Clinical Diagnosis

No clinical features are specific for factor V Leiden thrombophilia. The diagnosis of factor V Leiden thrombophilia requires 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 (Arg506Gln).

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.

There is a consensus that factor V Leiden testing is appropriate in the following circumstances [Grody et al 2001, Manco-Johnson et al 2002, Press et al 2002, Duhl et al 2007, Bates et al 2008]. However: (1) no randomized controlled trials have confirmed that testing for thrombophilia affects the risk for recurrent VTE; (2) recent consensus recommendations differ on the indications for screening women with adverse pregnancy outcomes [Duhl et al 2007, Bates et al 2008].

• A first unprovoked VTE at any age (especially age <50 years)
• 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

Factor V Leiden testing may be considered in the following individuals:

• Women with unexplained fetal loss after ten weeks’ gestation
• Selected women with unexplained severe preeclampsia/ ”HELLP” (hemolysis, elevated liver enzymes and low platelets), placental abruption, or a fetus with severe intrauterine growth restriction
• 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
• Neonates and children with non-catheter related idiopathic VTE or stroke

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 (e.g., women with stroke associated with oral contraceptives)
• Neonates and children with asymptomatic central venous catheter-related thrombosis

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, Dahlback 2008].

The 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 correspondingly low ratio. In the modified (“second generation”) assay currently available, 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. This test has a sensitivity and specificity for factor V Leiden approaching 100% [Kapiotis et al 1996]

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:

• Strong lupus inhibitors and a markedly prolonged baseline aPTT
• Very low 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 have 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 [Grody et al 2001].

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior confirmation of the disease-causing mutation in the family.

Genetically Related (Allelic) Disorders

Two different mutations (designated as Factor V Cambridge and Factor V Hong Kong) at the arginine 306 activated protein C cleavage site in F5 have been reported rarely in persons with thrombosis (see Molecular Genetics, Pathologic allelic variants).

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].

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 an 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 [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 (4070A>G) may confer mild APC resistance and interact with the factor V Leiden mutation to produce a more severe APC resistance phenotype [de Visser et al 2000, Mingozzi et al 2003]. In one study, coinheritance of the HR2 haplotype increased the risk for 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 for 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 for venous thromboembolism [Alhenc-Gelas et al 1999, Jadaon & Dashti 2005, Otrock et al 2008]. A comprehensive meta-analysis including 14 studies found a slight but statistically significant increase in risk for VTE (pooled OR =1.24) [Gohil et al 2009].

Other studies found no significant increase in thrombotic risk [de Visser et al 2000, Luddington et al 2000, Dindagur et al 2007].

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 for thrombosis is higher in studies of asymptomatic factor V Leiden heterozygotes from thrombophilic families than in unselected individuals identified by population screening. In a large systematic review, asymptomatic family members with heterozygous and homozygous factor V Leiden mutations had a three- to fourfold and 18-fold increased relative risk for VTE, respectively [Segal et al 2009].

In four retrospective studies of relatives of unselected symptomatic and asymptomatic factor V Leiden heterozygotes, the results were remarkably consistent.

• The thrombotic risk was low 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 for 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 for venous thromboembolism [Langlois & Wells 2003].

In a recent large family cohort study, the annual incidence of VTE was 0.49% in relatives with a heterozygous factor V Leiden mutation compared to 0.05% in relatives without the mutation. The risk was much higher in relatives with homozygous factor V Leiden (1.30%/year) and those with factor V Leiden in combination with other thrombophilic defects (0.62% -1.54%/year) [Lijfering et al 2009a].

In three prospective cohort studies [Middeldorp et al 2001b, Simioni et al 2002, Vossen et al 2005a]:

• 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.

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 et al 1997c]. It is present in:
  • 5.2% of Americans of European origin
  • 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.

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]. Note: In standard nomenclature (www.hgvs.org) this mutation is designated as c.*97G>A (reference sequence NM_000506.3).

A specific point mutation (677C>T) in MTHFR, encoding methylenetetrahydrofolate reductase, results in a variant thermolabile enzyme with reduced activity for the remethylation of homocysteine. Note: The standard nomenclature (www.hgvs.org) for this mutation is c.665C>T (reference sequence NM_005957.3).

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.

The results of recent studies indicate the MTHFR polymorphism is not associated with an increased risk for VTE independent of plasma homocysteine concentrations [Bezemer et al 2007].

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 MTHFR.

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. Persistently high titer IgG anticardiolipin antibodies, anti-beta₂-glycoprotein 1 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 anticardiolipin antibodies, anti-beta₂-glycoprotein 1 antibodies, and lupus inhibitors, as only 50% of individuals with the antiphospholipid antibody syndrome have more than one type 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 for recurrent thrombosis [Kyrle et al 2000].

Elevated plasma concentrations of factor IX and factor XI are associated with an approximately twofold increased risk for venous thromboembolism [Meijers et al 2000, van Hylckama Vlieg et al 2000].

Elevated plasma prothrombin levels greater than 110%-115% of normal are associated with a twofold increased risk for 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 including heparin cofactor II PAI-1, tissue factor pathway inhibitor (TFPI), thrombin activatable fibrinolysis inhibitor (TAFI), and protein Z, a causal association has not been established.

Other genetic risk factors for thrombosis under investigation include a fibrinogen gamma chain variant (10034T), genetic variants in the protein C promoter region, several single-nucleotide polymorphisms in coagulation proteins, and polymorphisms in the tissue factor pathway inhibitor gene [Smith et al 2007, Bezemer et al 2008].

A factor XIII polymorphism is associated with 30% lower risk for VTE [Rosendaal & Reitsma 2009].

Testing for these potential risk factors is not routinely recommended and in many cases, assays are not commercially available.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Evaluations Following Initial Diagnosis

To assess the risk for thrombosis in an individual diagnosed with factor V Leiden thrombophilia, the following evaluations are recommended:

• Individuals heterozygous for the factor V Leiden allele should be tested for other inherited or acquired thrombophilic disorders. Testing should include:
  • DNA testing for the prothrombin gene mutation (G-to-A substitution at nucleotide 20210)
  • Multiple phospholipid-dependent coagulation assays for a lupus inhibitor
  • Serologic assays for anticardiolipin antibodies and anti-beta₂-glycoprotein 1 antibodies
• Evaluation 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) should also include assays of:
  • Protein C activity
  • Antithrombin activity
  • Protein S activity or free protein S antigen

Note: (1) Measurement of serum concentration of homocysteine is no longer routinely recommended since no data support a change in duration of anticoagulation or the use of vitamin supplementation in individuals with hyperhomocysteinemia and a history of VTE. In a randomized placebo-controlled trial, supplementation with folic acid, vitamin B₁₂, and pyridoxine did not reduce the incidence of recurrent VTE [den Heijer et al 2007]. (2) There is no clinical rationale for DNA testing for MTHFR polymorphisms. (3) Although routine measurement of factor VIII levels is not recommended, testing may be useful in selected cases [Chandler et al 2002]. (4) It is still unclear whether assessment of clotting factor concentrations should be included in a thrombophilia evaluation [Chandler et al 2002].

Treatment of Manifestations

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%-3%/year risk for major bleeding from warfarin is greater than the estimated less than 1%/year risk for 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 2008].

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 [Kujovich 2004b, Duhl et al 2007, Bates et al 2008]. 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 [Bates et al 2008].
• 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 post partum [Duhl et al 2007, Bates et al 2008].
• Should be considered for heterozygous women with a prior estrogen-related thrombosis who are also at an increased risk for recurrence [Pabinger et al 2005, Bates et al 2008].
• 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 2001, Bates et al 2008].

Graduated elastic compression stockings are recommended for all women with a prior DVT [Bates et al 2008].

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 controls, 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 et al 2005b].

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 may 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 [Walker et al 2005].

ACCP 2008 and recent obstetric consensus guidelines and expert opinion do not routinely recommend antithrombotic therapy for women with factor V Leiden and pregnancy loss because of the lack of sufficient evidence confirming benefit [Duhl et al 2007, Bates et al 2008, Rodger et al 2008].

Several randomized trials with a no treatment or placebo arm are currently underway. Until the results are available, the risks and benefits of antithrombotic therapy and limited evidence of an improved pregnancy outcome should be discussed with the patient to allow an informed decision.

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 et al 2005a]. 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.

A recent pilot randomized trial compared dalteparin to no treatment in a group of women without thrombophilia and a prior history of placental-mediated complications. Prophylactic dose dalteparin significantly reduced the incidence of the composite outcome of severe preeclampsia, low birth weight, placental abruption, and fetal death after 20 weeks. However, the study design excluded women with factor V Leiden [Rey et al 2009].

ACCP 2008 guidelines recommend low-dose aspirin throughout pregnancy for women at high risk for preeclampsia. Unfractionated or low molecular-weight heparin is not routinely recommended for thrombophilic women with a history of preeclampsia or other adverse pregnancy outcomes [Bates et al 2008]. An obstetric expert consensus panel was also unable to make recommendations on the efficacy and safety of low molecular-weight heparin in this group [Duhl et al 2007].

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 estrogen contraception and HRT.

Asymptomatic women who are heterozygous for factor V Leiden should be counseled on the risks of estrogen-containing contraception 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 estrogen containing contraception and HRT.

For heterozygous women who require short-term hormone replacement therapy for severe menopausal symptoms, low-dose transdermal preparations may have a lower thrombotic risk [Straczek et al 2005, Canonico et al 2007].

Evaluation 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

Several novel inhibitors of the initiation of coagulation and fibrin formation are in various stages of clinical development. Two new oral direct factor Xa inhibitors (rivaroxaban and apixaban) and an oral direct thrombin inhibitor (dabigatran) were effective for prophylaxis and treatment of VTE in multiple randomized trials and will likely be available within the next several years. Long-acting pentasaccharides administered on a weekly basis are also in advanced clinical trials [Gross & Weitz 2008, Weitz et al 2008].

None of these new antithrombotic agents is 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.

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 on the genetic status of the proband's parents:

• If one parent of a heterozygous proband is heterozygous, each sib of the proband is at 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% chance of being heterozygous for the factor V Leiden allele.
• If both parents are heterozygous, each sib of the proband has a 25% chance of being homozygous for the factor V Leiden allele, a 50% chance 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% chance of being homozygous for the factor V Leiden allele, a 50% chance 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 on 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% chance of being homozygous for the factor V Leiden allele, a 50% chance 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 on the genetic status of the proband's parents. The family members of a person who is heterozygous or homozygous for factor V Leiden are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Informed consent. Specific informed consent is not generally required for factor V Leiden genetic testing, although it may be required in some states. However, prior to testing, individuals should be made aware that genetic test results have implications regarding risk to other family members and the attendant issues of confidentiality [Grody et al 2001].

Note: The Genetic Information Nondiscrimination Act passed in 2008 protects individuals from discrimination by health insurers or employers on the basis of genetic information.

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 for 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.

Molecular genetic testing of asymptomatic individuals younger than age 18 years. 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 decision to test for factor V Leiden should be made on an individual basis only after counseling the family about potential benefits and limitations. The results should be interpreted by a physician experienced in the management of children with thrombophilia and thrombosis [Raffini 2008]. 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 position statement on genetic testing of minors for adult-onset conditions 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.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

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.

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 approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately 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, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which one or two Factor V Leiden alleles have been identified in a parent. Although technically possible, PGD for factor V Leiden is rarely requested as the disorder may never cause thrombosis, and effective treatment is available.

Published Guidelines/Consensus Statements

1. 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. Available online. 1995. Accessed 9-18-12. [PMC free article: PMC1801355] [PubMed: 7485175]
2. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2012. Accessed 9-18-12.

Literature Cited

1. 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: 16818854]
2. 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: 12572596]
3. Albisetti M, Moeller A, Waldvogel K, Bernet-Buettiker V, Cannizzaro V, Anagnostopoulos A, Balmer C, Schmugge M. Congenital prothrombotic disorders in children with peripheral venous and arterial thromboses. Acta Haematol. 2007;117:149–55. [PubMed: 17159337]
4. 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: 11339929]
5. 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: 10235429]
6. 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: 15082697]
7. 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: 15116266]
8. Baba-Ahmed M, Le Gal G, Couturaud F, Lacut K, Oger E, Leroyer C. High frequency of factor V Leiden in surgical patients with symptomatic venous thromboembolism despite prophylaxis. Thromb Haemost. 2007;97:171–5. [PubMed: 17264942]
9. 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: 9531346]
10. 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: 12932383]
11. 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: 15634269]
12. Barbour LA. ACOG practice bulletin. Thrombembolism in pregnancy. Int J Gynaecol Obstet. 2001;75:203–12. [PubMed: 11724031]
13. Barnes C, Deveber G. Prothrombotic abnormalities in childhood ischaemic stroke. Thromb Res. 2006;118:67–74. [PubMed: 16039697]
14. 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: 16837676]
15. Bates SM, Greer IA, Pabinger I, Sofaer S, Hirsh J. American College of Chest Physicians; Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:844S–86S. [PubMed: 18574280]
16. Bezemer ID, Bare LA, Doggen CJ, Arellano AR, Tong C, Rowland CM, Catanese J, Young BA, Reitsma PH, Devlin JJ, Rosendaal FR. Gene variants associated with deep vein thrombosis. JAMA. 2008;299:1306–14. [PubMed: 18349091]
17. Bezemer ID, Doggen CJ, Vos HL, Rosendaal FR. No association between the common MTHFR 677C->T polymorphism and venous thrombosis: results from the MEGA study. Arch Intern Med. 2007;167:497–501. [PubMed: 17353498]
18. Bezemer ID, van der Meer FJ, Eikenboom JC, Rosendaal FR, Doggen CJ. The value of family history as a risk indicator for venous thrombosis. Arch Intern Med. 2009;169:610–5. [PubMed: 19307525]
19. 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: 16807645]
20. 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: 10823255]
21. 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: 10632304]
22. Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA. 2005a;293:715–22. [PubMed: 15701913]
23. 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: 16241945]
24. 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: 12083504]
25. Bounameaux H. Factor V Leiden paradox: risk of deep-vein thrombosis but not of pulmonary embolism. Lancet. 2000;356:182–3. [PubMed: 10963193]
26. 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. 2005a;84:770–3. [PubMed: 16169422]
27. 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: 10823264]
28. 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. 2005b;3:227–9. [PubMed: 15670024]
29. 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: 10456445]
30. 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: 11078768]
31. 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: 16359508]
32. 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: 9787136]
33. Canonico M, Oger E, Plu-Bureau G, Conard J, Meyer G, Lévesque H, Trillot N, Barrellier MT, Wahl D, Emmerich J, Scarabin PY. Estrogen and Thromboembolism Risk (ESTHER) Study Group; Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation. 2007;115:840–5. [PubMed: 17309934]
34. 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: 12871446]
35. 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: 9759618]
36. 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: 9454741]
37. 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: 12421150]
38. Christiansen SC, Cannegieter SC, Koster T, Vandenbroucke JP, Rosendaal FR. Thrombophilia, clinical factors, and recurrent venous thrombotic events. JAMA. 2005;293:2352–61. [PubMed: 15900005]
39. Clark P, Walker ID, Govan L, Wu O, Greer IA. The GOAL study: a prospective examination of the impact of factor V Leiden and ABO(H) blood groups on haemorrhagic and thrombotic pregnancy outcomes. Br J Haematol. 2008;140:236–40. [PubMed: 18028481]
40. 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: 15541404]
41. Coppens M, Folkeringa N, Teune MJ, Hamulyák K, van der Meer J, Prins MH, Büller HR, Middeldorp S. Outcome of the subsequent pregnancy after a first loss in women with the factor V Leiden or prothrombin 20210A mutations. J Thromb Haemost. 2007;5:1444–8. [PubMed: 17439630]
42. 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: 11342420]
43. 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: 9504649]
44. 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: 10376571]
45. 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: 16606815]
46. Curry CJ, Bhullar S, Holmes J, Delozier CD, Roeder ER, Hutchison HT. Risk factors for perinatal arterial stroke: a study of 60 mother-child pairs. Pediatr Neurol. 2007;37:99–107. [PubMed: 17675024]
47. 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: 15467059]
48. 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: 9609219]
49. Dahlback B. Advances in understanding pathogenic mechanisms of thrombophilic disorders. Blood. 2008;112:19–27. [PubMed: 18574041]
50. 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: 14531918]
51. 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: 15333035]
52. 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: 10930988]
53. 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: 10477778]
54. 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: 10780320]
55. 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: 9949170]
56. den Heijer M, Willems HP, Blom HJ, Gerrits WB, Cattaneo M, Eichinger S, Rosendaal FR, Bos GM. Homocysteine lowering by B vitamins and the secondary prevention of deep vein thrombosis and pulmonary embolism: A randomized,placebo-controlled, double-blind trial. Blood. 2007;109:139–44. [PubMed: 16960155]
57. 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: 16397131]
58. Dentali F, Gianni M, Agnelli G, Ageno W. Association between inherited thrombophilic abnormalities and central venous catheter thrombosis in patients with cancer: a meta-analysis. J Thromb Haemost. 2008;6:70–5. [PubMed: 17988232]
59. 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: 16781765]
60. Dizon-Townson D, Miller C, Sibai B, Spong CY, Thom E, Wendel G, 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: 16135581]
61. 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: 15564739]
62. 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: 9531249]
63. Donahue BS, Gailani D, Higgins MS, Drinkwater DC, George AL. Factor V Leiden protects against blood loss and transfusion after cardiac surgery. Circulation. 2003;107:1003–8. [PubMed: 12600914]
64. Dudding T, Heron J, Thakkinstian A, Nurk E, Golding J, Pembrey M, Ring SM, Attia J, Scott RJ. Factor V Leiden is associated with pre-eclampsia but not with fetal growth restriction: a genetic association study and meta-analysis. J Thromb Haemost. 2008;6:1869–75. [PubMed: 18752569]
65. 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: 15045131]
66. 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: 14512389]
67. Duhl AJ, Paidas MJ, Ural SH, Branch W, Casele H, Cox-Gill J, Hamersley SL, Hyers TM, Katz V, Kuhlmann R, Nutescu EA, Thorp JA, Zehnder JL. Pregnancy and Thrombosis Working Group; Antithrombotic therapy and pregnancy: consensus report and recommendations for prevention and treatment of venous thromboembolism and adverse pregnancy outcomes. Am J Obstet Gynecol. 2007;197:457. [PubMed: 17980177]
68. 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: 16556168]
69. 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: 15678277]
70. 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: 15009459]
71. 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: 10836365]
72. 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: 11583312]
73. Eroglu A, Egin Y, Cam R, Akar N. The 19-bp deletion of dihydrofolate reductase (DHFR), methylenetetrahydrofolate reductase (MTHFR) C677T, Factor V Leiden, prothrombin G20210A polymorphisms in cancer patients with and without thrombosis. Ann Hematol. 2009;88:73–6. [PubMed: 18682947]
74. Facchinetti F, Marozio L, Frusca T, Grandone E, Venturini P, Tiscia GL, Zatti S, Benedetto C (2009) Maternal thrombophilia and the risk of recurrence of preeclampsia. Am J Obstet Gynecol 200:46.e1-5. [PubMed: 18845284]
75. 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: 12857557]
76. Facco F, You W, Grobman W. Genetic thrombophilias and intrauterine growth restriction: a meta-analysis. Obstet Gynecol. 2009;113:1206–16. [PubMed: 19461414]
77. 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: 10556190]
78. 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: 12100159]
79. 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: 9747868]
80. Funai EF. Inherited thrombophilia and preeclampsia: is the evidence beginning to congeal? Am J Obstet Gynecol. 2009;200:121–2. [PubMed: 19185098]
81. 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: 12393574]
82. Ganesan V, Prengler M, Wade A, Kirkham FJ. Clinical and radiological recurrence after childhood arterial ischemic stroke. Circulation. 2006;114:2170–7. [PubMed: 17075014]
83. Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, Colwell CW. American College of Chest Physicians; Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:381S–453S. [PubMed: 18574271]
84. Gerhardt A, Goecke TW, Beckmann MW, Wagner KJ, Tutschek B, Willers R, Bender HG, Scharf RE, Zotz RB. The G20210A prothrombin-gene mutation and the plasminogen activator inhibitor (PAI-1) 5G/5G genotype are associated with early onset of severe preeclampsia. J Thromb Haemost. 2005;3:686–91. [PubMed: 15842353]
85. 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: 10666427]
86. 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: 12876629]
87. 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: 15306751]
88. Gohil R, Peck G, Sharma P. The genetics of venous thromboembolism. A meta-analysis involving approximately 120,000 cases and 180,000 controls. Thromb Haemost. 2009;102:360. [PubMed: 19652888]
89. 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: 16607075]
90. 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: 11675065]
91. 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: 10787361]
92. 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: 10102458]
93. 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: 11836168]
94. 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: 14739212]
95. 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: 10404763]
96. 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. [PMC free article: PMC3111091] [PubMed: 11280951]
97. Gross PL, Weitz JI. New anticoagulants for treatment of venous thromboembolism. Arterioscler Thromb Vasc Biol. 2008;28:380–6. [PubMed: 18296593]
98. Haywood S, Liesner R, Pindora S, Ganesan V. Thrombophilia and first arterial ischaemic stroke: a systematic review. Arch Dis Child. 2005;90:402–5. [PMC free article: PMC1720343] [PubMed: 15781933]
99. 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: 12506156]
100. 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: 9798979]
101. 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: 15670037]
102. 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: 12939214]
103. 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: 12067913]
104. 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: 9058717]
105. 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: 16765424]
106. 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: 8644593]
107. 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: 9457968]
108. 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: 16606808]
109. 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: 11858477]
110. 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: 15746660]
111. Huisman MV, Klok FA, Karami Djurabi R, Tormene D, Simioni P, Prandoni P. Factor V Leiden is associated with more distal location of deep vein thrombosis of the leg. J Thromb Haemost. 2008;6:544–5. [PubMed: 18182032]
112. 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: 9718051]
113. 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: 10090925]
114. 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: 12097536]
115. Jadaon MM, Dashti AA. HR2 haplotype in Arab population and patients with venous thrombosis in Kuwait. J Thromb Haemost. 2005;3:1467–71. [PubMed: 15978104]
116. 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: 16525593]
117. Jivraj S, Makris M, Saravelos S, Li TC. Pregnancy outcome in women with factor V Leiden and recurrent miscarriage. BJOG. 2009;116:995–8. [PubMed: 19522801]
118. Joseph JE, Low J, Courtenay B, Neil MJ, McGrath M, Ma D. A single-centre prospective study of clinical and haemostatic risk factors for venous thromboembolism following lower limb arthroplasty. Br J Haematol. 2005;129:87–92. [PubMed: 15801960]
119. 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: 10521389]
120. 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: 14996674]
121. Kahn SR, Platt R, McNamara H, Rozen R, Chen MF, Genest J Jr, Goulet L, Lydon J, Seguin L, Dassa C, Masse A, Asselin G, Benjamin A, Miner L, Ghanem A, Kramer MS (2009) Inherited thrombophilia and preeclampsia within a multicenter cohort: the Montreal peeclampsia study. Am J Obstet Gynecol 200:151.e1-9. [PubMed: 19070828]
122. Kamphuisen PW, Eikenboom JC, Bertina RM. Elevated factor VIII levels and the risk of thrombosis. Arterioscler Thromb Vasc Biol. 2001;21:731–8. [PubMed: 11348867]
123. 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: 8929467]
124. 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: 12695749]
125. Kearon C, Julian JA, Kovacs MJ, Anderson DR, Wells P, Mackinnon B, Weitz JI, Crowther MA, Dolan S, Turpie AG, Geerts W, Solymoss S, van Nguyen P, Demers C, Kahn SR, Kassis J, Rodger M, Hambleton J, Gent M, Ginsberg JS. ELATE Investigators; Influence of thrombophilia on risk of recurrent venous thromboembolism while on warfarin: results from a randomized trial. Blood. 2008a;112:4432–6. [PubMed: 18791166]
126. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ. American College of Chest Physicians; Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008b;133:454S–545S. [PubMed: 18574272]
127. Kenet G, Kirkham F, Niederstadt T, Heinecke A, Saunders D, Stoll M, Brenner B, Bidlingmaier C, Heller C, Knöfler R, Schobess R, Zieger B, Sébire G, Nowak-Göttl U. European Thromboses Study Group; Risk factors for recurrent venous thromboembolism in the European collaborative paediatric database on cerebral venous thrombosis: a multicentre cohort study. Lancet Neurol. 2007;6:595–603. [PMC free article: PMC1906729] [PubMed: 17560171]
128. 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: 10835445]
129. 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: 15667542]
130. 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: 12869495]
131. 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: 14660985]
132. Kist WJ, Janssen NG, Kalk JJ, Hague WM, Dekker GA, de Vries JI. Thrombophilias and adverse pregnancy outcome - A confounded problem! Thromb Haemost. 2008;99:77–85. [PubMed: 18217138]
133. 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: 12817161]
134. 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: 7823669]
135. 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: 15006834]
136. 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: 15467902]
137. Kujovich JL. Thrombophilia and thrombotic problems in renal transplant patients. Transplantation. 2004a;77:959–64. [PubMed: 15087754]
138. Kujovich JL. Hormones and pregnancy: thromboembolic risks for women. Br J Haematol. 2004b;126:443–54. [PubMed: 15287937]
139. 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. N Engl J Med. 1999;340:9–13. [PubMed: 9878639]
140. 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: 10862840]
141. 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: 12504973]
142. 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: 10950667]
143. Laczkovics C, Grafenhofer H, Kaider A, Quehenberger P, Simanek R, Mannhalter C, Lechner K, Pabinger I. Risk of recurrence after a first venous thromboembolic event in young women. Haematologica. 2007;92:1201–7. [PubMed: 17666369]
144. 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: 15947254]
145. 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: 12876621]
146. 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: 12069454]
147. 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: 11529860]
148. 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: 10896231]
149. 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: 12763384]
150. 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: 9746807]
151. Lijfering WM, Brouwer JL, Veeger NJ, Bank I, Coppens M, Middeldorp S, Hamulyák K, Prins MH, Büller HR, van der Meer J. Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives. Blood. 2009a;113:5314–22. [PubMed: 19139080]
152. Lijfering WM, Christiansen SC, Rosendaal FR, Cannegieter SC. Contribution of high factor VIII, IX and XI to the risk of recurrent venous thrombosis in factor V Leiden carriers. J Thromb Haemost. 2009b;7:1944–6. [PubMed: 19691477]
153. Lin J, August P. Genetic thrombophilias and preeclampsia: a meta-analysis. Obstet Gynecol. 2005;105:182–92. [PubMed: 15625161]
154. 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: 10348713]
155. 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: 10365737]
156. 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: 9459326]
157. 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: 10235434]
158. Linnemann B, Meister F, Schwonberg J, Schindewolf M, Zgouras D, Lindhoff-Last E. Hereditary and acquired thrombophilia in patients with upper extremity deep-vein thrombosis. Results from the MAISTHRO registry. Thromb Haemost. 2008a;100:440–6. [PubMed: 18766260]
159. Linnemann B, Schindewolf M, Zgouras D, Erbe M, Jarosch-Preusche M, Lindhoff-Last E. Are patients with thrombophilia and previous venous thromboembolism at higher risk to arterial thrombosis? Thromb Res. 2008b;121:743–50. [PubMed: 17804043]
160. 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: 16194196]
161. 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: 11483920]
162. 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: 15912114]
163. 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: 10780311]
164. 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: 10739373]
165. Mackay MT, Monagle P. Perinatal and early childhood stroke and thrombophilia. Pathology. 2008;40:116–23. [PubMed: 18203034]
166. Manco-Johnson MJ. How I treat venous thrombosis in children. Blood. 2006;107:21–9. [PMC free article: PMC1895344] [PubMed: 16099882]
167. 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: 12152657]
168. Mandalà M, Curigliano G, Bucciarelli P, Ferretti G, Mannucci PM, Colleoni M, Ventura A, Peruzzotti G, Severi G, Pelicci PG, Biffi R, Orsi F, Cinieri S, Goldhirsch A. Factor V Leiden and G20210A prothrombin mutation and the risk of subclavian vein thrombosis in patients with breast cancer and a central venous catheter. Ann Oncol. 2004;15:590–3. [PubMed: 15033664]
169. 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: 10896232]
170. Marchiori A, Mosena L, Prins MH, Prandoni P. The risk of recurrent venous thromboembolism among heterozygous carriers of factor V Leiden or prothrombin G20210A mutation. A systematic review of prospective studies. Haematologica. 2007;92:1107–14. [PubMed: 17650440]
171. 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: 15748240]
172. 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: 10397694]
173. 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: 15262837]
174. 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: 16769590]
175. Martinelli I, Battaglioli T, De Stefano V, Tormene D, Valdrè L, Grandone E, Tosetto A, Mannucci PM. The risk of first venous thromboembolism during pregnancy and puerperium in double heterozygotes for factor V Leiden and prothrombin G20210A. J Thromb Haemost. 2008;6:494–8. [PubMed: 18182035]
176. Martinelli I, Battaglioli T, Pedotti P, Cattaneo M, Mannucci PM. Hyperhomocysteinemia in cerebral vein thrombosis. Blood. 2003a;102:1363–6. [PubMed: 12714502]
177. Martinelli I, Battaglioli T, Razzari C, Mannucci PM. Type and location of venous thromboembolism in patients with factor V Leiden or prothrombin G20210A and in those with no thrombophilia. J Thromb Haemost. 2007;5:98–101. [PubMed: 17067362]
178. 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: 8725708]
179. 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: 10544900]
180. 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: 11583310]
181. 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. 2003b;163:2771–4. [PubMed: 14662632]
182. 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: 11018168]
183. 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: 12712097]
184. McRae S, Tran H, Schulman S, Ginsberg J, Kearon C. Effect of patient's sex on risk of recurrent venous thromboembolism: a meta-analysis. Lancet. 2006;368:371–8. [PubMed: 16876665]
185. Meier CR, Jick H. Tamoxifen and risk of idiopathic venous thromboembolism. Br J Clin Pharmacol. 1998;45:608–12. [PMC free article: PMC1873655] [PubMed: 9663819]
186. 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: 10706899]
187. 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: 11849222]
188. 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: 16246971]
189. 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: 9424976]
190. 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. 2001a;113:553–5. [PubMed: 11380431]
191. 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. 2001b;135:322–7. [PubMed: 11529695]
192. 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: 15131548]
193. Miller SP, Wu YW, Lee J, Lammer EJ, Iovannisci DM, Glidden DV, Bonifacio SL, Collins A, Shaw GM, Barkovich AJ, Ferriero DM. Candidate gene polymorphisms do not differ between newborns with stroke and normal controls. Stroke. 2006;37:2678–83. [PubMed: 17008620]
194. 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: 12783110]
195. 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: 16413847]
196. Monagle P, Chalmers E, Chan A, DeVeber G, Kirkham F, Massicotte P, Michelson AD. American College of Chest Physicians; Antithrombotic therapy in neonates and children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:887S–968S. [PubMed: 18574281]
197. 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: 12038776]
198. Muetze S, Leeners B, Ortlepp JR, Kuse S, Tag CG, Weiskirchen R, Gressner AM, Rudnik-Schoeneborn S, Zerres K, Rath W. Maternal factor V Leiden mutation is associated with HELLP syndrome in Caucasian women. Acta Obstet Gynecol Scand. 2008;87:635–42. [PubMed: 18568463]
199. 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: 8746345]
200. Murphy RP, Donoghue C, Nallen RJ. 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: 10634828]
201. Nath CA, Ananth CV, DeMarco C, Vintzileos AM, New Jersey Placental Abruption Study Investigators (2008) Low birthweight in relation to placental abruption and maternal thrombophilia status. Am J Obstet Gynecol 198:293.e1-5. [PMC free article: PMC2346588] [PubMed: 18191809]
202. Norstrom E, Thorelli E, Dahlback B. Functional characterization of recombinant FV Hong Kong and FV Cambridge. Blood. 2002;100:524–30. [PubMed: 12091344]
203. Nowak-Gottl U, Kosch A, Schlegel N. Thromboembolism in newborns, infants and children. Thromb Haemost. 2001;86:464–74. [PubMed: 11487037]
204. 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: 10572079]
205. 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: 16613994]
206. Otrock ZK, Taher AT, Shamseddeen WA, Zaatari G, Bazarbachi A, Mahfouz RA. Factor V HR2 haplotype: a risk factor for venous thromboembolism in individuals with absence of Factor V Leiden. Ann Hematol. 2008;87:1013–6. [PubMed: 18654780]
207. 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: 15869590]
208. 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: 11920167]
209. Palareti G, Cosmi B, Legnani C, Tosetto A, Brusi C, Iorio A, Pengo V, Ghirarduzzi A, Pattacini C, Testa S, Lensing AW, Tripodi A. PROLONG Investigators; D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med. 2006;355:1780–9. [PubMed: 17065639]
210. Pasquier E, Bohec C, Mottier D, Jaffuel S, Mercier B, Férec C, Collet M, De Saint Martin L. Inherited thrombophilias and unexplained pregnancy loss: an incident case-control study. J Thromb Haemost. 2009;7:306–11. [PubMed: 19036071]
211. Pezzini A, Grassi M, Zotto ED, Giossi A, Volonghi I, Costa P, Grau A, Magoni M, Padovani A, Lichy C. Do common prothrombotic mutations influence the risk of cerebral ischaemia in patients with patent foramen ovale? Systematic review and meta-analysis. Thromb Haemost. 2009;101:813–7. [PubMed: 19404532]
212. 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: 12923451]
213. 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: 12115343]
214. Pomp ER, Lenselink AM, Rosendaal FR, Doggen CJ. Pregnancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study. J Thromb Haemost. 2008;6:632–7. [PubMed: 18248600]
215. 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: 8916933]
216. Prandoni P, Prins MH, Lensing AW, Ghirarduzzi A, Ageno W, Imberti D, Scannapieco G, Ambrosio GB, Pesavento R, Cuppini S, Quintavalla R, Agnelli G. AESOPUS Investigators; Residual thrombosis on ultrasonography to guide the duration of anticoagulation in patients with deep venous thrombosis: a randomized trial. Ann Intern Med. 2009;150:577–85. [PubMed: 19414836]
217. Prandoni P, Simioni P, Girolami A. Antiphospholipid antibodies, recurrent thromboembolism, and intensity of warfarin anticoagulation. Thromb Haemost. 1996;75:859. [PubMed: 8725737]
218. 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. [PubMed: 12421138]
219. 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: 12742330]
220. Raffini L. Thrombophilia in children: who to test, how, when, and why? Hematology Am Soc Hematol Educ Program. 2008:228–35. [PubMed: 19074088]
221. 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: 11821292]
222. 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: 12871356]
223. Revel-Vilk S, Kenet G. Thrombophilia in children with venous thromboembolic disease. Thromb Res. 2006;118:59–65. [PubMed: 15993476]
224. Rey E, Garneau P, David M, Gauthier R, Leduc L, Michon N, Morin F, Demers C, Kahn SR, Magee LA, Rodger M. Dalteparin for the prevention of recurrence of placental-mediated complications of pregnancy in women without thrombophilia: a pilot randomized controlled trial. J Thromb Haemost. 2009;7:58–64. [PubMed: 19036070]
225. Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet. 2003;361:901–8. [PubMed: 12648968]
226. 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. 1997a;126:528–31. [PubMed: 9092318]
227. 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. 1997b;95:1777–82. [PubMed: 9107163]
228. 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: 9625662]
229. 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. 1997c;277:1305–7. [PubMed: 9109469]
230. Ringwald J, Berger A, Adler W, Kraus C, Pitto RP. Genetic polymorphisms in venous thrombosis and pulmonary embolism after total hip arthroplasty: a pilot study. Clin Orthop Relat Res. 2009;467:1507–15. [PMC free article: PMC2674155] [PubMed: 18800213]
231. Robertson L, Wu O, Langhorne P, Twaddle S, Clark P, Lowe GD, Walker ID, Greaves M, Brenkel I, Regan L, Greer IA. Thrombophilia in pregnancy: a systematic review. Br J Haematol. 2006;132:171–96. [PubMed: 16398652]
232. 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: 10215560]
233. Rodger MA, Paidas M, McLintock C, Middeldorp S, Kahn S, Martinelli I, Hague W, Rosene Montella K, Greer I. Inherited thrombophilia and pregnancy complications revisited. Obstet Gynecol. 2008;112:320–4. [PubMed: 18669729]
234. Rosendaal FR. Thrombosis in the young: epidemiology and risk factors. A focus on venous thrombosis. Thromb Haemost. 1997;78:1–6. [PubMed: 9198119]
235. Rosendaal FR, Reitsma PH. Genetics of venous thrombosis. J Thromb Haemost. 2009;7 Suppl 1:301–4. [PubMed: 19630821]
236. Rosendaal FR, Siscovick DS, Schwartz SM, Beverly RK, Psaty BM, Longstreth WT, 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: 9108400]
237. 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: 11886391]
238. 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: 12117397]
239. 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: 9471929]
240. 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: 15968408]
241. 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: 12927428]
242. Schulman S. Thrombophilia and location of venous thromboembolism. J Thromb Haemost. 2007;5:2151–2. [PubMed: 17666017]
243. Segal JB, Brotman DJ, Necochea AJ, Emadi A, Samal L, Wilson LM, Crim MT, Bass EB. Predictive value of factor V Leiden and prothrombin G20210A in adults with venous thromboembolism and in family members of those with a mutation: a systematic review. JAMA. 2009;301:2472–85. [PubMed: 19531787]
244. Sidney S, Petitti DB, Soff GA, Cundiff DL, Tolan KK, Quesenberry CP. Venous thromboembolic disease in users of low-estrogen combined estrogen-progestin oral contraceptives. Contraception. 2004;70:3–10. [PubMed: 15208046]
245. 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: 9423813]
246. Simchen MJ, Goldstein G, Lubetsky A, Strauss T, Schiff E, Kenet G. Factor v Leiden and antiphospholipid antibodies in either mothers or infants increase the risk for perinatal arterial ischemic stroke. Stroke. 2009;40:65–70. [PubMed: 18927445]
247. 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: 15961511]
248. 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: 11071624]
249. 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: 10063991]
250. 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: 11877263]
251. Siragusa S, Malato A, Anastasio R, Cigna V, Milio G, Amato C, Bellisi M, Attanzio MT, Cormaci O, Pellegrino M, Dolce A, Casuccio A, Bajardi G, Mariani G. Residual vein thrombosis to establish duration of anticoagulation after a first episode of deep vein thrombosis: the Duration of Anticoagulation based on Compression UltraSonography (DACUS) study. Blood. 2008;112:511–5. [PubMed: 18497320]
252. 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: 15946211]
253. Smith NL, Hindorff LA, Heckbert SR, Lemaitre RN, Marciante KD, Rice K, Lumley T, Bis JC, Wiggins KL, Rosendaal FR, Psaty BM. Association of genetic variations with nonfatal venous thrombosis in postmenopausal women. JAMA. 2007;297:489–98. [PubMed: 17284699]
254. 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: 16301339]
255. Strater R, Becker S, von Eckardstein A, Heinecke A, Gutsche S, Junker R, Kurnik K, Schobess R, Nowak-Göttl U. Prospective assessment of risk factors for recurrent stroke during childhood--a 5-year follow-up study. Lancet. 2002;360:1540–5. [PubMed: 12443591]
256. 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: 10357988]
257. Talamo GP, Ibrahim S, Claxton D, Tricot GJ, Fink LM, Zangari M. Hypercoagulable states in patients with multiple myeloma can affect the thalidomide-associated venous thromboembolism. Blood Coagul Fibrinolysis. 2009;20:337–9. [PubMed: 19367157]
258. 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: 12239149]
259. 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: 10544905]
260. Turebylu R, Salis R, Erbe R, Martin D, Lakshminrusimha S, Ryan RM. Genetic prothrombotic mutations are common in neonates but are not associated with umbilical catheter-associated thrombosis. J Perinatol. 2007;27:490–5. [PubMed: 17625574]
261. 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: 10987590]
262. 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: 8678388]
263. 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: 14521603]
264. 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: 10845896]
265. van Ommen CH, Heijboer H, van den Dool EJ, Hutten BA, Peters M. Pediatric venous thromboembolic disease in one single center: congenital prothrombotic disorders and the clinical outcome. J Thromb Haemost. 2003;1:2516–22. [PubMed: 14675086]
266. 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: 15003896]
267. van Stralen KJ, Doggen CJ, Bezemer ID, Pomp ER, Lisman T, Rosendaal FR. Mechanisms of the factor V Leiden paradox. Arterioscler Thromb Vasc Biol. 2008a;28:1872. [PubMed: 18617648]
268. van Stralen KJ, Rosendaal FR, Doggen CJ. Minor injuries as a risk factor for venous thrombosis. Arch Intern Med. 2008b;168:21–6. [PubMed: 18195191]
269. 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: 9531031]
270. 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: 9508106]
271. 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. 2005a;3:459–64. [PubMed: 15748234]
272. 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: 15102013]
273. 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. 2005b;25:1992–7. [PubMed: 15976329]
274. 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: 15842362]
275. Weitz JI, Hirsh J, Samama MM. American College of Chest Physicians; New antithrombotic drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:234S–256S. [PubMed: 18574267]
276. 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: 9855597]
277. 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: 12884202]
278. 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: 9454742]
279. 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: 16113779]
280. 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: 11502996]
281. 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: 16503463]
282. Young G, Albisetti M, Bonduel M, Brandao L, Chan A, Friedrichs F, Goldenberg NA, Grabowski E, Heller C, Journeycake J, Kenet G, Krümpel A, Kurnik K, Lubetsky A, Male C, Manco-Johnson M, Mathew P, Monagle P, van Ommen H, Simioni P, Svirin P, Tormene D, Nowak-Göttl U. Impact of inherited thrombophilia on venous thromboembolism in children: a systematic review and meta-analysis of observational studies. Circulation. 2008;118:1373–82. [PubMed: 18779442]
283. Young G, Becker S, Düring C, Friedrichs F, Goldenberg N, Kenet G, Manco-Johnson M, Scheffold C, Nowak-Göttl U. Influence of the factor II G20210A variant or the factor V G1691A mutation on symptomatic recurrent venous thromboembolism in children: an international multicenter cohort study. J Thromb Haemost. 2009;7:72–9. [PubMed: 18983482]
284. 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: 16601830]
285. 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: 9843168]
286. 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: 9002940]
287. 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: 8815575]

Author History

Scott H Goodnight, MD; Oregon Health & Science University (1998-2004)
Jody L Kujovich, MD (1998-present)

Revision History

• 9 March 2010 (me) Comprehensive update posted live
• 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