THROMBOPHILIA

Key points:

• Factor V Leiden (FVL) is a genetic mutation of which heterozygosity has been identified in 5.3% of Canadian blood donors
• The relative risk of VTE for FVL heterozygotes is between 2 and 7 times (i.e. Risk of VTE estimated ≤ 0.7% per year) and approximately 80 in homozygotes
• Use of oral contraceptive pill (OCP) in FVL heterozygotes increases the relative risk of VTE by 7 to 35 times
• Presently, recommendations for VTE prophylaxis around the time of surgery for FVL heterozygotes are the same as the general population

The question:
You follow a previously healthy obese Caucasian 21year old male in your clinic as well as several of his family members.  His grandfather was found to have heterozygous Factor V Leiden mutation after he developed a DVT post-hip replacement.  Your patient asks about his need for screening.  He gives his consent for “whatever you think is necessary” but does not seem overly anxious.

Do you think Factor V Leiden testing is indicated in this patient?

Yes                   No                                

Would you like to do any other thrombophilia screening in this patient?

On a scale from -1 (less likely to screen) to +1 (more likely to screen), how does the following information affect your choice to screen?                                

Issues addressed:

• Factor V Leiden
• Screening in asymptomatic relatives
• Gender and thrombophilia screening
• Obesity

Factor V Leiden

Factor V Leiden (FVL) is the most common inherited thrombophilia and occurs as the result of a genetic mutation.  The native activated Factor V protein acts as a cofactor in the conversion of prothrombin to thrombin, which then goes on to produce fibrin and promote platelet activation.  Activated Factor V is then cleaved by activated protein C (APC) and subsequently cleared from circulation.  The mutant version of Factor V is less susceptible to cleavage and is therefore inactivated more slowly.  This form of APC resistance results in a hypercoagulable state via production of thrombin.1  Other forms of both inherited and acquired resistance exist (ex. Factor V Cambridge).  Hence APC resistance adn FVL are not synonymous, but other states are much less common.  FVL can exist in a homozygous or heterozygous state (>90% of all cases) and is more common in Caucasian populations.  One study in Canadian blood donors identified heterozygosity in 5.3% of subjects.2  

The clinical significance of FVL remains greatly disputed.  In the Leiden thrombophilia study, heterozygotes experience increased incidence of DVT with a relative risk of approximately 7 as compared to homozygotes, who had a relative risk of 80. 3 ,4  However, in pedigree studies of families containing inherited thrombophilias, the lifetime risk of developing any VTE with FVL was only 2.2 times higher for carriers5.  Risk of recurrent DVT is even less well established in FVL carriers.  Meta-analyses have reported low odds ratios of 1.3 to 1.41 over 5 to 8 years of follow-up.6,7 back to issues 

Screening in asymptomatic relatives

Given the pedigree presented in this scenario, the patient has an approximate 28% possibility of carrying the FVL mutation.  2.6% (1/2 of 5.3%) of this risk comes from his mother (Canadian population) plus 25% from his father.  Similarly he has a about a 1.5% risk of homozygosity.  Given the fact that the patient’s grandfather did not have a DVT until the additional risk factors of age and immobility were present, it is highly unlikely that any additional non-FVL thrombophilia states are present.  Despite the moderate risk that the patient is a FVL carrier, screening is not indicated.  This is because the risk of major hemorrhage with prophylactic anticoagulation (1-4% per year), 8,9 exceeds the risk of first time VTE in this patient.  However, it remains worthwhile to educate the patient on identification of VTE and conservative measures such as those described below for long haul travel (see scenario 3 Long Haul Travel).  These methods are cheap and effective, and do not have the downside of genetic labeling, which has psychological consequences, and has occasionally been associated with difficulties in obtaining life insurance coverage.

Gender and Factor V Leiden

With respect to decision analysis, an argument could be made that the fact the patient is male makes one less likely to screen.  Oral contraceptives and hormone replacement have been associated with acquired APC resistance and the additional hypercoagulable state has been shown to increase the annual incidence of first VTE in FVL patients from 1 in 1667 to 1 in 345. 3  Recently, a systematic review looked at the evidence between FVL patients on combined oral contraceptive pills compared to carriers who were not taking OCP, and found risk ratios between 1.3 and 35 times for VTE.10, 3 However, the authors agreed with WHO recommendations against screening in asymptomatic females who are considering OCP given the low prevalence of thrombogenic mutations.  

Considerations of Age

Given the fact that Factor V Leiden is a genetic mutation, the patient’s age should not affect the decision to screen for this abnormality.  However, there are additional ethical arguments against the testing of minors that should be considered. back to issues

Obesity

In 2004, a Danish study which looked at Factor V Leiden mutations in the context of additional risk factors was published.  This included obesity (BMI>30).  In all three age categories studied, in both smokers and non-smokers, there was a progressive trend towards increased 10-year risk for venous thromboembolism with increasing BMI, which was more pronounced in homozygotes than heterozygotes.  However, this failed to reach significance.11  Another study found a small risk attributable to obesity (BMI≥30) in recurrent VTE with a ratio of 1.6.12  Obesity has also been described as a risk factor for postoperative VTE.  Interestingly, data from an Italian registry of patients with an acute thromboembolic event suggest that the mortality associated with VTE may be lower in obese patients even after correction for confounders such as cancer status.13  Further study is needed on the interactions of obesity and thrombophilia states. back to issues

Patient Anxiety

It is important to distinguish between a patient’s anxiety about diagnosis and their awareness of screening tests. The downside of testing including possible difficulties obtaining life insurance, implications for family testing etc. should first be discussed with the patient.  Moreover, Identification of FVL heterozygosity will not change the management of this individual. He should receive counseling about VTE identification regardless.  Furthermore, as yet, there is no data to support prophylaxis strategies in asymptomatic carriers of FVL outside usual DVT prophylaxis even around high risk events such as surgery.14 Given the above information, should a patient still wish to have FVL testing, general practitioners will need to determine a strategy on a case by case basis. back to issues