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Keywords:

  • Venous thromboembolism;
  • unprovoked DVT;
  • thrombophilia;
  • age;
  • screening

Summary

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Author contributions
  7. Disclosures
  8. References

Thrombophilia is a well-established risk factor for a venous thromboembolic event (VTE), and it has been proposed that hereditary thrombophilia may substantially contribute to the development of VTE in young patients. We aimed to analyse the prevalence of thrombophilia with special regard to the age of VTE manifestation. The study cohort consisted of 1490 patients (58% females) with a median age 43 years at the time of their first VTE. At least one thrombophilic disorder was identified in 50·1% of patients. The probability of detecting a hereditary thrombophilia declined significantly with advancing age (from 49·3% in patients aged 20 years and younger to 21·9% in patients over the age of 70 years; P < 0·001). This may be primarily attributed to the decreasing frequencies of the F5 R506Q (factor V Leiden) mutation and deficiencies of protein C or protein S with older age at the time of the initial VTE event. Moreover, thrombophilia was more prevalent in unprovoked compared with risk-associated VTE (57·7% vs. 47·7%; P = 0·001). The decline in the prevalence of hereditary thrombophilia with older ages supports the use of a selected thrombophilia screening strategy dependent on age and the presence or absence of additional VTE risk factors.

Thrombophilia has gained interest since the mutations responsible for more prevalent thrombophilias, such as F5 R506Q (factor V Leiden: FVL) and F2 G20210A (prothrombin) mutations, were discovered in the 1990s. At least one thrombophilic defect can now be detected in approximately 50–60% of patients with venous thromboembolism (VTE) (Lindhoff-Last & Luxembourg, 2008; Middeldorp & van Hylckama Vlieg, 2008). Over the past several decades, testing has increased tremendously for various conditions; however, whether the results of such tests aid the clinical management of patients has not been determined. In a recent retrospective study of clinical practices in 2003 and 2004 in the Netherlands, testing for thrombophilia yielded no specific clinical management for 77% of patients (Coppens et al, 2007). Moreover, the majority of subjects carrying the most common polymorphisms (i.e., F5 R506Q or F2 G20210A mutations) never develop VTE, and in carriers of these polymorphisms, the first episode of VTE occurs most often in association with other established VTE risk factors (Rosendaal, 1999). Furthermore, as approximately 70% of VTE events occur after the age of 60 years, it appears to be unlikely that mainly genetic factors contribute to the development of VTE in these patients. Genetic and environmental risk factors may therefore act differentially at various ages. In addition, it has been proposed that genetic risk factors are relevant particularly in VTE in young individuals and that other risk factors (e.g., cancer, immobilization) may play a more important role in the increased incidence of VTE in the elderly (Engbers et al, 2010; Monreal et al, 2012). Using data from the Main-ISar-THROmbosis registry, we aimed to analyse the prevalence of thrombophilia in different age groups to help determine whether to screen for thrombophilia.

Methods

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Author contributions
  7. Disclosures
  8. References

Study population

Between March 2000 and February 2010, 1500 patients with a history of VTE [i.e., deep venous thrombosis of the lower extremities (DVT) and/or pulmonary embolism (PE)] observed consecutively in our outpatients department were registered in the MAISTHRO (MAin-ISar-THROmbosis) database. Clinical data detailing VTE and contributing VTE risk factors were recorded using a standardized questionnaire. In cases of recurrent VTE, only the first VTE event was considered. The registry was approved by the local ethics committee and is registered at ClinicalTrials.gov (NCT 99683397). All patients provided written, informed consent.

Diagnosis of VTE

A diagnosis of DVT was based on non-compressibility of deep lower extremity veins on colour-coded duplex ultrasound examination or a demonstration of a filling defect of contrast media by venography. A diagnosis of PE was made by contrast-mediated multi-detector spiral computerized tomography (CT) scan or by ventilation-perfusion lung scanning. In the case of confirmed DVT, typical symptoms and echocardiographic signs of acute right heart strain (i.e., severe tricuspid regurgitation, right ventricular (RV) dilatation or hypokinesis without RV wall hypertrophy) were sufficient for the diagnosis of PE.

Unprovoked and risk-associated VTE

VTE was considered risk-associated if it was related to one of the following risk factors: long-term travel (>6 h), surgical intervention within the previous 4 weeks, immobilization for longer than 3 days, acute or chronic inflammatory disease, active malignant disease at the time of VTE manifestation or diagnosed within 6 months after the VTE event, oral contraceptive use or pregnancy. All remaining cases were classified as having unprovoked VTE. According to the above-mentioned criteria, carriers of thrombophilic disorders were also classified as having unprovoked VTE.

Laboratory tests

Thrombophilia testing was offered to all patients registered in the database, and testing was performed in 1490 patients (99·3%). Screening for thrombophilia included testing for the F5 R506Q (factor V Leiden [FVL]) mutation, the F2 G20210A (prothrombin) mutation, antiphospholipid antibodies (APL) and the activities of protein C (PC), protein S (PS) and antithrombin (AT) and factor VIII (FVIII). Hereditary thrombophilia was defined as the presence of either the F5 R506Q or F2 G20210A mutation or as a deficiency of AT, PC or PS.

Venous blood was collected in 5 ml EDTA tubes for genomic analysis. DNA analysis of the 1691 guanine-to-adenine substitution in the F5 gene and the 20210 guanine-to-adenine substitution in the 3′-untranslated region of the F2 gene was performed by DNA isolation (NucleoSpin Blood Quick Pure 250 preps; Macherey-Nagel GmbH, Düren, Germany) followed by polymerase chain reaction (PCR) (Thrombo Type; HAIN Lifescience GmbH, Crailshain, Germany). Functional assays for AT (Coamatic LR Antithrombin; Haemochrom Diagnostika, Essen, Germany), PC (Coamatic Protein C; Chromogenix, Essen, Germany), PS (STA Protein S clotting; Roche, Mannheim, Germany), and FVIII [STA activated partial thromboplastin time (APTT); Roche] using FVIII-deficient plasma (Instrumentation Laboratory, Munich, Germany), were performed on plasma samples obtained from blood anticoagulated with 3·8% sodium citrate. A persistent elevation of FVIII activity was diagnosed in cases of repeated FVIII activities above the 95th percentile (i.e., ≥159%) of 500 healthy blood donors. Patients with elevated FVIII activities attributed to malignancy, inflammatory disease or pregnancy were excluded from analysis. A deficiency of AT, PC or PS was diagnosed if activities were repeatedly below the lower reference values (i.e., AT < 86%, PC < 74%, and PS < 70% in males and <60% in females). Patients with transient or secondary deficiencies of these proteins (i.e., due to therapy with vitamin K antagonists in the cases of PC and PS or with heparin in the case of AT) were excluded from further analysis. All functional tests were performed on an STA coagulation analyser (Roche). APL levels were determined according to the international criteria of the ISTH (International Society on Thrombosis and Haemostasis) Scientific and Standardization Committee (Brandt et al, 1995; Pengo et al, 2009). Lupus anticoagulants (LA) were diagnosed by combining different tests [diluted Russell Viper Venom Time (LAC Screen and LAC Confirm; Instrumentation Laboratory), a lupus-sensitive APTT (Hemoliance SynthAFax APTT Reagent; Instrumentation Laboratory) and the Mixcon-LA for mixing and confirmation procedures (Instrumentation Laboratory)]. Anticardiolipin (ACL) antibodies were measured using an enzyme-linked immunosorbent assay (ACL IgG/IgM; Orgentec Diagnostika GmbH; Mainz, Germany). Only medium or high antibody titres (i.e., levels above 20 u/ml) were considered positive. Patients were considered positive for APL if at least two tests performed at a 12-week interval produced pathological results. As all recruited patients had suffered VTE in the past, the patients with confirmed APL fulfilled the diagnostic criteria of antiphospholipid syndrome (APS) (Miyakis et al, 2006).

Statistical analyses

Statistical analyses were performed using the Statistical Package for Social Sciences (SPSS version 20.0, Chicago, USA). In addition to calculating descriptive statistics including frequencies, mean, standard deviation, median and range, we performed a Chi-squared test in cross-tabulations and the Mann-Whitney U-Test for comparison of metric variables. The criterion for statistical significance was a P value less than 0·05. In the boxplot, the bare length indicated the interquartile range (25th–75th percentile). Outliers were defined as values differing >1·5 bare lengths from the upper or lower edge of the box.

Results

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Author contributions
  7. Disclosures
  8. References

Study population

One thousand four hundred and ninety patients were included in this analysis. The study cohort consisted of 627 males (42%) and 863 females (58%) with a median age 43 years at the time of the first VTE (range 8–87; interquartile range 30–58). The characteristics of the entire cohort and the prevalence of well-established VTE risk factors are presented in Table 1.

Table 1. Baseline characteristics of the study cohort (N = 1490).
 N (%)
  1. a

    Percentage related to females only.

  2. VTE, venous thromboembolism; DVT, deep vein thrombosis; PE, pulmonary embolism.

VTE event
Isolated DVT1056 (70·9)
Isolated PE125 (8·4)
DVT + PE309 (20·7)
Localization of DVT
Proximal DVT835 (56·0)
Distal DVT530 (35·6)
VTE aetiology
Unprovoked VTE350 (23·5)
Risk-associated VTE1140 (76·5)
Prevalence of VTE risk factors
Long-term travel194 (13·0)
Previous surgery317 (21·3)
Immobilization469 (31·5)
Malignant disease202 (13·6)
Inflammation168 (11·3)
Oral contraceptives usea310 (35·9%)
Pregnancy and lactation perioda89 (10·3)

Prevalence of thrombophilia according to age

At least one thrombophilic defect was present in 50·1% of patients. Thrombophilia was frequent in all decades of age (Table 2). It is notable that the prevalence of any thrombophilia decreased with age. In addition, the decline in prevalence with advancing age even became more apparent regarding the hereditary thrombophilias (i.e., F5 R506Q or F2 G20210A mutation or deficiencies of AT, PC or PS) (Table 2, Fig. 1). Among patients younger than 20 years, a hereditary thrombophilia was detected in 49·3% of cases, whereas the prevalence decreased to 21·9% in patients older than 70 years (P < 0·001). This observation could be attributed primarily to the lower frequencies of the F5 R506Q mutation and PC and PS deficiency with increasing age (Table 2). The differences were highly significant when comparing patients younger than 40 years old at the time of the first VTE manifestation with those older than 40 years (31·7% vs. 19·9%, P < 0·001; 4·2% vs. 1·1%, P < 0·001 and 4·3% vs. 1·7%, P = 0·009 for the F5 R506Q mutation, PC deficiency and PS deficiency, respectively). In addition, we observed a peak in the frequencies of AT deficiency among patients younger than 20 years at the time of their first VTE event (i.e., 7·2% of cases). No age-related changes in the frequencies of F2 G20210A mutation were detected.

image

Figure 1. Prevalence of genetic factors according to the age of the first venous thrombembolism.

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Table 2. Prevalence of thrombophilia according to age at first VTE manifestation (N = 1490).
 Total cohort N/N (%)Subgroups according to VTE manifestation age (years)P value
<2020–2930–3940–4950–5960–69≥70
  1. a

    Hereditary thrombophilia, F5 R506Q or F2 G20210A mutation or deficiency of AT, PC or PS. AT, antithrombin; PC, protein C; PS, protein S; FVIII, factor VIII; ACL, anticardiolipin; VTE, venous thromboembolism.

Any thrombophilia746/1490 (50·1)42/69 (60·9)172/298 (57·7)156/288 (54·2)134/264 (50·8)94/221 (42·5)86/204 (42·2)62/146 (42·5)<0·001
Hereditary thrombophiliaa531/1490 (35·6)35/69 (49·3)143/298 (48·0)111/288 (38·5)95/264 (36·0)67/221 (30·3)48/204 (23·5)32/146 (21·9)<0·001
F5 R506Q mutation368/1467 (25·1)22/67 (32·8)103/291 (35·4)79/285 (27·7)63/260 (24·2)47/218 (21·6)35/202 (17·3)19/144 (13·2)<0·001
F2 G20210A mutation117/1461 (8·0)5/65 (7·7)28/288 (9·7)23/285 (8·1)22/260 (8·5)16/217 (7·4)10/201 (5·0)13/145 (9·0)0·671
AT deficiency37/1464 (2·5)5/69 (7·2)8/296 (2·7)4/285 (1·4)4/258 (1·6)6/216 (2·8)8/199 (4·0)2/141 (1·4)0·080
PC deficiency30/1205 (2·5)3/56 (5·4)13/249 (5·2)7/242 (2·9)5/214 (2·3)0/179 (0·0)2/163 (1·2)0/102 (0·0)0·006
PS deficiency33/1167 (2·8)4/53 (7·5)5/233 (2·1)13/231 (5·6)6/210 (2·9)3/181 (1·7)1/159 (0·6)1/100 (1·0)0·013
Elevated FVIII279/1176 (23·7)8/61 (13·1)37/261 (14·2)70/254 (27·6)50/214 (23·4)40/156 (25·6)43/(138 (31·2)31/92 (33·7)<0·001
Lupus anticoagulant52/1454 (3·6)6/66 (9·1)10/289 (3·5)7/282 (2·5)10/257 (3·9)3/219 (1·4)8/200 (4·0)8/141 (5·7)0·065
ACL-IgG/-IgM16/1471 (1·1)3/67 (4·5)6/290 (2·1)2/287 (0·7)3/261 (1·1)1/220 (0·5)0/202 (0·0)0/144 (0·0)0·015
Family history of VTE490/1480 (33·1)27/69 (39·1)117/296 (39·5)95/285 (33·3)86/262 (32·8)75/219 (34·2)61/203 (30·0)29/146 (19·9)0·004

The probability of diagnosing hereditary thrombophilia was 1·92-fold (95% confidence interval [CI] 1·55–2·38) higher among patients with their first VTE diagnosed under the age of 40 years when compared with VTE manifestation at older ages (Table 3). Patients affected by VTE at younger ages more often exhibited a homozygous F5 R506Q or F2 G20210A mutation or a double heterozygous F5 R506Q/F2 G20210A mutation (odds ratio [OR] 2·66) or an inhibitor deficiency (i.e., AT, PC or PS; OR 2·20).

Table 3. Relative risk of diagnosing a thrombophilia among VTE patients younger than 40 years when compared with patients older than 40 years at the time of their first VTE event.
 OR (95%CI)P value
  1. Hereditary thrombophilia, F5 R506Q or F2 G20210A mutation or deficiencies of antithrombin (AT), Protein C (PC) or Protein S (PS); deficiencies of inhibitors, deficiencies of AT, PC or PS; antiphospholipid antibodies, lupus anticoagulants or anticardiolipin antibodies; OR, odds ratio; 95%CI, 95% confidence interval; VTE, venous thromboembolism.

Any thrombophilia1·59 (1·29–1·95)<0·001
Hereditary thrombophilia1·92 (1·55–2·38)<0·001
Heterozygous F5 R506Q mutation1·79 (1·40–2·28)<0·001
Heterozygous F2 G20210A mutation1·20 (0·81–1·76)0·361
Homozygous or double heterozygous F5 R506Q and/or F2 G20210A mutation2·66 (1·50–4·73)0·001
Deficiencies of inhibitors AT, PC or PS2·20 (1·45–3·36)<0·001
Persistently elevated FVIII0·66 (0·51–0·87)0·003
Antiphospholipid antibodies1·02 (0·58–1·78)0·950

Higher frequencies of persistently elevated FVIII activity not related to malignant disease, inflammatory disorders or pregnancy were observed with increasing age (Table 2 and Fig. 1). When compared with patients younger than 40 years old, the prevalence in older patients was significantly increased (27·3% vs. 20·0%, P = 0·003).

The number of patients with LA or ACL antibodies was too small to draw definitive conclusions for this acquired form of thrombophilia.

Age at VTE manifestation and type of thrombophilia

Figure 2 shows the distribution of the VTE manifestation age according to the type of thrombophilia. When compared with patients without thrombophilia, VTE occurred prematurely in the presence of a F5 R506Q mutation (P < 0·001), PC or PS deficiencies (P < 0·001 and P = 0·052, respectively) and in case of an antiphospholipid syndrome with persistent double positivity for APL (i.e., the presence of LA, and ACL antibodies) (P < 0·001). In these patients, the first VTE event occurred on average 11, 17, 9 and 21 years earlier than in patients with the presence of F5 R506Q mutation, PC or PS deficiency and APS respectively, when compared with patients with no thrombophilia (median age 46 years).

image

Figure 2. VTE manifestation age according to the presence and type of thrombophilia. The boxes indicate the interquartile range (25th–75th percentile), and the end of the whiskers indicate the maximum of 1·5 interquartile ranges. Outliers are defined as values differing more than 1·5 bare lengths and are illustrated as circles. AT, antithrombin; PC, protein C; PS, protein S; F8, factor VIII; ACL, anticardiolipin; LA, lupus anticoagulant.

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Thrombophilia in unprovoked and risk-associated VTE

Thrombophilia was more common among patients with unprovoked VTE when compared to those with risk-associated VTE (57·7% vs. 47·7%; P = 0·001). Moreover, patients younger than 40 years with unprovoked VTE had higher frequencies of hereditary thrombophilia when compared with older patients (48·0% vs. 34·1%, P = 0·015) (Fig. 3). Hereditary thrombophilia was also detected more frequently among younger patients with risk-associated VTE when compared with older ones (42·9% vs. 26·6%, P < 0·001). When stratifying patients according to the risk factors related to VTE occurrence, the frequencies of hereditary thrombophilia among patients younger than 40 years at the time of VTE manifestation remained high (i.e., 34·4–46·1%) (Fig. 3). However, in patients with cancer-related VTE, the prevalence of hereditary thrombophilia was substantially lower, and the difference between young and old patients using the 40-year-old cut-off was only small (25·0 and 20·1% respectively).

image

Figure 3. Frequencies of hereditary thrombophilia with unprovoked and risk-associated venous thrombembolism among patients younger and older than 40 years. VTE, venous thrombembolism; OR, odds ratio.

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Thrombophilia in males and females with and without oral contraceptives

Among female patients with VTE manifestation before the age of 40 years, the use of oral contraceptives (OC) was common (57·8%), and the probability of detecting a thrombophilic disorder was high (57·9%). The F5 R506Q mutation, as the most common form of hereditary thrombophilia, was detected in 34·7% of females who were using OC but less frequently among females not using OCs (22·9%) (Table 4). Interestingly, there was no difference in the prevalence of the F5 R506Q mutation between females with OC use and males of the same age group (34·7% vs. 36·5%; P = 0·783). On the other hand, females without hormonal treatment presented with a significantly lower prevalence of the F5 R506Q mutation when compared with males (22·9% vs. 36·5% (P = 0·004) and 15·3% vs. 22·4% (P = 0·012) respectively, for patients younger and older than 40 years).

Table 4. Prevalence of thrombophilia among males (M) and females (F) according to age. Females younger than 40 years were further stratified into those taking oral contraceptives (F/OC) and those who do not (F/-).
 Age < 40 yearsAge ≥ 40 years
M N (%)F/OC N (%)M versus F/OC P-valueF/- N (%)M versus F/- P valueM N (%)F/- N (%)M versus F/- P value
Any thrombophilia118 (58·7)154 (57·9)0·86098 (50·5)0·102199 (46·3)150 (41·3)0·173
F5 R506Q mutation70 (36·5)90 (34·7)0·78344 (22·9)0·00494 (22·4)55 (15·3)0·012
F2 G20210A mutation15 (7·9)27 (10·5)0·34714 (7·4)0·87035 (8·4)20 (5·6)0·129
Inhibitor deficiency37 (11·4)23 (8·6)0·31515/194 (7·7)0·21126 (6·0)10 (2·8)0·027
Elevated FVIII37 (20·4)48 (20·6)0·96830 (18·5)0·65475 (22·5)79 (34·5)0·002
Antiphospholipid antibodies10 (5·2)7 (2·7)0·1736 (3·2)0·34415 (3·6)12 (3·4)0·924

There was also a trend towards a lower prevalence of the inhibitor deficiencies among females and males. The difference was significant only in patients over the age of 40 years at the time of VTE manifestation (i.e., 6·0% vs. 2·8%; P = 0·027). In contrast, we observed a higher prevalence of an elevated FVIII activity among older females when compared with males (34·5% vs. 22·5%; P = 0·002). Concerning the other thrombophilias, no significant differences were detected comparing males and females (Figure 4).

image

Figure 4. Prevalence of thrombophilia in males (M) versus females (F) according to age. Comparison of patients aged < 40 years at the time of their first venous thrombembolism (VTE) compared with patients ≥40 years of age. Females aged less than 40 years were further stratified by whether (OC) or not (-) they were taking oral contraceptives at the time of their first VTE event.

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Family history of VTE according to age

Corresponding with hereditary thrombophilia, the prevalence of a positive family history of VTE decreased with advancing age. Although 39·1% of patients with VTE manifestation before the age of 20 years had at least one-first-degree relative also affected by VTE, only 19·9% of patients over the age of 70 years reported a positive family history (Table 2). The chance of detecting a hereditary thrombophilia was higher among patients with a family history of VTE when compared with patients with a negative family history (41·8% vs. 32·4%; P < 0·001).

Discussion

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Author contributions
  7. Disclosures
  8. References

Using a cross-sectional study, we revealed a 43–61% prevalence of thrombophilia for each decade of VTE manifestation age. The prevalence of any thrombophilia decreased slightly with age. There was a significant decline in the prevalence of hereditary thrombophilia with age, which could be primarily attributed to the decreasing frequencies of the F5 R506Q mutation and deficiencies of PC or PS with older age at the time of the initial VTE event. Moreover, the prevalence of hereditary thrombophilia was higher among patients with unprovoked or risk-associated VTE who were younger than 40 years old when compared with older patients. Interestingly, we discovered the F5 R506Q mutation to be more prevalent in males than in females without hormonal treatment, whereas the prevalence was approximately the same between females using OC and males of the same age group.

Only a few studies have analysed the prevalence of thrombophilia with special regard to the age of VTE manifestation. In one investigation (Paschoa & Guillaumon, 2006), 84 patients with previous VTE underwent screening for thrombophilia (i.e., APL; deficiencies of AT, PC and PS; F5 R506Q and F2 G20210A mutations, hyperhomocysteinaemia). The authors discovered no difference in the prevalence of thrombophilia when comparing patients older and younger than 50 years of age. Pottier et al (2005) investigated the presence of thrombophilia (i.e., APL; deficiencies of AT, PC or PS; F5 R506Q or F2 G20210A mutations) and common VTE risk factors in a cohort of 66 patients with unprovoked VTE. These authors discovered a higher frequency of thrombophilia among patients younger than 40 years old when compared with older patients (64% vs. 32%; P = 0·03). However, after exclusion of patients with lupus anticoagulant (N = 5), the frequency of thrombophilia did not differ between the two age groups (Pottier et al, 2005). In the Spanish Multicentric Study on Thrombophilia (EMET), which included 2132 VTE patients, a higher frequency of inhibitor deficiencies (AT, PC or PS) in VTE patients younger than 45 years was observed when compared with patients older than 45 years [17·9% vs. 10·7%; OR 1·8 (1·4–2·4)] (Mateo et al, 1997). In summary, the literature data are limited and contradictory. However, recently published findings of the large RIETE (Registro Informatizado de Enfermedad TromboEmbólica) registry support our results insofar as hereditary thrombophilia is more prevalent in younger VTE patients (Monreal et al, 2012). However, in the RIETE study, thrombophilia screening was not routinely performed, and only 21% of patients underwent testing (Monreal et al, 2012). Another study reported that hereditary thrombophilia (F5 R506Q or F2 G20210A mutation, deficiencies of AT, PC or PS) is especially more prevalent among younger patients with unprovoked DVT when compared with patients older than 45 years or with those with risk-associated DVT (De Stefano et al, 2002). This observation is consistent with our findings, and our study results indicate that a family history of VTE further enhances the chance of detecting a prothrombotic disorder.

The most common hereditary thrombophilias are the F5 R506Q and F2 G20210A mutations. The LITE study (Longitudinal Investigation of Thromboembolism Etiology) combined the data from the Atherosclerosis Risk in Communities (ARIC) study and the Cardiovascular Health Study (CHS). The combined study sample comprised 21 680 subjects. In a nested case-control analysis, the presence of an F5 R506Q mutation increased the risk of VTE by a factor of 4·6 in individuals aged 45–64 years in the ARIC study and by a factor of 2·2 in individuals aged 65 years and older from the CHS (Folsom, 2007). In contrast to these data, the results of earlier studies suggested that the relative risk of VTE with the F5 R506Q and F2 G20210A mutations is age-dependent and increases with age (Folsom et al, 2002; Heit et al, 2005). In the EPCOT (European Prospective Cohort on Thrombophilia) study, a large multicentre cohort study of familial thrombophilia, 575 asymptomatic carriers of a hereditary thrombophilia (F5 R506Q mutation or AT, PC or PS deficiency) were followed for an average of 5·7 years. The annual incidence rate for a first VTE was 0·8% compared with 0·1% per year among 1118 non-carriers who served as controls (Vossen et al, 2005). In this study, the initial VTE event occurred approximately 20 years earlier in patients with thrombophilia when compared with individuals without thrombophilia.

The overall incidence of VTE in the general population has been estimated to be 1–2 per 1000 per year (Rosendaal et al, 2007) and has been described to be similar between males and females. The risk is elevated among young females with risk factors associated with reproduction (i.e., OC use, pregnancy and lactation period), whereas a higher VTE risk has been described for elderly men when compared with women of the same age (Tsai et al, 2002; Naess et al, 2007). Furthermore, males have a higher risk of VTE recurrence than females (Kyrle et al, 2004; Cushman et al, 2006; Linnemann et al, 2008). The lower recurrence risk in females has been attributed to the lower risk after the removal of hormonal risk factors (Cushman et al, 2006). However, there is evidence from several studies that males exhibit a higher recurrence risk, irrespective of whether the initial VTE event was risk-associated or unprovoked (Christiansen et al, 2005; McRae et al, 2006; Linnemann et al, 2008). The higher recurrence risk in males may be explained by a higher prevalence of hereditary thrombophilia among males. Our own results indicate that males are more likely to have a F5 R506Q mutation or a deficiency of natural inhibitors than females with a VTE that was not related to OC use. However, other study groups did not find any difference in the prevalence of hereditary thrombophilia among males and females (Kyrle et al, 2004). Moreover, there is still controversy regarding whether hereditary thrombophilia significantly increases the risk of VTE recurrence.

In contrast to the hereditary thrombophilias, we observed higher frequencies of persistently elevated FVIII activity that was not related to malignancy or inflammatory disease with VTE manifestation at higher ages. It is known that FVIII activities are not only elevated in patients with cancer, inflammation or pregnancy but also increase with age (Conlan et al, 1993; Luxembourg et al, 2009). Therefore, it is not surprising that, even after the exclusion of patients with cancer, inflammatory disease or pregnancy, we observed higher frequencies of elevated FVIII activity among older VTE patients. It is debatable whether an age-dependent cut-off definition will offer any advantage. Plasma FVIII levels indicate a wide inter-individual variation that is due to environmental and genetic determinants. However, as shown in a previous study completed by our group, only 3% of the variance of FVIII activity was predicted by age, sex, body mass index, and OC use (Luxembourg et al, 2009). Although no specific F8 gene polymorphisms have been associated with elevated plasma FVIII levels, the variation due to heritability was estimated to be approximately 40% (Souto et al, 2000). In addition, FVIII levels have been demonstrated to be mainly influenced by the amount of von Willebrand factor (VWF), polymorphisms of the low-density lipoprotein receptor-related protein (LRP) and the ABO blood group (Jenkens et al, 2012). It has been demonstrated that elevated FVIII levels are associated with an approximately 5- to 7-fold increased relative risk of VTE and VTE recurrence. It has also been suggested that increasing plasma levels of coagulation factors (e.g., FVIII, FIX, FXI, fibrinogen) with advancing age are likely to contribute to the higher incidence of VTE in the elderly (Rosendaal et al, 2007; Jenkens et al, 2012).

There are only a few studies analysing the familial component of VTE. In a recently published large Danish nationwide study including 30 179 siblings of 19 599 VTE cases, siblings of the index patient had a 2- to 3-fold higher risk of VTE compared with the general population (Christiansen et al, 2005). The calculated standardized incidence ratios decreased with the age of the index case, from 11·4 (95% CI 6·8–19·3) for index cases below the age of 19 years to 1·9 (95% CI 1·4–2·5) for index cases aged more than 50 years at the time of their first VTE (P < 0·001). The family history was also evaluated among VTE patients and control subjects from the MEGA (Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis) study (Hansson et al, 2000). In this study, having a relative affected at a younger age and a higher number of affected relatives increased the chance of detecting a genetic risk factor up to 36%.

The identification of a thrombophilic defect may help clarify the cause of the first VTE. However, in the majority of cases, VTE is multicausal, and the laboratory diagnosis of thrombophilia does not exclude the presence of other diseases associated with increased thrombotic risk (e.g., malignant disease). It remains a matter of debate as to whether screening for thrombophilia is justified in clinical practice in symptomatic VTE patients. General testing for thrombophilia would be logical only if the knowledge of a thrombophilic defect would influence the future management of VTE patients in terms of the intensity and duration of anticoagulant therapy, taking preventive measures or avoiding exposure to avoidable risk factors. To date, there have been no prospective studies answering this question (Cohn & Middeldorp, 2008; Cohn et al, 2009). The only prospective randomized trial that aimed to assess the potential benefits and disadvantages of testing for thrombophilia, the Dutch NOSTRADAMUS trial, was terminated early due to insufficient patient enrolment (Cohn & Middeldorp, 2008).

There is agreement that the male sex, unprovoked VTE, proximal DVT, the presence of malignant disease, a positive D-dimer status after discontinuation of vitamin K-antagonists and residual venous thrombosis are risk factors for VTE recurrence (Zhu et al, 2009; Kearon et al, 2012). The relative risk of VTE recurrence with the presence of the common F5 R506Q and F2 G20210A gene mutations appears to be only mildly elevated (Ho et al, 2006; Segal et al, 2009). However, data from recently published studies provide evidence that inherited deficiencies of AT, PC or PS (Brouwer et al, 2009) and triple positivity of antiphospholipid antibodies are associated with a substantial increase to VTE recurrence risk (Pengo et al, 2010). Current guidelines do not recommend general screening for thrombophilia after VTE because the intensity or duration of anticoagulant therapy is not influenced by the test results in the majority of cases (Pernod et al, 2009; Baglin et al, 2010; Blaettler et al, 2010; Chong et al, 2012; Kearon et al, 2012). Moreover, one has to take into account the psychological and social consequences for the individual patient, such as persistent anxiety due to the knowledge of genetic test results or problems with acquiring life or disability insurance (Cohn et al, 2008). Another disadvantage is the cost of testing, which is approximately €500 for a complete thrombophilia screen (Machin, 2003). Although some cost-effectiveness studies have been published regarding testing for thrombophilia, which concluded that testing could indeed be cost-effective in some scenarios, the number of assumptions from inconsistent observational studies complicates the interpretation of the results of these studies (Wu et al, 2006; Simpson et al, 2009).

The present study has several potential limitations. We obtained data from a single-centre cross-sectional registry trial. This trial enrolled consecutive patients with acute or documented histories of VTE observed in our outpatients department. Therefore, there is a possibility of a patient selection bias. First, the proportion of patients with a first VTE at younger ages was high (median age of the entire cohort 43 years). Second, our university hospital is located near an international airport, which may heighten the proportion of patients with VTE related to long-term travel. Third, our university hospital operates several specialized tumour centres, which may increase the number of cancer-related VTEs at our institution.

Despite these limitations, our findings have several important implications. Because of the decline in the frequency of hereditary thrombophilia, selected screening strategies appear to be superior to the concept of overall general screening for thrombophilia. Screening for hereditary thrombophilia should be considered for patients younger than 40 years old after a first VTE episode, especially in cases of unprovoked VTE. The knowledge of presence or absence of a thrombophilic disorder may facilitate the decision as to whether to prolonged anticoagulant therapy should be continued in cases where there is uncertainty.

Author contributions

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Author contributions
  7. Disclosures
  8. References

BL and EL were responsible for study initiation and coordination; LW, BL, MS, JS, CH, ZW, ME, and EL performed the study and collected the data; LW and BL performed the data analyses and wrote the manuscript; and BL und EL reviewed the manuscript and approved its final version.

Disclosures

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Author contributions
  7. Disclosures
  8. References

The authors declare no competing financial interests.

References

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  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Author contributions
  7. Disclosures
  8. References
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