Familial risk of venous thromboembolism: a nationwide cohort study

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

2 Familial risk and venous thromboembolism 321 patients with diagnoses of venous thromboembolism in the Danish National Registry of Patients [19,20], and identified their parents and siblings in the Danish Civil Registration System [21 23]. Information on essentially all discharges from Danish acute-care hospitals has been recorded in the Danish National Registry of Patients since The recorded data include dates of admission and discharge, up to 20 discharge diagnoses, hospital department codes and the surgical procedures performed. Discharge diagnoses were classified according to the International Classification of Diseases (ICD), eighth revision, until the end of 1993, and the 10th revision from 1994 to Outpatient and emergency room visits have been recorded in the registry since The 10-digit Civil Registration Number, which is permanent and unique to each Danish citizen, is also recorded, enabling the compilation of a patientõs specific discharge history. Data were retrieved for all persons listed with a diagnosis of venous thrombosis or pulmonary embolism in the Danish National Registry of Patients from 1 January 1977 to 31 December We defined ÔprovokedÕ venous thromboembolism cases as those with a diagnosed malignancy before or within 90 days after the thrombotic event in the Danish National Registry of Patients, and those with a diagnosis of fracture, surgery, trauma or pregnancy within 90 days of hospitalization for venous thromboembolism. The remaining thromboembolism cohort members were classified as ÔunprovokedÕ [20,24]. ICD codes for all diagnoses are provided in the Appendix. Since 1 April 1968, all persons residing in Denmark have been registered with their civil registration number, date of birth, residency, date of immigration or emigration and date of death in the Civil Registration System [22]. Parents are also recorded if the person lived with them in 1968 or later. The completeness of information and the parental civil registration numbers increased from 10% from the cohorts born in 1950 to 43% in the 1952 cohort, 99% in the 1960 cohort and 100% for cohorts born after 1970 [21,22]. Adopted children cannot be identified as such in the registry, and are recorded under their adopted parents, but the magnitude of this misclassification is small [22]. For the purposes of our analyses, we defined siblings as individuals with the same mother. We retrieved data on vital status from the registry from the period 1 April 1968 to 31 December 2009 for members of the venous thromboembolism cohort, and identified siblings who could be traced in the Civil Registration System. For each sibship, the person discharged with a diagnosis of venous thromboembolism on the earliest date was designated the index case, and the sibling was subsequently followed for disease occurrence as described below. Statistical analysis Siblings living in Denmark on the dates of hospital diagnosis of the index cases were followed from those dates (or birth of the sibling if later) until a hospital diagnosis for venous thromboembolism, emigration, death or the end of the study period, whichever came first. We compared the incidence of venous thromboembolism in siblings of thromboembolism cases with the incidence in the general population. The population incidence rates were computed as the total number of first diagnoses for venous thromboembolism in a particular year divided by the number of Danish citizens at the beginning of that year. Incidence rates were computed for gender, as well as age group (0 100 in intervals of 5 years), calendar period (from 1975 to 2010, in 5-year periods) and time since diagnosis of the index case (as < 1 year, 1 2 years or 3 years). The incidence rates were multiplied by the corresponding person-years of observation to yield the expected numbers of cases. The number of cases among siblings was divided by the expected numbers to give a standardized incidence ratio (SIR). The person-years at risk and the events were counted for all combinations of gender, age group, calendar period and time since index diagnosis, and the SIRs were estimated. We used Poisson regression with robust (generalized estimating equations or ÔsandwichÕ) variance estimates, where the families were regarded as clusters [25]. If, for example, k gap is the rate of disease in siblings of gender g, age group a and calendar period p, and c gap is the rate of the disease in the general population for the same values of gender, age and period, then the Poisson model is k gap ¼ qc gap ; and the estimate of q, ^q, is the SIR. We used the score test to compute P-values for the difference in risk between groups. In a subanalysis, we restricted the study population to patients with unprovoked venous thromboembolism. Results We identified persons with a first diagnosis of venous thromboembolism within the study period in the Danish National Registry of Patients: patients with venous thrombosis and with pulmonary embolism. Of these, were born after 1952, and for (85.8%) we were able to identify the mother in the Civil Registration System. The prevalence of provoked venous thromboembolism among all venous thromboembolism cases was 0.39 before 1994 and decreased to 0.33 thereafter. We found a total of siblings followed for a total of person-years. Table 1 provides descriptive data of the study population. The overall incidence of venous thromboembolism in siblings of venous thromboembolism cases was 2.2 cases per 1000 person-years, and that in the general population was 0.7 cases per 1000 person-years. Siblings had a three-fold increased risk, with an age-adjusted and sex-adjusted SIR of 3.08 (95% confidence interval [CI] ) (Table 2) and an incidence difference of around 1.5 cases per 1000 person-years. The SIRs for siblings of male cases was 3.36 (95% CI ), higher than that for siblings of female cases (2.81, 95% CI ; P = 0.056). The relative risk differed with the gender of the index case and of the sibling. For female index

3 322 H. T. Sørensen et al Table 1 Descriptive data for index patients with venous thromboembolism Variables Cohort Deep venous thrombosis (N = ) Pulmonary embolism (N = 5387) Overall (N = ) N % N % N % Age (years) < > Gender Females Males Recent malignancy (before or up to 90 days after venous thromboembolism/index date) Yes No Recent pregnancy (within 90 days before venous thromboembolism/ index date) Yes No Recent surgery or trauma (within 90 days before venous thromboembolism/index date) Yes No Table 3 Observed and expected numbers of cases of venous thromboembolism among siblings of index cases, with standardized incidence ratios and 95% confidence intervals (CIs), by time since the diagnosis of the index case Years since diagnosis Observed Expected Standardized incidence ratio (95% CI) < ( ) ( ) ( ) substantial variation in the incidence differences with age, varying from 1.02 to 1.66 venous thrombosis cases per 100 person-years. We found a tendency for the SIR to decrease with increasing time (P for trend = 0.020) (Table 3). Within the first year of, we found an SIR of 4.28 (95% CI ), which decreased to 3.00 (95% CI ) after more than 3 years of. Restricting the analysis to unprovoked cases increased SIRs slightly (data not shown). The risk did not differ substantially between venous thrombosis and pulmonary embolism as the clinical presentation for index cases or siblings (Table 4). The SIR for femoral venous thrombosis was 2.12 (95% CI ) and that for distal venous thrombosis was 2.83 (95% CI ). Table 2 The observed and expected numbers of cases of venous thromboembolism among siblings, and standardized incidence ratios and 95% confidence intervals (CIs) Observed Expected Standardized incidence ratio (95% CI) Total ( ) Male index ( ) case Female index case ( ) Age of the index case (years) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) cases, the SIRs were 2.97 (95% CI ) for venous thromboembolism in a female sibling and 2.63 (95% CI ) 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 ) and 3.99 (95% CI ), respectively (P = 0.001). The SIRs decreased with the age of the index case, from (95% CI ) for index cases below the age of 19 years to 1.85 (95% CI ) for index cases aged more than 50 years (P for trend < 0.001). However, there was no Discussion In this large nationwide study, we found that siblings of patients with venous thromboembolism were at a two-fold to three-fold increased risk of venous thromboembolism as compared with the general population. The association was strongest for siblings of young cases, and was most pronounced in the 3 months after the diagnosis of the index case. Moreover, male siblings of male index cases had the highest risk, which is consistent with evidence obtained from twin registry data [26]. Our results are largely consistent with a population-based case control study from The Netherlands, in which 31.5% of venous thromboembolism cases and 17.3% of controls reported having one or more first-degree relatives with a history of venous thrombosis [11]. The relative risk estimates varied from 2.2 up to 4, depending on the number of relatives affected. An interesting finding was that a family history was poorly associated with known genetic factors, but the increased risk was particularly high if both a family history and known genetic factors were present. With our cohort design, we were able to estimate the incidence rate of venous thromboembolism among siblings and avoid reliance on potentially biased subject reports of relativesõ involvement. The sibling relative risks that we observed are similar to those for many diseases [27]. A family history represents the integration of risk within a family from shared genetic susceptibilities and family clustering of environmental exposures, lifestyles and behaviours [28]. However, an environmental factor must be very strong (carrying a relative risk at least 10) to

4 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 Standardized incidence ratio (95% CI) Clinical manifestation of the index case deep venous thrombosis Sibling risk of deep venous thrombosis ( ) Sibling risk of pulmonary embolism ( ) Clinical manifestation of the index case pulmonary embolism Sibling risk of deep vein thrombosis ( ) Sibling risk of pulmonary embolism ( ) explain the sibling SIRs that we observed [29]. If a single genetic variant were to explain the familial risks seen here, it would probably have a dominant mode of action, be relatively uncommon (allele frequency of at most 5%) and confer a relative risk of at least 10 [30,31]. Indeed, there is strong evidence that there are genetic risk factors for venous thromboembolism [5]. Several of the strong genetic risk factors (e.g. deficiencies of antithrombin and protein C) have a prevalence of less than 1% of the population [5], which could conceivably underlie the sort of associations that we observed. In contrast, moderate genetic risk factors such as FV Leiden, blood groups and prothrombin 20210A are much more common. These risk factors are associated with relative risks of two to five [5], which would not explain the sibling SIRs that we observed. Several small studies have assessed the risk of venous thrombosis in family members with FV Leiden and other mutations, and compared the risk in family members without mutations [8]. Many of the studies had little information about the eligibility criteria for family members and age and gender [8]. A systematic review of the studies showed that, in general, FV Leiden is a predictor for the risk among family members [8]. The Leiden Thrombophilia Study and the MEGA study examined approximately single-nucleotide polymorphisms (distributed over genes) [32]. Five new single-nucleotide polymorphisms across three candidate genes associated with the risk of venous thromboembolism were identified [32]. The clinical utility of a family history is not clear. We provided data on the relative risk among relatives in a subset of the entire Danish population with venous thromboembolism. Although we found a strong relative risk associated with a sibling history of venous thromboembolism, the incidence is still low, even among individuals with this risk factor. There is evidence that relatives of patients with venous thromboembolism and FV Leiden have a higher risk than those without [14]. It is, however, unknown whether testing for genetic risks among relatives of patients with venous thromboembolism or taking preventive measures will improve the clinical outcome. Thrombophilia testing has, like other screening procedures, potential harms [8,33]. Several issues should be taken into consideration in the interpretation of the data. The main strengths of our study are its large size, the well-defined population, the uniformly organized healthcare system and access to data in the entire population [23]. The universal provision of healthcare considerably reduces the likelihood that our findings are a result of substantial confounding by referral and diagnostic bias. On the other hand, we only had data on major risk factors associated with provoked venous thromboembolism, and lacked information on lifestyle factors. Obesity is an established risk factor for venous thromboembolism that has a weak familial component, and so may explain a part of the association [3,34]. Smoking also exhibits a familial tendency, but is only a weak risk factor for venous thromboembolism [24]. The particularly high SIRs in the few months after the index diagnosis suggest either heightened surveillance after the index case, or the sharing of time-limited environmental factors such as prolonged travel and acute illnesses. A potential weakness is that our data on venous thromboembolism were obtained from registry diagnoses, which may not be entirely accurate. About 10 26% of the patients listed in the hospital registries with an inpatient department might not fulfill strict criteria for the disease [35 37]. We only had access to outpatient data from 1994, but outpatient treatment of venous thrombosis in the legs has only taken place in Denmark for the last 5 10 years. Therefore, this limitation does not have an impact on the risk estimates. However, the accuracy of the venous thromboembolism diagnoses is unlikely to differ by family history, and so any misclassification would bias the observed estimates towards unity. The incidence rate estimated in our population corresponds to that reported in similar populations of younger people [38,39]. However, some prevalent cases would be considered to have a first episode in the years after the start of the registry in These cases would inflate the incidence rates for the first years. If relatives of patients with venous thrombosis had been advised to use antithrombotic prophylaxis, this would likewise lead to an underestimation of the real familial risk. In conclusion, siblings of patients with a hospital diagnosis of venous thromboembolism are at increased risk of such disease. The exact mechanisms behind the association are not clear and remain to be investigated. Acknowledgements This study received support from the Clinical Epidemiological Research Foundation. Disclosure of Conflict of Interests The authors declare that they no conflict of interest.

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