Factor V Leiden and DVTs: Interview with Elizabeth Varga, MS, CGC

To celebrate DVT Awareness Month, I asked the fabulous Elizabeth Varga for an interview. Liz has factor V Leiden, an inherited blood clotting disorder, and she has worked tirelessly to raise awareness about blood clots and thrombophilias, educating both patients and medical professionals. Liz is also a board-certified genetic counselor at Columbus Children’s Research Institute, where she also develops health promotion programs for the blood clotting disorders community.

Here is the first part of our interview. Stay tuned for more!
1. Can we talk about your personal life first? How did you learn you had factor V Leiden? How did it impact your personal and professional life?
Sure, I am always happy to share my story. My factor V Leiden story actually started with my mom. In 1999, she was traveling and hiking when her leg became painful and red. When she felt her leg, it felt like there was a large rope running down the inside of her thigh. She soon learned she had “superficial thrombophlebitis”; basically a blood clot running through the outer veins in her leg. She didn’t have to have any treatment for this, besides resting and taking pain killers. But when her doctor interviewed her, he learned that her father had had several similar episodes. It was then that he recommended testing for several clotting disorders. A couple weeks later, she learned she was heterozygous (had 1 copy) of the factor V Leiden mutation.
At the time, I was in college, so I didn’t know much about the incident. However, on a visit back home, I met with my family doctor for a checkup and she started to talk to me about the gene found in my mom. She told me that she had a colleague also had factor V Leiden. This woman had had a stroke at the age of 40; it was later learned that her colleague had a hole in her heart (called a patent foramen ovale or PFO) and that a small clot had developed in her leg veins that traveled to her brain.

My doctor also told me about birth control pills and how they could interact with factor V Leiden. She said she would recommend that I discontinue taking the pill if I tested positive. So, I decided to take the genetic test and go from there.

A couple of weeks later, on a Saturday morning that I still remember as clear as day, my doctor called me at home. She told me that the test had come back positive; I was heterozygous for factor V Leiden. She also read me the paragraph summary on the lab report and said that I had a “5-7 fold increase in risk for venous thromboembolism” and talked about the added risk with hormones. She then told me to stop taking the birth control pill.

I did what she suggested and went off the pill. I was glad to know my test result so I could make that decision. But, then I was left with a lot of questions. It was at that point that I really started to wonder “so what is venous thromboembolism anyway?” and “is it really worth all this hassle to lower my risk?”

The way I coped was through reading vigorously…I read everything I could get my hands on. I soon learned a lot more about clots. But I also learned a lot of other things, some that were scary. I found out I might have a harder time with pregnancy someday because there could be a higher risk of pregnancy loss from blood clots in the placenta. I also learned about placental abruption—where the placenta tears away from the uterus during pregnancy, causing bleeding. That’s when it hit me. My mom had something very similar while pregnant with me! I always remember her telling me that she felt she had “had the experience of having a miscarriage”, when they told her that there was no hope and she was going to lose me. Miraculously, hours later, when I still had a heartbeat, they realized I was not going away that easily! In fact, her pregnancy did continue, and although I was born 2 months premature, I did just fine!!!

It was amazing to me to see just how much factor V Leiden explained! It explained not only the episode my mom had in pregnancy, her clot and her dad’s, but as we researched the family history, we learned that other family members, including my mom’s cousins, had had blood clots. Yet, they had never been evaluated for thrombophilia!

During this period, I remember experiencing all different emotions. I was grateful because I knew…I could prevent clots and maybe problems with pregnancy down the road. But I was also a bit scared and bewildered. What would this really mean for me? What would it mean for my younger cousins? Some of them were on the pill…should they be tested?

As fate would have it, I started genetic counseling graduate school only a few months after learning my result. As I went through classes, and learned about all that is involved with genetic counseling, including extensive education and support that is offered pre- and post-testing, I was astounded. Why didn’t I get that kind of education? I had been left to learn so much on my own! I had been left to cope with all of my fears on my own. I had been left with questions about what to tell my family members, who were now turning to me for advice. I was just frustrated, and mad. But I wanted to do something about it!

It was really this experience that made me want to know…was my experience unique? Were other people out there getting testing, but not getting information? How did they “cope” with their test results? Did their results worry them—make them anxious, or was it just me? How well did they understand the implications of their results?

These questions evolved into my research thesis. I surveyed about 170 people with factor V Leiden and asked them about their knowledge, education needs and how testing had impacted their lives from a psychological point of view. The response I got was incredible. People wrote me essays on the back of the questionnaire. They shared their stories (including one who wrote me from her mother’s hospital bedside) and their fears; but they also showed me they were empowered! While many acknowledged that they did not get enough information when diagnosed and some worried more because of their results, overwhelmingly, people told me, they were glad to know! They also wanted their health care providers to know more, and they wanted to be educated themselves.

These results have shaped my entire personal life and my career path. After hearing the voices of so many with thrombophilia, many in desperate need for education about their disorder, I could not help but respond. Dr. Stephan Moll, my collaborator in my thesis research, invited me to come to North Carolina to speak at a patient symposium. We invited all of the respondents to my questionnaire and spent the whole evening teaching them about thrombophilia. Afterwards, people approached us to express their thanks. It felt so good to me to use my knowledge to help someone else. I realized I had something to offer.

From that point on, I have been dedicated to educating patients and families with thrombosis and thrombophilia. I want people to be tested appropriately, and when they are, I want them to understand their results. I want them to be empowered by the information. I want them to be able to prevent blood clots. I want to avoid unnecessary deaths.

I have been fortunate to be able to fulfill this dream by providing genetic counseling, speaking at education seminars for patients and by getting involved with organizations like the National Alliance for Thrombosis and Thrombophilia (NATT). It is incredibly rewarding to be able to assist in the creation of education materials, and to speak with others whose experiences amaze and enlighten me. I am also grateful to be able to assist with DNA Direct, who aspires to create quality education materials for patients with thrombophilia.

Battery powered car

(CNN) -- Sen. John McCain on Monday called for a $300 million prize to whoever can develop a battery that will "leapfrog" the gasoline-saving abilities of current hybrid and electric cars.

Sen. John McCain wants someone to develop a battery that can "leapfrog" those available in current electric cars.

Saying the U.S. needs to take action because of high oil prices, the Republican presidential candidate said he wants his offer to "deliver a power source at 30 percent of the current costs."
"[The prize would amount to] $1 for every man, woman and child in the U.S. -- a small price to pay for helping to break the back of our oil dependency," McCain said during a town hall-style meeting at California's Fresno State University.
McCain's Democratic rival, Sen. Barack Obama, also was expected to address energy issues Monday during a talk with working women at the Flying Star Cafe in Albuquerque, New Mexico.
McCain said the new automobile battery should have "the size, capacity, cost and power to leapfrog the commercially available plug-in hybrids or electric cars." Watch more on McCain's $300 million reward »
"In the quest for alternatives to oil, our government has thrown around enough money subsidizing special interests and excusing failure," McCain said. "From now on, we will encourage heroic efforts in engineering, and we will reward the greatest success."
McCain also called Monday for a "Clean Car Challenge" for U.S. automakers, hoping to spur them to develop and sell vehicles with no carbon emissions. The challenge would allow $5,000 tax credits to buyers of such cars, making those vehicles more appealing to consumers and thus easier to sell.
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"We're going to see technology for electric-powered cars that are going to be [made cheaper] with our incentives," McCain said.
McCain also spoke against policies that he said "prevent consumers from benefiting" from ethanol not made from corn. He cited the U.S. subsidies for corn-based ethanol and tariffs on sugar cane-based ethanol from Brazil.
"Instead of playing favorites, our government should level the playing field for all alcohol fuels that break the monopoly of gasoline, both lowering gasoline prices and carbon emissions," he said.
McCain's remarks came a day after Obama called for greater oversight for energy traders.
Obama on Sunday, blaming skyrocketing gas prices in part on speculation, proposed fully closing what he called a loophole that exempts most over-the-counter energy trades from regulation.
His campaign said many economists believe speculation could be adding between $20 and $50 to the price of a barrel of oil. The price per barrel closed near $135 on Friday.
He said current law prevents the Commodity Futures Trading Commission from fully overseeing the oil futures market and investigating cases in which excessive speculation may be increasing oil prices.
His campaign noted that the so-called loophole would be partially closed by a provision in a farm bill that was passed this year. But he said his plan would fully close it by requiring that U.S. energy futures are traded on regulated exchanges.
"My plan fully closes the ... loophole and restores common-sense regulation as part of my broader plan to ease the burden for struggling families today while investing in a better future," the Illinois Democrat said in a statement Sunday.
Meanwhile, monthly campaign finance reports filed in June show the candidates are nearly level in the amount of money they have available to spend before their parties' conventions.
According to a report filed with the Federal Election Commission, Obama had $43.1 million in the bank at the start of June. However, $9.8 million of that amount is designated for the general election, meaning only the remaining $33.3 million may be spent before the conventions.
McCain, according to his report filed with the FEC, began June with about $31.4 million available to spend before the conventions.
McCain had only $123,000 set aside for the general election. However, since indicating he will accept public financing for the general election, he has returned nearly all of the money he has raised for it.
Obama said last week he would not accept public financing. Republicans and outside analysts have said Obama found he could raise more money than public financing would allow him to spend.

Factor V Leiden Thrombophilia
[Hereditary Resistance to Activated Protein C, Factor V Leiden Mutation. Includes: Hereditary Resistance to Activated Protein C, Factor V Leiden Mutation]
Jody L Kujovich, MD
Northwest Cancer Specialists Clinical Assistant Professor Department of Medicine Division of Hematology/Oncology Oregon Health & Science University Portland kujovich@ohsu.edu 17022007 factor-v-leiden
Created May 14, 1999.
Last updated February 17, 2007.
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Summary
Disease characteristics. Factor V Leiden thrombophilia is characterized by a poor anticoagulant response to activated protein C (APC) and an increased risk of venous thromboembolism (VTE). Deep venous thrombosis (DVT) is the most common VTE, with the legs being the most common site. Thrombosis in unusual locations is less common. Evidence suggests that a heterozygous factor V Leiden mutation has at most a modest effect on the risk of recurrence after initial treatment of a first VTE. Heterozygosity for factor V Leiden is associated with a two- to threefold increase in relative risk of pregnancy loss, and possibly other pregnancy complications such as preeclampsia, fetal growth retardation, and placental abruption. The clinical expression of factor V Leiden thrombophilia is influenced by: (1) the number of factor V Leiden alleles (heterozygotes have a slightly increased risk for venous thrombosis; homozygotes have a much greater thrombotic risk); (2) coexisting genetic thrombophilic disorders, which have a supra-additive effect on overall thrombotic risk; (3) acquired thrombophilic disorders: hyperhomocysteinemia, high factor VIII levels, malignancy; (4) circumstantial risk factors: travel, central venous catheters, pregnancy, oral contraceptive use, hormone replacement therapy (HRT), selective estrogen receptor modulators (SERMs), organ transplantation, advancing age, and surgery.

Diagnosis/testing. Factor V Leiden thrombophilia is suspected in individuals with a history of venous thromboembolism (VTE) manifest as deep vein thrombosis (DVT) or pulmonary embolism, especially in women with a history of VTE during pregnancy or in association with oral contraceptive use, and in individuals with a personal or family history of recurrent thrombosis.The diagnosis of factor V Leiden thrombophilia is made either using a coagulation screening test or by DNA analysis of the F5 gene, which encodes the factor V protein. The term "factor V Leiden" refers to the specific G-to-A substitution at nucleotide 1691 in the gene for factor V that predicts a single amino acid replacement (R506Q) at one of three APC cleavage sites in the factor Va molecule.

Management. Treatment of manifestations: The first acute thrombosis is treated according to standard guidelines [course of intravenous unfractionated heparin or low molecular-weight heparin and concurrent oral administration of warfarin (except during pregnancy)]. The duration of oral anticoagulation therapy is debated. Long-term oral anticoagulation is considered in those with recurrent VTE, multiple thrombophilic disorders, or coexistent circumstantial risk factors and in factor V Leiden homozygotes. Prevention of primary manifestations: In the absence of a history of thrombosis, long-term prophylactic anticoagulation is not routinely recommended for asymptomatic factor V Leiden heterozygotes. A short course of prophylactic anticoagulation when circumstantial risk factors are present may prevent initial thrombosis in factor V Leiden heterozygotes. Prevention of secondary complications: Enoxaparin prophylaxis in women heterozygous for factor V Leiden who have a history of recurrent pregnancy loss seems to increase the likelihood of a favorable pregnancy outcome. Surveillance: periodic reevaluation of individuals on long-term anticoagulation to assess risks (bleeding) vs. benefits.

Agents/circumstances to avoid: oral contraceptives and HRT (homozygous women with or without prior VTE; heterozygous women and a history of VTE); asymptomatic heterozygous women using oral contraceptives should avoid third-generation formulations. Testing of relatives at risk: Molecular genetic testing can establish the genetic status of asymptomatic at-risk family members; however, the indications for family testing are unresolved. Clarification of factor V Leiden allele status may be useful in at-risk relatives considering hormonal contraception or pregnancy or in families with a strong history of recurrent venous thrombosis at a young age. Asymptomatic factor V Leiden heterozygotes and homozygotes should be aware of the signs and symptoms of VTE that require immediate medical attention and the potential need for prophylactic anticoagulation in high-risk circumstances.

Genetic counseling. Heterozygosity for the factor V Leiden allele and the associated risk for venous thrombosis are inherited in an autosomal dominant manner. Homozygosity for the factor V Leiden allele and a much greater risk for venous thrombosis are inherited in an autosomal recessive manner. Because of the high prevalence of the factor V Leiden allele in the general population, the genetic status of both parents and/or the reproductive partner of an affected individual needs to be evaluated before information regarding potential risks to sibs or offspring can be provided. While technically possible, prenatal testing does not seem relevant for this complex disorder, in which the genetic change is common in the general population and is predisposing to, but not predictive of, thrombosis.

Diagnosis
Clinical Diagnosis
No clinical features are specific for factor V Leiden thrombophilia. The diagnosis of factor V Leiden thrombophilia requires either the APC resistance assay as a coagulation screening test or DNA analysis of F5, the gene encoding factor V, to identify the Leiden mutation, a specific G-to-A substitution at nucleotide 1691 that predicts a single amino acid replacement (R506Q).
Factor V Leiden thrombophilia is suspected in individuals with a history of venous thromboembolism (VTE) manifest as deep vein thrombosis (DVT) or pulmonary embolism, especially in women with a history of VTE during pregnancy or in association with oral contraceptive use, and in individuals with a personal or family history of recurrent thrombosis.
The growing consensus is that factor V Leiden testing should be performed in the following circumstances [ACMG Consensus Statement 2001, CAP Consensus Conference Statement 2002, Manco-Johnson et al 2002, Bates et al 2004]:
A first VTE before age 50 years
A first unprovoked VTE at any age
A history of recurrent VTE
Venous thrombosis at unusual sites (e.g., cerebral, mesenteric, portal, and hepatic veins)
VTE during pregnancy or the puerperium
VTE associated with use of oral contraceptives or hormone replacement therapy (HRT)
A first VTE in an individual with a first-degree family member with VTE before age 50 years
Women with unexplained fetal loss after ten weeks' gestation
Factor V Leiden testing may be considered in the following individuals:
Selected women with unexplained severe preeclampsia, placental abruption, or a fetus with intrauterine growth retardation
A first VTE related to the use of tamoxifen or other selective estrogen receptor modulators (SERMs)
Female smokers younger than age 50 years with a myocardial infarction or stroke
Individuals older than age 50 years with a first provoked VTE in the absence of malignancy or an intravascular device
Asymptomatic adult family members of probands with a known factor V Leiden mutation, especially those with a strong family history of VTE at a young age
Asymptomatic female family members of probands with known factor V Leiden thrombophilia who are pregnant or are considering oral contraceptive use or pregnancy
Women with recurrent unexplained first-trimester pregnancy losses with or without second- or third-trimester pregnancy losses
Children with arterial thrombosis
Factor V Leiden testing is not recommended for the following:
General population screening
Routine initial test during pregnancy
Routine initial test prior to the use of oral contraceptives, hormone replacement therapy (HRT), or SERM
Prenatal or newborn testing
Routine testing in asymptomatic children
Routine initial test in individuals with arterial thrombosis. However, testing may be considered in individuals younger than age 50 years with unexplained arterial thrombosis (such as women with stroke associated with oral contraceptives)
Testing
Factor V Leiden is inactivated at a rate approximately ten times slower than normal factor V and persists longer in the circulation, resulting in increased thrombin generation and a mild hypercoagulable state, reflected by elevated levels of prothrombin fragment F1+2 and other activated coagulation markers [Martinelli et al 1996, Zoller et al 1996].
The APC resistance assay is a coagulation screening test based on the aPTT; two versions are available:
The "original" APC resistance assay involves performing an aPTT on the individual's plasma in the presence and absence of a standardized amount of exogenous APC; the two results are expressed as a ratio (aPTT + APC / aPTT – APC). This assay is based on the principle that when added to normal plasma, APC inactivates factors Va and VIIIa, which slows coagulation and prolongs the aPTT. The APC-resistant phenotype is characterized by a minimal prolongation of the aPTT in response to APC and a corresponding low ratio. The original assay has a sensitivity and specificity of 85%-90% for factor V Leiden. It is unreliable in individuals with a baseline prolonged aPTT resulting from warfarin or heparin anticoagulation, other coagulation defects, or a lupus inhibitor, and it may be altered by the hemostatic changes that occur during pregnancy or acute thrombosis.
The modified ("second-generation") APC resistance assay overcomes these limitations, is now more widely available, and has a sensitivity and specificity for factor V Leiden approaching 100% [Kapiotis et al 1996]. In this assay, the individual's plasma is first diluted (1:4) in factor V-deficient plasma that contains polybrene, a heparin neutralizer. The addition of the factor V-deficient plasma corrects for deficiencies of all other coagulation proteins, neutralizes therapeutic concentrations of heparin, and also eliminates the effect of some lupus inhibitors. The assay can be used for individuals receiving warfarin or heparin anticoagulation and for many individuals with lupus inhibitors, as well as in the setting of acute thrombosis, pregnancy, or inflammation [Svensson et al 1997].

Molecular Genetic Testing
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by at least one US CLIA-certified laboratory or a clinical laboratory outside the US. GeneTests does not independently verify information provided by laboratories and does not warrant any aspect of a laboratory's work. Listing in GeneTests does not imply that laboratories are in compliance with accreditation, licensure, or patent laws. Clinicians must communicate directly with the laboratories to verify information. —ED.
Gene. F5, the gene encoding factor V, is the only gene associated with factor V Leiden thrombophilia.
Clinical uses
Diagnostic testing
Predictive testing
Prenatal diagnosis
Preimplantation genetic diagnosis
Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).
Clinical testing
Targeted mutation analysis. Targeted mutation analysis for factor V Leiden is performed by a variety of comparable methods [ACMG Consensus Statement 2001].
Table 1 summarizes molecular genetic testing for this disorder.
Table 1. Molecular Genetic Testing Used in Factor V Leiden Thrombophilia
Test Method
Genetic Mechanism
Mutation Detection Rate
Test Availability
Targeted mutation analysis
G-to-A substitution at nucleotide 1691 in the F5 gene
100%

Clinical
Interpretation of test results. Molecular genetic tests are reliable in individuals on warfarin or heparin anticoagulation, and independent of thrombotic episodes.
Test results on DNA extracted from peripheral blood leukocytes should be interpreted with caution in the setting of liver transplantation or hematopoietic stem cell transplantation [Camire et al 1998, Loew et al 2005]. Diagnosis of factor V Leiden in hematopoietic stem cell transplant recipients requires molecular analysis of non-hematopoietic tissue [Crookston et al 1998].
Note: Hematopoietic stem cell transplantation from a donor with factor V Leiden thrombophilia should not increase the thrombotic risk in the recipient.
Resistance to APC resulting from factor V Leiden may be acquired or corrected by liver transplantation [Leroy-Matheron et al 2003, Willems et al 2003, Loew et al 2005]. "Acquired factor V Leiden" is suggested in a liver transplant recipient who has the combination of an abnormal APC resistance screening assay and a normal factor V genotype in DNA extracted from peripheral blood leukocytes. Diagnosis of factor V Leiden in liver transplant recipients requires molecular genetic testing of donor tissue.
Testing Strategy
When appropriate clinical care requires testing for the factor V Leiden allele, either direct DNA-based genotyping or a factor V Leiden-specific functional assay is recommended. Although the modified APC resistance assay is highly sensitive and specific for the factor V Leiden mutation, DNA-based testing for the factor V Leiden allele is recommended in individuals with the following:
A low value based on the original APC resistance assay, in order to distinguish between factor V Leiden and other causes of APC resistance
Strong lupus inhibitors and a markedly prolonged baseline aPTT
Very low second-generation APC resistance assay values, in order to differentiate heterozygotes, homozygotes, and "pseudohomozygotes" who are heterozygous for both factor V Leiden and a second mutation causing a factor V deficiency
Borderline APC resistance assay values
Individuals who test positive by a functional assay should then be further studied with the DNA test for confirmation and to distinguish heterozygotes from homozygotes.
When relatives of individuals known to have factor V Leiden thrombophilia are tested, the DNA method is recommended [ACMG Consensus Statement 2001].
Genetically Related (Allelic) Disorders
Two different mutations (designated as Factor V Cambridge, Factor V Hong Kong) at the arginine 306 activated protein C cleavage site in F5 have been reported rarely in persons with thrombosis (see Pathologic allelic variants).

Clinical Description
Natural History
The clinical expression of factor V Leiden thrombophilia is variable. Many individuals with the factor V Leiden allele never develop thrombosis [Heit et al 2005]. Although most individuals with factor V thrombophilia do not experience their first thrombotic event until adulthood, some have recurrent thromboembolism before age 30 years.
Two studies found that heterozygosity for the factor V Leiden allele was not associated with an increase in mortality or reduction in normal life expectancy [Hille et al 1997, Heijmans et al 1998].
Venous Thromboembolism (VTE)
The primary clinical manifestation of factor V Leiden thrombophilia is venous thromboembolism (VTE) (see Clinical expression of factor V Leiden thrombophilia).
Deep venous thrombosis (DVT) is the most common VTE. The most common site for DVT is the legs, but upper-extremity thrombosis also occurs.
Superficial venous thrombosis may also occur. Factor V Leiden is associated with a sixfold increased risk of superficial vein thrombosis [Martinelli, Cattaneo et al 1999]. A significant fraction of individuals with venous leg ulcerations have APC resistance and the factor V Leiden allele [Larsson et al 1996, Munkvad & Jorgensen 1996, Zuber et al 1996]. Superficial vein thrombosis was the most common thrombotic complication reported in factor V Leiden homozygotes [Ehrenforth et al 2004].
Thrombosis in unusual locations may also occur, but less commonly.
Factor V Leiden is associated with a three- to fourfold increased risk of cerebral vein thrombosis [Dentali et al 2006].
Factor V Leiden thrombophilia has also been reported in central retinal vein occlusion, ovarian thrombosis, and hepatic vein thrombosis.
An increased frequency of factor V Leiden has also been reported in children with cerebral and renal vein thrombosis [Heller et al 2003, Kuhle et al 2004].
Risk for VTE in adults. Multiple studies report that pulmonary embolism is less common than DVT in individuals with the factor V Leiden allele [Manten et al 1996, Vandenbroucke et al 1998]. Analysis of pooled data from these studies suggests that the prevalence of the factor V Leiden allele in individuals with isolated pulmonary embolism is approximately one half that in individuals with DVT [de Moerloose et al 2000]. Another study found that factor V Leiden heterozygotes had a nearly eightfold lower incidence of DVT involving the iliofemoral veins and significantly fewer extensive thromboses compared to individuals without the mutation [Karemaker et al 2000, de Moerloose et al 2000]. This observation could account for the lower risk of pulmonary embolism, as the iliofemoral veins are the most common source of pulmonary emboli [Bjorgell et al 2000]. Isolated DVT was also the most common major thrombotic event in a large cohort of factor V Leiden homozygotes [Ehrenforth et al 2004]. However, in a population-based cohort study, a factor V Leiden allele was not associated with a higher risk for DVT than for pulmonary embolism [Juul et al 2004].
A factor V Leiden allele was reported in 9%-12% of individuals with upper-extremity DVT, suggesting that the mutation confers a two- to sixfold increased risk of thrombosis in this location [Martinelli et al 2004, Blom et al 2005b].
Risk for VTE in children. Although venous thrombosis is far less common in children than in adults, the prevalence of thrombophilic disorders in children with thrombosis is higher than in a corresponding adult population. A combination of risk factors appears to be required to provoke thrombosis in children [Rosendaal 1997, Nowak-Gottl et al 2001, Revel-Vilk & Kenet 2006]. An increased prevalence of a factor V Leiden allele was found in neonates and children with venous thromboembolism in most, but not all studies. The variation in the reported prevalences of factor V Leiden likely reflects differences in study design and clinical characteristics of children studied [Revel-Vilk & Kenet 2006].
APC resistance and a factor V Leiden allele were found in 21%-52% of children with venous thromboembolism in several small series [Nowak-Gottl et al 1996, Sifontes et al 1998].
A heterozygous factor V Leiden mutation was found in 7.3% of unselected Argentinean children with DVT or pulmonary embolism, compared to 2.4% of controls, suggesting a three- to fourfold increase in thrombotic risk [Bonduel et al 2002].
In contrast, another study of unselected children with venous thromboembolism found a low prevalence of the mutation, similar to that reported in the general population [Revel-Vilk et al 2003].
The majority of the individuals reported had other coexisting inherited and circumstantial risk factors in addition to the factor V Leiden mutation. For example, in one study, 50% of factor V Leiden heterozygotes had a coexisting thrombophilic disorder, and circumstantial risk factors were present in all children with venous thromboembolism.
In a prospective study, asymptomatic heterozygous and homozygous children who were family members of symptomatic probands with the factor V Leiden mutation had no thrombotic complications during an average follow-up period of five years [Tormene et al 2002]. Thus, the available data suggest that asymptomatic children with a factor V Leiden allele are at low risk for thrombosis except in the setting of strong circumstantial risk factors.
Recurrent Thrombosis
Risk for recurrent thrombosis in adults heterozygous for factor V Leiden alone. Recent evidence suggests that a heterozygous factor V Leiden mutation has at most a modest effect on the risk of recurrence after initial treatment of a first VTE.
Several earlier studies suggested that individuals heterozygous for factor V Leiden had a two- to fourfold increased risk of recurrent thrombosis [Simioni et al 1997, Simioni et al 2000], althouth other studies found no significant increase in risk [Eichinger et al 1997, De Stefano et al 1999, Lindmarker et al 1999]. A meta-analysis including 3104 individuals with a first VTE concluded that a heterozygous factor V Leiden mutation is associated with a significantly increased risk of recurrent VTE after a first event (odds ratio 1.4) [Ho et al 2006].
In contrast, two recent prospective cohort studies that evaluated the risk of recurrent thrombosis in unselected individuals with a first VTE followed for a mean of two years [Baglin et al 2003] and seven years [Christiansen et al 2005] concluded that heterozygotes for factor V Leiden did not have a greater risk of recurrent VTE than those without the mutation. In addition, a prospective study of families with a strong history of thrombosis found that persons with factor V Leiden had the lowest rate of recurrent VTE (3.5%/year) [Vossen, Walker et al 2005].
Risk for recurrent thrombosis in factor V Leiden homozygotes and heterozygotes with other risk factors. The risk of recurrent VTE in factor V Leiden homozygotes is not well defined, but presumed to be higher than in heterozygotes. In a retrospective cohort study, 34% of factor V Leiden homozygotes had a history of recurrent VTE [Ehrenforth et al 2004]. A prospective follow-up of the Leiden Thrombophilia study reported a five year cumulative recurrence rate of 12.5% in a small group of factor V Leiden homozygotes not receiving long-term anticoagulation [Christiansen et al 2005]. Other studies included few or no factor V Leiden homozygotes, and those included were often on long-term anticoagulation [Vossen, Walker et al 2005].
Individuals who are heterozygous for both factor V Leiden and the prothrombin gene mutation or homozygous for factor V Leiden have a three- to ninefold higher risk of recurrence [De Stefano et al 1999, Lindmarker et al 1999, Meinardi et al 2002].
In one study, the annual incidence of recurrent VTE was 12%/year in persons with homozygous factor V Leiden or combined factor V Leiden and the prothrombin gene mutation, compared to 3%/year in those who were heterozygous for factor V Leiden alone [Gonzalez-Porras et al 2006].
The risk of recurrent VTE is four- to fivefold higher in factor V Leiden heterozygotes with hyperhomocysteinemia than in individuals with a factor V Leiden allele alone [Meinardi et al 2002].
Risk for recurrent thrombosis in children. The risk of recurrent VTE is likely higher in children with an initial spontaneous event, a strong family history of thrombosis, and multiple thrombophilic defects [Revel-Vilk & Kenet 2006].
Heterozygous and homozygous factor V Leiden mutations were found in 29% and 2.3% of children with a first spontaneous venous thrombosis, respectively.
Children with a factor V Leiden mutation had a four- to sixfold higher risk of recurrence, which occurred in 28% of homozygotes and 19% of heterozygotes, compared to 5% of those with a normal genotype [Nowak-Gottl et al 2001].
Risk for recurrent thrombosis in pregnant women. Women with a prior history of venous thrombosis probably have a higher risk of recurrence during pregnancy, although recurrence rates range from 0% to 15% among published studies. The risk is likely higher in women with a prior spontaneous event, and/or coexisting genetic or acquired risk factors. One prospective study evaluated the safety of withholding anticoagulation during pregnancy in 125 women with a history of venous thromboembolism. In subgroup analysis, women with a previous spontaneous thromboembolic event and thrombophilia (especially factor V Leiden), had the highest recurrence rate during pregnancy (20%, odds ratio 10). Women with either thrombophilia or a prior unprovoked VTE (but not both) had a recurrence rate of 13% and 7.7%, respectively [Brill-Edwards et al 2000].
Pregnancy Complications
Factor V Leiden thrombophilia may increase the risk of pregnancy loss and other obstetric complications. The available data indicate that heterozygosity for factor V Leiden is associated with a two- to threefold increase in relative risk of pregnancy loss, and possibly other complications such as preeclampsia, fetal growth retardation, and placental abruption; however, the precise risk is unknown pending prospective longitudinal studies. Overall, the probability of a successful pregnancy outcome is high.
Pregnancy loss. In addition to the increased risk of venous thromboembolism during pregnancy, a large number of case-control studies consistently found a high prevalence of factor V Leiden heterozygosity in women with unexplained recurrent pregnancy loss (30%), compared to 1%-10% of controls (odds ratio range: 2-5) [Ridker et al 1998, Brenner et al 1999, Gris et al 1999, Kupferminc et al 1999, Martinelli et al 2000].
A small prospective study reported miscarriage in 11% of factor V Leiden heterozygotes compared to 4.2% of women without a factor V Leiden allele [Murphy et al 2000]. In another prospective study, factor V Leiden heterozygotes with a history of recurrent early miscarriage had a significantly lower live birth rate than women with a similar history of unsuccessful pregnancies but without the mutation. The live birth rate was 38% in factor V Leiden heterozygotes compared to 69% in women with a normal factor V genotype, suggesting that the mutation confers a three- to fourfold higher risk of an adverse pregnancy outcome [Rai et al 2002].
In a meta-analysis including 3000 women, a factor V Leiden allele significantly increased the risk of early first-trimester recurrent loss (odds ratio 2.1) and late recurrent and non-recurrent loss (odds ratios 7.8 and 3.2, respectively) [Rey et al 2003]. Two other meta-analyses also found a strong association with fetal loss [Dudding & Attia 2004, Kovalevsky et al 2004].
In contrast, a prospective follow-up study of thrombophilic women with no prior history of pregnancy loss found that a factor V Leiden allele conferred only a slight increase in risk of fetal loss (relative risk 1.4) [Vossen et al 2004].
Evidence of increased second- and third-trimester losses. Some evidence suggests that thrombophilic women have a higher risk of loss in the second and third trimester. A large case-control study identified factor V Leiden as an independent risk factor for a first unexplained fetal loss after ten weeks' gestation (odds ratio 3.5) [Lissalde-Lavigne et al 2005]. Mulitple other studies and three meta-analyses suggest that factor V Leiden heterozygotes have a higher risk of late pregnancy loss than early first-trimester loss [Preston et al 1996, Rai et al 1996, Tormene et al 1999, Rey et al 2003, Dudding & Attia 2004, Kovalevsky et al 2004]. One possible explanation is that late-pregnancy losses reflect thrombosis of the placental vessels, in contrast to first-trimester losses, which are more commonly attributable to other causes. In several studies, the majority of placentas from women heterozygous for factor V Leiden and late fetal loss had evidence of thrombotic vasculopathy or infarction, supporting this hypothesis [Gris et al 1999, Martinelli et al 2000].
Evidence of increased first-trimester losses. A factor V Leiden allele also increases the risk of early first-trimester loss [Rey et al 2003].
Thirty-five per cent of all fetal losses in factor V Leiden heterozygotes were "pre-clinical" (prior to ultrasound confirmation of fetal heart activity), compared to 12% of those in women without the mutation [Tal et al 1999].
Preeclampsia, fetal growth retardation, and placental abruption. Although preeclampsia, fetal growth retardation, and placental abruption may also involve impaired placental perfusion, their association with thrombophilia remains controversial. The conflicting results reported in different studies may reflect the varying diagnostic and selection criteria, different ethnic groups, and small number of cases included.
Preeclampsia. Multiple case-control studies found a significantly higher prevalence of factor V Leiden in women with preeclampsia (8%-26%) compared to women with normal pregnancies (2%-10%) with odds ratios ranging from two to six [Grandone et al 1997, Grandone et al 1999, Kupferminc et al 1999, Agorastos et al 2002, Mello et al 2005].
Several large meta-analyses found an overall two to threefold increased risk of preeclampsa [Kosmas et al 2003, Dudding & Attia 2004, Lin & August 2005]. However, these risk estimates were based on pooled data from contradictory studies. The conflicting results reported may be due at least in part to differences in the severity of preeclampsia [Morrison et al 2002, Mello et al 2005]. Factor V Leiden has a stronger association with severe and early-onset preeclampsia than with mild forms of the disease [Mello et al 2005, Nurk et al 2006].
Women with thrombophilia including factor V Leiden and severe preeclampsia may have a higher risk of serious maternal complications and adverse perinatal outcomes than those without thrombophilia [Kupferminc et al 2000, Mello et al 2005].
In contrast, other studies found no association of the mutation with preeclampsia [Alfirevic et al 2001, Livingston et al 2001, Morrison et al 2002, De Maat et al 2004]. A factor V Leiden allele did not increase the risk of preeclampsia in three prospective studies of unselected women screened during the first trimester [Lindqvist et al 1999, Murphy et al 2000, Dizon-Townson et al 2005].
Fetal growth retardation. The data on the risk of fetal growth retardation are more limited and conflicting. A factor V Leiden allele was found in 8%-35% of women with pregnancies complicated by fetal growth retardation compared to 2%-4% of controls (odds ratio range: 7-13) [Kupferminc et al 1999, Martinelli et al 2001, Kupferminc et al 2002]. Another study suggested that factor V Leiden heterozygotes have a twofold higher risk of delivering a neonate with fetal growth retardation [Grandone et al 2002]. Two recent meta-analyses found that a factor V Leiden allele was associated with a significant three- to fivefold increased risk of fetal growth retardation [Dudding & Attia 2004, Howley et al 2005].
In contrast, two larger case-control studies found no significant association between factor V Leiden and fetal growth retardation [Infante-Rivard et al 2002, McCowan et al 2003].
In several prospective studies of unselected pregnant women, the mutation did not increase the risk of fetal growth retardation [Lindqvist et al 1999, Murphy et al 2000, Dizon-Townson et al 2005].
Placental abruption. The data on the risk of placental abruption are limited and conflicting. Factor V Leiden was found in 22%-30% of women with placental abruption compared to 3%-6% of control women (odds ratio range: 5-12) [Wiener-Megnagi et al 1998, Kupferminc et al 1999, Facchinetti et al 2003].
Several other studies found no significant association [Lindqvist et al 1999, Alfirevic et al 2001, Prochazka et al 2003].
Clinical Expression of Factor V Leiden Thrombophilia
The clinical expression of factor V Leiden thrombophilia is influenced by four factors:
1
The number of factor V Leiden alleles
Factor V Leiden heterozygotes. The relative risk of venous thrombosis is increased approximately three - to eightfold in individuals who are heterozygous for the factor V Leiden allele. Lower relative risks are reported in heterozygotes identified from general population screening [Juul et al 2004, Heit et al 2005].
Factor V Leiden homozygotes. The relative risk of venous thrombosis is increased 18- to 80-fold in individuals who are homozygous. Although homozygotes have a higher thrombotic risk and tend to develop thrombosis at a younger age, the risk is much lower than that associated with homozygous protein C or S deficiency.
2
Coexisting genetic abnormalities. The presence of at least one factor V Leiden allele increases the risk associated with other inherited and acquired thrombophilic disorders (including protein C deficiency, protein S deficiency, and antithrombin deficiency), the prothrombin 20210G>A gene mutation, and hyperhomocystinemia [Ridker, Hennekens et al 1997]. The combination of factor V Leiden heterozygosity and most thrombophilic disorders has a supra-additive effect on overall thrombotic risk.
Prothrombin thrombophilia. Individuals with either a single factor V Leiden allele or prothrombin gene mutation had a four- to fivefold increase in thrombotic risk, in contrast to double heterozygotes who had a 20-fold increase in relative risk, illustrating the multiplicative effect of these two factors on overall thrombotic risk [Emmerich et al 2001]. A prothrombin 20210G>A allele was four- to fivefold more common in symptomatic factor V Leiden homozygotes with VTE than in controls with no thrombotic history [Ehrenforth et al 2004].
3
Acquired thrombophilic disorders
Hyperhomocysteinemia. In the Physicians' Health Study, individuals with either at least one factor V Leiden allele or hyperhomocystinemia had a three- to fourfold increased risk of idiopathic thrombosis, but the relative risk increased 22-fold in individuals with both abnormalities [Ridker, Hennekens et al 1997].
High factor VIII levels. Factor V Leiden heterozygotes with high factor VIII levels (>150% of normal) had a two- to threefold higher incidence of VTE than those with a factor V Leiden allele alone [Lensen et al 2001].
Malignancy. Cancer patients have an increased risk of VTE. A heterozygous factor V Leiden mutation increased the risk of VTE in patients with malignancy in several studies, although the results did not achieve statistical significance in one small study [Pihusch et al 2002, Blom et al 2005a, Kennedy et al 2005]. A large population-based case-control study found that factor V Leiden heterozygotes with malignancy had a twofold higher risk of VTE than cancer patients without the mutation, and a 12-fold higher risk than those with neither risk factor [Blom et al 2005a].
Cancer patients with a heterozygous factor V Leiden or prothrombin gene mutation had a 20-fold higher risk of developing an upper-extremity thrombosis than cancer patients with neither prothrombotic mutation [Blom et al 2005b].
4
Circumstantial risk factors. Other predisposing factors include: travel, central venous catheter use, pregnancy, oral contraceptive use, hormone replacement therapy (HRT), selective estrogen receptor modulators (SERMs), organ transplantation, age, and surgery. These predisposing factors are associated with the first thrombotic episode in at least 50% of individuals with a factor V Leiden allele.
In a retrospective study of a large cohort of symptomatic factor V Leiden homozygotes, the initial VTE was associated with circumstantial risk factors in 81% of women and 29% of men [Ehrenforth et al 2004]. Oral contraceptives and pregnancy were the most common predisposing factors in symptomatic women. Thirteen percent of major surgeries were complicated by VTE, suggesting a nearly 20-fold increase in risk. Leg trauma was associated with a ninefold increased risk of a first VTE, which occurred in 15% of factor V Leiden homozygotes compared to 1.8% of control individuals without the mutation.
VTE after travel. The combination of air travel and thrombophilia, including factor V Leiden, was associated with a 16-fold increased risk of VTE [Martinelli, Taioli et al 2003].
Central venous catheters. Individuals heterozygous for factor V Leiden have a two- to threefold increased risk of central venous catheter-related thrombosis [van Rooden et al 2004]. A factor V Leiden allele increases the risk of central venous catheter-associated thrombosis in individuals with advanced or metastatic breast cancer and those undergoing allogeneic bone marrow transplantation [Fijnheer et al 2002, Mandala et al 2004].
Pregnancy. A factor V Leiden allele is associated with a five- to 16-fold increase in thrombotic risk during pregnancy and the puerperium, when compared to non-pregnant women without thrombophilia. A factor V Leiden mutation was confirmed by DNA testing in 20%-46% of women with pregnancy-associated venous thrombosis [Bokarewa et al 1996, Hirsch et al 1996, Hallak et al 1997, Grandone et al 1999, Gerhardt et al 2000, Hiltunen et al 2007]. For example, in one study, factor V Leiden thrombophilia was found in 44% of women with a history of venous thrombosis during pregnancy, compared to 8% of matched controls, with a corresponding ninefold increase in thrombotic risk [Gerhardt et al 2000].
Two recent meta-analyses found that a heterozygous factor V Leiden mutation is associated with an eightfold increased risk of pregnancy-related VTE [Biron-Andreani et al 2006, Robertson et al 2006]. The overall risk is likely higher in women with coexisting acquired or circumstantial risk factors. One study found the combination of a factor V Leiden allele and advanced maternal age (>35 years) and obesity (BMI >30) conferred a 44-fold and 75-fold increased risk, respectively, compared to younger and normal weight women without the mutation [Hiltunen et al 2007].
Women with multiple or homozygous thrombophilic defects have the highest risk of pregnancy-associated VTE. The risk of pregnancy-related VTE is increased 20- to 40-fold in women with homozygous factor V Leiden [Martinelli et al 2001, Gerhardt et al 2003, Robertson et al 2006].
The risk of thrombosis during pregnancy was increased more than 100-fold in women with both a factor V Leiden allele and the prothrombin gene mutation, illustrating the marked increase in overall risk when thrombophilic mutations are combined [Gerhardt et al 2000]. In studies of thrombophilic families, VTE complicated 4% of pregnancies in women doubly heterozygous for factor V Leiden and the prothrombin gene mutation, and 16% of pregnancies in factor V Leiden homozygotes, compared with 0.5% of those in unaffected relatives [Martinelli et al 2001; Middeldorp, Libourel et al 2001]. The prevalence of pregnancy-related VTE was 9% in a series of unselected homozygous women [Pabinger et al 2000].
Although presence of a factor V Leiden allele increases the relative risk of VTE during pregnancy and the puerperium, the true risk in asymptomatic heterozygotes is not well defined. The results of the following studies suggest that although factor V Leiden heterozygosity is an independent risk factor, the absolute incidence of thrombosis during pregnancy is low. Notes: (1) Two prospective studies of unselected pregnant women screened for factor V Leiden both observed very low rates of VTE in heterozygous women (1.1% and 0%, respectively) [Lindqvist et al 1999, Dizon-Townson et al 2005]. (2) No VTE events occurred during pregnancy or postpartum among a cohort of 129 women with factor V Leiden identified by general population screening [Heit et al 2005].
In several retrospective studies and meta-analyses, the estimated risk of VTE during pregnancy and the puerperium in factor V Leiden heterozygotes was in the range of one in 125 to 400 pregnancies [McColl et al 1997, Gerhardt et al 2000, Gerhardt et al 2003, Robertson et al 2006].
In contrast, women with homozygous factor V Leiden or combined thrombophilia have a much higher probability of VTE, in the range of one in 20 to one in 100 pregnancies [Martinelli et al 2001, Gerhardt et al 2003, Robertson et al 2006].
Oral contraceptive use. The use of oral contraceptives substantially increases the risk of venous thromboembolism (VTE) in women heterozygous for a factor V Leiden allele. A heterozygous mutation is found in 20%-35% of women with a history of venous thrombosis during oral contraceptive use [Hirsch et al 1996, Schambeck et al 1997]. In the Leiden Thrombophilia study, the risk of venous thrombosis was increased fourfold in oral contraceptive users, and sevenfold in women with a heterozygous factor V Leiden mutation. However, the risk was increased 35-fold in heterozygous women who used oral contraceptives, indicating a multiplicative rather than additive effect on overall thrombotic risk.
The supra-additive effect of a factor V Leiden allele and oral contraceptives was confirmed in other studies and a meta-analysis, with odds ratios ranging from 11 to 41 for the combination of both risk factors [Martinelli, Taioli et al 1999, Legnani et al 2002, Sidney et al 2004].
A meta-analysis found the combination of factor V Leiden and oral contraceptives conferred a 16-fold increase in relative thrombotic risk, which was fivefold higher than that observed with either risk factor alone [Wu et al 2005]. Heterozygous women who use oral contraceptives have a 30-fold higher risk of cerebral vein thrombosis than non-users without the mutation [Martinelli, Battaglioli et al 2003].
The corresponding risk is increased more than 100-fold in women homozygous for the factor V Leiden allele who use oral contraceptives. The risk of VTE is also markedly increased in oral contraceptive users who are doubly heterozygous for factor V Leiden and the prothrombin gene mutation, with reported odds ratios ranging from 17 to 110 [Mohllajee et al 2006].
Women with inherited thrombophilic disorders, such as factor V Leiden thrombophilia, tend to develop thrombotic complications sooner, with a much higher risk of thrombosis during the first year of oral contraceptive use [Bloemenkamp et al 2000].
Oral contraceptives containing the third-generation progestagen desogestrel are associated with a twofold higher risk of venous thromboembolism than second-generation preparations, with an especially high risk in factor V Leiden heterozygotes. The risk was increased 50-fold in factor V Leiden heterozygotes who used third-generation preparations containing desogestrel, compared to women without the factor V Leiden allele who were not using oral contraceptives.
Despite the marked increase in relative risk, the absolute incidence of VTE may still be low because of the low baseline risk in young healthy women. For example, the combination of factor V Leiden and oral contraceptives is estimated to result in an additional 28 VTE events per 10,000 women per year. Long-term use of oral contraceptives in asymptomatic factor V Leiden heterozygotes without complications has been reported, underscoring the multifactorial etiology of VTE [Girolami et al 2004].
Unopposed progestin contraception carries a much lower risk of thrombosis than estrogen-containing contraceptives, although the risk in thrombophilic women is not well defined. A retrospective study found that oral progestin alone did not increase the risk of VTE in high-risk women with a history of thrombosis and/or thrombophilia, including 28 women with factor V Leiden [Conard et al 2004].
However, no prospective studies confirm the safety of progestin-alone contraception in women with factor V Leiden.
Hormone replacement therapy (HRT). Multiple studies have confirmed a significant (two- to fourfold) increase in relative risk of VTE in current users of HRT compared to non-users [Daly et al 1996, Grodstein et al 1996, Jick et al 1996, Perez-Guthann et al 1997, Hulley et al 1998, Varas-Lorenzo et al 1998, Grady et al 2000, Rossouw et al 2002].
The landmark Women's Health Initiative (WHI) randomized trial of estrogen and progesterone HRT versus placebo in postmenopausal women found that HRT was associated with a twofold increased risk of VTE [Rossouw et al 2002]. In a parallel WHI trial of estrogen-only HRT in women who had a hysterectomy, estrogen replacement increased the risk of VTE, although the risk was statistically significant only for DVT (hazard ratio 1.47) [Anderson et al 2004, Curb et al 2006].
Most of the observational studies of HRT excluded women with known thrombophilia. Based on the known interaction with estrogen, the use of HRT is expected to significantly increase the risk of VTE in women with a factor V Leiden allele. Evidence is now compelling that women with factor V Leiden who use HRT have a markedly increased risk of developing VTE. In one study, the combination of HRT use and activated protein C resistance was associated with a 13-fold increase in relative thrombotic risk compared to that found in women with neither risk factor [Lowe et al 2000]. Reinvestigation of this same group of women for prothrombotic mutations (factor V Leiden or the prothrombin gene mutation) demonstrated a 15-fold increased risk of venous thrombosis in HRT users with a heterozygous factor V Leiden mutation [Rosendaal et al 2002].
In another study of postmenopausal women with coronary heart disease, factor V Leiden heterozygotes who used HRT had a 14-fold higher thrombotic risk than non-users without the mutation. The estimated absolute incidence of VTE in women with coronary heart disease and factor V Leiden who used HRT was 15 VTE events per 1000 women per year, compared to two VTE events per 1000 women per year for non-users with a normal genoype [Herrington et al 2002]. A meta-analysis of the data from these confirmed that factor V Leiden heterozygotes who use HRT have a 13-fold higher risk of VTE [Wu et al 2005].
In a nested case-control study of the WHI, factor V Leiden heterozygotes who used estrogen and progestin HRT had a nearly sevenfold higher risk of VTE than non-users without the mutation [Cushman et al 2004]. The estimated absolute risk of VTE in factor V Leiden heterozygotes who used HRT was eight VTE events per 1000 women per year.
Some evidence suggests that the thrombotic risk from transdermal HRT is lower than the thrombotic risk from oral preparations, in women with and without prothrombotic mutations [Scarabin et al 2003, Straczek et al 2005]. In one study, women with factor V Leiden who used oral estrogen had a 16-fold higher risk of VTE than non-users without the mutation. In contrast, the thrombotic risk in women with factor V Leiden who used transdermal estrogen was similar to that in women with a mutation who did not use estrogen. Among women with factor V Leiden, the use of oral estrogen was associated with a fourfold higher risk of VTE than transdermal estrogen [Straczek et al 2005]. However, there are no prospective trials confirming the safety in women with thrombophilia and/or prior VTE.
Selective estrogen receptor modulators (SERMs). The limited data available suggest that SERMs, such as tamoxifen and raloxifene, are associated with a similar increase in thrombotic risk [Fisher et al 1998, Meier & Jick 1998, Cummings et al 1999, Abramson et al 2006, Barrett-Connor et al 2006].
The risk of venous thromboembolism in women with factor V Leiden who use SERMs is unknown but likely higher than that associated with SERMs alone. There are several case reports of tamoxifen-associated thrombosis in women with factor V Leiden thrombophilia [Wietz et al 1997]. Two nested case-control studies of high-risk healthy women enrolled in the breast cancer prevention trials did not find a statistically significant effect of factor V Leiden on the risk of VTE associated with tamoxifen [Duggan et al 2003, Abramson et al 2006]. However, both studies were limited by the small number of cases included. In light of the interaction of factor V Leiden with HRT, it is likely that factor V Leiden thrombophilia will be shown to increase the risk of SERM-associated thrombosis in larger studies.
Organ transplantation. The prevalence of factor V Leiden in individuals who have undergone renal transplantation is similar to that in the general population, suggesting that it is not a risk factor for developing end-stage renal disease (ESRD) [Wuthrich et al 2001]. However, recent evidence suggests that the factor V Leiden mutation may contribute to thrombotic and other complications after renal transplantation [Kujovich 2004a]. In several retrospective studies, thromboembolic complications occurred in up to 39% of factor V Leiden heterozygotes, compared to 6%-15% of recipients without a factor V Leiden allele [Irish et al 1997, Wuthrich et al 2001]. The mutation conferred an overall fourfold increased risk of graft vein thrombosis and venous thromboembolism [Irish et al 1997].
Factor V Leiden has been associated with both delayed graft function and early graft loss [Wuthrich et al 2001, Hocher et al 2002]. In one study, factor V Leiden heterozygotes had a 12-fold higher risk of an early graft perfusion defect, and a markedly increased risk of graft loss within the first week (25%) compared to individuals with a normal genotype (<1%) class="int-reflink bibref 5" id="id184123" href="http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&partid=1368#factor-v-leiden.grID62221">Wuthrich et al 2001]. Factor V Leiden heterozygotes also had a significantly higher risk of graft loss within the first year in some [Ekberg et al 2000, Wuthrich et al 2001], but not all, studies [Pherwani et al 2003]. In the single study that screened kidney donors, grafts from donors heterozygous for factor V Leiden had a 30-day and one-year survival similar to those from donors without the mutation [Pherwani et al 2003].
Factor V Leiden may also increase the risk of acute rejection after renal transplantation. Although the number of individuals and frequency of rejection varied, a consistent pattern of more frequent rejection episodes was observed in recipients with a factor V Leiden allele. Several studies found that factor V Leiden heterozygotes have a three- to fourfold higher risk of acute rejection than those without the mutation [Ekberg et al 2000, Hocher et al 2002, Heidenreich et al 2003].
A recent study of renal transplantation outcomes in 394 stable recipients found that factor V Leiden heterozygotes were also significantly more likely to develop chronic graft dysfunction, reflected by both a steeper slope of the 1/creatinine-versus-time curve, and a higher annual increase in the rate of urinary protein excretion [Hocher et al 2002].
The contribution of factor V Leiden to thrombotic complications after other types of organ transplantation is not well defined. DVT, pulmonary embolism, and hepatic artery thrombosis have been reported in liver transplantation recepients whose donors were heterozygous or homozygous for factor V Leiden [Leroy-Matheron et al 2003, Willems et al 2003, Dunn et al 2006]. A retrospective study suggested that a liver transplantation from a heterozygous donor was associated with a twofold overall risk of postoperative venous or hepatic vessel thrombosis [Hirshfield et al 1998]. Another study found that recipients with acquired activated protein C resistance after liver transplantation had a fourfold increased risk of subsequent venous thromboembolic complications [Loew et al 2005].
Age. The risk increases at a greater rate with advancing age in individuals with a factor V Leiden mutation, also suggesting that thrombosis involves acquired, as well as genetic, predisposing factors [Ridker, Glynn et al 1997]. In the Physicians' Health Study, a factor V Leiden allele was found in nearly one-third of men over age 60 years with an initial spontaneous unprovoked thrombotic event.
In a population-based cohort study, the risk of VTE was significantly increased only among factor V Leiden heterozygotes over age 60 years (relative risk 3.6) [Heit et al 2005]. Another prospective study found that the absolute risk of VTE in unselected individuals with factor V Leiden increased with age, body mass index (BMI), and smoking. The ten-year risk of VTE among factor V Leiden heterozygotes was 10% in smokers over age 60 with a BMI greater than 30 kg/m2, in contrast to a less than 1% risk in nonsmokers younger than age 40 years who were not overweight [Juul et al 2004]. The corresponding absolute ten-year risks for factor V Leiden homozygotes with and without these risk factors were 51% and 3%, respectively.
Surgery. It is still unclear to what extent the factor V Leiden mutation adds to the overall thrombotic risk in individuals undergoing orthopedic surgery. In one study, individuals with APC resistance had a fivefold increased risk of symptomatic postoperative venous thromboembolism during the two months after elective hip or knee replacement [Lindahl et al 1999]. In contrast, in another study of individuals receiving standard prophylactic antithrombotic therapy, the mutation was not associated with a significantly increased risk of DVT during the immediate postoperative period [Ryan et al 1998].
Individuals heterozygous for factor V Leiden or the prothrombin gene mutation undergoing surgery had a nearly 13-fold higher risk of upper-extremity DVT than controls with neither risk factor [Blom et al 2005b].
Children. In several studies, 62%-91% of children with VTE had coexisting circumstantial risk factors, with central venous catheters, malignancy and congenital heart disease among the most frequently reported [Junker et al 1999, Revel-Vilk et al 2003].
Thrombosis NOT Convincingly Associated with Factor V Leiden Thrombophilia
Arterial thrombosis. The role of factor V Leiden in arterial disease is controversial, with conflicting results from different studies. Most studies of unselected adult populations found no association between presence of a factor V Leiden allele and an increased risk of myocardial infarction or stroke [Cushman et al 1998]. A meta-analysis of 33 studies and including 25,053 individuals found no significant association with myocardial infarction, stroke, or peripheral vascular disease either collectively or individually [Kim & Becker 2003], However, a more recent larger meta-analysis found that a factor V Leiden allele conferred a moderately increased risk for coronary disease and myocardial infarction [Ye et al 2006]. Although consensus holds that the presence of a factor V Leiden allele is not a major risk factor for MI or stroke, some data suggest that it may contribute to the risk of arterial thrombotic events in selected subgroups of individuals.
Myocardial infarction. The results of several studies suggest that the factor V Leiden allele may contribute to myocardial infarction in younger individuals and in those with concomittant cardiovascular risk factors.
One study reported a significantly increased risk of myocardial infarction in young women with other cardiovascular risk factors, particularly smoking. Young women with a heterozygous factor V Leiden mutation who smoked had a 30-fold increased risk of myocardial infarction compared to women with neither risk factor [Rosendaal et al 1997].
Several other studies found that the simultaneous presence of prothrombotic mutations, including factor V Leiden, and one or more cardiovascular risk factors substantially increased the risk of acute myocardial infarction. The combination of a prothrombotic mutation and smoking was associated with the highest risk (odds ratio range: 6-18) [Doggen et al 1998, Inbal et al 1999].
Two studies found a significantly higher prevalence of a factor V Leiden allele in young individuals with premature myocardial infarction and normal coronary angiography than in matched controls with significant coronary artery disease, with odds ratios of 2.6 and 4.7, respectively [Mansourati et al 2000, Van de Water et al 2000].
A case-control study found that a heterozygous factor V Leiden mutation was associated with a significant two- to threefold increased risk of myocardial infarction. All of the individuals with factor V Leiden and myocardial infarction had coexisting cardiovascular risk factors [Middendorf et al 2004].
The risk of arterial thrombosis in factor V Leiden homozygotes is unknown, as very few homozygous individuals were included in the available studies.
Stroke in adults. Most studies of unselected adult populations did not find a significant association between factor V Leiden and ischemic stroke [Cushman et al 1998, Lalouschek et al 2005]. There was no difference in the prevalence of factor V Leiden between unselected individuals with severe carotid atherosclerosis and healthy controls, even in the subgroup with symptomatic disease [Marcucci et al 2005]. Although the available data suggest that factor V Leiden is not a general risk factor for stroke, it may contribute in selected populations.
A factor V Leiden allele was associated with a threefold increased risk of stroke in individuals younger than age 45-50 years, and the risk was even higher in women in this age group (odds ratio range: 4-6) [Margaglione et al 1999, Aznar et al 2004].
The interaction of factor V Leiden with other vascular risk factors may increase the risk of ischemic stroke. Two studies found that young women with a factor V Leiden allele who used oral contraceptives had a nine- to 13-fold increased risk of stroke, compared to women with neither risk factor [Slooter et al 2005, Martinelli et al 2006]. Several studies also found a six- to ninefold increased risk of stroke in young adults and women up to age 60 years [Margaglione et al 1999, Lalouschek et al 2005, Slooter et al 2005]. The combination of a factor V Leiden allele with one or more other cardiovascular risk factors (hypertension, diabetes, hypercholesterolemia) was associated with a nearly 11-fold increase in stroke risk [Margaglione et al 1999].
Arterial thromboembolism may also occur "paradoxically" through a patent foramen ovale in the heart of individuals with venous thrombosis [Karttunen et al 2003].
Stroke in children. Arterial ischemic stroke in children usually occurs in the setting of multiple predisposing factors [Barnes & Deveber 2006]. Data on the association of thrombophilia with ischemic stroke are conflicting. The majority of published case-control studies found a significantly increased prevalence of factor V Leiden in children with ischemic stroke (17%-23%) compared to control children (3%-4%), with odds ratios of 4 to 5 [Zenz et al 1998, Nowak-Gottl et al 1999, Kenet et al 2000, Duran et al 2005]. Analysis of the data from five studies suggests that the mutation confers an overall fourfold increase in stroke risk [Barnes & Deveber 2006]. However, another meta-analysis reported that children with a factor V Leiden allele had a lower risk of a first ischemic stroke (odds ratio 1.2), which was not statistically significant [Haywood et al 2005].
Stroke in the fetus. Arterial thrombosis may also occur in the fetus as a result of placental venous thrombi entering the fetal circulation, crossing the foramen ovale, and entering the cerebral arterial vasculature [Thorarensen et al 1997].
Genotype-Phenotype Correlations
Individuals homozygous for factor V Leiden have a higher risk for thrombosis than heterozygotes (see Clinical Description. However, the clinical course of an acute thrombotic episode is not more severe or more resistant to anticoagulation in homozygotes than in heterozygotes.
"Pseudo-homozygous" APC resistance. Other genetic abnormalities may affect the expression of a heterozygous factor V Leiden allele. One example is "pseudo-homozygous" APC resistance, which occurs in individuals who are doubly heterozygous for the factor V Leiden mutation and a factor V null mutation. Rather than attenuating the effect of the factor V Leiden mutation, coexisting factor V deficiency appears to enhance it, producing a more severe APC-resistant phenotype, reflected by a extremely low APC resistance ratio [Brugge et al 2005]. Factor V Leiden pseudohomozygotes show a degree of APC resistance indistinguishable from that of individuals homozygous for the mutation [Brugge et al 2005]. The diagnosis of pseudohomozygous APC resistance is based on the combination of a heterozygous factor V Leiden mutation, reduced factor V activity levels (approximately 50% of normal), and a low APC resistance ratio in the range typical for a homozygous mutation. Several different mutations associated with a quantitative factor V deficiency have been described, including one polymorphism (the "R2 allele") found in up to 7.5% of the Italian population [Castaman et al 1997, Castoldi et al 1998, Simioni et al 2005].
Coinheritance of a factor V null allele is estimated in approximately 1/1000 individuals heterozygous for factor V Leiden [Simioni et al 2005]. Most of the individuals described have had a history of thrombosis. Recent data suggest that individuals with pseudohomozygous APC resistance have an increased thrombotic risk comparable to that of factor V Leiden homozygotes [Simioni et al 2005]. Pseudohomozygous APC resistance has also been reported in individuals doubly heterozygous for factor V Leiden and factor V Cambridge [Santamaria et al 2005].
In rare cases, both a null allele and factor V Leiden mutation occur on the same chromosome in cis configuration. In these individuals, the resulting quantitative factor V deficiency prevents expression of the factor V Leiden mutation [Dargaud et al 2003].
Factor V polymorphisms. A factor V gene haplotype (HR2) defined by the R2 polymorphism (A4070G) may confer mild APC resistance and interact with the factor V Leiden mutation to produce a more severe APC resistance phenotype [Bernardi et al 1997, de Visser et al 2000, Mingozzi et al 2003]. In one study, coinheritance of the HR2 haplotype increased the risk of venous thromboembolism associated with factor V Leiden by approximately threefold [Faioni et al 1999]. However, double heterozygosity for factor V Leiden and the R2 polymorphism was not associated with a significantly higher risk of early or late pregnancy loss than a heterozygous factor V Leiden mutation alone [Zammiti et al 2006]. Whether the HR2 haplotype alone is an independent thrombotic risk factor is still unclear. Several studies have suggested that the HR2 haplotype is associated with a twofold increase in risk of venous thromboembolism [Alhenc-Gelas et al 1999, Jadaon & Dashti 2005]. In contrast, other studies found no significant increase in thrombotic risk [de Visser 2000, Luddington et al 2000, Dindagur et al 2006].
Penetrance
Factor V Leiden heterozygotes identified from general population screening had a low absolute incidence of VTE of approximately two VTE events per 1000 persons per year in several studies [Juul et al 2004, Heit et al 2005]. The cumulative incidence of VTE was 6.5% at age 65 years. Homozygotes had an absolute incidence of 15 VTE events/1000 persons/year [Juul et al 2004].
The risk of thrombosis is higher in studies of asymptomatic factor V Leiden heterozygotes from thrombophilic families than in unselected individuals identified by population screening. Four retrospective studies of relatives of unselected symptomatic and asymptomatic factor V Leiden heterozygotes also reported a low thrombotic risk. The results were remarkably consistent, with the absolute incidence of venous thrombosis ranging from 0.19%/year to 0.45%/year, compared to 0.10%/year in individuals without a factor V Leiden allele [Middeldorp et al 1998, Simioni et al 1999, Lensen et al 2000, Martinelli et al 2000]. Venous thrombosis occurred in 7%-12% of relatives with factor V Leiden heterozygosity compared to 2%-3% of individuals without a factor V Leiden allele, consistent with other estimates that the lifetime risk of thrombosis in a heterozygote is approximately 10% [Grody et al 2001]. At least 50% of thrombotic events were associated with other risk factors, especially pregnancy. One study found a higher thrombotic risk in relatives from families with a factor V Leiden allele in which multiple family members had a history of thrombosis. The absolute incidence of venous thrombosis in heterozygous first-degree relatives was 1.7%/year, suggesting that a strong family history is a risk factor for thrombosis [Martinelli et al 2000]. A systematic review of these four studies found a pooled nearly fourfold increased relative risk of venous thromboembolism [Langlois & Wells 2003]. In three prospective cohort studies, the overall incidence of VTE in asymptomatic factor V Leiden heterozygotes was in the range of 0.1% to 0.67% per year. The majority (50%-75%) of thrombotic episodes were associated with other risk factors despite the common use of prophylactic anticoagulation during high-risk periods [Middeldorp, Meinardi et al 2001; Simioni et al 2002; Vossen, Conard et al 2005].
Anticipation
Anticipation is not observed.
Prevalence
Factor V Leiden thrombophilia is the most common inherited form of thrombophilia. The prevalence varies by population.
Heterozygosity for factor V Leiden occurs in 3%-8% of the general US and European populations. The highest heterozygosity rate is found in Europe; the mutation is extremely rare in Asian, African, and indigenous Australian populations.
Within Europe, prevalence varies from 10%-15% in southern Sweden and Greece to 2%-3% in Italy and Spain.
In the US, prevalence reflects the world distribution of the mutation [Ridker, Miletich et al 1997]. It is present in:
5.2% of Caucasian Americans
2.2% of Hispanic Americans
1.2% of African Americans
0.45% of Asian Americans
1.25% of Native Americans
The frequency of homozygosity for factor V Leiden is approximately 1:5000.
The factor V Leiden mutation is present in:
Approximately 15%-20% of individuals with a first DVT;
Up to 50% of individuals with recurrent venous thromboembolism or an estrogen-related thrombosis.
Differential Diagnosis
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
APC resistance. Although 95% of cases of APC resistance reflect the presence of the factor V Leiden mutation, 5% of individuals have repeatedly abnormal APC resistance tests in the absence of the factor V Leiden allele. Depending on the screening assay used, some cases may represent acquired APC resistance caused by high factor VIII levels, pregnancy, or a lupus anticoagulant effect. Two studies suggested that APC resistance not caused by the factor V Leiden allele is also a risk factor for venous thrombosis [de Visser et al 1999, Rodeghiero & Tosetto 1999]. In another study, resistance to APC was associated with an increased risk of stroke and TIA, independent of the factor V Leiden mutation [van der Bom et al 1996]. In rare cases, other genetic abnormalities may produce an APC-resistant phenotype (see Molecular Genetics).
Thrombophilic disorders. The differential diagnosis of venous thromboembolism includes several other inherited and acquired thrombophilic disorders. Because these thrombophilic disorders are not clinically distinguishable, laboratory testing is required for diagnosis in each case. Laboratory testing should be considered even after the identification of the factor V Leiden allele, as it often coexists with other disorders.
Inherited
Prothrombin thrombophilia. The mutation 20210G>A in the 3' untranslated region of the gene encoding prothrombin is found in 2% of the general population, 6% of individuals presenting with a first DVT, and up to 18% of individuals with a personal and family history of thrombosis. Coinheritance of both a factor V Leiden allele and the prothrombin gene mutation occurs in approximately one in 1000 in the general population and 1%-5% of individuals with venous thromboembolism [De Stefano et al 1999, Emmerich et al 2001].
A specific point mutation (677C>T) in the gene MTHFR, encoding methylenetetrahydrofolate reductase results in a variant thermolabile enzyme with reduced activity for the remethylation of homocysteine. Homozygosity for 677C>T predisposes to mild hyperhomocysteinemia, usually in the setting of suboptimal serum concentration of folate. Homozygosity for 677C>T occurs in 10%-20% of the general population.
Inherited abnormalities or deficiencies of the natural anticoagulant proteins C, S, and antithrombin are approximately tenfold less common than the factor V Leiden allele, with a combined prevalence of less than 1%-2% of the population. Anticoagulant protein deficiencies are found in 1%-3% of individuals with a first VTE.
Hereditary dysfibrinogenemias are rare and infrequently cause thrombophilia and thrombosis.
Acquired
High plasma concentration of homocysteine occurs in 10% of individuals with a first VTE and is associated with a two- to threefold increase in relative risk The plasma concentration of homocysteine reflects genetic as well as environmental factors and is more directly associated with thrombotic risk than molecular genetic testing of the MTHFR gene.
Antiphospholipid antibodies (APA) comprise a heterogeneous group of autoantibodies directed against proteins bound to phospholipids. Anticardiolipin antibodies and the related anti-beta2-glycoprotein 1 antibodies are detected by solid-phase immunoassays. High titer IgG anticardiolipin antibodies and persistent lupus inhibitors are most strongly associated with arterial and venous thromboembolism [Galli et al 2003]. Antiphospholipid antibodies are frequently identified in individuals with factor V Leiden allele but can also cause APC resistance in the absence of the factor V Leiden mutation. The acquired APC resistance associated with APA should be distinguished from the spuriously low APC resistance ratio that occurs in individuals with a prolonged aPTT resulting from a lupus inhibitor. Testing for antiphospholipid antibodies should include assays for both anticardiolipin antibodies and lupus inhibitors, as only 50% of individuals with the antiphospholipid antibody syndrome have both types of antibodies.
Elevated clotting factor levels. A factor VIII level greater than 150% of normal is an independent risk factor for venous thromboembolism, conferring a four- to fivefold increase in risk in several studies [Koster et al 1995, Bank et al 2005]. High factor VIII concentrations also significantly increase the risk of recurrent thrombosis [Kyrle et al 2000].
Elevated plasma concentrations of factor IX and factor XI are associated with an approximately twofold increased risk of venous thromboembolism [Meijers et al 2000, van Hyickama et al 2000].
Elevated plasma prothrombin levels greater than 110%-115% of normal are associated with a twofold increased risk of VTE in the absence of prothrombin 20210G>A heterozygosity [Poort et al 1996, Legnani et al 2002]. The combination of oral contraceptives and high levels of prothrombin, factor V, or factor XI had a supra-additive effect on thrombotic risk (odds ratio range: 10-13) [van Hylckama Vlieg & Rosendaal 2003]. However, it is still unclear whether assessment of clotting factor concentrations should be included in a thrombophilia evaluation [Kamphuisen et al 2001].
Other
Although thrombosis has been reported in association with abnormalities in other coagulation or fibrinolytic proteins such as heparin cofactor II and PAI-1, a causal association has not been established.
Management
Evaluations Following Initial Diagnosis
Individuals heterozygous for the factor V Leiden allele should be tested for other inherited or acquired thrombophilic disorders. Testing should include the following:
DNA testing for the prothrombin gene mutation (G-to-A substitution at nucleotide 20210)
Measurement of total plasma concentration of homocysteine
Multiple phospholipid-dependent coagulation assays for a lupus inhibitor
Serologic assays for anticardiolipin antibodies (and in some cases anti-beta2-glycoprotein 1 antibodies)
In high-risk individuals (i.e., those with a history of recurrent VTE, especially at young age, or those with strong family history of VTE at young age) testing should also include assays of the following:
Protein C activity
Antithrombin activity
Protein S activity or free protein S antigen
Although routine measurement of factor VIII levels is not recommended, testing may be useful in selected cases [Chandler et al 2002]. It is still unclear whether assessment of clotting factor concentrations should be included in a thrombophilia evaluation [Chandler et al 2002].
Treatment of Manifestations
Thrombosis
The management of individuals with factor V Leiden thrombophilia depends on the clinical circumstances.
The first acute thrombosis should be treated according to standard guidelines with a course of intravenous unfractionated heparin or low molecular weight heparin [Buller et al 2004]. Oral administration of warfarin is started concurrently with heparin (except during pregnancy) and monitored with the international normalized ratio (INR). A target international normalized ratio (INR) of 2.5 (therapeutic range 2.0-3.0) provides effective anticoagulation, even in individuals with homozygous factor V Leiden [Baglin et al 1998]. Heparin and warfarin therapy should be overlapped for at least five days, and until the INR has been within the therapeutic range on two consecutive measurements over two days. The use of warfarin is safe in breast-feeding women.
The duration of oral anticoagulation therapy should be tailored to the individual, based on an assessment of the risks of VTE recurrence and anticoagulant-related bleeding. Approximately 30% of individuals with an incident VTE develop recurrent thrombosis within the subsequent ten years [Prandoni et al 1996]. Because individuals remain at risk for recurrence even after ten years, VTE is now considered a chronic disease. The optimal duration of anticoagulation for individuals who are heterozygous for the factor V Leiden allele is debated. Individuals with a spontaneous thrombosis and no identifiable provoking factors or persistent risk factors require a longer course of anticoagulation (e.g., ≥6-12 months). In contrast, individuals with transient (reversible) risk factors such as surgery require a shorter course of therapy [Hirsh et al 1997, Buller et al 2004]
Long-term oral anticoagulation should be considered in individuals with recurrent VTE, multiple thrombophilic disorders, or coexistent circumstantial risk factors and in individuals homozygous for the factor V Leiden allele. In these individuals at high risk for recurrence, the potential benefits from long-term warfarin may outweigh the bleeding risks.
Although unfractionated and low molecular-weight heparin and warfarin are still the primary antithrombotic agents in use, new antithrombotic agents are available for prophylaxis and treatment of arterial and venous thromboembolism. A pentasaccharide (fondaparinux) and several direct thrombin inhibitors (lepirudin, argatroban) are approved for use in specific circumstances [Weitz et al 2004].
Graduated compression stockings should be worn for at least two years following an acute DVT.
Prevention of Primary Manifestations
In the absence of a history of thrombosis, long-term anticoagulation is not routinely recommended for asymptomatic individuals who are heterozygous for the factor V Leiden allele because the 1%-2%/year risk of major bleeding from warfarin is greater than the estimated less than 1%/year risk of thrombosis.
Prophylactic anticoagulation. Because the initial thrombosis in factor V Leiden heterozygotes occurs in association with other circumstantial risk factors in 50% of cases, a short course of prophylactic anticoagulation during exposure to hemostatic stresses may prevent some of these episodes.
Prophylactic anticoagulation should be considered in high-risk clinical settings such as surgery, pregnancy, or prolonged immobilization, although currently no evidence confirms the benefit of primary prophylaxis for all asymptomatic carriers.
Decisions regarding prophylactic anticoagulation should be based on a risk/benefit assessment in each individual case. Factors that may influence decisions about the indication for and duration of anticoagulation include age, family history, and other coexisting risk factors. Recommendations for prophylaxis at the time of surgery and other high risk situations are available in consensus guidelines [Geerts et al 2004].
Pregnancy. No consensus exists on the optimal management of factor V Leiden thrombophilia during pregnancy; guidelines are similar to those for individuals who are not pregnant [Bates et al 2004, Kujovich 2004b]. Until more specific guidelines are defined by prospective trials, decisions about anticoagulation should be individualized based on the thrombophilic defects, coexisting risk factors, and personal and family history of thrombosis.
Prophylactic anticoagulation during pregnancy:
Is not routinely recommended in asymptomatic heterozygous women with no history of thrombosis. These women should be warned about potential thrombotic complications, counseled about the risks and benefits of anticoagulation during pregnancy, and offered a four- to six-week course of anticoagulation after delivery, as the greatest thrombotic risk is in the initial postpartum period.
Is recommended for women with a factor V Leiden allele and a history of unprovoked VTE. Unfractionated or low molecular-weight heparin should be given during pregnancy, followed by a four- to six-week course of anticoagulation postpartum.
Should be considered for heterozygous women with a prior estrogen-related thrombosis who are also at an increased risk of recurrence [Bates et al 2004, Pabinger et al 2005].
Should be considered for asymptomatic women with homozygous factor V Leiden or double heterozygosity for factor V Leiden and the prothrombin 20210G>A mutation, or with other combined thrombophilic defects, especially those with circumstantial risk factors (obesity, immobilization, multiple gestation) [Barbour et al 2001, Bates et al 2004].
Graduated elastic compression stockings are recommended for all women with a prior DVT [Bates et al 2004].
Prevention of Secondary Complications
Prevention of pregnancy loss. The current data on antithrombotic therapy in women with inherited thrombophilia and recurrent pregnancy loss are limited to several observational studies and two randomized trials.
In one study, 50 women with thrombophilia (including 20 factor V Leiden heterozygotes) and recurrent pregnancy loss were treated with enoxaparin throughout 61 subsequent pregnancies. The live birth rate was 75% with enoxaparin prophylaxis, compared to 20% in prior untreated pregnancies [Brenner et al 2000].
Another study reported a similar live birth rate of 77% with enoxaparin prophylaxis compared to 44% in untreated historical control women, suggesting a threefold greater likelihood of a favorable outcome. The beneficial effect of anticoagulation was most pronounced in women with factor V Leiden thrombophilia, although the small number of individuals studied precluded definitive conclusions [Carp et al 2003].
A prospective randomized trial compared prophylactic-dose enoxaparin and low-dose aspirin in women with factor V Leiden, the prothrombin 20210G>A mutation, or protein S deficiency and a single unexplained fetal loss. Enoxaparin prophylaxis was associated with a significantly higher live birth rate of 86% compared to 29% with aspirin, suggesting a 15-fold higher likelihood of a successful outcome. In the subgroup of women with heterozygous factor V Leiden (n=72) the live birth rate was 94% with enoxaparin prophylaxis, compared to 33% with aspirin, suggesting a 34-fold higher likelihood of a successful pregnancy outcome [Gris et al 2004].
A prospective randomized trial (Live-Enox) compared two different prophylactic doses of enoxaparin in thrombophilic women with a history of recurrent pregnancy loss (including 55 heterozygous for factor V Leiden). Both prophylactic doses (40 mg/day and 80 mg/day) achieved similar high live birth rates of 84% and 78%, respectively. These rates were substantially higher than the 23% live birth rate in prior untreated pregnancies [Brenner, Hoffman et al 2005].
No prospective randomized trials including an untreated control group confirming the benefit of low molecular weight heparin in preventing pregnancy loss in thrombophilic women have been performed. However, the concordant results of the studies cited above suggest that anticoagulation may improve pregnancy outcome in thrombophilic women.
Antithrombotic prophylaxis should be considered in selected women with factor V Leiden and unexplained pregnancy loss after an informed discussion of the risks and the data suggesting benefit [Kujovich 2005]. The evolving consensus in favor of prophylactic anticoagulation is reflected by the recent recommendations of the Seventh American College of Chest Physicians' Conference (ACCP) on antithrombotic therapy [Bates et al 2004]. ACCP guidelines suggest prophylactic-dose low molecular-weight or unfractionated heparin and low-dose aspirin for women with inherited thrombophilia and recurrent pregnancy loss or a single second- or third-trimester loss [Bates et al 2004].
Other pregnancy complications. Data supporting the benefit of antithrombotic therapy in thrombophilic women with other pregnancy complications are considerably more limited. In the Live-Enox study, the incidence of preeclampsia, placental abruption, and fetal growth retardation was substantially lower with enoxaparin prophylaxis than in prior untreated pregnancies [Brenner, Bar et al 2005]. A study of thrombophilic women with prior fetal loss who received either enoxaparin or aspirin during a subsequent pregnancy showed that those who received enoxaparin had newborns with significantly higher birth weights and fewer classified as small for gestational age [Gris et al 2004]. However, neither study was designed to evaluate these complications as primary outcomes. ACCP guidelines suggest low-dose aspirin and prophylactic-dose low molecular-weight or unfractionated heparin for thrombophilic women with a history of severe or recurrent preeclampsia or placental abruption [Bates et al 2004]. Decisions about antithrombotic therapy in women with factor V Leiden and pregnancy complications should be based on an individual risk/benefit assessment. Assessment of the maternal thrombotic risk during pregnancy should also be incorporated into the decision regarding prophylaxis.
Surveillance
Individuals on long-term anticoagulation require periodic reevaluation of their clinical course to confirm that the benefits of anticoagulation continue to outweigh the bleeding risk.
Selected factor V Leiden heterozygotes who do not require long-term anticoagulation may benefit from evaluation prior to exposure to circumstantial risk factors such as surgery or pregnancy. (See Prevention of Primary Manifestations.)
Agents/Circumstances to Avoid
Women with a factor V Leiden allele and a history of VTE should avoid oral contraceptive use and HRT.
Asymptomatic women who are heterozygous for factor V Leiden should be counseled on the risks of oral contraceptive and HRT use and should be encouraged to consider alternative forms of contraception and control of menopausal symptoms.
Asymptomatic heterozygous women electing to use oral contraceptives should avoid third-generation formulations because of their higher thrombotic risk.
Homozygous women with or without prior VTE should avoid oral contraceptives.
For heterozygous women who require short-term hormone replacement therapy for severe menopausal symptoms, low-dose transdermal preparations may have a lower thrombotic risk [Scarabin et al 2003, Straczek et al 2005].
Testing of Relatives at Risk
The genetic status of asymptomatic at-risk family members can be established using molecular genetic testing; however, the indications for family testing are unresolved. In the absence of evidence that early diagnosis of factor V Leiden reduces morbidity or mortality, decisions regarding testing should be made on an individual basis.
Clarification of factor V Leiden allele status may be useful in women considering hormonal contraception or pregnancy or in families with a strong history of recurrent venous thrombosis at a young age.
Asymptomatic factor V Leiden heterozygotes and homozygotes should be aware of the signs and symptoms of venous thromboembolism that require immediate medical attention and the potential need for prophylactic anticoagulation in high-risk circumstances. They should be informed that although a factor V allele is an established risk factor, it does not predict thrombosis with certainty because the clinical course is variable, even within the same family.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Novel inhibitors of the initiation of coagulation and fibrin formation are still investigational [Weitz et al 2004]. None of these new antithrombotic agents are specific for factor V Leiden or thrombophilia in general.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Other
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —ED.
Mode of Inheritance
The phenotypes associated with factor V Leiden are inherited in an incomplete autosomal dominant manner.
Risk to Family Members — Proband Heterozygous for Factor V Leiden
Parents of a proband
In most instances, one parent of a proband heterozygous for the factor V Leiden allele is also heterozygous for the factor V Leiden allele.
Because of the relatively high prevalence of this allele in the general population, occasionally one parent is homozygous or both parents are heterozygous.
Sibs of a proband
The risk to the sibs of the proband depends upon the genetic status of the proband's parents.
If one parent of a heterozygous proband is heterozygous, each sib of the proband has a 50% risk of being heterozygous for the factor V Leiden allele.
If one parent is homozygous, each sib of the proband has a 100% risk of being heterozygous for the factor V Leiden allele.
If both parents are heterozygous, each sib of the proband has a 25% risk of being homozygous for the factor V Leiden allele, a 50% risk of being heterozygous, and a 25% chance of inheriting both normal factor V alleles.
Offspring of a proband
Each offspring of a proband heterozygous for the factor V Leiden allele has a 50% chance of inheriting the factor V Leiden allele.
If the proband's reproductive partner is heterozygous, each offspring has a 25% risk of being homozygous for the factor V Leiden allele, a 50% risk of being heterozygous for the factor V Leiden allele, and a 25% chance of being homozygous for both normal factor V alleles.
Risk to Family Members — Proband Homozygous for Factor V Leiden
Parents of a proband
In most instances, both parents of an individual homozygous for the factor V Leiden mutation are heterozygous for factor V Leiden.
Because of the relatively high prevalence of this allele in the general population, occasionally one parent is homozygous and the other parent is heterozygous.
Sibs of a proband
The risk to the sibs of the proband depends upon the genetic status of the proband's parents.
If the parents of a proband homozygous for the factor V Leiden allele are heterozygotes, the sibs of the proband have a 25% risk of being homozygous for the factor V Leiden allele, a 50% risk of being heterozygous for the factor V Leiden allele, and a 25% chance of inheriting both normal factor V alleles.
If one parent is homozygous for the factor V Leiden allele and the other parent is heterozygous, the sibs of the proband have a 50% chance of being homozygous for the factor V Leiden allele and a 50% chance of being heterozygous.
Offspring of a proband
Each offspring of a proband homozygous for the factor V Leiden allele has a 100% chance of inheriting one factor V Leiden allele.
If the affected person's reproductive partner is heterozygous, each offspring has a 50% chance of inheriting two factor V Leiden alleles and a 50% chance of inheriting one factor V Leiden allele.
Other family members of a proband. The risk to other family members depends upon the genetic status of the proband's parents. The family members of a person found to be heterozygous or homozygous for factor V Leiden are at risk.
Related Genetic Counseling Issues
Informed consent. Specific informed consent is not generally required for factor V Leiden genetic testing. However, prior to testing, individuals should be made aware that genetic test results have implications regarding risk to other family members and that attendant issues of confidentiality and possible insurance discrimination may arise [Grody et al 2001].
Testing at-risk family members. The presence of one or two factor V Leiden alleles can be identified in asymptomatic at-risk family members using molecular genetic testing.
The indications for testing at-risk family members are unresolved. Since heterozygosity for the factor V Leiden allele confers only a mildly increased risk of thrombosis, routine testing of at-risk family members is not recommended.
The low absolute thrombotic risk in asymptomatic heterozygotes argues against a general policy of testing at-risk family members. In the absence of evidence that early diagnosis of the heterozygous state reduces morbidity or mortality, the decision to test at-risk family members should be made on an individual basis. Clarification of factor V Leiden allele status may be beneficial in women considering use of oral contraception or pregnancy or in families with a strong history of recurrent venous thrombosis at a young age. At-risk family members often request factor V Leiden testing prior to exposure to recognized risk factors or simply from a desire to know their status. Individuals requesting testing for factor V Leiden and those identified as heterozygotes should be counseled regarding the implications of the diagnosis, including the need for prophylactic anticoagulation in high risk settings and the signs and symptoms that require immediate medical attention. They should be informed that although the presence of the factor V Leiden allele is an established risk factor, it does not predict thrombosis with certainty because the clinical course is variable even within the same family.
Testing of at-risk individuals during childhood. Asymptomatic at-risk individuals younger than age 18 years are not usually tested because thrombosis rarely occurs before young adulthood, even in homozygous individuals. Earlier testing may be considered in families with other known thrombophilic disorders or a strong history of thrombosis at a young age. The subcommittee for perinatal and pediatric hemostasis of the International Society for Thrombosis and Haemostasis has published guidelines for laboratory testing for thrombophilia in pediatric patients. A complete evaluation for genetic and acquired thrombophilic disorders is recommended for children with thrombosis [Manco-Johnson et al 2002] (See also the National Society of Genetic Counselors resolution on genetic testing of children and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.)
Family planning. The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See DNA Banking for a list of laboratories offering this service.
Prenatal Testing
Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. The diagnosis of factor V Leiden should be confirmed in an affected family member before prenatal testing is performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Requests for prenatal testing for factor V Leiden are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, careful discussion of these issues is appropriate.
Preimplantation genetic diagnosis (PGD) may be available for families in which one or two Factor V Leiden alleles have been identified in a parent. For laboratories offering PGD, see . Although technically possible, PGD for factor V Leiden is rarely requested as the disorder may never cause thrombosis, and effective treatment is available.
Molecular Genetics
Information in the Molecular Genetics tables may differ from that in the text; tables may contain more recent information. —ED.
Table A. Molecular Genetics of Factor V Leiden Thrombophilia
Gene Symbol
Chromosomal Locus
Protein Name
F5
1q23
Coagulation factor V
Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
Table B. OMIM Entries for Factor V Leiden Thrombophilia
188055
THROMBOPHILIA DUE TO DEFICIENCY OF ACTIVATED PROTEIN C COFACTOR
227400
FACTOR V DEFICIENCY
Table C. Genomic Databases for Factor V Leiden Thrombophilia
Gene Symbol
Entrez Gene
HGMD
GeneCards
GDB
GenAtlas
F5
2153 (MIM No. 227400)
F5
F5
119896
F5
For a description of the genomic databases listed, click here.
Normal allelic variants: Haplotype analysis of the factor V gene strongly suggests that the mutation at nucleotide 1691 was a single event that occurred 20,000-30,000 years ago, after the evolutionary separation of Caucasians from Asians and Africans [Zivelin et al 1997]. The high prevalence of factor V Leiden among Caucasians suggests a balanced polymorphism with some type of survival advantage associated with the heterozygous state. Some investigators speculate that the mild hypercoagulable state conferred by the mutation might have had a beneficial effect in reducing mortality from bleeding associated with childbirth or trauma in pre-modern times [Zivelin et al 1997]. One retrospective study reported a significantly reduced risk of intrapartum bleeding complications in women heterozygous for factor V Leiden compared to women without the mutation [Lindqvist et al 1998]. Factor V Leiden hterozygotes undergoing elective cardiac surgery had significantly less blood loss and a lower risk of requiring a blood transfusion than individuals with a normal factor V genotype [Donahue et al 2003]. Another study suggested that the mutation is associated with a fivefold lower risk of spontaneous intracranial hemorrhage, consistent with the proposed protective effect [Corral et al 2001]. A study of women who had successful in vitro fertilization suggested that factor V Leiden enhances embryo implantation, thereby favoring the early survival of heterozygotes [Gopel et al 2001]. Analysis of a large randomized trial of individuals with severe sepsis showed that factor V Leiden heterozygotes had a threefold greater probability of survival, confirming animal models of sepsis that suggest a similar survival benefit [Kerlin et al 2003]. Although each of these hypothesized beneficial effects could account for the persistence of the mutation, a survival advantage remains to be confirmed.
Pathologic allelic variants: Two different mutations at the R306 APC cleavage site have been reported, only one of which is associated with APC resistance. A G-to-C point mutation in the codon for the R306 APC cleavage site (factor V Cambridge) was identified in a British individual with a history of thrombosis and APC resistance in the absence of the factor V Leiden mutation [Williamson et al 1998]. The mutation predicts the replacement of R with T at position 306, the second of three sequential APC cleavage sites in the factor V molecule. The same mutation was found in the individual's mother, who also had an abnormally low APC resistance value. However, it was not found in 600 other individuals presenting with thromboembolism or in a population of normal blood donors, suggesting that it is a very rare factor V variant. Factor V Cambridge was not found in several other series of individuals with VTE or unexplained recurrent pregnancy loss, or in healthy controls from other ethnic groups [Djordjevic et al 2004, Zammiti et al 2006].
A different mutation in the same codon predicting an R-to-G substitution at position 306 in factor V was identified in two of 43 Chinese individuals with a history of thrombosis and one control individual [Chan et al 1998]. The R306G mutation was not associated with APC resistance in the one individual tested with a coagulation screening assay. However, in a recombinant system, factor V Cambridge and the R306G variants showed identical APC resistance patterns with ratio values intermediate between those of wild type factor V and factor V Leiden [Norstrom et al 2002]. Another study found the R306G mutation in 4.7% of Hong Kong Chinese individuals, but did not identify it as a risk factor for thrombosis [Liang et al 1998].
Although the available evidence suggests that the R306T and R306G mutations alone are not major risk factors for thrombosis, they may contribute when combined with other genetic or acquired risk factors. There are anecdotal reports of double heterozygosity for factor V Cambridge and factor V Leiden or the prothrombin 20210G>A mutation in individuals with VTE [Santamaria et al 2005, Jeanne-Yvonne et al 2006].
Normal gene product: Coagulation factor V
Abnormal gene product: The point mutation predicts the replacement of a single amino acid (R506Q) at one of three APC cleavage sites in the factor Va molecule. The mutant factor V Leiden is inactivated at an approximately tenfold slower rate than normal and persists longer in the circulation, resulting in increased thrombin generation and a mild hypercoagulable state, reflected by elevated levels of prothrombin fragment F1+2 and other activated coagulation markers [Martinelli et al 1996, Zoller et al 1996].
Resources
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The National Alliance for Thrombosis and ThrombophiliaPO Box 66018 Washington DC 20035-6018 Email: nattinfo@nattinfo.org www.nattinfo.org
National Library of Medicine Genetics Home ReferenceFactor V Leiden thrombophilia
March of DimesThe Thrombophilias and Pregnancy
Teaching Case-Genetic ToolsCases designed for teaching genetics in the primary care setting.Case 39. Two Patients Presenting to a Walk-In Clinic with Symptoms of a Blood Clot
References
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
Published Statements and Policies Regarding Genetic Testing
American Society of Human Genetics; American College of Medical Genetics. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents . 1995
American College of Medical Genetics. Consensus statement on factor V Leiden mutation testing . 2001
Manco-Johnson MJ, Grabowski EF, Hellgreen M, Kemahli AS, Massicotte MP, Muntean W, Peters M, Nowak-Gottl U. Laboratory testing for thrombophilia in pediatric patients. On behalf of the Subcommittee for Perinatal and Pediatric Thrombosis of the Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis (ISTH). Thromb Haemost. 2002; 88: 155–6.
National Society of Genetic Counselors. Resolution on prenatal and childhood testing for adult-onset disorders . 1995
Press RD, Bauer KA, Kujovich JL, Heit JA. Clinical utility of factor V Leiden (R506Q) testing for the diagnosis and management of thromboembolic disorders. Arch Pathol Lab Med. 2002; 126: 1304–18.
Literature Cited
Abramson N, Costantino JP, Garber JE, Berliner N, Wickerham DL, Wolmark N. Effect of Factor V Leiden and prothrombin G20210-->A mutations on thromboembolic risk in the national surgical adjuvant breast and bowel project breast cancer prevention trial. J Natl Cancer Inst. 2006; 98: 904–10. [PubMed]
Agorastos T, Karavida A, Lambropoulos A, Constantinidis T, Tzitzimikas S, Chrisafi S, Saravelos H, Vavilis D, Kotsis A, Bontis J. Factor V Leiden and prothrombin G20210A mutations in pregnancies with adverse outcome. J Matern Fetal Neonatal Med. 2002; 12: 267–73. [PubMed]
Alfirevic Z, Mousa HA, Martlew V, Briscoe L, Perez-Casal M, Toh CH. Postnatal screening for thrombophilia in women with severe pregnancy complications. Obstet Gynecol. 2001; 97: 753–9. [PubMed]
Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, Bonds D, Brunner R, Brzyski R, Caan B, Chlebowski R, Curb D, Gass M, Hays J, Heiss G, Hendrix S, Howard BV, Hsia J, Hubbell A, Jackson R, Johnson KC, Judd H, Kotchen JM, Kuller L, LaCroix AZ, Lane D, Langer RD, Lasser N, Lewis CE, Manson J, Margolis K, Ockene J, O'Sullivan MJ, Phillips L, Prentice RL, Ritenbaugh C, Robbins J, Rossouw JE, Sarto G, Stefanick ML, Van Horn L, Wactawski-Wende J, Wallace R, Wassertheil-Smoller S. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004; 291: 1701–12. [PubMed]
Alhenc-Gelas M, Arnaud E, Nicaud V, Aubry ML, Fiessinger JN, Aiach M, Emmerich J. Venous thromboembolic disease and the prothrombin, methylene tetrahydrofolate reductase and factor V genes. Thromb Haemost. 1999; 81: 506–10. [PubMed]
Aznar J, Mira Y, Vaya A, Corella D, Ferrando F, Villa P, Estelles A. Factor V Leiden and prothrombin G20210A mutations in young adults with cryptogenic ischemic stroke. Thromb Haemost. 2004; 91: 1031–4. [PubMed]
Baglin C, Brown K, Luddington R, Baglin T. Risk of recurrent venous thromboembolism in patients with the factor V Leiden (FVR506Q) mutation: effect of warfarin and prediction by precipitating factors. East Anglian Thrombophilia Study Group. Br J Haematol. 1998; 100: 764–8. [PubMed]
Baglin T, Luddington R, Brown K, Baglin C. Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. Lancet. 2003; 362: 523–6. [PubMed]
Bank I, Libourel EJ, Middeldorp S, Hamulyak K, van Pampus EC, Koopman MM, Prins MH, van der Meer J, Buller HR. Elevated levels of FVIII:C within families are associated with an increased risk for venous and arterial thrombosis. J Thromb Haemost. 2005; 3: 79–84. [PubMed]
Barbour LA. ACOG practice bulletin. Thrombembolism in pregnancy. Int J Gynaecol Obstet. 2001; 75: 203–12. [PubMed]
Barnes C, Deveber G. Prothrombotic abnormalities in childhood ischaemic stroke. Thromb Res. 2006; 118: 67–74. [PubMed]
Barrett-Connor E, Mosca L, Collins P, Geiger MJ, Grady D, Kornitzer M, McNabb MA, Wenger NK. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med. 2006; 355: 125–37. [PubMed]
Bates SM, Greer IA, Hirsh J, Ginsberg JS. Use of antithrombotic agents during pregnancy: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126 Suppl. 2004; 3: 627–44. [PubMed]
Bernardi F, Faioni EM, Castoldi E, Lunghi B, Castaman G, Sacchi E, Mannucci PM. A factor V genetic component differing from factor V R506Q contributes to the activated protein C resistance phenotype. Blood. 1997; 90: 1552–7. [PubMed]
Biron-Andreani C, Schved JF, Daures JP. Factor V Leiden mutation and pregnancy-related venous thromboembolism: what is the exact risk? Results from a meta-analysis. Thromb Haemost. 2006; 96: 14–8. [PubMed]
Bjorgell O, Nilsson PE, Nilsson JA, Svensson PJ. Location and extent of deep vein thrombosis in patients with and without FV:R 506Q mutation. Thromb Haemost. 2000; 83: 648–51. [PubMed]
Bloemenkamp KW, Rosendaal FR, Helmerhorst FM, Vandenbroucke JP. Higher risk of venous thrombosis during early use of oral contraceptives in women with inherited clotting defects. Arch Intern Med. 2000; 160: 49–52. [PubMed]
Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA. 2005a; 293: 715–22. [PubMed]
Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Old and new risk factors for upper extremity deep venous thrombosis. J Thromb Haemost. 2005b; 3: 2471–8. [PubMed]
Bokarewa MI, Bremme K, Blomback M. Arg506-Gln mutation in factor V and risk of thrombosis during pregnancy. Br J Haematol. 1996; 92: 473–8. [PubMed]
Bonduel M, Hepner M, Sciuccati G, Pieroni G, Feliu-Torres A, Mardaraz C, Frontroth JP. Factor V Leiden and prothrombin gene G20210A mutation in children with venous thromboembolism. Thromb Haemost. 2002; 87: 972–7. [PubMed]
Brenner B, Bar J, Ellis M, Yarom I, Yohai D, Samueloff A. Effects of enoxaparin on late pregnancy complications and neonatal outcome in women with recurrent pregnancy loss and thrombophilia: results from the Live-Enox study. Fertil Steril. 2005; 84: 770–3. [PubMed]
Brenner B, Hoffman R, Blumenfeld Z, Weiner Z, Younis JS. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin. Thromb Haemost. 2000; 83: 693–7. [PubMed]
Brenner B, Hoffman R, Carp H, Dulitsky M, Younis J. Efficacy and safety of two doses of enoxaparin in women with thrombophilia and recurrent pregnancy loss: the LIVE-ENOX study. J Thromb Haemost. 2005; 3: 227–9. [PubMed]
Brenner B, Sarig G, Weiner Z, Younis J, Blumenfeld Z, Lanir N. Thrombophilic polymorphisms are common in women with fetal loss without apparent cause. Thromb Haemost. 1999; 82: 6–9. [PubMed]
Brill-Edwards P, Ginsberg JS, Gent M, Hirsh J, Burrows R, Kearon C, Geerts W, Kovacs M, Weitz JI, Robinson KS, Whittom R, Couture G. Safety of withholding heparin in pregnant women with a history of venous thromboembolism. Recurrence of Clot in This Pregnancy Study Group. N Engl J Med. 2000; 343: 1439–44. [PubMed]
Brugge JM, Simioni P, Bernardi F, Tormene D, Lunghi B, Tans G, Pagnan A, Rosing J, Castoldi E. Expression of the normal factor V allele modulates the APC resistance phenotype in heterozygous carriers of the factor V Leiden mutation. J Thromb Haemost. 2005; 3: 2695–702. [PubMed]
Buller HR, Agnelli G, Hull RD, Hyers TM, Prins MH, Raskob GE. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126 Suppl. 2004; 3: 401–28. [PubMed]
Camire RM, Pollak ES, Kaushansky K, Tracy PB. Secretable human platelet-derived factor V originates from the plasma pool. Blood. 1998; 92: 3035–41. [PubMed]
Carp H, Dolitzky M, Inbal A. Thromboprophylaxis improves the live birth rate in women with consecutive recurrent miscarriages and hereditary thrombophilia. J Thromb Haemost. 2003; 1: 433–8. [PubMed]
Castaman G, Lunghi B, Missiaglia E, Bernardi F, Rodeghiero F. Phenotypic homozygous activated protein C resistance associated with compound heterozygosity for Arg506Gln (factor V Leiden) and His1299Arg substitutions in factor V. Br J Haematol. 1997; 99: 257–61. [PubMed]
Castoldi E, Kalafatis M, Lunghi B, Simioni P, Ioannou PA, Petio M, Girolami A, Mann KG, Bernardi F. Molecular bases of pseudo-homozygous APC resistance: the compound heterozygosity for FV R506Q and a FV null mutation results in the exclusive presence of FV Leiden molecules in plasma. Thromb Haemost. 1998; 80: 403–6. [PubMed]
Chan WP, Lee CK, Kwong YL, Lam CK, Liang R. A novel mutation of Arg306 of factor V gene in Hong Kong Chinese. Blood. 1998; 91: 1135–9. [PubMed]
Chandler WL, Rodgers GM, Sprouse JT, Thompson AR. Elevated hemostatic factor levels as potential risk factors for thrombosis. Arch Pathol Lab Med. 2002; 126: 1405–14. [PubMed]
Christiansen SC, Cannegieter SC, Koster T, Vandenbroucke JP, Rosendaal FR. Thrombophilia, clinical factors, and recurrent venous thrombotic events. JAMA. 2005; 293: 2352–61. [PubMed]
Conard J, Plu-Bureau G, Bahi N, Horellou MH, Pelissier C, Thalabard JC. Progestogen-only contraception in women at high risk of venous thromboembolism. Contraception. 2004; 70: 437–41. [PubMed]
Corral J, Iniesta JA, Gonzalez-Conejero R, Villalon M, Vicente V. Polymorphisms of clotting factors modify the risk for primary intracranial hemorrhage. Blood. 2001; 97: 2979–82. [PubMed]
Crookston KP, Henderson R, Chandler WL. False negative factor V Leiden assay following allogeneic stem cell transplant. Br J Haematol. 1998; 100: 600–2. [PubMed]
Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, Norton L, Nickelsen T, Bjarnason NH, Morrow M, Lippman ME, Black D, Glusman JE, Costa A, Jordan VC. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA. 1999; 281: 2189–97. [PubMed]
Curb JD, Prentice RL, Bray PF, Langer RD, Van Horn L, Barnabei VM, Bloch MJ, Cyr MG, Gass M, Lepine L, Rodabough RJ, Sidney S, Uwaifo GI, Rosendaal FR. Venous thrombosis and conjugated equine estrogen in women without a uterus. Arch Intern Med. 2006; 166: 772–80. [PubMed]
Cushman M, Kuller LH, Prentice R, Rodabough RJ, Psaty BM, Stafford RS, Sidney S, Rosendaal FR. Estrogen plus progestin and risk of venous thrombosis. JAMA. 2004; 292: 1573–80. [PubMed]
Cushman M, Rosendaal FR, Psaty BM, Cook EF, Valliere J, Kuller LH, Tracy RP. Factor V Leiden is not a risk factor for arterial vascular disease in the elderly: results from the Cardiovascular Health Study. Thromb Haemost. 1998; 79: 912–5. [PubMed]
Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh S. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet. 1996; 348: 977–80. [PubMed]
Dargaud Y, Trzeciak MC, Meunier S, Angei C, Pellechia D, Negrier C, Vinciguerra C, Dargaud Y. Two novel factor V null mutations associated with activated protein C resistance phenotype/genotype discrepancy. Br J Haematol. 2003; 123: 342–5. [PubMed]
De Maat MP, Jansen MW, Hille ET, Vos HL, Bloemenkamp KW, Buitendijk S, Helmerhorst FM, Wladimiroff JW, Bertina RM, De Groot CJ. Preeclampsia and its interaction with common variants in thrombophilia genes. J Thromb Haemost. 2004; 2: 1588–93. [PubMed]
de Moerloose P, Reber G, Perrier A, Perneger T, Bounameaux H. Prevalence of factor V Leiden and prothrombin G20210A mutations in unselected patients with venous thromboembolism. Br J Haematol. 2000; 110: 125–9. [PubMed]
De Stefano V, Martinelli I, Mannucci PM, Paciaroni K, Chiusolo P, Casorelli I, Rossi E, Leone G. The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation. N Engl J Med. 1999; 341: 801–6. [PubMed]
de Visser MC, Guasch JF, Kamphuisen PW, Vos HL, Rosendaal FR, Bertina RM. The HR2 haplotype of factor V: effects on factor V levels, normalized activated protein C sensitivity ratios and the risk of venous thrombosis. Thromb Haemost. 2000; 83: 577–82. [PubMed]
de Visser MC, Rosendaal FR, Bertina RM. A reduced sensitivity for activated protein C in the absence of factor V Leiden increases the risk of venous thrombosis. Blood. 1999; 93: 1271–6. [PubMed]
Dentali F, Crowther M, Ageno W. Thrombophilic abnormalities, oral contraceptives, and risk of cerebral vein thrombosis: a meta-analysis. Blood. 2006; 107: 2766–73. [PubMed]
Dindagur N, Kruthika-Vinod TP, Christopher R. Factor V gene A4070G mutation and the risk of cerebral veno-sinus thrombosis occurring during puerperium. Thromb Res. 2007; 119: 497–500. [PubMed]
Dizon-Townson D, Miller C, Sibai B, Spong CY, Thom E, Wendel G Jr, Wenstrom K, Samuels P, Cotroneo MA, Moawad A, Sorokin Y, Meis P, Miodovnik M, O'Sullivan MJ, Conway D, Wapner RJ, Gabbe SG. The relationship of the factor V Leiden mutation and pregnancy outcomes for mother and fetus. Obstet Gynecol. 2005; 106: 517–24. [PubMed]
Djordjevic V, Rakicevic LJ, Mikovic D, Kovac M, Miljic P, Radojkovic D, Savic A. Prevalence of factor V leiden, factor V cambridge, factor II G20210A and methylenetetrahydrofolate reductase C677T mutations in healthy and thrombophilic Serbian populations. Acta Haematol. 2004; 112: 227–9. [PubMed]
Doggen CJ, Cats VM, Bertina RM, Rosendaal FR. Interaction of coagulation defects and cardiovascular risk factors: increased risk of myocardial infarction associated with factor V Leiden or prothrombin 20210A. Circulation. 1998; 97: 1037–41. [PubMed]
Donahue BS, Gailani D, Higgins MS, Drinkwater DC, George AL Jr. Factor V Leiden protects against blood loss and transfusion after cardiac surgery. Circulation. 2003; 107: 1003–8. [PubMed]
Dudding TE, Attia J. The association between adverse pregnancy outcomes and maternal factor V Leiden genotype: a meta-analysis. Thromb Haemost. 2004; 91: 700–11. [PubMed]
Duggan C, Marriott K, Edwards R, Cuzick J. Inherited and acquired risk factors for venous thromboembolic disease among women taking tamoxifen to prevent breast cancer. J Clin Oncol. 2003; 21: 3588–93. [PubMed]
Dunn TB, Linden MA, Vercellotti GM, Gruessner RW. Factor V Leiden and hepatic artery thrombosis after liver transplantation. Clin Transplant. 2006; 20: 132–5. [PubMed]
Duran R, Biner B, Demir M, Celtik C, Karasalihoglu S. Factor V Leiden mutation and other thrombophilia markers in childhood ischemic stroke. Clin Appl Thromb Hemost. 2005; 11: 83–8. [PubMed]
Ehrenforth S, Nemes L, Mannhalter C, Rosendaal FR, Koder S, Zoghlami-Rintelen C, Scharrer I, Pabinger I. Impact of environmental and hereditary risk factors on the clinical manifestation of thrombophilia in homozygous carriers of factor V:G1691A. J Thromb Haemost. 2004; 2: 430–6. [PubMed]
Ekberg H, Svensson PJ, Simanaitis M, Dahlback B. Factor V R506Q mutation (activated protein C resistance) is an additional risk factor for early renal graft loss associated with acute vascular rejection. Transplantation. 2000; 69: 1577–81. [PubMed]
Eichinger S, Pabinger I, Stumpflen A, Hirschl M, Bialonczyk C, Schneider B, Mannhalter C, Minar E, Lechner K, Kyrle PA. The risk of recurrent venous thromboembolism in patients with and without factor V Leiden. Thromb Haemost. 1997; 77: 624–8. [PubMed]
Emmerich J, Rosendaal FR, Cattaneo M, Margaglione M, De Stefano V, Cumming T, Arruda V, Hillarp A, Reny JL. Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism--pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Study Group for Pooled-Analysis in Venous Thromboembolism. Thromb Haemost. 2001; 86: 809–16. [PubMed]
Facchinetti F, Marozio L, Grandone E, Pizzi C, Volpe A, Benedetto C. Thrombophilic mutations are a main risk factor for placental abruption. Haematologica. 2003; 88: 785–8. [PubMed]
Faioni EM, Franchi F, Bucciarelli P, Margaglione M, De Stefano V, Castaman G, Finazzi G, Mannucci PM. Coinheritance of the HR2 haplotype in the factor V gene confers an increased risk of venous thromboembolism to carriers of factor V R506Q (factor V Leiden). Blood. 1999; 94: 3062–6. [PubMed]
Fijnheer R, Paijmans B, Verdonck LF, Nieuwenhuis HK, Roest M, Dekker AW. Factor V Leiden in central venous catheter-associated thrombosis. Br J Haematol. 2002; 118: 267–70. [PubMed]
Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark N. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998; 90: 1371–88. [PubMed]
Galli M, Luciani D, Bertolini G, Barbui T. Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood. 2003; 101: 1827–32. [PubMed]
Geerts WH, Pineo GF, Heit JA, Bergqvist D, Lassen MR, Colwell CW, Ray JG. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126 Suppl. 2004; 3: 338–400. [PubMed]
Gerhardt A, Scharf RE, Beckmann MW, Struve S, Bender HG, Pillny M, Sandmann W, Zotz RB. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med. 2000; 342: 374–80. [PubMed]
Gerhardt A, Scharf RE, Zotz RB. Effect of hemostatic risk factors on the individual probability of thrombosis during pregnancy and the puerperium. Thromb Haemost. 2003; 90: 77–85. [PubMed]
Girolami A, Tormene D, Gavasso S, Bertolo C, Girolami B. Long term use of oral contraceptives without thrombosis in patients with FV Leiden polymorphism: a study of 37 patients (2 homozygous and 35 heterozygous). J Thromb Thrombolysis. 2004; 17: 145–9. [PubMed]
Gonzalez-Porras JR, Garcia-Sanz R, Alberca I, Lopez ML, Balanzategui A, Gutierrez O, Lozano F, San Miguel J. Risk of recurrent venous thrombosis in patients with G20210A mutation in the prothrombin gene or factor V Leiden mutation. Blood Coagul Fibrinolysis. 2006; 17: 23–8. [PubMed]
Gopel W, Ludwig M, Junge AK, Kohlmann T, Diedrich K, Moller J. Selection pressure for the factor-V-Leiden mutation and embryo implantation. Lancet. 2001; 358: 1238–9. [PubMed]
Grady D, Wenger NK, Herrington D, Khan S, Furberg C, Hunninghake D, Vittinghoff E, Hulley S. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/progestin Replacement Study. Ann Intern Med. 2000; 132: 689–96. [PubMed]
Grandone E, Margaglione M, Calaizzo D, d Addedda M, Cappucci G, Vecchione G. et al. Factor V Leiden is associated with repeated and recurrent unexplained fetal losses. Thrombosis and Haemostasis. 1997; 77: 822–24. [PubMed]
Grandone E, Margaglione M, Colaizzo D, Cappucci G, Scianname N, Montanaro S, Paladini D, Martinelli P, Di Minno G. Prothrombotic genetic risk factors and the occurrence of gestational hypertension with or without proteinuria. Thromb Haemost. 1999; 81: 349–52. [PubMed]
Grandone E, Margaglione M, Colaizzo D, Pavone G, Paladini D, Martinelli P, Di Minno G. Lower birth-weight in neonates of mothers carrying factor V G1691A and factor II A(20210) mutations. Haematologica. 2002; 87: 177–81. [PubMed]
Gris JC, Mercier E, Quere I, Lavigne-Lissalde G, Cochery-Nouvellon E, Hoffet M, Ripart-Neveu S, Tailland ML, Dauzat M, Mares P. Low-molecular-weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder. Blood. 2004; 103: 3695–9. [PubMed]
Gris JC, Quere I, Monpeyroux F, Mercier E, Ripart-Neveu S, Tailland ML, Hoffet M, Berlan J, Daures JP, Mares P. Case-control study of the frequency of thrombophilic disorders in couples with late foetal loss and no thrombotic antecedent--the Nimes Obstetricians and Haematologists Study5 (NOHA5). Thromb Haemost. 1999; 81: 891–9. [PubMed]
Grody WW, Griffin JH, Taylor AK, Korf BR, Heit JA. American College of Medical Genetics consensus statement on factor V Leiden mutation testing. Genet Med. 2001; 3: 139–48. [PubMed]
Grodstein F, Stampfer MJ, Goldhaber SZ, Manson JE, Colditz GA, Speizer FE, Willett WC, Hennekens CH. Prospective study of exogenous hormones and risk of pulmonary embolism in women. Lancet. 1996; 348: 983–7. [PubMed]
Hallak M, Senderowicz J, Cassel A, Shapira C, Aghai E, Auslender R, Abramovici H. Activated protein C resistance (factor V Leiden) associated with thrombosis in pregnancy. Am J Obstet Gynecol. 1997; 176: 889–93. [PubMed]
Haywood S, Liesner R, Pindora S, Ganesan V. Thrombophilia and first arterial ischaemic stroke: a systematic review. Arch Dis Child. 2005; 90: 402–5. [PubMed]
Heidenreich S, Junker R, Wolters H, Lang D, Hessing S, Nitsche G, Nowak-Gottl U. Outcome of kidney transplantation in patients with inherited thrombophilia: data of a prospective study. J Am Soc Nephrol. 2003; 14: 234–9. [PubMed]
Heijmans BT, Westendorp RG, Knook DL, Kluft C, Slagboom PE. The risk of mortality and the factor V Leiden mutation in a population- based cohort. Thromb Haemost. 1998; 80: 607–9. [PubMed]
Heit JA, Sobell JL, Li H, Sommer SS. The incidence of venous thromboembolism among Factor V Leiden carriers: a community-based cohort study. J Thromb Haemost. 2005; 3: 305–11. [PubMed]
Heller C, Heinecke A, Junker R, Knofler R, Kosch A, Kurnik K, Schobess R, von Eckardstein A, Strater R, Zieger B, Nowak-Gottl U. Cerebral venous thrombosis in children: a multifactorial origin. Circulation. 2003; 108: 1362–7. [PubMed]
Herrington DM, Vittinghoff E, Howard TD, Major DA, Owen J, Reboussin DM, Bowden D, Bittner V, Simon JA, Grady D, Hulley SB. Factor V Leiden, hormone replacement therapy, and risk of venous thromboembolic events in women with coronary disease. Arterioscler Thromb Vasc Biol. 2002; 22: 1012–7. [PubMed]
Hille ET, Westendorp RG, Vandenbroucke JP, Rosendaal FR. Mortality and causes of death in families with the factor V Leiden mutation (resistance to activated protein C). Blood. 1997; 89: 1963–7. [PubMed]
Hiltunen L, Rautanen A, Rasi V, Kaaja R, Kere J, Krusius T, Vahtera E, Paunio M. An unfavorable combination of factor V Leiden with age, weight, and blood group causes high risk of pregnancy-associated venous thrombosis-a population-based nested case-control study. Thromb Res. 2007; 119: 423–32. [PubMed]
Hirsch DR, Mikkola KM, Marks PW, Fox EA, Dorfman DM, Ewenstein BM, Goldhaber SZ. Pulmonary embolism and deep venous thrombosis during pregnancy or oral contraceptive use: prevalence of factor V Leiden. Am Heart J. 1996; 131: 1145–8. [PubMed]
Hirsh J, Kearon C, Ginsberg J. Duration of anticoagulant therapy after first episode of venous thrombosis in patients with inherited thrombophilia [editorial; comment]. Arch Intern Med. 1997; 157: 2174–7. [PubMed]
Hirshfield G, Collier JD, Brown K, Taylor C, Frick T, Baglin TP, Alexander GJ. Donor factor V Leiden mutation and vascular thrombosis following liver transplantation. Liver Transpl Surg. 1998; 4: 58–61. [PubMed]
Ho WK, Hankey GJ, Quinlan DJ, Eikelboom JW. Risk of recurrent venous thromboembolism in patients with common thrombophilia: a systematic review. Arch Intern Med. 2006; 166: 729–36. [PubMed]
Hocher B, Slowinski T, Hauser I, Vetter B, Fritsche L, Bachert D, Kulozik A, Neumayer HH. Association of factor V Leiden mutation with delayed graft function, acute rejection episodes and long-term graft dysfunction in kidney transplant recipients. Thromb Haemost. 2002; 87: 194–8. [PubMed]
Howley HE, Walker M, Rodger MA. A systematic review of the association between factor V Leiden or prothrombin gene variant and intrauterine growth restriction. Am J Obstet Gynecol. 2005; 192: 694–708. [PubMed]
Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998; 280: 605–13. [PubMed]
Inbal A, Freimark D, Modan B, Chetrit A, Matetzky S, Rosenberg N, Dardik R, Baron Z, Seligsohn U. Synergistic effects of prothrombotic polymorphisms and atherogenic factors on the risk of myocardial infarction in young males. Blood. 1999; 93: 2186–90. [PubMed]
Infante-Rivard C, Rivard GE, Yotov WV, Genin E, Guiguet M, Weinberg C, Gauthier R, Feoli-Fonseca JC. Absence of association of thrombophilia polymorphisms with intrauterine growth restriction. N Engl J Med. 2002; 347: 19–25. [PubMed]
Irish AB, Green FR, Gray DW, Morris PJ. The factor V Leiden (R506Q) mutation and risk of thrombosis in renal transplant recipients. Transplantation. 1997; 64: 604–7. [PubMed]
Jadaon MM, Dashti AA. HR2 haplotype in Arab population and patients with venous thrombosis in Kuwait. J Thromb Haemost. 2005; 3: 1467–71. [PubMed]
Jeanne-Yvonne B, Le Cam-Duchez V, Chretien MH, Saugier-Veber P. Factor V Cambridge mutation and activated protein C resistance assays. Thromb Haemost. 2006; 95: 581–3. [PubMed]
Jick H, Derby LE, Myers MW, Vasilakis C, Newton KM. Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens. Lancet. 1996; 348: 981–3. [PubMed]
Junker R, Koch HG, Auberger K, Munchow N, Ehrenforth S, Nowak-Gottl U. Prothrombin G20210A gene mutation and further prothrombotic risk factors in childhood thrombophilia. Arterioscler Thromb Vasc Biol. 1999; 19: 2568–72. [PubMed]
Juul K, Tybjaerg-Hansen A, Schnohr P, Nordestgaard BG. Factor V Leiden and the risk for venous thromboembolism in the adult Danish population. Ann Intern Med. 2004; 140: 330–7. [PubMed]
Kamphuisen PW, Eikenboom JC, Bertina RM. Elevated factor VIII levels and the risk of thrombosis. Arterioscler Thromb Vasc Biol. 2001; 21: 731–8. [PubMed]
Kapiotis S, Quehenberger P, Jilma B, Handler S, Pabinger-Fasching I, Mannhalter C, Speiser W. Improved characteristics of aPC-resistance assay: Coatest aPC resistance by predilution of samples with factor V deficient plasma. Am J Clin Pathol. 1996; 106: 588–93. [PubMed]
Karemaker R, Emmerich MG, KTurkstra F, Kuijer P, Buler HR, Helley D. Factor V Leiden paradox: risk of deep-vein thrombosis but not of pulmonary embolism. Lancet. 2000; 356: 182–3. [PubMed]
Karttunen V, Hiltunen L, Rasi V, Vahtera E, Hillbom M. Factor V Leiden and prothrombin gene mutation may predispose to paradoxical embolism in subjects with patent foramen ovale. Blood Coagul Fibrinolysis. 2003; 14: 261–8. [PubMed]
Kenet G, Sadetzki S, Murad H, Martinowitz U, Rosenberg N, Gitel S, Rechavi G, Inbal A. Factor V Leiden and antiphospholipid antibodies are significant risk factors for ischemic stroke in children. Stroke. 2000; 31: 1283–8. [PubMed]
Kennedy M, Andreescu AC, Greenblatt MS, Jiang H, Thomas CA, Chassereau L, Wong C, Durda P, Cushman M. Factor V Leiden, prothrombin 20210A and the risk of venous thrombosis among cancer patients. Br J Haematol. 2005; 128: 386–8. [PubMed]
Kerlin BA, Yan SB, Isermann BH, Brandt JT, Sood R, Basson BR, Joyce DE, Weiler H, Dhainaut JF. Survival advantage associated with heterozygous factor V Leiden mutation in patients with severe sepsis and in mouse endotoxemia. Blood. 2003; 102: 3085–92. [PubMed]
Kim RJ, Becker RC. Association between factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations and events of the arterial circulatory system: a meta-analysis of published studies. Am Heart J. 2003; 146: 948–57. [PubMed]
Kosmas IP, Tatsioni A, Ioannidis JP. Association of Leiden mutation in factor V gene with hypertension in pregnancy and pre-eclampsia: a meta-analysis. J Hypertens. 2003; 21: 1221–8. [PubMed]
Koster T, Blann AD, Briet E, Vandenbroucke JP, Rosendaal FR. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet. 1995; 345: 152–5. [PubMed]
Kovalevsky G, Gracia CR, Berlin JA, Sammel MD, Barnhart KT. Evaluation of the association between hereditary thrombophilias and recurrent pregnancy loss: a meta-analysis. Arch Intern Med. 2004; 164: 558–63. [PubMed]
Kuhle S, Massicotte P, Chan A, Mitchell L. A case series of 72 neonates with renal vein thrombosis. Data from the 1-800-NO-CLOTS Registry. Thromb Haemost. 2004; 92: 729–33. [PubMed]
Kujovich JL. Thrombophilia and thrombotic problems in renal transplant patients. Transplantation. 2004a; 77: 959–64. [PubMed]
Kujovich JL. Hormones and pregnancy: thromboembolic risks for women. Br J Haematol. 2004; 126: 443–54. [PubMed]
Walker ID, Kujovich JL, Greer IA, Rey E, David M, Salmon JE, Hunt BJ, Zotz RB, Gerhardt A, Scharf RE, Middeldorf S, Martinelli I, Cetin I, Grandone E. The use of LMWH in pregnancies at risk: new evidence or perception? J Thromb Haemost. 2005; 3: 778–93. [PubMed]
Kupferminc MJ, Eldor A, Steinman N, Many A, Bar-Am A, Jaffa A, Fait G, Lessing JB. Increased frequency of genetic thrombophilia in women with complications of pregnancy. [published erratum in N Engl J Med 1999 Jul 29;341(5):384] N Engl J Med. 1999; 340: 9–13. [PubMed]
Kupferminc MJ, Fait G, Many A, Gordon D, Eldor A, Lessing JB. Severe preeclampsia and high frequency of genetic thrombophilic mutations. Obstet Gynecol. 2000; 96: 45–9. [PubMed]
Kupferminc MJ, Many A, Bar-Am A, Lessing JB, Ascher-Landsberg J. Mid-trimester severe intrauterine growth restriction is associated with a high prevalence of thrombophilia. BJOG. 2002; 109: 1373–6. [PubMed]
Kyrle PA, Minar E, Hirschl M, Bialonczyk C, Stain M, Schneider B, Weltermann A, Speiser W, Lechner K, Eichinger S. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med. 2000; 343: 457–62. [PubMed]
Lalouschek W, Schillinger M, Hsieh K, Endler G, Tentschert S, Lang W, Cheng S, Mannhalter C. Matched case-control study on factor V Leiden and the prothrombin G20210A mutation in patients with ischemic stroke/transient ischemic attack up to the age of 60 years. Stroke. 2005; 36: 1405–9. [PubMed]
Langlois NJ, Wells PS. Risk of venous thromboembolism in relatives of symptomatic probands with thrombophilia: a systematic review. Thromb Haemost. 2003; 90: 17–26. [PubMed]
Larsson J, Olafsdottir E, Bauer B. Activated protein C resistance in young adults with central retinal vein occlusion. Br J Ophthalmol. 1996; 80: 200–2. [PubMed]
Legnani C, Palareti G, Guazzaloca G, Cosmi B, Lunghi B, Bernardi F, Coccheri S. Venous thromboembolism in young women; role of thrombophilic mutations and oral contraceptive use. Eur Heart J. 2002; 23: 984–90. [PubMed]
Lensen R, Bertina RM, Vandenbroucke JP, Rosendaal FR. High factor VIII levels contribute to the thrombotic risk in families with factor V Leiden. Br J Haematol. 2001; 114: 380–6. [PubMed]
Lensen RP, Bertina RM, de Ronde H, Vandenbroucke JP, Rosendaal FR. Venous thrombotic risk in family members of unselected individuals with factor V Leiden. Thromb Haemost. 2000; 83: 817–21. [PubMed]
Leroy-Matheron C, Duvoux C, Van Nhieu JT, Leroy K, Cherqui D, Gouault-Heilmann M. Activated protein C resistance acquired through liver transplantation and associated with recurrent venous thrombosis. J Hepatol. 2003; 38: 866–9. [PubMed]
Liang R, Lee CK, Wat MS, Kwong YL, Lam CK, Liu HW. Clinical significance of Arg306 mutations of factor V gene. Blood. 1998; 92: 2599–600. [PubMed]
Lin J, August P. Genetic thrombophilias and preeclampsia: a meta-analysis. Obstet Gynecol. 2005; 105: 182–92. [PubMed]
Lindahl TL, Lundahl TH, Nilsson L, Andersson CA. APC-resistance is a risk factor for postoperative thromboembolism in elective replacement of the hip or knee--a prospective study. Thromb Haemost. 1999; 81: 18–21. [PubMed]
Lindmarker P, Schulman S, Sten-Linder M, Wiman B, Egberg N, Johnsson H. The risk of recurrent venous thromboembolism in carriers and non- carriers of the G1691A allele in the coagulation factor V gene and the G20210A allele in the prothrombin gene. DURAC Trial Study Group. Duration of Anticoagulation. Thromb Haemost. 1999; 81: 684–9. [PubMed]
Lindqvist PG, Svensson PJ, Dahlback B, Marsal K. Factor V Q506 mutation (activated protein C resistance) associated with reduced intrapartum blood loss--a possible evolutionary selection mechanism. Thromb Haemost. 1998; 79: 69–73. [PubMed]
Lindqvist PG, Svensson PJ, Marsaal K, Grennert L, Luterkort M, Dahlback B. Activated protein C resistance (FV:Q506) and pregnancy. Thromb Haemost. 1999; 81: 532–7. [PubMed]
Lissalde-Lavigne G, Fabbro-Peray P, Cochery-Nouvellon E, Mercier E, Ripart-Neveu S, Balducchi JP, Daures JP, Perneger T, Quere I, Dauzat M, Mares P, Gris JC. Factor V Leiden and prothrombin G20210A polymorphisms as risk factors for miscarriage during a first intended pregnancy: the matched case-control 'NOHA first' study. J Thromb Haemost. 2005; 3: 2178–84. [PubMed]
Livingston JC, Barton JR, Park V, Haddad B, Phillips O, Sibai BM. Maternal and fetal inherited thrombophilias are not related to the development of severe preeclampsia. Am J Obstet Gynecol. 2001; 185: 153–7. [PubMed]
Loew A, Jacob D, Neuhaus P, Riess H. Resistance to activated protein C caused by factor V Leiden mutation and orthotopic liver transplantation. Transplantation. 2005; 79: 1422–7. [PubMed]
Lowe G, Woodward M, Vessey M, Rumley A, Gough P, Daly E. Thrombotic variables and risk of idiopathic venous thromboembolism in women aged 45-64 years. Relationships to hormone replacement therapy. Thromb Haemost. 2000; 83: 530–5. [PubMed]
Luddington R, Jackson A, Pannerselvam S, Brown K, Baglin T. The factor V R2 allele: risk of venous thromboembolism, factor V levels and resistance to activated protein C. Thromb Haemost. 2000; 83: 204–8. [PubMed]
Manco-Johnson MJ, Grabowski EF, Hellgreen M, Kemahli AS, Massicotte MP, Muntean W, Peters M, Nowak-Gottl U. Laboratory testing for thrombophilia in pediatric patients. On behalf of the Subcommittee for Perinatal and Pediatric Thrombosis of the Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis (ISTH). Thromb Haemost. 2002; 88: 155–6. [PubMed]
Mansourati J, Da Costa A, Munier S, Mercier B, Tardy B, Ferec C, Isaaz K, Blanc JJ. Prevalence of factor V Leiden in patients with myocardial infarction and normal coronary angiography. Thromb Haemost. 2000; 83: 822–5. [PubMed]
Manten B, Westendorp RG, Koster T, Reitsma PH, Rosendaal FR. Risk factor profiles in patients with different clinical manifestations of venous thromboembolism: a focus on the factor V Leiden mutation [see comments]. Thromb Haemost. 1996; 76: 510–3. [PubMed]
Marcucci R, Sofi F, Fedi S, Lari B, Sestini I, Cellai AP, Pulli R, Pratesi G, Pratesi C, Gensini GF, Abbate R. Thrombophilic risk factors in patients with severe carotid atherosclerosis. J Thromb Haemost. 2005; 3: 502–7. [PubMed]
Margaglione M, D'Andrea G, Giuliani N, Brancaccio V, De Lucia D, Grandone E, De Stefano V, Tonali PA, Di Minno G. Inherited prothrombotic conditions and premature ischemic stroke: sex difference in the association with factor V Leiden. Arterioscler Thromb Vasc Biol. 1999; 19: 1751–6. [PubMed]
Martinelli I, Battaglioli T, Bucciarelli P, Passamonti SM, Mannucci PM. Risk factors and recurrence rate of primary deep vein thrombosis of the upper extremities. Circulation. 2004; 110: 566–70. [PubMed]
Martinelli I, Battaglioli T, Burgo I, Di Domenico S, Mannucci PM. Oral contraceptive use, thrombophilia and their interaction in young women with ischemic stroke. Haematologica. 2006; 91: 844–7. [PubMed]
Martinelli I, Battaglioli T, Pedotti P, Cattaneo M, Mannucci PM. Hyperhomocysteinemia in cerebral vein thrombosis. Blood. 2003; 102: 1363–6. [PubMed]
Martinelli I, Bottasso B, Duca F, Faioni E, Mannucci PM. Heightened thrombin generation in individuals with resistance to activated protein C. Thromb Haemost. 1996; 75: 703–5. [PubMed]
Martinelli I, Cattaneo M, Taioli E, De Stefano V, Chiusolo P, Mannucci PM. Genetic risk factors for superficial vein thrombosis. Thromb Haemost. 1999; 82: 1215–7. [PubMed]
Martinelli I, Legnani C, Bucciarelli P, Grandone E, De Stefano V, Mannucci PM. Risk of pregnancy-related venous thrombosis in carriers of severe inherited thrombophilia. Thromb Haemost. 2001; 86: 800–3. [PubMed]
Martinelli I, Taioli E, Battaglioli T, Podda GM, Passamonti SM, Pedotti P, Mannucci PM. Risk of venous thromboembolism after air travel: interaction with thrombophilia and oral contraceptives. Arch Intern Med. 2003; 163: 2771–4. [PubMed]
Martinelli I, Taioli E, Cetin I, Marinoni A, Gerosa S, Villa MV, Bozzo M, Mannucci PM. Mutations in coagulation factors in women with unexplained late fetal loss. N Engl J Med. 2000; 343: 1015–8. [PubMed]
McColl MD, Ramsay JE, Tait RC, Walker ID, McCall F, Conkie JA, Carty MJ, Greer IA. Risk factors for pregnancy associated venous thromboembolism. Thromb Haemost. 1997; 78: 1183–8. [PubMed]
McCowan LM, Craigie S, Taylor RS, Ward C, McLintock C, North RA. Inherited thrombophilias are not increased in "idiopathic" small-for-gestational-age pregnancies. Am J Obstet Gynecol. 2003; 188: 981–5. [PubMed]
Meier CR, Jick H. Tamoxifen and risk of idiopathic venous thromboembolism. Br J Clin Pharmacol. 1998; 45: 608–12. [PubMed]
Meijers JC, Tekelenburg WL, Bouma BN, Bertina RM, Rosendaal FR. High levels of coagulation factor XI as a risk factor for venous thrombosis. N Engl J Med. 2000; 342: 696–701. [PubMed]
Meinardi JR, Middeldorp S, de Kam PJ, Koopman MM, van Pampus EC, Hamulyak K, Prins MH, Buller HR, van der Meer J. The incidence of recurrent venous thromboembolism in carriers of factor V Leiden is related to concomitant thrombophilic disorders. Br J Haematol. 2002; 116: 625–31. [PubMed]
Mello G, Parretti E, Marozio L, Pizzi C, Lojacono A, Frusca T, Facchinetti F, Benedetto C. Thrombophilia is significantly associated with severe preeclampsia: results of a large-scale, case-controlled study. Hypertension. 2005; 46: 1270–4. [PubMed]
Middeldorp S, Henkens CM, Koopman MM, van Pampus EC, Hamulyak K, van der Meer J, Prins MH, Buller HR. 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. [PubMed]
Middeldorp S, Libourel EJ, Hamulyak K, Van der Meer J, Buller HR. The risk of pregnancy-related venous thromboembolism in women who are homozygous for factor V Leiden. Br J Haematol. 2001; 113: 553–5. [PubMed]
Middeldorp S, Meinardi JR, Koopman MM, van Pampus EC, Hamulyak K, van Der Meer J, Prins MH, Buller HR. 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. [PubMed]
Middendorf K, Gohring P, Huehns TY, Seidel D, Steinbeck G, Nikol S. Prevalence of resistance against activated protein C resulting from factor V Leiden is significantly increased in myocardial infarction: investigation of 507 patients with myocardial infarction. Am Heart J. 2004; 147: 897–904. [PubMed]
Mingozzi F, Legnani C, Lunghi B, Scanavini D, Castoldi E, Palareti G, Marchetti G, Bernardi F. A FV multiallelic marker detects genetic components of APC resistance contributing to venous thromboembolism in FV Leiden carriers. Thromb Haemost. 2003; 89: 983–9. [PubMed]
Mohllajee AP, Curtis KM, Martins SL, Peterson HB. Does use of hormonal contraceptives among women with thrombogenic mutations increase their risk of venous thromboembolism? A systematic review. Contraception. 2006; 73: 166–78. [PubMed]
Morrison ER, Miedzybrodzka ZH, Campbell DM, Haites NE, Wilson BJ, Watson MS, Greaves M, Vickers MA. Prothrombotic genotypes are not associated with pre-eclampsia and gestational hypertension: results from a large population-based study and systematic review. Thromb Haemost. 2002; 87: 779–85. [PubMed]
Munkvad S, Jorgensen M. Resistance to activated protein C: a common anticoagulant deficiency in patients with venous leg ulceration. Br J Dermatol. 1996; 134: 296–8. [PubMed]
Murphy RP, Donoghue C, Nallen RJ, D Mello M, Regan C, Whitehead AS. et al. Prospective evaluation of the risk conferred by factor V Leiden and thermolabile methylenetetrahydrofolate reductase polymorphisms in pregnancy. Arteriosclerosis, Thrombosis, and Vascular Biology. 2000; 20: 266–70. [PubMed]
Norstrom E, Thorelli E, Dahlback B. Functional characterization of recombinant FV Hong Kong and FV Cambridge. Blood. 2002; 100: 524–30. [PubMed]
Nowak-Gottl U, Koch HG, Aschka I, Kohlhase B, Vielhaber H, Kurlemann G, Oleszcuk-Raschke K, Kehl HG, Jurgens H, Schneppenheim R. Resistance to activated protein C (APCR) in children with venous or arterial thromboembolism. Br J Haematol. 1996; 92: 992–8. [PubMed]
Nowak-Gottl U, Kosch A, Schlegel N. Thromboembolism in newborns, infants and children. Thromb Haemost. 2001; 86: 464–74. [PubMed]
Nowak-Gottl U, Strater R, Heinecke A, Junker R, Koch HG, Schuierer G, von Eckardstein A. Lipoprotein (a) and genetic polymorphisms of clotting factor V, prothrombin, and methylenetetrahydrofolate reductase are risk factors of spontaneous ischemic stroke in childhood. Blood. 1999; 94: 3678–82. [PubMed]
Nurk E, Tell GS, Refsum H, Ueland PM, Vollset SE. Factor V Leiden, pregnancy complications and adverse outcomes: the Hordaland Homocysteine Study. QJM. 2006; 99: 289–98. [PubMed]
Pabinger I, Grafenhofer H, Kaider A, Kyrle PA, Quehenberger P, Mannhalter C, Lechner K. Risk of pregnancy-associated recurrent venous thromboembolism in women with a history of venous thrombosis. J Thromb Haemost. 2005; 3: 949–54. [PubMed]
Pabinger I, Nemes L, Rintelen C, Koder S, Lechler E, Loreth RM, Kyrle PA, Scharrer I, Sas G, Lechner K, Mannhalter C, Ehrenforth S. Pregnancy-associated risk for venous thromboembolism and pregnancy outcome in women homozygous for factor V Leiden. Hematol J. 2000; 1: 37–41. [PubMed]
Perez Gutthann S, Garcia Rodriguez LA, Castellsague J, Duque Oliart A. Hormone replacement therapy and risk of venous thromboembolism: population based case-control study. BMJ. 1997; 314: 796–800. [PubMed]
Pherwani AD, Winter PC, McNamee PT, Patterson CC, Hill CM, Connolly JK, Maxwell AP. Is screening for factor V Leiden and prothrombin G20210A mutations in renal transplantation worthwhile? Results of a large single-center U.K. study. Transplantation. 2003; 76: 603–5. [PubMed]
Pihusch R, Danzl G, Scholz M, Harich D, Pihusch M, Lohse P, Hiller E. Impact of thrombophilic gene mutations on thrombosis risk in patients with gastrointestinal carcinoma. Cancer. 2002; 94: 3120–6. [PubMed]
Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood. 1996; 88: 3698–703. [PubMed]
Prandoni P, Simioni P, Girolami A. Antiphospholipid antibodies, recurrent thromboembolism, and intensity of warfarin anticoagulation. Thromb Haemost. 1996; 75: 859. [PubMed]
Preston FE, Rosendaal FR, Walker ID, Briet E, Berntorp E, Conard J, Fontcuberta J, Makris M, Mariani G, Noteboom W, Pabinger I, Legnani C, Scharrer I, Schulman S, van der Meer FJ. Increased fetal loss in women with heritable thrombophilia. Lancet. 1996; 348: 913–6. [PubMed]
Prochazka M, Happach C, Marsal K, Dahlback B, Lindqvist PG. Factor V Leiden in pregnancies complicated by placental abruption. BJOG. 2003; 110: 462–6. [PubMed]
Rai R, Backos M, Elgaddal S, Shlebak A, Regan L. Factor V Leiden and recurrent miscarriage-prospective outcome of untreated pregnancies. Hum Reprod. 2002; 17: 442–5. [PubMed]
Rai R, Regan L, Hadley E, Dave M, Cohen H. Second-trimester pregnancy loss is associated with activated C resistance. Br J Haematol. 1996; 92: 489–90. [PubMed]
Revel-Vilk S, Chan A, Bauman M, Massicotte P. Prothrombotic conditions in an unselected cohort of children with venous thromboembolic disease. J Thromb Haemost. 2003; 1: 915–21. [PubMed]
Revel-Vilk S, Kenet G. Thrombophilia in children with venous thromboembolic disease. Thromb Res. 2006; 118: 59–65. [PubMed]
Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet. 2003; 361: 901–8. [PubMed]
Ridker PM, Glynn RJ, Miletich JP, Goldhaber SZ, Stampfer MJ, Hennekens CH. Age-specific incidence rates of venous thromboembolism among heterozygous carriers of factor V Leiden mutation. Ann Intern Med. 1997; 126: 528–31. [PubMed]
Ridker PM, Hennekens CH, Selhub J, Miletich JP, Malinow MR, Stampfer MJ. Interrelation of hyperhomocyst(e)inemia, factor V Leiden, and risk of future venous thromboembolism. Circulation. 1997; 95: 1777–82. [PubMed]
Ridker PM, Miletich JP, Buring JE, Ariyo AA, Price DT, Manson JE, Hill JA. Factor V Leiden mutation as a risk factor for recurrent pregnancy loss. Ann Intern Med. 1998; 128: 1000–3. [PubMed]
Ridker PM, Miletich JP, Hennekens CH, Buring JE. Ethnic distribution of factor V Leiden in 4047 men and women. Implications for venous thromboembolism screening. JAMA. 1997; 277: 1305–7. [PubMed]
Robertson L, Wu O, Langhorne P, Twaddle S, Clark P, Lowe GD, Walker ID, Greaves M, Brenkel I, Regan L, Greer IA. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Thrombophilia in pregnancy: a systematic review. Br J Haematol. 2006; 132: 171–96. [PubMed]
Rodeghiero F, Tosetto A. Activated protein C resistance and factor V Leiden mutation are independent risk factors for venous thromboembolism. Ann Intern Med. 1999; 130: 643–50. [PubMed]
Rosendaal FR. Thrombosis in the young: epidemiology and risk factors. A focus on venous thrombosis. Thromb Haemost. 1997; 78: 1–6. [PubMed]
Rosendaal FR, Siscovick DS, Schwartz SM, Beverly RK, Psaty BM, Longstreth WT Jr, Raghunathan TE, Koepsell TD, Reitsma PH. Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women. Blood. 1997; 89: 2817–21. [PubMed]
Rosendaal FR, Vessey M, Rumley A, Daly E, Woodward M, Helmerhorst FM, Lowe GD. Hormonal replacement therapy, prothrombotic mutations and the risk of venous thrombosis. Br J Haematol. 2002; 116: 851–4. [PubMed]
Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002; 288: 321–33. [PubMed]
Ryan DH, Crowther MA, Ginsberg JS, Francis CW. Relation of factor V Leiden genotype to risk for acute deep venous thrombosis after joint replacement surgery. Ann Intern Med. 1998; 128: 270–6. [PubMed]
Santamaria A, Soria JM, Tirado I, Mateo J, Coll I, Souto JC, Fontcuberta J. Double heterozygosity for Factor V Leiden and Factor V Cambridge mutations associated with low levels of activated protein C resistance in a Spanish thrombophilic family. Thromb Haemost. 2005; 93: 1193–5. [PubMed]
Scarabin PY, Oger E, Plu-Bureau G. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet. 2003; 362: 428–32. [PubMed]
Schambeck CM, Schwender S, Haubitz I, Geisen UE, Grossmann RE, Keller F. Selective screening for the Factor V Leiden mutation: is it advisable prior to the prescription of oral contraceptives? Thromb Haemost. 1997; 78: 1480–3. [PubMed]
Sidney S, Petitti DB, Soff GA, Cundiff DL, Tolan KK, Quesenberry CP Jr. Venous thromboembolic disease in users of low-estrogen combined estrogen-progestin oral contraceptives. Contraception. 2004; 70: 3–10. [PubMed]
Sifontes MT, Nuss R, Hunger SP, Waters J, Jacobson LJ, Manco-Johnson M. Activated protein C resistance and the factor V Leiden mutation in children with thrombosis. Am J Hematol. 1998; 57: 29–32. [PubMed]
Simioni P, Castoldi E, Lunghi B, Tormene D, Rosing J, Bernardi F. An underestimated combination of opposites resulting in enhanced thrombotic tendency. Blood. 2005; 106: 2363–5. [PubMed]
Simioni P, Prandoni P, Lensing AW, Scudeller A, Sardella C, Prins MH, Villalta S, Dazzi F, Girolami A. The risk of recurrent venous thromboembolism in patients with an Arg506- ->Gln mutation in the gene for factor V (factor V Leiden). N Engl J Med. 1997; 336: 399–403. [PubMed]
Simioni P, Prandoni P, Lensing AW, Manfrin D, Tormene D, Gavasso S, Girolami B, Sardella C, Prins M, Girolami A. Risk for subsequent venous thromboembolic complications in carriers of the prothrombin or the factor V gene mutation with a first episode of deep-vein thrombosis. Blood. 2000; 96: 3329–33. [PubMed]
Simioni P, Tormene D, Prandoni P, Zerbinati P, Gavasso S, Cefalo P, Girolami A. Incidence of venous thromboembolism in asymptomatic family members who are carriers of factor V Leiden: a prospective cohort study. Blood. 2002; 99: 1938–42. [PubMed]
Simioni P, Sanson BJ, Prandoni P, Tormene D, Friederich PW, Girolami B, Gavasso S, Huisman MV, Buller HR, Wouter ten Cate J, Girolami A, Prins MH. Incidence of venous thromboembolism in families with inherited thrombophilia. Thromb Haemost. 1999; 81: 198–202. [PubMed]
Slooter AJ, Rosendaal FR, Tanis BC, Kemmeren JM, van der Graaf Y, Algra A. Prothrombotic conditions, oral contraceptives, and the risk of ischemic stroke. J Thromb Haemost. 2005; 3: 1213–7. [PubMed]
Straczek C, Oger E, Yon de Jonage-Canonico MB, Plu-Bureau G, Conard J, Meyer G, Alhenc-Gelas M, Levesque H, Trillot N, Barrellier MT, Wahl D, Emmerich J, Scarabin PY. Prothrombotic mutations, hormone therapy, and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration. Circulation. 2005; 112: 3495–500. [PubMed]
Svensson PJ, Zoller B, Dahlback B. Evaluation of original and modified APC-resistance tests in unselected outpatients with clinically suspected thrombosis and in healthy controls. Thromb Haemost. 1997; 77: 332–5. [PubMed]
Tal J, Schliamser LM, Leibovitz Z, Ohel G, Attias D. A possible role for activated protein C resistance in patients with first and second trimester pregnancy failure. Hum Reprod. 1999; 14: 1624–7. [PubMed]
Thorarensen O, Ryan S, Hunter J, Younkin DP. Factor V Leiden mutation: an unrecognized cause of hemiplegic cerebral palsy, neonatal stroke, and placental thrombosis. Ann Neurol. 1997; 42: 372–5. [PubMed]
Tormene D, Simioni P, Prandoni P, Franz F, Zerbinati P, Tognin G, Girolami A. The incidence of venous thromboembolism in thrombophilic children: a prospective cohort study. Blood. 2002; 100: 2403–5. [PubMed]
Tormene D, Simioni P, Prandoni P, Luni S, Innella B, Sabbion P, Girolami A. The risk of fetal loss in family members of probands with factor V Leiden mutation. Thromb Haemost. 1999; 82: 1237–9. [PubMed]
Van de Water NS, French JK, Lund M, Hyde TA, White HD, Browett PJ. Prevalence of factor V Leiden and prothrombin variant G20210A in patients age less than 50 years with no significant stenoses at angiography three to four weeks after myocardial infarction. J Am Coll Cardiol. 2000; 36: 717–22. [PubMed]
van der Bom JG, Bots ML, Haverkate F, Slagboom PE, Meijer P, de Jong PT, Hofman A, Grobbee DE, Kluft C. Reduced response to activated protein C is associated with increased risk for cerebrovascular disease. Ann Intern Med. 1996; 125: 265–9. [PubMed]
van Hylckama Vlieg A, van der Linden IK, Bertina RM, Rosendaal FR. High levels of factor IX increase the risk of venous thrombosis. Blood. 2000; 95: 3678–82. [PubMed]
van Hylckama Vlieg A, Rosendaal FR. Interaction between oral contraceptive use and coagulation factor levels in deep venous thrombosis. J Thromb Haemost. 2003; 1: 2186–90. [PubMed]
Van Rooden CJ, Rosendaal FR, Meinders AE, Van Oostayen JA, Van Der Meer FJ, Huisman MV. The contribution of factor V Leiden and prothrombin G20210A mutation to the risk of central venous catheter-related thrombosis. Haematologica. 2004; 89: 201–6. [PubMed]
Vandenbroucke JP, Bertina RM, Holmes ZR, Spaargaren C, van Krieken JH, Manten B, Reitsma PH. Factor V Leiden and fatal pulmonary embolism. Thromb Haemost. 1998; 79: 511–6. [PubMed]
Varas-Lorenzo C, Garcia-Rodriguez LA, Cattaruzzi C, Troncon MG, Agostinis L, Perez-Gutthann S. Hormone replacement therapy and the risk of hospitalization for venous thromboembolism: a population-based study in southern Europe. Am J Epidemiol. 1998; 147: 387–90. [PubMed]
Vossen CY, Conard J, Fontcuberta J, Makris M, VAN DER Meer FJ, Pabinger I, Palareti G, Preston FE, Scharrer I, Souto JC, Svensson P, Walker ID, Rosendaal FR. 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: 459–64. [PubMed]
Vossen CY, Preston FE, Conard J, Fontcuberta J, Makris M, van der Meer FJ, Pabinger I, Palareti G, Scharrer I, Souto JC, Svensson P, Walker ID, Rosendaal FR. Hereditary thrombophilia and fetal loss: a prospective follow-up study. J Thromb Haemost. 2004; 2: 592–6. [PubMed]
Vossen CY, Walker ID, Svensson P, Souto JC, Scharrer I, Preston FE, Palareti G, Pabinger I, van der Meer FJ, Makris M, Fontcuberta J, Conard J, Rosendaal FR. Recurrence rate after a first venous thrombosis in patients with familial thrombophilia. Arterioscler Thromb Vasc Biol. 2005; 25: 1992–7. [PubMed]
Weitz JI, Hirsh J, Samama MM. New anticoagulant drugs: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126 Suppl. 2004; 3: 265–86. [PubMed]
Wiener-Megnagi Z, Ben-Shlomo I, Goldberg Y, Shalev E. Resistance to activated protein C and the leiden mutation: high prevalence in patients with abruptio placentae. Am J Obstet Gynecol. 1998; 179: 1565–7. [PubMed]
Weitz IC, Israel VK, Liebman HA. Tamoxifen-associated venous thrombosis and activated protein C resistance due to factor V Leiden. Cancer. 1997; 79: 2024–7. [PubMed]
Willems M, Sterneck M, Langer F, Jung R, Haddad M, Hagel C, Kuetemeier R, Eifrig B, Broering D, Fischer L, Rogiers X. Recurrent deep-vein thrombosis based on homozygous factor V Leiden mutation acquired after liver transplantation. Liver Transpl. 2003; 9: 870–3. [PubMed]
Williamson D, Brown K, Luddington R, Baglin C, Baglin T. Factor V Cambridge: a new mutation (Arg306-->Thr) associated with resistance to activated protein C. Blood. 1998; 91: 1140–4. [PubMed]
Wu O, Robertson L, Langhorne P, Twaddle S, Lowe GD, Clark P, Greaves M, Walker ID, Brenkel I, Regan L, Greer IA. Oral contraceptives, hormone replacement therapy, thrombophilias and risk of venous thromboembolism: a systematic review. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Thromb Haemost. 2005; 94: 17–25. [PubMed]
Wuthrich RP, Cicvara-Muzar S, Booy C, Maly FE. Heterozygosity for the factor V Leiden (G1691A) mutation predisposes renal transplant recipients to thrombotic complications and graft loss. Transplantation. 2001; 72: 549–50. [PubMed]
Ye Z, Liu EH, Higgins JP, Keavney BD, Lowe GD, Collins R, Danesh J. Seven haemostatic gene polymorphisms in coronary disease: meta-analysis of 66,155 cases and 91,307 controls. Lancet. 2006; 367: 651–8. [PubMed]
Zammiti W, Mtiraoui N, Mercier E, Abboud N, Saidi S, Mahjoub T, Almawi WY, Gris JC. Association of factor V gene polymorphisms (Leiden; Cambridge; Hong Kong and HR2 haplotype) with recurrent idiopathic pregnancy loss in Tunisia. A case-control study. Thromb Haemost. 2006; 95: 612–7. [PubMed]
Zenz W, Bodo Z, Plotho J, Streif W, Male C, Bernert G, Rauter L, Ebetsberger G, Kaltenbrunner K, Kurnik P, Lischka A, Paky F, Ploier R, Hofler G, Mannhalter C, Muntean W. Factor V Leiden and prothrombin gene G 20210 A variant in children with ischemic stroke. Thromb Haemost. 1998; 80: 763–6. [PubMed]
Zivelin A, Griffin JH, Xu X, Pabinger I, Samama M, Conard J, Brenner B, Eldor A, Seligsohn U. A single genetic origin for a common Caucasian risk factor for venous thrombosis. Blood. 1997; 89: 397–402. [PubMed]
Zoller B, Holm J, Svensson P, Dahlback B. Elevated levels of prothrombin activation fragment 1 + 2 in plasma from patients with heterozygous Arg506 to Gln mutation in the factor V gene (APC-resistance) and/or inherited protein S deficiency. Thromb Haemost. 1996; 75: 270–4. [PubMed]
Zuber M, Toulon P, Marnet L, Mas JL. Factor V Leiden mutation in cerebral venous thrombosis. Stroke. 1996; 27: 1721–3. [PubMed]
Chapter Notes
Author History
Scott H Goodnight, MD; Oregon Health & Science University (1998-2004) Jody L Kujovich, MD (1998-present)
Revision History
12 February 2007 (me) Comprehensive update posted to live Web site
20 May 2004 (me) Comprehensive update posted to live Web site
18 June 2002 (me) Comprehensive update posted to live Web site
14 May 1999 (pb) Review posted to live Web site
29 December 1998 (jk) Original submission

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