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Keywords:

  • Factor V Leiden;
  • venous thromboembolism

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Study population
  6. Identification of FV Leiden carriers and non-carriers
  7. Study design and data collection
  8. Diagnostic criteria for venous thromboembolism
  9. Analysis
  10. Results
  11. Discussion
  12. Acknowledgements
  13. References

Summary.  While Factor V (FV) Leiden is a risk factor for venous thromboembolism (VTE), the incidence of VTE among FV Leiden carriers is uncertain. The objective of the study was to estimate the overall age-specific and pregnancy-related VTE incidence and the relative risk among FV Leiden carriers. In a community-based sample of 3424 south-eastern Minnesota residents, 230 (6.7%) were genotyped as FV Leiden carriers; 220 carriers (mean age = 68 years) could be matched to a non-carrier on age, gender, ethnicity and length of medical history. We performed a retrospective cohort study of carriers and non-carriers by reviewing the complete medical records in the community for demographic and baseline characteristics, pregnancies and live births, and first lifetime VTE. Over 14 722 person-years, 24 (10.9%) carriers developed VTE [overall incidence = 163 (95% CI 104, 242) per 100 000 person-years]. VTE incidence rates for ages 15–29, 30–44, 45–59 and ≥ 60 years were 0, 61, 244 and 764 per 100 000 person-years, respectively (cumulative VTE incidence at age 65 years = 6.3%). VTE incidence for carriers did not differ significantly from that for non-carriers except for those ≥ 60 years old (relative risk = 3.6; 95% CI 2.0, 6.0). There were 311 live births among 130 women carriers; no VTE events occurred during pregnancy or postpartum [incidence = 0 (95% CI 0, 1186) per 100 000 women-years]. Most FV Leiden carriers do not develop VTE. Among all carriers, those ≥ 60 years old are at the highest risk for VTE. The incidence of VTE among asymptomatic women carriers during pregnancy is low and insufficient to warrant prophylaxis.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Study population
  6. Identification of FV Leiden carriers and non-carriers
  7. Study design and data collection
  8. Diagnostic criteria for venous thromboembolism
  9. Analysis
  10. Results
  11. Discussion
  12. Acknowledgements
  13. References

Activated protein C (APC)-resistance is characterized by plasma resistance to the anticoagulant effect of exogenous APC [1]. Early epidemiological data suggested that APC-resistance was familial, with an autosomal co-dominant inheritance [2]. In a procoagulant Factor Va (FVa) activity assay, FV or FVa isolated from APC-resistant plasma was inactivated more slowly by APC compared to normal plasma FVa [3,4]. Subsequently, four investigative groups independently described a guanine-1691 to adenine (G1691A) nucleotide transition within exon 10 of the factor V gene (Factor V Leiden) [5–8]. The FV Leiden mutation predicts a substitution of glutamine for arginine(R)-506, one of three APC-cleavage sites (R306, R506, R679) within the heavy chain of FVa [9]. Initial APC cleavage at position R506 is required for optimal exposure and subsequent rapid inactivation of FVa by additional APC cleavage at R306 [10,11]. Depending on the assay, 85–100% of patients with APC-resistance have the FV Leiden mutation [5,6,12,13].

Among predominantly white patients with a first lifetime venous thromboembolism, the FV Leiden carrier frequency or APC-resistance prevalence range from about 12 to 20% and are associated with a 2.7- to 6.6-fold increased risk for venous thromboembolism [14–16]. While the magnitude of the increased risk is useful for identifying those factors that are most important for possible modification [17], the incidence (e.g. ‘absolute risk’) of venous thromboembolism is most useful for individual patient counseling. However, the incidence of venous thromboembolism among FV Leiden carriers is uncertain. Reported crude incidence rates for carriers older than 15 years vary markedly, ranging from 280 to 670 per 100 000 person-years [18–22]. Moreover, most studies followed asymptomatic family members identified through a symptomatic proband FV Leiden carrier [18–22]. Venous thromboembolism incidence among these family members may differ substantially from that in the general population because of other heritable thrombophilias operating in the family [23]. Likewise, while the risk of venous thromboembolism during pregnancy or postpartum among women FV Leiden carriers is increased [24,25], the incidence remains uncertain [18–22].

Consequently, we performed a population-based, retrospective cohort study to estimate the overall and age-specific incidence of venous thromboembolism among FV Leiden carriers and among age-, sex-, and ethnicity-matched FV Leiden non-carriers, and to determine the relative risk of venous thromboembolism by age group. For women carriers and non-carriers, we also estimated the incidence of venous thromboembolism during pregnancy or postpartum. Because carriers and non-carriers were matched, drawn from the same population, and had lengthy and equal durations of medical follow-up, these data provide relatively unbiased estimates of the overall, age-, and pregnancy/postpartum-specific incidence rates for venous thromboembolism.

Study population

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Study population
  6. Identification of FV Leiden carriers and non-carriers
  7. Study design and data collection
  8. Diagnostic criteria for venous thromboembolism
  9. Analysis
  10. Results
  11. Discussion
  12. Acknowledgements
  13. References

The study population included residents of south-eastern Minnesota (n = 3424) identified within the Mayo Clinic Community Medicine Building venepuncture area over the 8-year period, 1987–95. All such residents who were ≥ 45 years of age and had ≥ 10 years of Mayo Clinic medical records were approached for inclusion without regard to the indication for venepuncture. Consenting residents provided an additional blood sample for DNA extraction, storage and testing and completed a questionnaire regarding personal family ethnic ancestry. Based on self-reported paternal and maternal ethnic ancestry, residents were categorized into one of 15 geographic regions or ethnicities: African, African-American, Arabic, Asian, Asian-American, Asian-Indian, Hispanic, Ashkenazi Jew, Sephardic Jew, Native-American, Northern-, Southern-, Eastern-, or Western-European; or unknown. Leukocyte genomic DNA was extracted from whole blood as previously described [26]. Agarose gel electrophoresis with ethidium bromide staining and polymerase chain reaction (PCR) amplification of each patient genomic DNA sample was performed to ensure both the quality of the DNA extraction as well as the absence of amplification inhibitors. The study protocol was approved by the Mayo Clinic Institutional Review Board.

Identification of FV Leiden carriers and non-carriers

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Study population
  6. Identification of FV Leiden carriers and non-carriers
  7. Study design and data collection
  8. Diagnostic criteria for venous thromboembolism
  9. Analysis
  10. Results
  11. Discussion
  12. Acknowledgements
  13. References

We developed a genotyping assay for the FV Leiden mutation based on PCR amplification of specific alleles [27,28]. Briefly, a 298-base pair fragment of exon 10 of the factor V gene was amplified using an upstream primer whose 3′ end was complementary to nucleotide 1691 A (i.e. the mutant allele). Additional primers for the H region of the factor IX gene were included as an internal control for successful PCR amplification. The amplification products and a DNA standard of known molecular weight were electrophoresed on a 2.5% agarose gel, ethidium bromide-stained and photographed under ultraviolet illumination. A band at the appropriate molecular weight detected the presence of a mutant allele. Appropriate wild-type, heterozygous, and no-DNA controls were included in each amplification. Sensitivity experiments demonstrated that our assay detected one mutant allele in 40 chromosomes (or one heterozygote in 20 patient DNA samples). Therefore, we used a strategy of assaying four patient samples per PCR reaction tube to screen for the FV Leiden mutation, and performed a second genotyping assay individually and in a blinded fashion on the four genomic DNA samples from each positive combined sample. For each positive individual sample, the FV Leiden mutation and zygosity were confirmed by direct sequencing. Similarly, we sequenced a random sample of 100 patient DNA samples drawn from the cohort who were genotyped as negative for the FV Leiden mutation. For each carrier, one age- (± 5 years), sex-, and ethnicity-matched non-carrier was drawn from the residents who were homozygous for the wild-type allele. Non-carriers were also matched to carriers on closest Mayo Clinic medical record number. Because Mayo Clinic medical record numbers are unique and assigned sequentially, matching on medical record number provides a similar duration of clinical follow-up.

Study design and data collection

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Study population
  6. Identification of FV Leiden carriers and non-carriers
  7. Study design and data collection
  8. Diagnostic criteria for venous thromboembolism
  9. Analysis
  10. Results
  11. Discussion
  12. Acknowledgements
  13. References

The FV Leiden carriers and non-carriers were followed forward in time through their linked medical records in the community (retrospective cohort study) until death or the most recent clinical contact [29,30]. A study nurse abstractor who was blinded to carrier status reviewed all medical records in the community (in-patient and out-patient) for each subject. A mean (± SD) of 38 ± 16 years of medical history was available for carriers and non-carriers. The nurse abstractor collected the following information for both carriers and non-carriers: date of birth, vital status (if dead, the immediate and underlying cause of death and any autopsy results were recorded), date of death or last clinical follow-up, and date of the venous thromboembolism event. In addition, data were collected on baseline characteristics previously identified as risk factors for venous thromboembolism [31], which included congestive heart failure, active malignant neoplasm (excluding non-melanoma skin cancer), serious neurological disease (stroke or other disease affecting the nervous system with associated extremity paresis, or acute stroke with extremity paresis requiring hospitalization within the previous 3 months), surgery requiring general or regional (spinal or epidural) anesthesia, trauma requiring hospital admission (major fracture or severe soft tissue injury), previous superficial vein thrombosis, and among women, pregnancy or the postpartum period and oral contraceptive use. Active malignant neoplasm, surgery, trauma, pregnancy or the postpartum period, and oral contraceptive use were recorded as present only if documented within the 3 months prior to a venous thromboembolic event. Congestive heart failure, serious neurologic disease, and superficial thrombophlebitis were recorded as present if documented anytime prior to the incident venous thromboembolic event. Finally, for women carriers and non-carriers, the numbers of pregnancies and live births were also recorded.

Diagnostic criteria for venous thromboembolism

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Study population
  6. Identification of FV Leiden carriers and non-carriers
  7. Study design and data collection
  8. Diagnostic criteria for venous thromboembolism
  9. Analysis
  10. Results
  11. Discussion
  12. Acknowledgements
  13. References

A deep vein thrombosis or pulmonary embolism was diagnosed based on previously described criteria [32]. Briefly, a deep vein thrombosis or pulmonary embolism was diagnosed when confirmed by objective diagnostic testing, or when the medical record documented that (i) a physician made a diagnosis of deep vein thrombosis or pulmonary embolism, (ii) signs and symptoms consistent with deep vein thrombosis or pulmonary embolism were present and (iii) the patient received a course of anticoagulation therapy with heparin, warfarin, or a similar agent, or a surgical procedure for deep vein thrombosis or pulmonary embolism. A short period of anticoagulation therapy while awaiting completion of diagnostic evaluation for suspected deep vein thrombosis or pulmonary embolism was insufficient grounds for inclusion.

Analysis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Study population
  6. Identification of FV Leiden carriers and non-carriers
  7. Study design and data collection
  8. Diagnostic criteria for venous thromboembolism
  9. Analysis
  10. Results
  11. Discussion
  12. Acknowledgements
  13. References

The observed factor V G1691A genotype distribution was compared to the expected distribution based on the estimated allele frequency and the Hardy–Weinberg equilibrium. The age-specific incidence rates of first lifetime venous thromboembolism were calculated among carriers and non-carriers by dividing the number of symptomatic patients in each group by the respective person-years of observation. The age-specific relative risk of venous thromboembolism was calculated by dividing the incidence in carriers by the incidence in non-carriers. Confidence interval estimates were based on the Poisson distribution. The Kaplan–Meier product limit estimator method was used to estimate probability of venous thromboembolism (one minus the survival free of venous thromboembolism).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Study population
  6. Identification of FV Leiden carriers and non-carriers
  7. Study design and data collection
  8. Diagnostic criteria for venous thromboembolism
  9. Analysis
  10. Results
  11. Discussion
  12. Acknowledgements
  13. References

Of the 3424 residents screened, 230 were positive by our FV Leiden genotyping assay (carrier frequency 6.7%); all were confirmed to have the FV Leiden mutation by direct sequencing. A random sample of 100 residents from the 3194 who were negative by our FV Leiden genotyping assay were confirmed to be homozygous wild-type by direct sequencing. Of the 230 FV Leiden carriers, two were homozygotes (FV Leiden allele frequency 3.4%). The observed genotype distribution did not differ significantly from the expected distribution as predicted by the Hardy–Weinberg equilibrium (χ2 = 0.703), suggesting no survival disadvantage among FV Leiden carriers. Consequently, a retrospective cohort study of FV Leiden carriers was performed to estimate the incidence of venous thromboembolism.

Two hundred and twenty FV Leiden carriers could be matched to a non-carrier. The mean (± SD) ages for carriers and non-carriers were 67.7 years (± 11.0) and 67.3 years (± 10.6), respectively, and 59% were female. Of the carriers and non-carriers, 99% were white and of Western European ancestry, while the remainder were white and of Eastern European ancestry. This ethnic distribution is consistent with that in south-eastern Minnesota. The mean body mass index was significantly higher for carriers (Table 1). Otherwise, carriers and non-carriers were similar with regard to persistent baseline characteristics previously identified as potential risk factors for venous thromboembolism.

Table 1.  Demographic and persistent baseline characteristics that are potential risk factors for venous thromboembolism among FV Leiden carriers and non-carriers
Baseline characteristicCarrierNon-carrier
Age, years (SD)67.7 (11.0)67.3 (10.6)
Age range, years45–9546–92
Height, cm (SD)165.7 (13.9)166.4 (9.4)
Weight, kg (SD)76.6 (16.3)78.6 (19.1)
Body mass index, kg m−2 (SD)33.5 (5.0)28.4 (6.8)
Congestive heart failure, n (%)18 (8.2)19 (8.6)
Previous superficial vein thrombosis, n (%)11 (5.0)8 (3.6)
Neurologic disease with extremity paresis, n (%)1 (0.5)5 (2.3)
Malignant neoplasm, n (%)01 (0.2)

Twenty-four of the 220 carriers (10.9%) developed a first lifetime deep vein thrombosis or pulmonary embolism during the 14 722 person-years of observation, giving an overall incidence rate of 163 per 100 000 person-years (95% CI 104, 243). If the period at risk was restricted to those 15 years of age or older, the overall incidence rate was 210 per 100 000 person-years (95% CI 135, 313).

Venous thromboembolism incidence rates varied by age group for both FV Leiden carriers and non-carriers (Table 2). Venous thromboembolism was uncommon among carriers < 60 years of age. The age-specific venous thromboembolism incidence rates among carriers increased dramatically with older age (Fig. 1). The age-specific incidence rate for non-carriers also increased progressively with age. The cumulative venous thromboembolism incidence at age 65 years was 6.3% (95% CI 2.7%, 9.7%) among carriers, and 5.2% (95% CI 2.0%, 8.4%) among non-carriers.

Table 2.  Age-specific annual incidence of first lifetime venous thromboembolism among south-eastern Minnesota FV Leiden carriers and non-carriers
VariableAge group (years)
15–2930–4445–59≥ 60
  1. VTE, venous thromboembolism.

Factor V Leiden carrier
 Number per age group, n (female)220 (130)220 (130)217 (128)153 (89)
 First episode of VTE, n02715
 Observation period, years3300328928691963
 Annual incidence per 100 000 (95% CI)0 (0, 111.8)60.8 (7.4, 218.9)244.0 (98.1, 501.8)764.0 (427.8, 1260.2)
Factor V Leiden non-carrier
 Number per age group, n (female)220 (130)217 (127)216 (126)152 (82)
 First episode of VTE, n3144
 Observation period, years3289324928871860
 Annual incidence per 100 000 (95% CI)91.2 (18.9, 266.1)30.8 (0.8, 179.8)138.5 (37.8, 355.0)215.1 (58.6, 551.1)
 Relative risk (95% CI)0 (0, 1.22)1.96 (0.24, 7.04)1.73 (0.70, 3.56)3.61 (2.02, 5.95)
image

Figure 1. Cumulative incidence of first lifetime deep vein thrombosis or pulmonary embolism among a cohort of south-eastern Minnesota FV Leiden mutation carriers (solid line), and age-, sex-, and ethnic ancestry-matched-non-carriers (broken line).

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The relative risk for venous thromboembolism among carriers was increased approximately two-fold between age groups 30–44 years and 45–59 years, although the increase in risk did not reach statistical significance (Table 2). However, the relative risk was significantly increased 3.6-fold for FV Leiden carriers that were ≥ 60 years.

Among the 24 FV Leiden carriers who developed venous thromboembolism, three had a persistent risk factor for venous thromboembolism [congestive heart failure, n = 2 (8.3%); previous superficial thrombophlebitis, n = 1 (4.2%)], and six had had a transient risk factor within the 3 months prior to the event [surgery, n = 4 (17.7%); trauma, n = 2 (8.3%)]. The venous thromboembolism event was idiopathic for almost two-thirds of the affected carriers.

There were 348 pregnancies (gravida) and 311 live births (para) among 129 FV Leiden women carriers, and 413 pregnancies and 365 live births among 130 non-carriers (data regarding pregnancy were missing for one carrier). For both carriers and non-carriers, the number of pregnancies per woman ranged from zero to 10. The distribution of the difference between gravida and para per woman did not differ significantly among carriers and non-carriers (Fisher's exact P-value = 0.7). No venous thromboembolism events occurred during pregnancy or postpartum among carriers [venous thromboembolism incidence = 0 (95% CI 0, 1186) per 100 000 women-years], while two events occurred among pregnant or postpartum non-carriers [venous thromboembolism incidence = 548 (95% CI 66, 1979) per 100 000 women-years].

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Study population
  6. Identification of FV Leiden carriers and non-carriers
  7. Study design and data collection
  8. Diagnostic criteria for venous thromboembolism
  9. Analysis
  10. Results
  11. Discussion
  12. Acknowledgements
  13. References

Our observed 6.7% FV Leiden carrier frequency among residents in south-eastern Minnesota is similar to the frequency reported in other populations of predominantly white European ancestry [2,33,34] but somewhat higher than the frequency reported in white Americans [35] or Canadians [36]. To avoid sampling bias, we included residents in our cohort without knowledge of either medical diagnoses or indication for venepuncture. However, it is possible that our observed carrier rate may have overestimated the true rate because residents with thrombosis (and carriers of the FV Leiden allele) might be more likely to undergo venepuncture.

We found a FV Leiden allele frequency of 3.4%. Based on the Hardy–Weinberg equilibrium, our observed genotype distribution did not differ significantly from the expected distribution. This finding is consistent with the hypothesis that the FV Leiden allele conveys no survival disadvantage and is supported by other studies suggesting no excess mortality among FV Leiden carriers [34,37,38]. Thus, we believe our estimates of cumulative incidence and age-specific venous thromboembolism incidence rates were unaffected by survival disadvantage.

Of the 220 FV Leiden carriers studied in the matched retrospective cohort analysis, the cumulative incidence of venous thromboembolism by age 65 years was 6.3% (95% CI 2.7%, 9.7%). While our estimate is 2.6-fold higher than the 2.4% cumulative incidence by age 65 years estimated by Rodeghiero et al. [13], the lower limit of our 95% CI is similar (2.7% vs. 2.4%). Selection bias is unlikely to have affected our findings because even if residents with thrombosis were more likely to undergo venepuncture and be ascertained for study, this would have occurred regardless of FV Leiden status. The cohort was obtained prior to the discovery of the FV Leiden mutation and there is no reason to expect that unobserved genotype would have influenced medical care protocols. For the same reasons, our observed incidence rates cannot be lower than the true rates because of more aggressive prophylaxis for carriers.

The reported venous thromboembolism incidence rates among FV Leiden carriers over 15 years of age vary widely, ranging from 280 to 670 per 100 000 person-years [18–22]. At 210 per 100 000 person-years, our observed incidence rate for carriers 15 years of age or older was about 25% lower than the lowest previously reported incidence rate. We believe our lower rate is the result of differences in study design. Most previously reported studies identified asymptomatic FV Leiden carriers by studying members of families identified from a proband FV Leiden carrier with venous thromboembolism. Because other heritable (but unmeasured or as yet, unidentified) risk factors for venous thromboembolism may be operating in these families [39,40], the incidence of venous thromboembolism may be increased among asymptomatic FV Leiden carrier family members compared to carriers identified from the general population. This may also account for our lower age-specific incidence among FV Leiden carriers of younger age (Table 2). We found no episodes of venous thromboembolism among carriers aged 15–30 years, compared to previously reported rates of 180–259 per 100 000 person-years (Table 3) [18,20]. Similarly, our rates for the 30–44 and 45–59 years age groups (61 and 244 per 100 000, respectively) were considerably lower than other reported rates in asymptomatic FV Leiden family members (260–470, and 380–820 per 100 000, respectively; Table 3). In the only other non-family member study that reported incidence rates, the Physician's Health Study also found rates that were much lower in younger age male carriers compared to family member carriers (Table 3) [41].

Table 3.  Reported age-specific annual incidence (95% CI) and relative risk of first lifetime venous thromboembolism among FV Leiden carriers
AuthorVenous thromboembolism incidence per 100 000 person-years (95% CI) by age group
  • *

    Compared to Factor V Leiden non-carriers.

Ridker et al.[41]
 Age group (years)  40–4950–5960–69≥ 70
 Incidence  0197 (72, 428)258 (95, 561)783 (358, 1486)
 Relative risk*  2.72.74.2
Middeldorp et al.[18]
 Age group (years) 15–3030–4545–60> 60 
 Incidence 250 (120, 490)470 (230, 860)820 (350, 1610)1100 (240, 3330) 
 Relative risk* ∼154.32.42.8 
Simioni et al.[20]
 Age group (years)< 1516–3031–4546–60> 60 
 Incidence0182 (59, 424)264 (86, 616)380 (104, 973)730 (150, 2128) 
 Relative risk*3.63.71.4∼700 

Also similar to the Physician's Health Study results [41], our relative risk of venous thromboembolism was only significantly increased among FV Leiden carriers of older age. However, we cannot exclude the possibility that a true increase in relative risk for venous thromboembolism among carriers in the age groups 30–44 and 45–59 years was missed because of sample size. Nevertheless, when counseling a FV Leiden carrier regarding the current and future risk of venous thromboembolism, patient age must be considered in the estimate. We do not believe a difference in exposure to persistent risk factors for venous thromboembolism accounted for the difference in the observed venous thromboembolism incidence among older carriers compared to non-carriers. The prevalence of persistent risk factors among carriers and non-carriers was similar. Moreover, because almost two-thirds of the venous thromboembolism events among carriers were idiopathic, exposure to transient risk factors also cannot explain the higher venous thromboembolism incidence in carriers. The mean body mass index was moderately, but significantly, higher among carriers. While we previously showed that body mass index is not an independent risk factor for venous thromboembolism [31], a recent study found that body mass index, tobacco smoking, patient age, and the FV Leiden mutation interacted to increase the incidence of venous thromboembolism [34]. Our sample size had insufficient power to test for such an interaction. Thus, we cannot exclude the possibility that the higher body mass index among carriers accounted for at least a part of the increased venous thromboembolism incidence among carriers with advancing age.

The total number of pregnancies among non-carriers was greater compared to FV Leiden carriers. While the FV Leiden mutation may affect ovum fertilization, embryo implantation, or very early embryo viability [42,43], carrier status had no effect on the number of pregnancies progressing to term or on delivery of a live child. In our study, medical record evidence of oral contraceptive use was inadequate to estimate the number of women-years of oral contraceptive use. However, women of reproductive age presenting with acute venous thromboembolism are always questioned regarding the use of oral contraceptives in our institution, and none of the venous thromboembolism episodes among carriers occurred during oral contraceptive use. Thus, we believe the incidence of venous thromboembolism among women carriers receiving oral contraceptives is low even though the relative risk is increased [44]. Likewise, the venous thromboembolism incidence among pregnant or postpartum FV Leiden carriers was low.

Our findings have several important implications. First, almost 90% of FV Leiden carriers reached older age or lived their entire lives without developing venous thromboembolism. Given the current cost of oral anticoagulant prophylaxis (including both health-care charges and the risk of bleeding), a policy of general population screening for the FV Leiden allele and chronic prophylaxis of asymptomatic carriers is clearly unwarranted. Second, given the extremely low incidence of venous thromboembolism among carriers during pregnancy and the lack of an effect of the FV Leiden mutation on carrying a pregnancy to term and delivery of a live child, screening asymptomatic women prior to pregnancy also appears unwarranted [18,22]. However, the incidence of venous thromboembolism among older female carriers is substantially higher and a policy of screening women considering hormone therapy for FV Leiden may be warranted [44], especially if the indication for potential estrogen replacement could be managed by other non-estrogen therapy. For pregnant carriers, the incidence of venous thromboembolism is low and prophylaxis is unwarranted. However, the risk of venous thromboembolism during the puerperium is substantially higher than during pregnancy for all postpartum women [45], and the period of risk is shorter. Thus, a policy of prophylaxis for asymptomatic postpartum FV Leiden carriers may be appropriate [18]. Finally, similar to the general population [32,46], the incidence of venous thromboembolism among FV Leiden carriers increases with age. Consequently, a policy of only testing those patients who develop a first lifetime venous thromboembolism before age 45 years will miss most symptomatic FV Leiden carriers.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Study population
  6. Identification of FV Leiden carriers and non-carriers
  7. Study design and data collection
  8. Diagnostic criteria for venous thromboembolism
  9. Analysis
  10. Results
  11. Discussion
  12. Acknowledgements
  13. References

This work was funded, in part, by grants from the National Institutes of Health (HL60279 and HL 66216), US Public Health Service and by the Mayo Foundation. We thank Mary Till R.N. for assistance in medical record abstraction, and Ann Beauseigneur for secretarial assistance.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Study population
  6. Identification of FV Leiden carriers and non-carriers
  7. Study design and data collection
  8. Diagnostic criteria for venous thromboembolism
  9. Analysis
  10. Results
  11. Discussion
  12. Acknowledgements
  13. References
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