Reference
The complete bibliographic reference for the article according to AJE format.

Middeldorp S, Meinardi JR, Koopman MMW, et al.  A prospective study of asymptomatic carriers of the factor V Leiden mutation to determine the incidence of venous thromboembolism.  Ann Intern Med 2001;135:322-7.

Category of HuGE information
Specify the types of information (from the list below) available in the article:

1. Prevalence of gene variant
2. Gene-disease association
3. Gene-environment interaction
4. Gene-gene interaction
5. Genetic test evaluation/monitoring

2. Gene-disease association
3. Gene-environment association

Objective:  Measure incidence of venous thromboembolism (VTE) in asymptomatic carriers of the factor V Leiden mutation.

Gene(s)
Identification of the following:

1. Gene name
2. Chromosome location
3. Gene product/function
4. Alleles
5. OMIM #

1. Gene name: F5
2. Chromosome location:  1q21-q25
3. Gene product/function: Activated factor V is a cofactor for the conversion of prothrombin to thrombin, a key step in blood clotting.  Thrombin inactivates factor V, creating a feedback mechanism.  The F5 R506Q variant slows the inactivation of factor V, resulting in thrombophilia.
4. Alleles:  R506Q (or 506Q), also known as F5 G1691A or factor V Leiden.
5. OMIM #: 227400

Environmental factor(s)
Identification of the major environmental factors studied (infectious, chemical, physical, nutritional, and behavioral)

Surgery/trauma/immobilization
Pregnancy
Oral contraceptive use
Hormone replacement therapy

Health outcome(s)
Identification of the major health outcome(s) studied

1. Case-control
2. Cohort 
3. Cross-sectional
4. Descriptive or case series
5. Clinical trial
6. Population screening

1. Cohort case definition
2. Exclusion criteria
3. Gender
4. Race/ethnicity
5. Age
6. Time period
7. Geographic location
8. Number of participants

1. Cohort selection criteria: Factor V Leiden carriers who were parents, siblings, or children (>15 years of age) of patients who had a proven episode of VTE
2. Exclusion criteria: History of VTE or long-term therapy with vitamin K antagonists
3. Gender: 234 men, 236 women
4. Race/ethnicity: Not stated
5. Age: 15 to 88 years, mean 43 years
6. Time period: December 1, 1997 to February 1, 2000
7. Geographic location: Netherlands (Amsterdam, Groningen, Maastricht)
8. Number of participants: 470.

1. Environmental factor
2. Exposure assessment
3. Exposure definition
4. Number of participants with exposure data (% of total eligible)

1. Environmental factors:
   Surgery/trauma/immobilization:  
       29 episodes treated with anticoagulation therapy (ACT)
   Pregnancy:
       17 full-term deliveries 
            2 C-sections with ACT
            6 with postpartum ACT
            1 with ACT during first and second trimesters
            8 with no ACT
         7 pregnancies ongoing at end of study
         5 spontaneous abortions (4 women; no additional information provided)
   Oral contraceptive (OC) use:
       66 women (166 person-years)
   Hormone replacement therapy (HRT):
       21 women (34 person-years) 

All exposures were assessed by standardized questionnaire during regular follow-up contacts every 6 months.

1. Gene
2. DNA source
3. Methodology
4. Number of participants genotyped (% of total eligible)

1. Gene: F5
2. DNA source: Not stated
3. Methodology: Polymerase chain reaction-based assay as described in reference
4. Number of Participants genotyped: 470 (100%)

1. Prevalence of gene variant
2. Gene-disease association
3. Gene-environment interaction
4. Gene-gene interaction
5. Genetic test evaluation

2. Gene-disease association
3. Gene-environment interaction

Table 1.  Relation Between Venous Thromboembolism and “High-Risk Situations”

*VTE = venous thromboembolism
**Number of episodes
***Iincludes surgery/trauma/immobilization
****9 women received some anticoagulant prophylaxis, either after C-section (2), first week postpartum (6), or during first and second trimesters (1).

Table 2. Relation Between Venous Thromboembolism and "High-Risk Situations

**Person-years of observation in this group include other “high-risk situations” (table 3. below).

Table 3. **Person-Years of Observation in Other "High-Risk Situations"

Exposure Number of Exposures Number Treated*** VTE Incidence (%) 95% CI  Surgery/trauma/  immobilization 29 29 1 3.5 (0.1 - 7.8)  Full-term pregnancy 17 9 0 0 (0 - 19.5)  Ongoing pregnancy 7 **** 0 0 (0 - 41.0)

“The absolute annual incidence of spontaneous venous thromboembolism in asymptomatic carriers of the factor V Leiden mutation is low (0.26 per 100 person-years) and does not justify routine screening of the families of symptomatic patients.”

The authors state that this is the largest prospective cohort study of asymptomatic factor V Leiden carriers but acknowledge that it is too small to draw conclusions about absolute risk for VTE in “high-risk situations,” such as surgery, pregnancy, or hormone use.  For example, although incidence of VTE among women using HRT  was estimated as 3 per 100 person-years, this estimate was based on one event observed during 34 person-years of HRT among 21 women.

Comparing women who took exogenous hormones (oral contraceptives or hormone replacement therapy) with all others in this study (see Table 2), an estimate of the attributable fraction (exposed) is:

AFe =  (Ie - Iu ) / Ie  =  ([4/200] - [5/1364]) / (4/200) » 0.8,

suggesting that 80% of the risk for VTE in these women was due to hormone use.

Appropriate use of screening and clinical management of factor V Leiden carriers receiving HRT require further study.  Such studies must consider onset and duration of therapy, since data on VTE in OC users (and limited data on HRT users) suggest that risk is greatest soon after beginning hormone use.  When risk varies in this way, a summary point estimate of incidence/person-years does not provide a comprehensive picture of risk.