutations, and compared the risk in family members without access to outpatient data from 1994, but outpatient treatment
mutations [8]. Many of the studies had little information about of venous thrombosis in the legs has only taken place in
the eligibility criteria for family members and age and gender [8]. Denmark for the last 5–10 years. Therefore, this limitation
A systematic review of the studies showed that, in general, FV does not have an impact on the risk estimates. However, the
Leiden is a predictor for the risk among family members [8]. The accuracy of the venous thromboembolism diagnoses is
Leiden Thrombophilia Study and the MEGA study examined unlikely to differ by family history, and so any misclassifica-
approximately 20 000 single-nucleotide polymorphisms (dis- tion would bias the observed estimates towards unity. The
tributed over 11 000 genes) [32]. Five new single-nucleotide incidence rate estimated in our population corresponds to
polymorphisms across three candidate genes associated with the that reported in similar populations of younger people [38,39].
risk of venous thromboembolism were identified [32]. However, some prevalent cases would be considered to have a
first episode in the years after the start of the registry in 1977.
The clinical utility of a family history is not clear. We These cases would inflate the incidence rates for the first
provided data on the relative risk among relatives in a subset of years. If relatives of patients with venous thrombosis had
the entire Danish population with venous thromboembolism. been advised to use antithrombotic prophylaxis, this would
Although we found a strong relative risk associated with a likewise lead to an underestimation of the real familial risk.
sibling history of venous thromboembolism, the incidence is
still low, even among individuals with this risk factor. There is In conclusion, siblings of patients with a hospital diagnosis
evidence that relatives of patients with venous thromboembo- of venous thromboembolism are at increased risk of such
lism and FV Leiden have a higher risk than those without [14]. disease. The exact mechanisms behind the association are not
It is, however, unknown whether testing for genetic risks clear and remain to be investigated.
among relatives of patients with venous thromboembolism or
taking preventive measures will improve the clinical outcome. Acknowledgements
Thrombophilia testing has, like other screening procedures,
potential harms [8,33]. This study received support from the Clinical Epidemiological
Research Foundation.
Several issues should be taken into consideration in the
interpretation of the data. The main strengths of our study Disclosure of Conflict of Interests
are its large size, the well-defined population, the uniformly
organized healthcare system and access to data in the entire The authors declare that they no conflict of interest.
population [23]. The universal provision of healthcare
considerably reduces the likelihood that our findings are a

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324 H. T. Sørensen et al

Appendix 19 Sørensen HT, Mellemkjaer L, Steffensen FH, Olsen JH, Nielsen GL.
The risk of a diagnosis of cancer after primary deep venous thrombosis
Deep venous thrombosis International Classification of or pulmonary embolism. N Engl J Med 1998; 338: 1169–73.
Diseases (ICD)-8 451.00, and ICD-10 I80.1–3.
Pulmonary embolism: ICD-8 450.99; ICD-10 I26.0 and I26.9. 20 Sørensen HT, Horvath-Puho E, Pedersen L, Baron JA, Prandoni P.
Cancer: ICD-8 140–209; ICD-10 C00–C99. Venous thromboembolism and subsequent hospitalisation due to acute
Pregnancy or delivery: ICD-8 630–680; ICD-10 O00–O99. arterial cardiovascular events: a 20-year cohort study. Lancet 2007;
Fractures or trauma: ICD-8 800–999; ICD-10 S00–T14. 370: 1773–9.

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