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Factors That Predict Risk of Thrombosis in Relatives of Patients With Unprovoked Venous Thromboembolism
CHEST
Original Research VENOUS THROMBOEMBOLISM
Factors That Predict Risk of Thrombosis in Relatives of Patients With Unprovoked Venous Thromboembolism Francis Couturaud, MD, PhD; Christophe Leroyer, MD, PhD; Jim A. Julian, Mmath; Susan R. Kahn, MD, MSc; Jeffrey S. Ginsberg, MD; Philip S. Wells, MD, MSc; James D. Douketis, MD, FCCP; Dominique Mottier, MD; and Clive Kearon, MB, PhD
Background: Factors that predict the risk of venous thromboembolism in the first-degree relatives of patients with unprovoked venous thromboembolism are uncertain but important for counseling. We aimed to identify risk factors for, and quantify the risk of, venous thromboembolism in first-degree relatives of patients (index case patients) with a first episode of unprovoked venous thromboembolism. Methods: In a cross-sectional study, using a standardized method and without knowledge of whether patients or their relatives had thrombophilia, we assessed the prevalence of previous venous thromboembolism in 1,916 first-degree relatives of 378 unselected patients with a first episode of unprovoked venous thromboembolism. Patient characteristics, and the presence of factor V Leiden or the G20210A prothrombin gene mutation in patients, were assessed as predictors of venous thromboembolism in patient’s relatives. Results: There were 102 previous episodes of venous thromboembolism in the first-degree relatives (prevalence, 5.3%). Thrombosis at a young age in patients was the strongest predictor of venous thromboembolism in relatives, with an adjusted odds ratio (OR) for younger patients (ie, patients < 45 years of age when venous thromboembolism occurred; lowest quartile) compared with older patients (ie, patients > 71 years of age; highest quartile) of 3.27 (95% CI, 1.68 to 6.38). The presence of factor V Leiden or the G20210A prothrombin gene in patients was a weak independent predictor of venous thromboembolism in relatives (adjusted OR, 1.48; 95% CI, 0.94 to 2.33). Conclusion: Unprovoked venous thromboembolism at a young age is associated with a substantially increased risk of venous thromboembolism in patients’ families. (CHEST 2009; 136:1537–1545) Abbreviation: OR ⫽ odds ratio
one-quarter of patients in whom deep vein A bout thrombosis or pulmonary embolism, collectively referred to as venous thromboembolism, has developed have no apparent provoking factor to explain why thrombosis occurred (termed unprovoked venous thromboembolism).1–7 One-third of such patients have identifiable genetic predispositions to thrombosis, termed hereditary thrombophilia, with factor V Leiden and the G20210A prothrombin gene accounting for about 90% of such defects.4,5,8,9 If patients with unprovoked venous thromboembolism www.chestjournal.org
do not have a hereditary thrombophilia, it is often assumed that their relatives do not have an increased risk of thrombosis. However, this may not be true as such relatives may have an increased risk of thrombosis because of the presence of a hereditary thrombophilia that has yet to be discovered.10,11 We performed a study to identify factors in patients with unprovoked venous thromboembolism that influenced the risk of thrombosis in their firstdegree relatives. Our primary hypothesis was that the risk of thrombosis would be similar in relatives CHEST / 136 / 6 / DECEMBER, 2009
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(ie, families) of patients who have either factor V Leiden or the G20210A prothrombin gene mutation compared with relatives of patients with neither of these two abnormalities. The basis for this hypothesis was a suspicion that most patients with an unprovoked episode of venous thromboembolism who have negative test results for thrombophilia have other hereditary defects that have yet to be discovered, and that these abnormalities increase the risk of thrombosis in their relatives. An additional aim was to determine whether other characteristics of patients with unprovoked venous thromboembolism predict the risk of thrombosis in their relatives. This information is important for counseling patients’ relatives.
Materials and Methods Study Design and Population Previous venous thromboembolism in study subjects was determined cross-sectionally (ie, at enrollment) by using predefined criteria. Study subjects were the first-degree relatives (ie, parents, siblings, and children) of patients (index case patients) with a first episode of unprovoked proximal deep vein thrombosis or pulmonary embolism. Index cases of thrombosis consisted of patients who consecutively received a diagnosis of unprovoked venous thromboembolism, and new patients with cases of unprovoked venous thromboembolism who had been enrolled in a 2003 study by the authors.6 Index case patients had to satisfy all of the following eligibility criteria: (1) patients had objectively confirmed proximal deep vein thrombosis or pulmonary embolism5,12,13; (2) patients Manuscript received April 4, 2009; revision accepted June 15, 2009. Affiliations: From the Department of Internal Medicine and Chest Diseases (Drs. Couturaud, Leroyer, and Mottier), Groupe d’Etude de la Thrombose de Bretagne Occidentale, Brest, France; McMaster University and the Henderson Research Centre (Mr. Julian, and Drs. Ginsberg, Douketis, and Kearon), Hamilton, ON, Canada; McGill University (Dr. Kahn), Montreal, QC, Canada; and Ottawa University (Dr. Wells), Ottawa, ON, Canada. Funding/Support: This study was supported by grants from Programme Hospitalier de Recherche Clinique, France, and the Heart and Stroke Foundation of Ontario. Dr. Kahn is a recipient of a Senior Clinical Investigator Award from the Fonds de la Recherche en Sante´ du Que´bec and receives grant support from the Heart and Stroke Foundation of Canada and the Canadian Institutes of Health Research; Dr. Ginsberg is a Career Investigator of the Heart and Stroke Foundation of Ontario and holds a David Braley and Nancy Gordon Chair in Thromboembolic Disease; Dr. Wells is supported by a Canada Research Chair and a Heart and Stroke of Ontario Program Grant; Dr. Kearon is supported by the Canadian Institutes of Health Research. Correspondence to: Francis Couturaud, MD, PhD, GETBO, EA 3878, Department of Internal Medicine and Chest Diseases, University Hospital Centre La Cavale Blanche, 29609 Brest cedex, France; e-mail: [email protected] © 2009 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/ misc/reprints.xhtml). DOI: 10.1378/chest.09-0757 1538
were willing to provide blood for testing for factor V Leiden and the G20210A prothrombin gene; and (3) patients were willing to provide written informed consent to participate in the study and to allow one or more of their first-degree relatives to be approached for the study. To be considered unprovoked, venous thromboembolism had to have occurred in the absence of the following major risk factors: major surgery, trauma, or immobilization (ie, confined to bed for at least 3 consecutive days) within the past 3 months; and active malignancy within the past 2 years.6 To be eligible, relatives had to be at least 16 years of age and provide informed consent. First-degree relatives who were dead could be included as study subjects provided the index case patient agreed, and information about previous venous thromboembolism was available. Research ethics boards of the participating centers approved the study. Previous Venous Thromboembolism in First-Degree Relatives Using an explicit algorithm, relatives were classified as “have had venous thromboembolism” if they satisfied either of the following criteria: (1) results of diagnostic testing were available that documented previous deep vein thrombosis (including thrombosis confined to the distal deep veins) or pulmonary embolism12,13; or (2) they had a history of symptoms that were suggestive of venous thromboembolism and at least one other condition14 (they had received anticoagulant therapy for at least 2 months without another indication,14; they had a current ultrasound examination showing that the proximal deep veins were not fully compressible or that there was reflux in a popliteal vein15; or they had current symptoms and signs consistent with the postthrombotic syndrome, as assessed by a score of ⱖ 5 on the Villalta scale16). Relatives were classified as “have not had venous thromboembolism” if they satisfied all of the following criteria: (1) no known or suspected previous diagnosis of venous thromboembolism; (2) no unexplained anticoagulation in the past; and (3) no history of symptoms suggestive of venous thromboembolism and minimal current symptoms or signs consistent with the post thrombotic syndrome (ie, a score of ⬍ 5 on the Villalta scale). Relatives were classified as “uncertain for previous venous thromboembolism” if they did not satisfy the criteria for either previous or no previous venous thromboembolism. Genetic Testing for Factor V Leiden and the Prothrombin Gene Mutation After relatives had completed assessments for previous venous thromboembolism, index case patients were categorized as being positive for factor V Leiden or the G20210A prothrombin gene, or negative for both.17,18 Personnel who were unaware of the subject’s family history of venous thromboembolism performed these assays in a central laboratory either in France or in Canada. Statistical Analysis The sample size was selected to test the hypothesis that there was no difference in the incidence of venous thromboembolism in relatives of index case patients with either factor V Leiden or the G20210A prothrombin gene compared with relatives of index case patients who had neither of these abnormalities. With an expected prevalence of factor V Leiden and/or the G20210A prothrombin gene in index case patients of 33%, 99 episodes of previous venous thromboembolism in relatives were required for the 95% CI for the odds ratio (OR) for previous thrombosis between the two groups of relatives to not exceed the boundaries of 0.66 and 1.5, assuming a true-risk ratio of 1. Original Research
The average annual incidence of venous thromboembolism was calculated by dividing the number of first episodes of venous thromboembolism that occurred during the total number of years of observation (expressed as events per 100 person-years). The period of observation was from 16 years of age until the time of the first venous thromboembolism, death, or study enrollment. The influence of the characteristics of index case patients (factor V Leiden or G20210A prothrombin gene mutation vs neither; age at diagnosis; gender; deep vein thrombosis vs pulmonary embolism) and the characteristics of relatives (age at enrollment; gender; relation as parent, sibling, or child; alive vs dead) on the risk of venous thromboembolism in the relatives was determined by using logistic regression in which the clustering effect within families (intracluster correlation) was adjusted for using a random intercept mixed model.19 Associations were assessed as follows: first, single characteristics were assessed by using univariable analysis; second, all characteristics were included in a full multivariable model20; and finally, a multivariable model was fitted that contained only those characteristics that were associated with a significance level of p ⬍ 0.1 in the full model.20 Statistical analyses were performed by using a statistical software package (SPSS, version 12.0; SPSS, Inc; Chicago, IL) except for the random coefficient logistic modeling, which was performed using another software package (SAS PROC GLIMMIX, version 9.1; SAS Institute, Inc; Cary, NC).
Results Between September 2002 and January 2006, 530 patients were eligible as index case patients. Of these, 32 did not consent to be tested for factor V Leiden and the G20210A prothrombin gene, and 120 did not consent to having any of their relatives contacted; the remaining 378 index case patients were enrolled in the study (Fig 1). The 378 index case patients had a total of 2,541 first-degree
relatives, of whom 585 were excluded, 40 were eligible but did not agree to participate, and 1,916 were enrolled in the study. Of those patients who were enrolled, however, there was uncertainty about the occurrence of venous thromboembolism in 164 relatives (Fig 1). Therefore, the analysis was conducted on the 1,752 first-degree relatives of 369 index case patients (9 index case patients only had relatives who were uncertain for previous venous thromboembolism). Incidence of Venous Thromboembolism According to Whether Study Subjects Were Relatives of an Index Case Patient With, or Without, Either Factor V Leiden or the G20210A Prothrombin Gene Of the 369 index case patients, 105 (28%) had either factor V Leiden or the G20210A prothrombin gene, and they had 502 first-degree relatives with known status for previous venous thromboembolism (Table 1). Among these 502 relatives, there were 40 episodes of venous thromboembolism during a total of 19,200 years of observation, corresponding to an average annual incidence of 0.21 events per 100 person-years (95% CI, 0.15 to 0.28) [Table 2]. The remaining 264 index case patients (72%) did not have factor V Leiden or the G20210A prothrombin gene, and they had 1,250 first-degree relatives with known status for previous venous thromboembolism (Table 1). Among these 1,250 relatives, there were 62 episodes of venous thromboembolism during a total of 48,866 years of observation correspond-
2,541 First-Degree Relatives of 378 Index Cases 585 Excluded First-Degree Relatives 10 Adopted 50 Step or half relative 65 No permission to contact this relative 90 Alive but not contactable 125 <16 years 245 Deceased and no available information 40 Refused to participate
1,916 First-Degree Relatives Enrolled
544 First-Degree Relatives of 106 Index Cases With either Factor V Leiden or the G20210A Prothrombin gene 42 with uncertain previous VTE status observed for 2276 years 502 with known previous VTE status observed
1,372 First-Degree Relatives of 272 Index Cases Without either Factor V Leiden or the G20210A Prothrombin gene 122 with uncertain previous VTE status observed for 6274 years 1250 with known previous VTE status observed
for 19,200 years, of which 40 had VTE
for 48,866 years, of which 62 had VTE
(0.21 events per 100 person-years)
(0.13 events per 100 person-years)
Figure 1. Enrolled relatives and incidence of previous venous thromboembolism. VTE ⫽ venous thromboembolism. www.chestjournal.org
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Table 1—Characteristics of the Index Cases and the Relatives According to the Presence or Absence of Either Factor V Leiden or G20210A Prothrombin Gene in the Index Case Patients Characteristics Index case patients No. Female patients* Age at diagnosis, yr† FDR per index case† Included FDR per index case† Pulmonary embolism*‡ Deep vein thrombosis only*‡ Thrombophilia Factor V Leiden heterozygote* Factor V Leiden homozygote* G20210A prothrombin gene heterozygote* G20210A prothrombin gene homozygote* Factor V Leiden heterozygote and G20210A prothrombin gene heterozygote* Factor V Leiden homozygote and G20210A prothrombin gene heterozygote* FDRs No. Female patients* Alive* Relationship to the index case patient Parent* Sibling* Child* Age, yr†§
Total
Factor V Leiden or G20210A Prothrombin Gene
Neither Factor V Leiden nor G20210A Prothrombin Gene
369 179 (49) 56.8 (17.9) 6.7 (3.1) 4.8 (2.8) 192 (52) 177 (48)
105 50 (48) 53.0 (18.1) 6.5 (2.5) 4.8 (2.6) 51 (49) 54 (51)
264 129 (49) 58.3 (17.6) 6.8 (3.3) 4.8 (2.8) 141 (53) 123 (47)
68 (18) 3 (1) 28 (8) 1 (0) 4 (1)
68 (65) 3 (3) 28 (27) 1 (1) 4 (4)
0 0 0 0 0
1 (0)
1 (1)
0
1,752 881 (50) 1228 (70)
502 256 (51) 372 (74)
1,250 625 (50) 856 (68)
549 (31) 677 (39) 526 (30) 39.7 (0.6)
162 (32) 195 (39) 145 (29) 39.4 (0.8)
387 (31) 482 (39) 381 (31) 39.9 (0.5)
p Value
0.54 0.01 0.36 0.90 0.40
0.70 0.02 0.80
0.60
FDR ⫽ First-degree relative. *Values are given as No. (%). †Values are given as the mean (SD). ‡Refers to presentation of venous thromboembolism; all patients with confirmed symptomatic pulmonary embolism are included in the pulmonary embolism category, whether they were also diagnosed with deep vein thrombosis. §Age was not available for 101 relatives, mostly because these persons were dead (information obtained from relatives). For all analyses, the age of these relatives was assumed to be the same as the average age of other enrolled relatives in the corresponding category as follows: 49 years old for alive men with venous thromboembolism; 47 years old for alive women with venous thromboembolism; 47 years old for alive men without venous thromboembolism; 49 years old for alive women without venous thromboembolism; 62 years old for deceased men without venous thromboembolism; 70 years old for deceased women without venous thromboembolism; 75 years old for deceased men with venous thromboembolism; and 59 years old for deceased women with venous thromboembolism.
ing to an average annual incidence of 0.13 per 100 person-years (95% CI, 0.10 to 0.16) [Table 2]. Using logistic regression analysis, which controlled only for within-family clustering of venous thromboembolism, the OR for venous thromboembolism in families of index case patients with either factor V Leiden or the G20210A prothrombin gene was 1.68 (95% CI, 1.09 to 2.59) compared with families of index case patients without those abnormalities (Table 2, 3). Other Index Case Characteristics That Predict the Incidence of Venous Thromboembolism in Relatives Index case patients with either factor V Leiden or the G20210A prothrombin gene were younger than index case patients without these abnormalities (age, 53.0 vs 58.3 years, respectively; p ⫽ 0.01). This 1540
observation prompted analysis of whether the age of the index case patient was associated with the incidence of venous thromboembolism in their relatives. In a univariable analysis that included all 1,752 relatives with known venous thromboembolism status, there was an inverse association between the age of the index case patient and the risk of venous thromboembolism in family members; for each year that the index case patient was younger, the incidence of venous thromboembolism increased by 1.7% in the relatives (OR, 0.98 per year older in the index case patient; p ⫽ 0.004) [Table 3]. When the age of the index case patients was divided into quartiles, the incidence of venous thromboembolism in all relatives was 0.09 per 100 person-years when the index case patient was ⬎ 71 years of age (referent group), 0.15 per 100 person-years when the Original Research
Duration of observation, yr Previous VTE, No.* Incidence per 100 person-yr (95% CI) Unadjusted odds ratio (95% CI) Adjusted odds ratio (95% CI)†
FVL ⫽ factor V Leiden; hetero ⫽ heterozygous; homo ⫽ homozygous; PGM ⫽ G20210A prothrombin gene mutation; VTE ⫽ venous thromboembolism. *Of the 40 episodes of venous thromboembolism in first-degree relatives of index cases with factor V Leiden or G20210A prothrombin gene, 10 were unprovoked, 1 was associated with cancer, 12 were provoked by major reversible risk factors (i.e., recent surgery, plaster cast immobilization of the leg, or immobilization for more than 72 h), 10 were provoked by minor reversible risk factors (i.e., air travel, pregnancy, or estrogen therapy), and risk factors were uncertain in 6. Of the 62 episodes of venous thromboembolism in first-degree relatives of index cases without factor V Leiden or G20210A prothrombin gene, 11 were unprovoked, 4 were associated with cancer, 23 were provoked by major reversible risk factors, 10 were provoked by minor reversible risk factors, and risk factors were uncertain in 14. †Adjusted for intrafamily clustering, age of index cases, age and sex of relatives, and whether the relatives were dead or alive. As shown in Table 3, there was a difference in incidence according to whether the first-degree relatives were alive or dead.
19,200 40 0.21 (0.15–0.28) 1.68 (1.09–2.59) 1.48 (0.94–2.33) 340 1 0.29 (0.0–1.63) 2.32 (0.32–16.67) 2.20 (0.27–17.79) 417 2 0.48 (0.0–1.70) 3.78 (0.93–15.40) 2.12 (0.45–10.02) 116 0 0 (0.0–2.74) 4,882 10 0.20 (1.0–3.8) 1.61 (0.83–3.15) 1.64 (0.81–3.30) 12,858 26 0.20 (0.13–0.30) 1.59 (1.01–2.52) 1.46 (0.90–2.37) 19,200 40 0.21 (0.15–0.28) 1.68 (1.09–2.59) 1.48 (0.94–2.33) 48,866 62 0.13 (0.10–0.16) 1.0 (reference) 1.0 (reference)
Findings in Relatives
587 1 0.17 (0.0–0.95) 1.34 (0.1–9.67) 1.69 (0.21–13.36)
Any FVL or PGM (n ⫽ 502) FVL Homo ⫹ PGM Hetero (n ⫽ 10) FVL Hetero ⫹ PGM Hetero (n ⫽ 14) PGM Homo (n ⫽ 4) PGM Hetero (n ⫽ 122) FVL Homo (n ⫽ 13) FVL Hetero (n ⫽ 339) Any FVL or PGM in Index Cases (n ⫽ 502) No FVL and No PGM in Index Cases (n ⫽ 1,250)
Subgroups of Any FVL or PGM in Index Cases
Table 2—Incidence and Odds Ratio of Venous Thromboembolism in Relatives According to the Presence or Absence of Factor V Leiden or the G20210A Prothrombin Gene in Index Cases
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index case patient was 61 to 71 years of age (OR, 1.85; 95% CI, 0.97 to 3.53), 0.16 per 100 personyears when the index case patient was 45 to 60 years of age (OR, 1.72; 95% CI, 0.92 to 3.41), and 0.27 per 100 person-years when the index case patient was ⬍ 45 years of age (OR, 3.27; 95% CI, 1.68 to 6.38) [Table 3, 4]. The increased risk of venous thromboembolism in the relatives of younger index case patients compared with the relatives of older index case patients was present whether the index case patient was positive or negative for either factor V Leiden or the G20210A prothrombin gene, although there was a suggestion (p ⫽ 0.07 for interaction) that this effect may have been more marked when the index case patient did not have either abnormality (Table 4). In a multivariable analysis that included both the age of the index case patient and whether the index case patient was positive or negative for either factor V Leiden or the G20210A prothrombin gene, the age of the index case patient was inversely associated with the incidence of venous thromboembolism in relatives (OR, 0.97 per year older; 95% CI, 0.96 to 0.99; p ⬍ 0.001), whereas the association with the presence of factor V Leiden or the G20210A prothrombin gene in index case patients and venous thromboembolism in relatives no longer achieved statistical significance (OR, 1.48; 95% CI, 0.94 to 2.33; p ⫽ 0.09) [Table 3]. The incidence of venous thromboembolism in relatives was not associated with the sex of index case patients (p ⫽ 0.68) or whether venous thromboembolism had presented as pulmonary embolism or deep vein thrombosis in index case patients (p ⫽ 0.86) [Table 3]. Incidence of Venous Thromboembolism According to Whether Study Subjects Had the Hereditary Thrombophilia That Was Present in Their Index Case Among study subjects who were relatives of index case patients who had either factor V Leiden or the G20210A prothrombin gene, 225 relatives were available and underwent testing for the same abnormality as was present in the index case patient. Of these, 107 study subjects had the same hereditary abnormality as their index case patient, and 118 did not have the abnormality that was present in their index case patient. The incidence of previous venous thromboembolism was higher in study subjects with the same abnormality as their index case patient compared with study subjects who did not share the same abnormality as their index case patient (OR, 3.81; 95% CI, 1.22 to 11.91; p ⫽ 0.022) [Table 5]. CHEST / 136 / 6 / DECEMBER, 2009
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Table 3—Predictors of Venous Thromboembolism in Relatives According to the Characteristics of the Index Cases and of the Relatives Multivariable Univariable (Each Variable Separately) Characteristics Index case FVL and/or PGM vs neither Age at diagnosis (per year) Female patient vs male patient Pulmonary embolism/deep vein thrombosis First–degree relatives Female patient vs male patient Age, per year Relationship to index case Parent Sibling Child, reference Dead vs alive†
All Variables Included in Full Model
OR (95% CI)
p Value
1.68 (1.09–2.59) 0.98 (0.97–0.99) 0.97 (0.64–1.48) 0.99 (0.65–1.50)
0.018 0.004 0.90 0.95
1.48 (0.92–2.37) 0.96 (0.94–0.99) 1.10 (0.70–1.73) 1.05 (0.64–1.70)
0.11 0.003 0.68 0.86
1.80 (1.18–2.73) 1.04 (1.03–1.06)
0.006 ⬍ 0.001 ⬍ 0.001 ⬍ 0.001 ⬍ 0.001
1.50 (0.97–2.32) 1.07 (1.05–1.10)
5.52 (2.67–11.44) 4.06 (1.96–8.41) 1.0 0.60 (0.37–0.98)
0.042
OR (95% CI)
0.84 (0.16–2.83) 1.10 (0.42–2.85) 1.0 0.42 (0.21–0.83)
p Value
Only Variables With p ⬍ 0.1 in Full Model OR (95% CI)
p Value
1.48 (0.94–2.33) 0.97 (0.96–0.99)*
0.09 ⬍ 0.001
0.07 ⬍ 0.001 0.38 0.23 0.61
1.50 (0.97–2.31) 1.06 (1.05–1.08)
0.07 ⬍ 0.001
0.013
0.35 (0.20–0.60)
⬍ 0.001
See Table 2 for abbreviations not used in the text. *When age was divided into quartiles with the fourth quartile (⬎ 71 years old) as the reference, the adjusted odds ratio for venous thromboembolism was 1.85 (95% CI, 0.97 to 3.53; p ⫽ 0.06) in the third quartile (61 to 71 years old), 1.77 (95% CI, 0.92 to 3.41; p ⫽ 0.09) in the second quartile (45 to 60 years old), and 3.27 (95% CI, 1.68 to 6.38; p ⬍ 0.001) in the first quartile (⬍ 45 years old). †Independently of other predictor variables, incidence of venous thromboembolism was lower in relatives who were dead compared with those who were alive, probably because of poor ascertainment of previous venous thromboembolism in deceased relatives.
Discussion The results of this study suggest that the risk of thrombosis is about 50% higher in the relatives of patients with unprovoked venous thromboembolism who had factor V Leiden or the G20210A prothrombin gene than in relatives of patients who did not have either of these abnormalities. However, a more striking finding was that the age of patients with unprovoked venous thromboembolism strongly influenced the risk of venous thromboembolism in their relatives; the risk of venous thromboembolism in relatives was three times as high when index case patients were ⬍ 45 years of age (lowest quartile)
compared with when they were ⬎ 71 years of age (highest quartile). Younger age and the presence of factor V Leiden or the G20210A prothrombin gene in patients with unprovoked venous thromboembolism were independent predictors of a higher risk of venous thromboembolism in their relatives, although the former of these two factors appeared to dominate the risk of thrombosis in relatives (Table 4). Consistent with the known epidemiology of venous thromboembolism, the risk of thrombosis increased with the age of the relatives (Table 3). The authors of previous studies who have evaluated the risk of venous thromboembolism in family
Table 4 —Incidence of Venous Thromboembolism in Relatives According to Presence or Absence of Factor V Leiden or G20210A Prothrombin Gene, or Both, in Index Case Patients and Age of Index Case Patients Divided in Quartiles Incidence of VTE in Relatives, Events per 100 Person-yr (95% CI) Age of Index Cases, Quartiles ⬍ 45 yr 45–60 yr 61–71 yr ⬎ 71 yr
Index Case With FVL or PGM
Index Case With No FVL and No PGM
All Relatives
Age at Onset of VTE in Relatives, yr
0.28 (0.13–0.54) 0.22 (0.12–0.37) 0.26 (0.14–0.44) 0.09 (0.02–0.22)
0.27 (0.16–0.41) 0.13 (0.07–0.23) 0.11 (0.06–0.18) 0.08 (0.05–0.14)
0.27 (0.18–0.39) 0.16 (0.11–0.24) 0.15 (0.10–0.22) 0.09 (0.05–0.13)
42.8 ⫾ 14.5* 53.1 ⫾ 20.2 54.0 ⫾ 18.5 56.9 ⫾ 17.9*
VTE ⫽ venous thromboembolism. See Table 2 for abbreviations not used in the text. There was a trend suggesting that the decrease in the incidence of venous thromboembolism in relatives as index cases got older was more marked when the index cases did not have either factor V Leiden or the G20210A prothrombin gene compared with when the index cases had either of these abnormalities (test for interaction between the age of index cases 关continuous variable兴 and the presence of factor V Leiden or the G20210A prothrombin gene in index cases: p ⫽ 0.07). *p ⫽ 0.037 for comparison. 1542
Original Research
Table 5—Risk of Venous Thromboembolism According to Whether Study Subjects Shared the Same Hereditary Thrombophilia as Their Index Case
Variables
Living Relatives of Index Case Patients Without FVL or PGM (Study Subjects Not Tested for FVL or PGM 关n ⫽ 856兴)*
Study Subjects Without FVL and PGM (n ⫽ 107)
Study Subjects With FVL or PGM (n ⫽ 118)†
Duration of observation, yr Previous VTE, No. Incidence, per 100 person-yr (95% CI) OR (95% CI)‡
29,463 50 0.17 (0.13–0.22) 1.79 (0.63–5.09)
3,524 4 0.11 (0.03–0.29) Referent group
3,910 15 0.38 (0.21–0.63) 3.81 (1.22–11.91)
Alive Relatives of Index Cases With FVL or PGM
See Tables 2 and 4 for abbreviations not used in the text. *Only alive study subjects who were related to index cases without factor V Leiden or the G20210A prothrombin gene are included in this analysis so that that they would be comparable to relatives of index cases with factor V Leiden or the G20210A prothrombin gene who were tested for the same hereditary abnormality. †Of these 118 study subjects, 76 were heterozygote and 8 were homozygote for factor V Leiden, 24 were heterozygote and 0 were homozygote for the G20210A prothrombin gene, 5 were heterozygote for factor V Leiden and heterozygote for the G20210A prothrombin gene, and 5 were homozygote for factor V Leiden and heterozygote for the G20210A prothrombin gene. ‡Adjusted for intrafamily clustering, age of index cases, and age and sex of study subjects.
members of patients with venous thrombosis have restricted this evaluation to the families of patients with a hereditary thrombophilia, and then compared the risk of thrombosis between relatives with and without the abnormality.21–25 To our knowledge, this is the first study to compare the incidence of venous thromboembolism in families of patients with venous thromboembolism, according to whether the patient (ie, the index case) with venous thromboembolism does, or does not, have a hereditary thrombophilia. In addition, we are not aware of authors of previous studies who have evaluated whether other characteristics of patients with unprovoked venous thromboembolism, such as their age, influence the risk of thrombosis in their relatives. Among relatives of patients with venous thromboembolism and factor V Leiden, we previously reported a trend to more frequent venous thrombosis in the relatives of younger index case patients (younger vs older than 60 years: relative risk, 1.7; 95% CI, 0.8 to 3.3). However, that study included index case patients with provoked and recurrent venous thromboembolism, and was confined to families of index case patients with factor V Leiden (there is no overlap between the subjects enrolled in our previous study21 and those enrolled in the current study). The strengths of our study include the enrollment of a large number of study subjects (ie, relatives), that index case patients were unselected cases of unprovoked venous thromboembolism, that we used an explicit approach to determining whether study subjects had a history of venous thromboembolism, and that study subjects and assessors did not know whether the study subjects or the index case patients had factor V Leiden or the G20210A prothrombin gene.26 www.chestjournal.org
This study has a number of limitations. First, index case patients were not evaluated for the presence of known hereditary thrombophilias other than factor V Leiden and the G20210A prothrombin gene mutation, particularly deficiencies of protein C, protein S, and antithrombin. However, the prevalence of these abnormalities is expected to have been low and similar in the two groups of families.27,28 Second, the association between the younger age of patients and the higher risk of venous thromboembolism in their relatives was identified through an analysis of the data and, therefore, requires independent confirmation. The findings of this study have important clinical and pathophysiologic implications. First, the age of patients with unprovoked venous thromboembolism appears to be the single best way to stratify the risk of venous thromboembolism in patients’ families, with a higher risk in relatives if the patients are younger (eg, ⬍ 45 years). Second, testing for factor V Leiden or the G20210A prothrombin gene in a patient with unprovoked venous thromboembolism has a limited ability to predict the risk of thrombosis in a patient’s first-degree relatives, although knowing whether the patient has a recognized hereditary thrombophilia and, if present, whether a relative shares the same abnormality, does appear to improve the predictive value associated with knowing the age of the patient when thrombosis occurred. Third, the association between the young age of patients and a heightened risk of thrombosis in relatives is indirect evidence of the presence of yet-to-be-discovered hereditary thrombophilic abnormalities in many patients with unprovoked venous thromboembolism. In conclusion, this study revealed that unprovoked venous thromboembolism at a young age identifies a CHEST / 136 / 6 / DECEMBER, 2009
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substantially heightened risk of thrombosis in patient’s family members, and that this association occurs independently of whether patients, and their relatives, have factor V Leiden or the G20210A prothrombin gene.
Appendix Participating Nurses and Institutions G. Meach, G. Treguer, L. Gourhant, Brest University Hospital Centre, Brest, France (n ⫽ 877); T. Winkworth, Hamilton Health Sciences-Henderson Hospital, Hamilton, ON, Canada (n ⫽ 373); L. Sardo, P. Stevens, J. Joval, Hamilton Health Sciences-McMaster Medical Centre, Hamilton, ON, Canada (n ⫽ 202); P. Waddell, Ottawa Hospitals-Civic Campus, Ottawa, ON, Canada (n ⫽ 161); C. Strulovitch, Jewish General Hospital, Montreal, QC, Canada (n ⫽ 114); and K. Woods, T. Schnurr, St. Joseph’s Hospital, Hamilton, ON, Canada (n ⫽ 25). Coordinating and Methods Centers Groupe d’Etude de la Thrombose de Bretagne Occidentale, University Hospital Centre, Brest, France, and Mc Master University and Henderson Research Centre, Hamilton, ON, Canada. Central Laboratories P. Joshua, G. Mattina, M. Lauzon, M. Johnston, Hemostasis Reference Laboratory, Hamilton, ON, Canada; and C. Ferec, B. Mercier, INSERMU613, Laboratory Molecular Genetic, Brest, France.
Acknowledgments Author contributions: Dr. Couturaud had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Conception and design: Drs. Couturaud and Kearon. Analysis and interpretation of the data: Drs. Couturaud, Kearon, Leroyer, and Mottier, and Mr. Julian. Drafting of the article: Drs. Couturaud, Kearon, Leroyer, and Mottier, and Mr. Julian. Critical revision of the article for important intellectual content: Drs. Couturaud, Leroyer, Kahn, Ginsberg, Wells, Douketis, Mottier, and Kearon, and Mr. Julian. Final approval of the article: Drs. Couturaud, Leroyer, Kahn, Ginsberg, Wells, Douketis, Mottier, and Kearon, and Mr. Julian. Provision of study material or patients: Drs. Couturaud, Leroyer, Kahn, Ginsberg, Wells, Douketis, Mottier, and Kearon. Obtaining of funding: Drs. Couturaud and Kearon. Administrative, technical, and logistic support: Drs. Couturaud, Kearon, Leroyer, and Mottier. Collection and assembly of data: Drs. Couturaud and Kearon, and Mr. Julian. Financial/nonfinancial disclosures: The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Role of sponsors: Funding sources had no role relating to the following: the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the article. 1544
References 1 Kearon C, Salzman E, Hirsh J. Epidemiology, pathogenesis, and natural history of venous thrombosis. In: Colman R, Hirsh J, Marder JV, et al, eds. Hemostasis and thrombosis. Philadelphia, PA: Lippincott Williams and Wilkins, 2001 2 Heit JA, O’Fallon M, Petterson TM, et al. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study. Arch Intern Med 2002; 162:1245–1248 3 Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353:1167–1173 4 Baglin T, Luddington R, Brown K, et al. Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. Lancet 2003; 138:19 –25 5 Kearon C, Gent M, Hirsh J, et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999; 340:901–907 6 Kearon C, Ginsberg JS, Kovacs MJ, et al. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent thrombo-embolism. N Engl J Med 2003; 349:631– 639 7 Kearon C, Kahn SR, Agnelli G, et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest 2008; 133(suppl):454S–545S 8 Simioni P, Prandoni P, Lensing AWA, et al. The risk of recurrent venous thromboembolism in patients with an Arg5063 Gln mutation in the gene for factor V (factor V Leiden). N Engl J Med 1997; 336:399 – 403 9 Mateo J, Oliver A, Borrell M, et al. Laboratory evaluation and clinical characteristics of 2,132 consecutive unselected patients with venous thromboembolism: results of the Spanish multicentric study on thrombophilia (EMET-study). Thromb Haemost 1997; 77:444 – 451 10 Van Sluis GL, So¨hne M, Elkheir DY, et al. Family history and inherited thrombophilia. J Thromb Haemost 2006; 4:2182– 2187 11 Cosmi B, Legnani C, Bernardi F, et al. Role of family history in identifying women with thrombophilia and higher risk of venous thromboembolism during oral contraception. Arch Intern Med 2003; 163:1105–1109 12 Kearon C, Julian JA, Newman TE, et al, for the McMaster Diagnostic Imaging Practice Guidelines Initiative. Non-invasive diagnosis of deep vein thrombosis. Ann Intern Med 1998; 128:663– 677 13 Kearon C. Diagnosis of pulmonary embolism. Can Med Assoc J 2003; 168:183–194 14 Frezzato M, Tosetto A, Rodeghiero F. Validated questionnaire for the identification of previous personal or familial venous thromboembolism. Am J Epidemiol 1996; 143:1257– 1265 15 Ginsberg JS, Shin A, Turpie AGG, et al. Detection of previous proximal venous thrombosis with doppler ultrasonography and photoplethysmography. Arch Intern Med 1989; 149:2255–2261 16 Villalta S, Prandoni P, Cogo A, et al. The utility of noninvasive tests for detection of previous proximal-vein thrombosis. Thromb Haemost 1995; 73:592–596 17 Bertina RM, Koeleman BPC, Koster T, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369:64 – 67 18 Poort SR, Rosendaal FR, Reitsma PH, et al. A common genetic variation in the 3⬘-untranslated region of the proOriginal Research
19 20 21
22
23
thrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88:3698 –3703 Zou G, Donner A. Confidence interval estimation of the intraclass correlation coefficient for binary outcome data. Biometrics 2004; 60:807– 811 Hosmer DW, Lemeshow S. Applied logistic regression. New York, NY: John Wiley and Sons, 1989 Couturaud F, Kearon C, Leroyer C, et al, for the Groupe d’Etude de la Thrombose de Bretagne Occidentale (G.E.T.B.O). Incidence of venous thromboembolism in first-degree relatives of patients with venous thromboembolism who have factor V Leiden. Thromb Haemost 2006; 96:744 –749 Middeldorp S, Henkens CMA, Koopman MMW, et al. The incidence of venous thromboembolism in family members of patients with factor V leiden mutation and venous thrombosis. Ann Intern Med 1998; 128:15–20 Simioni P, Sanson BJ, Prandoni P, et al. Incidence of venous
www.chestjournal.org
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25 26
27 28
thromboembolism in families with inherited thrombophilia. Thromb Haemost 1999; 81:198 –202 Vossen CY, Conard J, Fontcuberta J, et al. Risk of a first venous thrombotic event in carriers of a familial thrombophilic defect: the European Prospective Cohort on Thrombophilia (EPCOT). J Thromb Haemost 2005; 3:459 – 464 Briet E, van der Meer FJM, Rosendaal FR, et al. The family history and inherited thrombophilia. Br J Haematol 1994; 87:348 –352 Vandenbroucke JP, von Elm E, Altman DG, et al, for the STROBE initiative. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration. Ann Intern Med 2007; 147:W163– W194 Lane DA, Mannucci PM, Bauer KA, et al. Inherited thrombophilia: part 1. Thromb Haemost 1996; 76:651– 662 Lane DA, Mannucci PM, Bauer KA, et al. Inherited thrombophilia: part 2. Thromb Haemost 1996; 76:824 – 834
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Original Research VENOUS THROMBOEMBOLISM
Factors That Predict Risk of Thrombosis in Relatives of Patients With Unprovoked Venous Thromboembolism Francis Couturaud, MD, PhD; Christophe Leroyer, MD, PhD; Jim A. Julian, Mmath; Susan R. Kahn, MD, MSc; Jeffrey S. Ginsberg, MD; Philip S. Wells, MD, MSc; James D. Douketis, MD, FCCP; Dominique Mottier, MD; and Clive Kearon, MB, PhD
Background: Factors that predict the risk of venous thromboembolism in the first-degree relatives of patients with unprovoked venous thromboembolism are uncertain but important for counseling. We aimed to identify risk factors for, and quantify the risk of, venous thromboembolism in first-degree relatives of patients (index case patients) with a first episode of unprovoked venous thromboembolism. Methods: In a cross-sectional study, using a standardized method and without knowledge of whether patients or their relatives had thrombophilia, we assessed the prevalence of previous venous thromboembolism in 1,916 first-degree relatives of 378 unselected patients with a first episode of unprovoked venous thromboembolism. Patient characteristics, and the presence of factor V Leiden or the G20210A prothrombin gene mutation in patients, were assessed as predictors of venous thromboembolism in patient’s relatives. Results: There were 102 previous episodes of venous thromboembolism in the first-degree relatives (prevalence, 5.3%). Thrombosis at a young age in patients was the strongest predictor of venous thromboembolism in relatives, with an adjusted odds ratio (OR) for younger patients (ie, patients < 45 years of age when venous thromboembolism occurred; lowest quartile) compared with older patients (ie, patients > 71 years of age; highest quartile) of 3.27 (95% CI, 1.68 to 6.38). The presence of factor V Leiden or the G20210A prothrombin gene in patients was a weak independent predictor of venous thromboembolism in relatives (adjusted OR, 1.48; 95% CI, 0.94 to 2.33). Conclusion: Unprovoked venous thromboembolism at a young age is associated with a substantially increased risk of venous thromboembolism in patients’ families. (CHEST 2009; 136:1537–1545) Abbreviation: OR ⫽ odds ratio
one-quarter of patients in whom deep vein A bout thrombosis or pulmonary embolism, collectively referred to as venous thromboembolism, has developed have no apparent provoking factor to explain why thrombosis occurred (termed unprovoked venous thromboembolism).1–7 One-third of such patients have identifiable genetic predispositions to thrombosis, termed hereditary thrombophilia, with factor V Leiden and the G20210A prothrombin gene accounting for about 90% of such defects.4,5,8,9 If patients with unprovoked venous thromboembolism www.chestjournal.org
do not have a hereditary thrombophilia, it is often assumed that their relatives do not have an increased risk of thrombosis. However, this may not be true as such relatives may have an increased risk of thrombosis because of the presence of a hereditary thrombophilia that has yet to be discovered.10,11 We performed a study to identify factors in patients with unprovoked venous thromboembolism that influenced the risk of thrombosis in their firstdegree relatives. Our primary hypothesis was that the risk of thrombosis would be similar in relatives CHEST / 136 / 6 / DECEMBER, 2009
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(ie, families) of patients who have either factor V Leiden or the G20210A prothrombin gene mutation compared with relatives of patients with neither of these two abnormalities. The basis for this hypothesis was a suspicion that most patients with an unprovoked episode of venous thromboembolism who have negative test results for thrombophilia have other hereditary defects that have yet to be discovered, and that these abnormalities increase the risk of thrombosis in their relatives. An additional aim was to determine whether other characteristics of patients with unprovoked venous thromboembolism predict the risk of thrombosis in their relatives. This information is important for counseling patients’ relatives.
Materials and Methods Study Design and Population Previous venous thromboembolism in study subjects was determined cross-sectionally (ie, at enrollment) by using predefined criteria. Study subjects were the first-degree relatives (ie, parents, siblings, and children) of patients (index case patients) with a first episode of unprovoked proximal deep vein thrombosis or pulmonary embolism. Index cases of thrombosis consisted of patients who consecutively received a diagnosis of unprovoked venous thromboembolism, and new patients with cases of unprovoked venous thromboembolism who had been enrolled in a 2003 study by the authors.6 Index case patients had to satisfy all of the following eligibility criteria: (1) patients had objectively confirmed proximal deep vein thrombosis or pulmonary embolism5,12,13; (2) patients Manuscript received April 4, 2009; revision accepted June 15, 2009. Affiliations: From the Department of Internal Medicine and Chest Diseases (Drs. Couturaud, Leroyer, and Mottier), Groupe d’Etude de la Thrombose de Bretagne Occidentale, Brest, France; McMaster University and the Henderson Research Centre (Mr. Julian, and Drs. Ginsberg, Douketis, and Kearon), Hamilton, ON, Canada; McGill University (Dr. Kahn), Montreal, QC, Canada; and Ottawa University (Dr. Wells), Ottawa, ON, Canada. Funding/Support: This study was supported by grants from Programme Hospitalier de Recherche Clinique, France, and the Heart and Stroke Foundation of Ontario. Dr. Kahn is a recipient of a Senior Clinical Investigator Award from the Fonds de la Recherche en Sante´ du Que´bec and receives grant support from the Heart and Stroke Foundation of Canada and the Canadian Institutes of Health Research; Dr. Ginsberg is a Career Investigator of the Heart and Stroke Foundation of Ontario and holds a David Braley and Nancy Gordon Chair in Thromboembolic Disease; Dr. Wells is supported by a Canada Research Chair and a Heart and Stroke of Ontario Program Grant; Dr. Kearon is supported by the Canadian Institutes of Health Research. Correspondence to: Francis Couturaud, MD, PhD, GETBO, EA 3878, Department of Internal Medicine and Chest Diseases, University Hospital Centre La Cavale Blanche, 29609 Brest cedex, France; e-mail: [email protected] © 2009 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/ misc/reprints.xhtml). DOI: 10.1378/chest.09-0757 1538
were willing to provide blood for testing for factor V Leiden and the G20210A prothrombin gene; and (3) patients were willing to provide written informed consent to participate in the study and to allow one or more of their first-degree relatives to be approached for the study. To be considered unprovoked, venous thromboembolism had to have occurred in the absence of the following major risk factors: major surgery, trauma, or immobilization (ie, confined to bed for at least 3 consecutive days) within the past 3 months; and active malignancy within the past 2 years.6 To be eligible, relatives had to be at least 16 years of age and provide informed consent. First-degree relatives who were dead could be included as study subjects provided the index case patient agreed, and information about previous venous thromboembolism was available. Research ethics boards of the participating centers approved the study. Previous Venous Thromboembolism in First-Degree Relatives Using an explicit algorithm, relatives were classified as “have had venous thromboembolism” if they satisfied either of the following criteria: (1) results of diagnostic testing were available that documented previous deep vein thrombosis (including thrombosis confined to the distal deep veins) or pulmonary embolism12,13; or (2) they had a history of symptoms that were suggestive of venous thromboembolism and at least one other condition14 (they had received anticoagulant therapy for at least 2 months without another indication,14; they had a current ultrasound examination showing that the proximal deep veins were not fully compressible or that there was reflux in a popliteal vein15; or they had current symptoms and signs consistent with the postthrombotic syndrome, as assessed by a score of ⱖ 5 on the Villalta scale16). Relatives were classified as “have not had venous thromboembolism” if they satisfied all of the following criteria: (1) no known or suspected previous diagnosis of venous thromboembolism; (2) no unexplained anticoagulation in the past; and (3) no history of symptoms suggestive of venous thromboembolism and minimal current symptoms or signs consistent with the post thrombotic syndrome (ie, a score of ⬍ 5 on the Villalta scale). Relatives were classified as “uncertain for previous venous thromboembolism” if they did not satisfy the criteria for either previous or no previous venous thromboembolism. Genetic Testing for Factor V Leiden and the Prothrombin Gene Mutation After relatives had completed assessments for previous venous thromboembolism, index case patients were categorized as being positive for factor V Leiden or the G20210A prothrombin gene, or negative for both.17,18 Personnel who were unaware of the subject’s family history of venous thromboembolism performed these assays in a central laboratory either in France or in Canada. Statistical Analysis The sample size was selected to test the hypothesis that there was no difference in the incidence of venous thromboembolism in relatives of index case patients with either factor V Leiden or the G20210A prothrombin gene compared with relatives of index case patients who had neither of these abnormalities. With an expected prevalence of factor V Leiden and/or the G20210A prothrombin gene in index case patients of 33%, 99 episodes of previous venous thromboembolism in relatives were required for the 95% CI for the odds ratio (OR) for previous thrombosis between the two groups of relatives to not exceed the boundaries of 0.66 and 1.5, assuming a true-risk ratio of 1. Original Research
The average annual incidence of venous thromboembolism was calculated by dividing the number of first episodes of venous thromboembolism that occurred during the total number of years of observation (expressed as events per 100 person-years). The period of observation was from 16 years of age until the time of the first venous thromboembolism, death, or study enrollment. The influence of the characteristics of index case patients (factor V Leiden or G20210A prothrombin gene mutation vs neither; age at diagnosis; gender; deep vein thrombosis vs pulmonary embolism) and the characteristics of relatives (age at enrollment; gender; relation as parent, sibling, or child; alive vs dead) on the risk of venous thromboembolism in the relatives was determined by using logistic regression in which the clustering effect within families (intracluster correlation) was adjusted for using a random intercept mixed model.19 Associations were assessed as follows: first, single characteristics were assessed by using univariable analysis; second, all characteristics were included in a full multivariable model20; and finally, a multivariable model was fitted that contained only those characteristics that were associated with a significance level of p ⬍ 0.1 in the full model.20 Statistical analyses were performed by using a statistical software package (SPSS, version 12.0; SPSS, Inc; Chicago, IL) except for the random coefficient logistic modeling, which was performed using another software package (SAS PROC GLIMMIX, version 9.1; SAS Institute, Inc; Cary, NC).
Results Between September 2002 and January 2006, 530 patients were eligible as index case patients. Of these, 32 did not consent to be tested for factor V Leiden and the G20210A prothrombin gene, and 120 did not consent to having any of their relatives contacted; the remaining 378 index case patients were enrolled in the study (Fig 1). The 378 index case patients had a total of 2,541 first-degree
relatives, of whom 585 were excluded, 40 were eligible but did not agree to participate, and 1,916 were enrolled in the study. Of those patients who were enrolled, however, there was uncertainty about the occurrence of venous thromboembolism in 164 relatives (Fig 1). Therefore, the analysis was conducted on the 1,752 first-degree relatives of 369 index case patients (9 index case patients only had relatives who were uncertain for previous venous thromboembolism). Incidence of Venous Thromboembolism According to Whether Study Subjects Were Relatives of an Index Case Patient With, or Without, Either Factor V Leiden or the G20210A Prothrombin Gene Of the 369 index case patients, 105 (28%) had either factor V Leiden or the G20210A prothrombin gene, and they had 502 first-degree relatives with known status for previous venous thromboembolism (Table 1). Among these 502 relatives, there were 40 episodes of venous thromboembolism during a total of 19,200 years of observation, corresponding to an average annual incidence of 0.21 events per 100 person-years (95% CI, 0.15 to 0.28) [Table 2]. The remaining 264 index case patients (72%) did not have factor V Leiden or the G20210A prothrombin gene, and they had 1,250 first-degree relatives with known status for previous venous thromboembolism (Table 1). Among these 1,250 relatives, there were 62 episodes of venous thromboembolism during a total of 48,866 years of observation correspond-
2,541 First-Degree Relatives of 378 Index Cases 585 Excluded First-Degree Relatives 10 Adopted 50 Step or half relative 65 No permission to contact this relative 90 Alive but not contactable 125 <16 years 245 Deceased and no available information 40 Refused to participate
1,916 First-Degree Relatives Enrolled
544 First-Degree Relatives of 106 Index Cases With either Factor V Leiden or the G20210A Prothrombin gene 42 with uncertain previous VTE status observed for 2276 years 502 with known previous VTE status observed
1,372 First-Degree Relatives of 272 Index Cases Without either Factor V Leiden or the G20210A Prothrombin gene 122 with uncertain previous VTE status observed for 6274 years 1250 with known previous VTE status observed
for 19,200 years, of which 40 had VTE
for 48,866 years, of which 62 had VTE
(0.21 events per 100 person-years)
(0.13 events per 100 person-years)
Figure 1. Enrolled relatives and incidence of previous venous thromboembolism. VTE ⫽ venous thromboembolism. www.chestjournal.org
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Table 1—Characteristics of the Index Cases and the Relatives According to the Presence or Absence of Either Factor V Leiden or G20210A Prothrombin Gene in the Index Case Patients Characteristics Index case patients No. Female patients* Age at diagnosis, yr† FDR per index case† Included FDR per index case† Pulmonary embolism*‡ Deep vein thrombosis only*‡ Thrombophilia Factor V Leiden heterozygote* Factor V Leiden homozygote* G20210A prothrombin gene heterozygote* G20210A prothrombin gene homozygote* Factor V Leiden heterozygote and G20210A prothrombin gene heterozygote* Factor V Leiden homozygote and G20210A prothrombin gene heterozygote* FDRs No. Female patients* Alive* Relationship to the index case patient Parent* Sibling* Child* Age, yr†§
Total
Factor V Leiden or G20210A Prothrombin Gene
Neither Factor V Leiden nor G20210A Prothrombin Gene
369 179 (49) 56.8 (17.9) 6.7 (3.1) 4.8 (2.8) 192 (52) 177 (48)
105 50 (48) 53.0 (18.1) 6.5 (2.5) 4.8 (2.6) 51 (49) 54 (51)
264 129 (49) 58.3 (17.6) 6.8 (3.3) 4.8 (2.8) 141 (53) 123 (47)
68 (18) 3 (1) 28 (8) 1 (0) 4 (1)
68 (65) 3 (3) 28 (27) 1 (1) 4 (4)
0 0 0 0 0
1 (0)
1 (1)
0
1,752 881 (50) 1228 (70)
502 256 (51) 372 (74)
1,250 625 (50) 856 (68)
549 (31) 677 (39) 526 (30) 39.7 (0.6)
162 (32) 195 (39) 145 (29) 39.4 (0.8)
387 (31) 482 (39) 381 (31) 39.9 (0.5)
p Value
0.54 0.01 0.36 0.90 0.40
0.70 0.02 0.80
0.60
FDR ⫽ First-degree relative. *Values are given as No. (%). †Values are given as the mean (SD). ‡Refers to presentation of venous thromboembolism; all patients with confirmed symptomatic pulmonary embolism are included in the pulmonary embolism category, whether they were also diagnosed with deep vein thrombosis. §Age was not available for 101 relatives, mostly because these persons were dead (information obtained from relatives). For all analyses, the age of these relatives was assumed to be the same as the average age of other enrolled relatives in the corresponding category as follows: 49 years old for alive men with venous thromboembolism; 47 years old for alive women with venous thromboembolism; 47 years old for alive men without venous thromboembolism; 49 years old for alive women without venous thromboembolism; 62 years old for deceased men without venous thromboembolism; 70 years old for deceased women without venous thromboembolism; 75 years old for deceased men with venous thromboembolism; and 59 years old for deceased women with venous thromboembolism.
ing to an average annual incidence of 0.13 per 100 person-years (95% CI, 0.10 to 0.16) [Table 2]. Using logistic regression analysis, which controlled only for within-family clustering of venous thromboembolism, the OR for venous thromboembolism in families of index case patients with either factor V Leiden or the G20210A prothrombin gene was 1.68 (95% CI, 1.09 to 2.59) compared with families of index case patients without those abnormalities (Table 2, 3). Other Index Case Characteristics That Predict the Incidence of Venous Thromboembolism in Relatives Index case patients with either factor V Leiden or the G20210A prothrombin gene were younger than index case patients without these abnormalities (age, 53.0 vs 58.3 years, respectively; p ⫽ 0.01). This 1540
observation prompted analysis of whether the age of the index case patient was associated with the incidence of venous thromboembolism in their relatives. In a univariable analysis that included all 1,752 relatives with known venous thromboembolism status, there was an inverse association between the age of the index case patient and the risk of venous thromboembolism in family members; for each year that the index case patient was younger, the incidence of venous thromboembolism increased by 1.7% in the relatives (OR, 0.98 per year older in the index case patient; p ⫽ 0.004) [Table 3]. When the age of the index case patients was divided into quartiles, the incidence of venous thromboembolism in all relatives was 0.09 per 100 person-years when the index case patient was ⬎ 71 years of age (referent group), 0.15 per 100 person-years when the Original Research
Duration of observation, yr Previous VTE, No.* Incidence per 100 person-yr (95% CI) Unadjusted odds ratio (95% CI) Adjusted odds ratio (95% CI)†
FVL ⫽ factor V Leiden; hetero ⫽ heterozygous; homo ⫽ homozygous; PGM ⫽ G20210A prothrombin gene mutation; VTE ⫽ venous thromboembolism. *Of the 40 episodes of venous thromboembolism in first-degree relatives of index cases with factor V Leiden or G20210A prothrombin gene, 10 were unprovoked, 1 was associated with cancer, 12 were provoked by major reversible risk factors (i.e., recent surgery, plaster cast immobilization of the leg, or immobilization for more than 72 h), 10 were provoked by minor reversible risk factors (i.e., air travel, pregnancy, or estrogen therapy), and risk factors were uncertain in 6. Of the 62 episodes of venous thromboembolism in first-degree relatives of index cases without factor V Leiden or G20210A prothrombin gene, 11 were unprovoked, 4 were associated with cancer, 23 were provoked by major reversible risk factors, 10 were provoked by minor reversible risk factors, and risk factors were uncertain in 14. †Adjusted for intrafamily clustering, age of index cases, age and sex of relatives, and whether the relatives were dead or alive. As shown in Table 3, there was a difference in incidence according to whether the first-degree relatives were alive or dead.
19,200 40 0.21 (0.15–0.28) 1.68 (1.09–2.59) 1.48 (0.94–2.33) 340 1 0.29 (0.0–1.63) 2.32 (0.32–16.67) 2.20 (0.27–17.79) 417 2 0.48 (0.0–1.70) 3.78 (0.93–15.40) 2.12 (0.45–10.02) 116 0 0 (0.0–2.74) 4,882 10 0.20 (1.0–3.8) 1.61 (0.83–3.15) 1.64 (0.81–3.30) 12,858 26 0.20 (0.13–0.30) 1.59 (1.01–2.52) 1.46 (0.90–2.37) 19,200 40 0.21 (0.15–0.28) 1.68 (1.09–2.59) 1.48 (0.94–2.33) 48,866 62 0.13 (0.10–0.16) 1.0 (reference) 1.0 (reference)
Findings in Relatives
587 1 0.17 (0.0–0.95) 1.34 (0.1–9.67) 1.69 (0.21–13.36)
Any FVL or PGM (n ⫽ 502) FVL Homo ⫹ PGM Hetero (n ⫽ 10) FVL Hetero ⫹ PGM Hetero (n ⫽ 14) PGM Homo (n ⫽ 4) PGM Hetero (n ⫽ 122) FVL Homo (n ⫽ 13) FVL Hetero (n ⫽ 339) Any FVL or PGM in Index Cases (n ⫽ 502) No FVL and No PGM in Index Cases (n ⫽ 1,250)
Subgroups of Any FVL or PGM in Index Cases
Table 2—Incidence and Odds Ratio of Venous Thromboembolism in Relatives According to the Presence or Absence of Factor V Leiden or the G20210A Prothrombin Gene in Index Cases
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index case patient was 61 to 71 years of age (OR, 1.85; 95% CI, 0.97 to 3.53), 0.16 per 100 personyears when the index case patient was 45 to 60 years of age (OR, 1.72; 95% CI, 0.92 to 3.41), and 0.27 per 100 person-years when the index case patient was ⬍ 45 years of age (OR, 3.27; 95% CI, 1.68 to 6.38) [Table 3, 4]. The increased risk of venous thromboembolism in the relatives of younger index case patients compared with the relatives of older index case patients was present whether the index case patient was positive or negative for either factor V Leiden or the G20210A prothrombin gene, although there was a suggestion (p ⫽ 0.07 for interaction) that this effect may have been more marked when the index case patient did not have either abnormality (Table 4). In a multivariable analysis that included both the age of the index case patient and whether the index case patient was positive or negative for either factor V Leiden or the G20210A prothrombin gene, the age of the index case patient was inversely associated with the incidence of venous thromboembolism in relatives (OR, 0.97 per year older; 95% CI, 0.96 to 0.99; p ⬍ 0.001), whereas the association with the presence of factor V Leiden or the G20210A prothrombin gene in index case patients and venous thromboembolism in relatives no longer achieved statistical significance (OR, 1.48; 95% CI, 0.94 to 2.33; p ⫽ 0.09) [Table 3]. The incidence of venous thromboembolism in relatives was not associated with the sex of index case patients (p ⫽ 0.68) or whether venous thromboembolism had presented as pulmonary embolism or deep vein thrombosis in index case patients (p ⫽ 0.86) [Table 3]. Incidence of Venous Thromboembolism According to Whether Study Subjects Had the Hereditary Thrombophilia That Was Present in Their Index Case Among study subjects who were relatives of index case patients who had either factor V Leiden or the G20210A prothrombin gene, 225 relatives were available and underwent testing for the same abnormality as was present in the index case patient. Of these, 107 study subjects had the same hereditary abnormality as their index case patient, and 118 did not have the abnormality that was present in their index case patient. The incidence of previous venous thromboembolism was higher in study subjects with the same abnormality as their index case patient compared with study subjects who did not share the same abnormality as their index case patient (OR, 3.81; 95% CI, 1.22 to 11.91; p ⫽ 0.022) [Table 5]. CHEST / 136 / 6 / DECEMBER, 2009
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Table 3—Predictors of Venous Thromboembolism in Relatives According to the Characteristics of the Index Cases and of the Relatives Multivariable Univariable (Each Variable Separately) Characteristics Index case FVL and/or PGM vs neither Age at diagnosis (per year) Female patient vs male patient Pulmonary embolism/deep vein thrombosis First–degree relatives Female patient vs male patient Age, per year Relationship to index case Parent Sibling Child, reference Dead vs alive†
All Variables Included in Full Model
OR (95% CI)
p Value
1.68 (1.09–2.59) 0.98 (0.97–0.99) 0.97 (0.64–1.48) 0.99 (0.65–1.50)
0.018 0.004 0.90 0.95
1.48 (0.92–2.37) 0.96 (0.94–0.99) 1.10 (0.70–1.73) 1.05 (0.64–1.70)
0.11 0.003 0.68 0.86
1.80 (1.18–2.73) 1.04 (1.03–1.06)
0.006 ⬍ 0.001 ⬍ 0.001 ⬍ 0.001 ⬍ 0.001
1.50 (0.97–2.32) 1.07 (1.05–1.10)
5.52 (2.67–11.44) 4.06 (1.96–8.41) 1.0 0.60 (0.37–0.98)
0.042
OR (95% CI)
0.84 (0.16–2.83) 1.10 (0.42–2.85) 1.0 0.42 (0.21–0.83)
p Value
Only Variables With p ⬍ 0.1 in Full Model OR (95% CI)
p Value
1.48 (0.94–2.33) 0.97 (0.96–0.99)*
0.09 ⬍ 0.001
0.07 ⬍ 0.001 0.38 0.23 0.61
1.50 (0.97–2.31) 1.06 (1.05–1.08)
0.07 ⬍ 0.001
0.013
0.35 (0.20–0.60)
⬍ 0.001
See Table 2 for abbreviations not used in the text. *When age was divided into quartiles with the fourth quartile (⬎ 71 years old) as the reference, the adjusted odds ratio for venous thromboembolism was 1.85 (95% CI, 0.97 to 3.53; p ⫽ 0.06) in the third quartile (61 to 71 years old), 1.77 (95% CI, 0.92 to 3.41; p ⫽ 0.09) in the second quartile (45 to 60 years old), and 3.27 (95% CI, 1.68 to 6.38; p ⬍ 0.001) in the first quartile (⬍ 45 years old). †Independently of other predictor variables, incidence of venous thromboembolism was lower in relatives who were dead compared with those who were alive, probably because of poor ascertainment of previous venous thromboembolism in deceased relatives.
Discussion The results of this study suggest that the risk of thrombosis is about 50% higher in the relatives of patients with unprovoked venous thromboembolism who had factor V Leiden or the G20210A prothrombin gene than in relatives of patients who did not have either of these abnormalities. However, a more striking finding was that the age of patients with unprovoked venous thromboembolism strongly influenced the risk of venous thromboembolism in their relatives; the risk of venous thromboembolism in relatives was three times as high when index case patients were ⬍ 45 years of age (lowest quartile)
compared with when they were ⬎ 71 years of age (highest quartile). Younger age and the presence of factor V Leiden or the G20210A prothrombin gene in patients with unprovoked venous thromboembolism were independent predictors of a higher risk of venous thromboembolism in their relatives, although the former of these two factors appeared to dominate the risk of thrombosis in relatives (Table 4). Consistent with the known epidemiology of venous thromboembolism, the risk of thrombosis increased with the age of the relatives (Table 3). The authors of previous studies who have evaluated the risk of venous thromboembolism in family
Table 4 —Incidence of Venous Thromboembolism in Relatives According to Presence or Absence of Factor V Leiden or G20210A Prothrombin Gene, or Both, in Index Case Patients and Age of Index Case Patients Divided in Quartiles Incidence of VTE in Relatives, Events per 100 Person-yr (95% CI) Age of Index Cases, Quartiles ⬍ 45 yr 45–60 yr 61–71 yr ⬎ 71 yr
Index Case With FVL or PGM
Index Case With No FVL and No PGM
All Relatives
Age at Onset of VTE in Relatives, yr
0.28 (0.13–0.54) 0.22 (0.12–0.37) 0.26 (0.14–0.44) 0.09 (0.02–0.22)
0.27 (0.16–0.41) 0.13 (0.07–0.23) 0.11 (0.06–0.18) 0.08 (0.05–0.14)
0.27 (0.18–0.39) 0.16 (0.11–0.24) 0.15 (0.10–0.22) 0.09 (0.05–0.13)
42.8 ⫾ 14.5* 53.1 ⫾ 20.2 54.0 ⫾ 18.5 56.9 ⫾ 17.9*
VTE ⫽ venous thromboembolism. See Table 2 for abbreviations not used in the text. There was a trend suggesting that the decrease in the incidence of venous thromboembolism in relatives as index cases got older was more marked when the index cases did not have either factor V Leiden or the G20210A prothrombin gene compared with when the index cases had either of these abnormalities (test for interaction between the age of index cases 关continuous variable兴 and the presence of factor V Leiden or the G20210A prothrombin gene in index cases: p ⫽ 0.07). *p ⫽ 0.037 for comparison. 1542
Original Research
Table 5—Risk of Venous Thromboembolism According to Whether Study Subjects Shared the Same Hereditary Thrombophilia as Their Index Case
Variables
Living Relatives of Index Case Patients Without FVL or PGM (Study Subjects Not Tested for FVL or PGM 关n ⫽ 856兴)*
Study Subjects Without FVL and PGM (n ⫽ 107)
Study Subjects With FVL or PGM (n ⫽ 118)†
Duration of observation, yr Previous VTE, No. Incidence, per 100 person-yr (95% CI) OR (95% CI)‡
29,463 50 0.17 (0.13–0.22) 1.79 (0.63–5.09)
3,524 4 0.11 (0.03–0.29) Referent group
3,910 15 0.38 (0.21–0.63) 3.81 (1.22–11.91)
Alive Relatives of Index Cases With FVL or PGM
See Tables 2 and 4 for abbreviations not used in the text. *Only alive study subjects who were related to index cases without factor V Leiden or the G20210A prothrombin gene are included in this analysis so that that they would be comparable to relatives of index cases with factor V Leiden or the G20210A prothrombin gene who were tested for the same hereditary abnormality. †Of these 118 study subjects, 76 were heterozygote and 8 were homozygote for factor V Leiden, 24 were heterozygote and 0 were homozygote for the G20210A prothrombin gene, 5 were heterozygote for factor V Leiden and heterozygote for the G20210A prothrombin gene, and 5 were homozygote for factor V Leiden and heterozygote for the G20210A prothrombin gene. ‡Adjusted for intrafamily clustering, age of index cases, and age and sex of study subjects.
members of patients with venous thrombosis have restricted this evaluation to the families of patients with a hereditary thrombophilia, and then compared the risk of thrombosis between relatives with and without the abnormality.21–25 To our knowledge, this is the first study to compare the incidence of venous thromboembolism in families of patients with venous thromboembolism, according to whether the patient (ie, the index case) with venous thromboembolism does, or does not, have a hereditary thrombophilia. In addition, we are not aware of authors of previous studies who have evaluated whether other characteristics of patients with unprovoked venous thromboembolism, such as their age, influence the risk of thrombosis in their relatives. Among relatives of patients with venous thromboembolism and factor V Leiden, we previously reported a trend to more frequent venous thrombosis in the relatives of younger index case patients (younger vs older than 60 years: relative risk, 1.7; 95% CI, 0.8 to 3.3). However, that study included index case patients with provoked and recurrent venous thromboembolism, and was confined to families of index case patients with factor V Leiden (there is no overlap between the subjects enrolled in our previous study21 and those enrolled in the current study). The strengths of our study include the enrollment of a large number of study subjects (ie, relatives), that index case patients were unselected cases of unprovoked venous thromboembolism, that we used an explicit approach to determining whether study subjects had a history of venous thromboembolism, and that study subjects and assessors did not know whether the study subjects or the index case patients had factor V Leiden or the G20210A prothrombin gene.26 www.chestjournal.org
This study has a number of limitations. First, index case patients were not evaluated for the presence of known hereditary thrombophilias other than factor V Leiden and the G20210A prothrombin gene mutation, particularly deficiencies of protein C, protein S, and antithrombin. However, the prevalence of these abnormalities is expected to have been low and similar in the two groups of families.27,28 Second, the association between the younger age of patients and the higher risk of venous thromboembolism in their relatives was identified through an analysis of the data and, therefore, requires independent confirmation. The findings of this study have important clinical and pathophysiologic implications. First, the age of patients with unprovoked venous thromboembolism appears to be the single best way to stratify the risk of venous thromboembolism in patients’ families, with a higher risk in relatives if the patients are younger (eg, ⬍ 45 years). Second, testing for factor V Leiden or the G20210A prothrombin gene in a patient with unprovoked venous thromboembolism has a limited ability to predict the risk of thrombosis in a patient’s first-degree relatives, although knowing whether the patient has a recognized hereditary thrombophilia and, if present, whether a relative shares the same abnormality, does appear to improve the predictive value associated with knowing the age of the patient when thrombosis occurred. Third, the association between the young age of patients and a heightened risk of thrombosis in relatives is indirect evidence of the presence of yet-to-be-discovered hereditary thrombophilic abnormalities in many patients with unprovoked venous thromboembolism. In conclusion, this study revealed that unprovoked venous thromboembolism at a young age identifies a CHEST / 136 / 6 / DECEMBER, 2009
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substantially heightened risk of thrombosis in patient’s family members, and that this association occurs independently of whether patients, and their relatives, have factor V Leiden or the G20210A prothrombin gene.
Appendix Participating Nurses and Institutions G. Meach, G. Treguer, L. Gourhant, Brest University Hospital Centre, Brest, France (n ⫽ 877); T. Winkworth, Hamilton Health Sciences-Henderson Hospital, Hamilton, ON, Canada (n ⫽ 373); L. Sardo, P. Stevens, J. Joval, Hamilton Health Sciences-McMaster Medical Centre, Hamilton, ON, Canada (n ⫽ 202); P. Waddell, Ottawa Hospitals-Civic Campus, Ottawa, ON, Canada (n ⫽ 161); C. Strulovitch, Jewish General Hospital, Montreal, QC, Canada (n ⫽ 114); and K. Woods, T. Schnurr, St. Joseph’s Hospital, Hamilton, ON, Canada (n ⫽ 25). Coordinating and Methods Centers Groupe d’Etude de la Thrombose de Bretagne Occidentale, University Hospital Centre, Brest, France, and Mc Master University and Henderson Research Centre, Hamilton, ON, Canada. Central Laboratories P. Joshua, G. Mattina, M. Lauzon, M. Johnston, Hemostasis Reference Laboratory, Hamilton, ON, Canada; and C. Ferec, B. Mercier, INSERMU613, Laboratory Molecular Genetic, Brest, France.
Acknowledgments Author contributions: Dr. Couturaud had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Conception and design: Drs. Couturaud and Kearon. Analysis and interpretation of the data: Drs. Couturaud, Kearon, Leroyer, and Mottier, and Mr. Julian. Drafting of the article: Drs. Couturaud, Kearon, Leroyer, and Mottier, and Mr. Julian. Critical revision of the article for important intellectual content: Drs. Couturaud, Leroyer, Kahn, Ginsberg, Wells, Douketis, Mottier, and Kearon, and Mr. Julian. Final approval of the article: Drs. Couturaud, Leroyer, Kahn, Ginsberg, Wells, Douketis, Mottier, and Kearon, and Mr. Julian. Provision of study material or patients: Drs. Couturaud, Leroyer, Kahn, Ginsberg, Wells, Douketis, Mottier, and Kearon. Obtaining of funding: Drs. Couturaud and Kearon. Administrative, technical, and logistic support: Drs. Couturaud, Kearon, Leroyer, and Mottier. Collection and assembly of data: Drs. Couturaud and Kearon, and Mr. Julian. Financial/nonfinancial disclosures: The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Role of sponsors: Funding sources had no role relating to the following: the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the article. 1544
References 1 Kearon C, Salzman E, Hirsh J. Epidemiology, pathogenesis, and natural history of venous thrombosis. In: Colman R, Hirsh J, Marder JV, et al, eds. Hemostasis and thrombosis. Philadelphia, PA: Lippincott Williams and Wilkins, 2001 2 Heit JA, O’Fallon M, Petterson TM, et al. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study. Arch Intern Med 2002; 162:1245–1248 3 Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353:1167–1173 4 Baglin T, Luddington R, Brown K, et al. Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. Lancet 2003; 138:19 –25 5 Kearon C, Gent M, Hirsh J, et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999; 340:901–907 6 Kearon C, Ginsberg JS, Kovacs MJ, et al. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent thrombo-embolism. N Engl J Med 2003; 349:631– 639 7 Kearon C, Kahn SR, Agnelli G, et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest 2008; 133(suppl):454S–545S 8 Simioni P, Prandoni P, Lensing AWA, et al. The risk of recurrent venous thromboembolism in patients with an Arg5063 Gln mutation in the gene for factor V (factor V Leiden). N Engl J Med 1997; 336:399 – 403 9 Mateo J, Oliver A, Borrell M, et al. Laboratory evaluation and clinical characteristics of 2,132 consecutive unselected patients with venous thromboembolism: results of the Spanish multicentric study on thrombophilia (EMET-study). Thromb Haemost 1997; 77:444 – 451 10 Van Sluis GL, So¨hne M, Elkheir DY, et al. Family history and inherited thrombophilia. J Thromb Haemost 2006; 4:2182– 2187 11 Cosmi B, Legnani C, Bernardi F, et al. Role of family history in identifying women with thrombophilia and higher risk of venous thromboembolism during oral contraception. Arch Intern Med 2003; 163:1105–1109 12 Kearon C, Julian JA, Newman TE, et al, for the McMaster Diagnostic Imaging Practice Guidelines Initiative. Non-invasive diagnosis of deep vein thrombosis. Ann Intern Med 1998; 128:663– 677 13 Kearon C. Diagnosis of pulmonary embolism. Can Med Assoc J 2003; 168:183–194 14 Frezzato M, Tosetto A, Rodeghiero F. Validated questionnaire for the identification of previous personal or familial venous thromboembolism. Am J Epidemiol 1996; 143:1257– 1265 15 Ginsberg JS, Shin A, Turpie AGG, et al. Detection of previous proximal venous thrombosis with doppler ultrasonography and photoplethysmography. Arch Intern Med 1989; 149:2255–2261 16 Villalta S, Prandoni P, Cogo A, et al. The utility of noninvasive tests for detection of previous proximal-vein thrombosis. Thromb Haemost 1995; 73:592–596 17 Bertina RM, Koeleman BPC, Koster T, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369:64 – 67 18 Poort SR, Rosendaal FR, Reitsma PH, et al. A common genetic variation in the 3⬘-untranslated region of the proOriginal Research
19 20 21
22
23
thrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88:3698 –3703 Zou G, Donner A. Confidence interval estimation of the intraclass correlation coefficient for binary outcome data. Biometrics 2004; 60:807– 811 Hosmer DW, Lemeshow S. Applied logistic regression. New York, NY: John Wiley and Sons, 1989 Couturaud F, Kearon C, Leroyer C, et al, for the Groupe d’Etude de la Thrombose de Bretagne Occidentale (G.E.T.B.O). Incidence of venous thromboembolism in first-degree relatives of patients with venous thromboembolism who have factor V Leiden. Thromb Haemost 2006; 96:744 –749 Middeldorp S, Henkens CMA, Koopman MMW, et al. The incidence of venous thromboembolism in family members of patients with factor V leiden mutation and venous thrombosis. Ann Intern Med 1998; 128:15–20 Simioni P, Sanson BJ, Prandoni P, et al. Incidence of venous
www.chestjournal.org
24
25 26
27 28
thromboembolism in families with inherited thrombophilia. Thromb Haemost 1999; 81:198 –202 Vossen CY, Conard J, Fontcuberta J, et al. Risk of a first venous thrombotic event in carriers of a familial thrombophilic defect: the European Prospective Cohort on Thrombophilia (EPCOT). J Thromb Haemost 2005; 3:459 – 464 Briet E, van der Meer FJM, Rosendaal FR, et al. The family history and inherited thrombophilia. Br J Haematol 1994; 87:348 –352 Vandenbroucke JP, von Elm E, Altman DG, et al, for the STROBE initiative. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration. Ann Intern Med 2007; 147:W163– W194 Lane DA, Mannucci PM, Bauer KA, et al. Inherited thrombophilia: part 1. Thromb Haemost 1996; 76:651– 662 Lane DA, Mannucci PM, Bauer KA, et al. Inherited thrombophilia: part 2. Thromb Haemost 1996; 76:824 – 834
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