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Factor V Leiden and activated protein C resistance

Factor V Leiden and activated protein C resistance
Literature review current through: May 2024.
This topic last updated: May 30, 2023.

INTRODUCTION — Factor V Leiden (FVL) results from a point mutation in the F5 gene, which encodes the factor V protein in the coagulation cascade. FVL renders factor V (both the activated and inactive forms) insensitive to the actions of activated protein C (aPC), a natural anticoagulant. As a result, individuals who carry the FVL variant are at increased risk of venous thromboembolism (VTE). However, FVL is very common in the population, and many individuals with the variant will never have a VTE. For these reasons, the ramifications of carrying FVL may present challenging management decisions, both with respect to primary prevention and prevention of recurrent VTE.

This topic review discusses the diagnosis of FVL and the management of individuals who carry this variant. A brief overview of FVL genetic testing is presented separately. (See "Gene test interpretation: Factor V Leiden".)

Separate topic reviews discuss other thrombophilias and the role of thrombophilia screening in various populations:

Other thrombophilias:

Prothrombin G20210A variant – (See "Prothrombin G20210A".)

Protein C deficiency – (See "Protein C deficiency".)

Protein S deficiency – (See "Protein S deficiency".)

AT deficiency – (See "Antithrombin deficiency".)

APS – (See "Diagnosis of antiphospholipid syndrome".)

PNH – (See "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria".)

MPN – (See "Overview of the myeloproliferative neoplasms".)

Role of screening:

Children – (See "Thrombophilia testing in children and adolescents".)

Asymptomatic individuals – (See "Hereditary thrombophilia testing in adults without VTE".)

Pregnancy – (See "Inherited thrombophilias in pregnancy", section on 'Selection of patients for testing'.)

Individuals with VTE – (See "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors".)

Ischemic stroke – (See "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis", section on 'Hypercoagulable evaluation' and "Overview of the evaluation of stroke", section on 'Blood tests'.)

PHYSIOLOGY

Biology of factor V and protein C — Factor V, encoded by the F5 gene, is a procoagulant clotting factor that amplifies the production of thrombin, the central enzyme that converts fibrinogen to fibrin, which leads to clot formation (figure 1 and figure 2). Factor V is synthesized as an inactive factor that circulates in plasma. A small amount of thrombin at the site of a wound activates factor V by limited proteolysis. This activated factor V (factor Va) then serves as a cofactor in the prothrombinase complex, which cleaves prothrombin to generate more thrombin, in a positive feedback loop. (See "Overview of hemostasis", section on 'Multicomponent complexes'.)

Thrombin (bound to thrombomodulin on the surface of endothelial cells) also slows its own production by creating a separate negative feedback loop. It does this by converting protein C to activated protein C (aPC), a protease that acts as a potent natural anticoagulant. aPC degrades activated factor Va (and activated factor VIIIa, upstream in the coagulation cascade), ultimately reducing thrombin production. aPC uses protein S as a cofactor in all of its cleavage reactions. (See "Overview of hemostasis", section on 'Activated protein C and protein S'.)

Factor V Leiden (FVL) results from a single point mutation in the F5 gene (guanine to adenine at nucleotide 1691), which leads to a single amino acid change (replacement of arginine with glutamine at amino acid 506); hence the names factor V R506Q and factor V Arg506Gln. This abolishes the Arg506 cleavage site for aPC in factor V and factor Va. This was initially termed "aPC resistance" because the anticoagulant activity of aPC was reduced in a modified activated partial thromboplastin time (aPTT) assay.

aPC-mediated cleavage of factor V and factor Va have different consequences for protein function. aPC cleavage of the procoagulant factor Va causes factor Va degradation, whereas aPC cleavage of the anticoagulant factor V enhances factor V function. FVL is insensitive to both of these cleavages because it lacks the Arg506 cleavage site, as illustrated in the figure (figure 3).

Thus, FVL increases coagulation by creating two distinct changes in the coagulation cascade:

Enhanced procoagulant role of factor Va – aPC destroys factor Va in a series of sequential cleavages. The first cleavage at Arg506 exposes additional cleavage sites at Arg306 and Arg679. Since activated FVL cannot be cleaved at Arg506, these other sites remain buried in the protein, resulting in 20-fold slower degradation of activated FVL. The extended presence of activated FVL results in continued thrombin generation.

Reduced anticoagulant role of factor V – aPC cleavage of unactivated factor V at position 506 enhances its ability to act as a cofactor in the degradation of factors Va and VIIIa. Since unactivated FVL cannot be cleaved at Arg506, it is less effective as a cofactor for aPC, resulting in reduced degradation of factors Va and VIIIa [1-3].

The reduced cleavage of activated FVL by aPC and the impaired cleavage of unactivated FVL by aPC appear to contribute equally to the phenomenon of FVL-associated aPC resistance and the ensuing hypercoagulable state [2,4]. The FVL variant accounts for more than the vast majority of cases of hereditary aPC resistance, with the remainder of aPC resistance cases due to other inherited and acquired factors. (See 'Other causes of aPC resistance' below.)

The dual roles of factor V also help to explain why the risk of venous thromboembolism (VTE) is greater in patients homozygous or pseudo-homozygous for FVL (compound heterozygous for FVL and factor V deficiency) [2,5]. In contrast, the plasma of FVL heterozygotes contains both FVL and normal factor V. The normal factor V has aPC cofactor activity for the inactivation of factor VIIIa, affording some protection against thrombosis. (See 'FVL genotypes' below.)

FVL genotypes — FVL is an autosomal dominant condition, and 99 percent of individuals with FVL are heterozygous for the variant. The other 1 percent are homozygous or the extremely rare cases with pseudo-homozygosity for FVL due to heterozygous FVL plus a variant on the other F5 allele that causes factor V deficiency, resulting in FVL as the only available form of factor V in their circulation [6-9]. These individuals appear to be more thrombosis prone than heterozygous carriers with FVL alone, with a clinical phenotype similar to or more severe than that of individuals who are homozygous for FVL [5,10,11]. The plasma of these individuals manifests severe aPC resistance in aPTT assays. FVL homozygous or pseudo-homozygous individuals are disproportionately represented clinically because of a higher thrombotic risk. (See 'Clinical manifestations' below.)

Other genetic variants — Only 5 to 10 percent of FVL heterozygotes will experience VTE during their lifetime. The reasons for the highly variable phenotype are incompletely understood; it may be explained in part by the coexistence of other inherited thrombophilias or other genetic modifiers not yet elucidated that can increase thrombosis risk.

Other inherited thrombophilias – The presence of a second thrombophilic variant may increase the risk of VTE associated with FVL.

There have been reports of early presentations of thrombosis in patients with antithrombin (AT) deficiency as well as FVL [12]. As the genes for AT and factor V are both on the long arm of chromosome 1, when the variants are on the same chromosome they will almost always occur together.

There is evidence of a higher prevalence of protein S and protein C deficiencies in individuals with FVL who have had a VTE compared with individuals with FVL who have not had a VTE. As an example, in a series of 18 thrombophilic families with protein S deficiency, concomitant FVL was present in 39 percent of the affected individuals [13].

It is not uncommon for an individual to have both heterozygous prothrombin G20210A variant and heterozygous FVL. While older data indicated that the combination further increases VTE risk, a large meta-analysis surprisingly did not find this to be the case [14]. An international multicenter case series of 100 patients with rare compound combinations of homozygous FVL with heterozygous prothrombin G20210A or heterozygous FVL with homozygous prothrombin G20210A showed that these patients are not exceedingly thrombosis-prone, even though they have a substantial risk for VTE [15]. (See 'Risk of initial VTE' below.)

Variants in genes other than coagulation factors – Other gene variants may not increase thrombophilia risk appreciably on their own but may increase risk in the setting of FVL.

Non-O blood groups (eg, A, B, or AB) are associated with higher levels of the procoagulant factor VIII than blood group O [16-18]. Non-O blood groups appear to increase the risk of VTE in both heterozygotes and homozygotes for FVL by two- to fourfold [16,19,20].

Protein Z is a vitamin K-dependent protein that may serve as a cofactor for activated factors X and XI in the coagulation cascade. Variants in the gene for protein Z have been reported to increase the risk of VTE in individuals with FVL. However, a relationship between the level of protein Z or its inhibitor (protein Z-dependent protease inhibitor) and venous thrombosis was not detected among individuals participating in the Leiden Thrombophilia Study [21]. (See "Vitamin K-dependent clotting factors: Gamma carboxylation and functions of Gla", section on 'Function of Gla in clotting proteins'.)

Factor V haplotypes – Factor V haplotypes such as haplotype HR2 are found more frequently in heterozygotes for FVL who have the lowest aPC resistance ratios [22-24]. Most studies, however, have found either no increase or only a modest increase in thromboembolic risk to be associated with the HR2 haplotype in the absence of FVL [2,24-30].

We generally base management decisions on the clinical phenotype of the patient and family and generally do not search for additional genetic or biologic modifiers (eg, factor V haplotypes, other gene variants causing aPC resistance, levels of factor VIII activity, protein Z, or protein Z-dependent protease inhibitor), although some experts do test for additional thrombophilic variants in some settings. (See 'Management' below.)

We recommend not obtaining homocysteine levels or genetic tests for MTHFR variants (C677T or A1298C). (See "Overview of homocysteine".)

Other causes of aPC resistance — In rare cases, variants in factor V other than FVL produce the aPC resistance phenotype. Examples include:

Factor V Cambridge (replacement of Arg306 with threonine) [31]

Factor V Nara (replacement of Trp1920 with arginine) [32]

Factor V Liverpool (replacement of Ile359 with threonine) [33,34]

Factor V Bonn (replacement of Ala512 with valine) [35]

Replacement of Arg306 with glycine (in Hong Kong Chinese) has uncertain clinical significance, as the variant is present in the same frequency in healthy Chinese blood donors as in patients with thrombosis (slightly <5 percent in both groups) [36,37].

aPC resistance is defined by a functional coagulation assay, and the definition of aPC resistance depends on the assay used (see 'Functional aPC resistance assays' below). In addition to FVL, a number of conditions that impair the activity of aPC in vitro have been identified using first-generation aPC resistance assays.

Protein S deficiency – Deficiency of the protein C cofactor protein S can cause the appearance of aPC resistance in some functional aPC resistance assays; it should not be considered an independent cause of aPC resistance. (See "Protein S deficiency", section on 'Causes of reduced protein S'.)

Increased factor VIII – aPC resistance has been described in patients with elevated levels of coagulation factor VIII (figure 1). Circulating levels of factor VIII can be increased in inflammatory disorders and pregnancy. (See "Overview of the causes of venous thrombosis", section on 'Factor VIII'.)

Estrogens – Increased estrogen levels can cause resistance to the anticoagulant effect of aPC through multiple effects on clotting factors including reduced protein S, increased prothrombin, increased factors VIII, IX, and X, and others [38].

Oral contraceptives – Estrogen-containing oral contraceptives (OCs), have been associated with acquired aPC resistance. The strength of aPC resistance corresponds strongly to the epidemiologically observed risk increase and type of OC. In the Leiden Thrombophilia Study, the risk of thrombosis in individuals who were heterozygous for FVL and taking OCs was 1 in 345, significantly greater than that of individuals with FVL or OC use alone (table 1) [39]. (See "Combined estrogen-progestin contraception: Side effects and health concerns", section on 'Venous thromboembolism'.)

Menopausal hormone therapy – Menopausal hormone therapy has been associated with acquired aPC resistance [40]. (See "Menopausal hormone therapy and cardiovascular risk", section on 'Venous thromboembolism' and "Overview of the causes of venous thrombosis", section on 'Oral and transdermal contraceptives'.)

Pregnancy – Pregnancy also leads to resistance to aPC that increases through pregnancy and correlates to changes in factor VIII, factor V, and protein S and may in part explain the thrombotic risk during pregnancy [41].

Antiphospholipid antibodies – Antiphospholipid antibodies cause a hypercoagulable state through several mechanisms that include resistance to aPC. (See "Pathogenesis of antiphospholipid syndrome".)

Cancer – A variety of solid tumors and hematologic malignancies produce variation in the levels of clotting factors that can confer aPC resistance [38]. The etiology of the hypercoagulable state in cancer is discussed separately. (See "Cancer-associated hypercoagulable state: Causes and mechanisms" and "Overview of the causes of venous thrombosis", section on 'Malignancy'.)

Other – Additional factors associated with aPC resistance include a variety of phenomena such as proteinuria, elevated body mass index, and smoking [42-44]. The mechanisms are multifactorial through effects on several clotting factors. Additional patients have been described with aPC resistance of unknown cause [45,46].

EPIDEMIOLOGY — Heterozygosity for FVL is the most common inherited thrombophilia in White individuals with venous thromboembolism (VTE) (table 2):

In 121 males with VTE in the Physicians' Health Study, approximately 12 percent were heterozygous for FVL [47]. In 31 males over age 60 with VTE, FVL was present in 8 (26 percent).

In 301 individuals with VTE in the Leiden Thrombophilia Study, resistance to aPC (a surrogate for FVL) was found in 64 (21 percent) [48]. In a subsequent series from the same group that included 471 individuals with VTE, 85 (18 percent) were heterozygous for FVL and 7 (approximately 1 percent) were homozygous for FVL [49].

In the general population without a personal history of VTE, a study involving 1690 unrelated individuals from Europe found a prevalence of FVL of approximately 4 percent, and a study involving 356 individuals from Canada found an incidence of approximately 5 percent [50,51]. In a series of 4047 individuals participating in the Physicians' Health Study and the Women's Health Study (both in the United States), the following frequencies for FVL heterozygosity were found [52]:

White Americans – 5.3 percent

Hispanic Americans – 2.2 percent

Native Americans – 1.2 percent

African Americans – 1.2 percent

Asian Americans – 0.45 percent

A higher prevalence of FVL (12 to 14 percent) has been reported in populations in parts of Greece, Sweden, and Lebanon [53-55].

FVL has not been reported in certain populations of Black African people, Chinese people, or Japanese people. However, in many regions of the world it may not be possible to infer ancestry from skin color or country of origin.

FVL is very prevalent and is the most common thrombophilia in individuals with VTE; as such, it contributes importantly to the thrombosis burden in the population, although the relative risk increase of VTE conferred by FVL is lower than that associated with an inherited deficiency of protein C, protein S, or antithrombin (AT). (See 'Risk of initial VTE' below.)

CLINICAL MANIFESTATIONS

Overview — The major clinical manifestation of heterozygosity for FVL is venous thromboembolism (VTE). However, only a small percentage of individuals with FVL will develop VTE in their lifetime (approximate risk, 5 to 10 percent for FVL heterozygosity in the general population and up to 20 percent in affected individuals from thrombophilic families). (See 'Venous thromboembolism' below.)

FVL has been implicated in arterial thromboembolism, although the data are mixed; the effect, if present, is likely to be small compared with other risk factors. (See 'Arterial thromboembolism' below and "Myocardial infarction or ischemia with no obstructive coronary atherosclerosis", section on 'Causes of MINOCA' and "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors", section on 'Etiologies and risk factors'.)

Some data suggest that FVL may play a role in some cases of unexplained recurrent late pregnancy loss, presumably due to thrombosis of placental vessels [56-59]. (See 'Fetal loss and obstetric complications' below and "Inherited thrombophilias in pregnancy".)

Despite the increase in risk of VTE, there is no evidence that heterozygosity for FVL increases overall mortality [60,61].

Venous thromboembolism — Venous thromboembolism (VTE) is the major clinical manifestation of FVL. However, it is important to note that most individuals with FVL heterozygotes will not experience VTE during their lifetime.

Risk of initial VTE — Multiple studies have demonstrated an increased risk of VTE in individuals with FVL (table 2) [47-49,62-65]. As noted above, the risk of VTE can be further increased by older age, coinheritance of another thrombophilia with FVL, homozygosity for FVL, and synergistically, hormonal risk factors such as pregnancy or estrogen-containing contraceptives. (See 'Physiology' above.)

The magnitude of risk is illustrated by the following studies:

A 2013 meta-analysis involving 11,239 cases of VTE with 21,521 controls found that VTE risk was increased with heterozygosity and homozygosity for FVL (odds ratios [ORs] 4.2; 95% CI 3.4-5.32 and 11.5; 95% CI 6.8-19.3, respectively) [14]. It should be noted that the OR of 11.5 is considerably lower for homozygous FVL individuals than earlier estimates; an OR of 79.4 (95% CI 22-289) was estimated from a small number of cases in the Leiden Thrombophilia Study [49].

A 2012 meta-analysis involving over 11,000 individuals found that FVL more often leads to deep vein thrombosis (DVT), with or without concomitant pulmonary embolism (PE), than to isolated PE (OR 2.39; 95% CI 2.08–2.75) [66].

It is not uncommon for an individual to have both prothrombin G20210A and FVL (also called double or compound heterozygosity). In the 2013 meta-analysis mentioned above, the risk of VTE in heterozygotes for prothrombin G20210A alone (without FVL) was 2.79 (95% CI 2.25-3.46) [49]. Several studies indicated that the combination of FVL plus prothrombin G20210A further increases VTE risk. In a pooled analysis of eight case-control studies involving 2310 individuals with VTE and 3204 controls, 51 of the cases (2 percent) were doubly heterozygous for both FVL and prothrombin G20210A (none of the controls were doubly heterozygous) [67]. ORs for VTE were as follows:

Prothrombin G20210A – 3.8 (95% CI 3.0-4.9)

FVL – 4.9 (95% CI 4.1-5.9)

Both variants – 20.0 (95% CI 11.1-36.1)

Other studies have also documented an increased thrombotic risk in association with the combination of prothrombin G20201A and FVL [68,69].

However, a meta-analysis published in 2013 found that the OR for individuals with compound heterozygosity for FVL and prothrombin G20210A was 3.42 (95% CI 1.64-7.13), which is considerably lower than previously thought [14]. This result is surprising and the reason for this difference is not clear; it should be noted that the CI is larger than for the individual genetic defects.

An international multicenter case series of 100 patients with rare compound combinations of homozygous FVL with heterozygous prothrombin G20210A or heterozygous FVL with homozygous prothrombin G20210A showed that these patients are not exceedingly thrombosis-prone, even though they have a substantial risk for VTE [15].

Risk of recurrent VTE — Numerous studies and systematic reviews have evaluated the risk of VTE recurrence in individuals with FVL and a previous VTE episode [65,68,70-80]. In a 2006 systematic review that evaluated the risk of VTE recurrence in individuals with FVL compared with those lacking the variant, there was a modest increase in the recurrence risk due to FVL (OR 1.4, 95% CI 1.1-1.8) [70]. It is widely accepted that heterozygosity for FVL does not confer a clinically relevant increased risk for recurrent VTE among patients with a first unprovoked VTE, and the presence of FVL generally does not alter decision-making regarding the duration of anticoagulation. However, the decision to test for FVL when VTE occurs in the setting of pregnancy or hormonal therapy, or when there is a strong family history plus a major transient risk factor, is complex. The 1.4-fold increase may lead to an absolute risk increase of recurrent VTE that may warrant consideration of indefinite treatment in some patients. (See 'Patients with VTE' below and "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)".)

Vascular beds affected — The most common site of VTE in individuals with FVL is DVT and PE. Individuals with FVL may also develop thrombosis in the cerebral, mesenteric, or portal veins; it is also a risk factor for superficial vein thrombosis [81-83].

Data regarding some of these other sites of thromboembolism include the following:

Superficial vein thrombosis – Thrombosis involving the superficial veins of the lower extremities (SVT) can occur in individuals with FVL and also in the absence of other risk factors for SVT such as varicosities, malignancy, or autoimmune disease [84-86]. (See "Superficial vein thrombosis and phlebitis of the lower extremity veins".)

Isolated PE – Isolated PE (ie, without evidence of DVT) can occur in individuals with FVL, but this is a less common presentation of VTE in individuals with FVL compared with the general population, a phenomenon that has been referred to as the "FVL paradox" [87-92]. The explanation for this observation is unknown, but it may reflect a lower frequency of thrombi in the lower extremities that are likely to embolize, such as those affecting the large proximal ileofemoral vessels. (See "Epidemiology and pathogenesis of acute pulmonary embolism in adults".)

Cerebral vein thrombosis – Cerebral vein thrombosis (CVT, including cerebral sinus thrombosis) can occur in individuals with FVL, especially in individuals taking an estrogen-containing oral contraceptive (OC). In a series that evaluated the presence of inherited thrombophilia in 40 women with CVT and 2248 controls, the likelihood of CVT was increased three- to fourfold in the presence of an inherited thrombophilia, and 30-fold in those with a thrombophilia plus OC use [93]. In a 2013 meta-analysis of 18 studies, including 919 cases and 3168 healthy controls, FVL was associated with an increased risk of CVT (pooled OR 2.89; 95% CI 2.10-3.97) [94]. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".)

Portal or hepatic vein thrombosis – A 2014 meta-analysis of studies involving 516 patients with Budd-Chiari syndrome and 1342 controls found that FVL was associated with an increased risk of Budd-Chiari syndrome (OR 6.3; 95% CI 4.2-9.4) [95].

Arterial thromboembolism — An association between FVL and arterial thromboembolism remains controversial and is likely to be relatively small if present.

Myocardial infarction – In the Physicians' Health Study, involving almost 15,000 apparently healthy males, FVL was equally prevalent in those with myocardial infarction (MI) or stroke as controls [47]. Other small studies (<1000 patients) also have not found an association [96-101]. However, a 2006 meta-analysis found a modest increase in the risk of coronary artery disease with FVL (relative risk [RR] 1.17, 95% CI 1.08-1.28) [102]. Another meta-analysis involving over 66,000 cases of MI in patients under age 45 and over 91,000 controls also found an increased risk of MI with FVL (OR 1.66, 95% CI 1.15-2.38) [103]. (See "Coronary artery disease and myocardial infarction in young people".)

Stroke – In small series of patients with stroke or transient ischemic attack, FVL has been associated with an increased risk, especially in younger individuals, females, and smokers [101,104-106]. A 2019 meta-analysis found that compared with controls, patients with arterial ischemic stroke were significantly more likely to have factor V Leiden (OR, 1.25, 95% CI 1.08-1.44). (See "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors".)

Fetal loss and obstetric complications — Whether FVL is a risk factor for recurrent fetal loss is debated, and the role of FVL is likely to be modest compared with other risk factors. This subject is discussed separately. (See "Inherited thrombophilias in pregnancy", section on 'Adverse pregnancy outcome risk'.)

DIAGNOSIS

Indications for testing — FVL may be suspected in a member of a thrombophilic kindred or in an individual with venous thromboembolism (VTE), especially VTE at a young age (eg, <50 years), VTE in an unusual location (eg, portal vein, cerebral vein), or recurrent VTE. However, FVL may also contribute to thrombosis risk in older individuals with VTE.

However, we generally do not perform testing in individuals with a first provoked episode of VTE (eg, due to prolonged immobility) or a first VTE in an individual ≥50 years of age in the absence of a family history of VTE. We also do not perform FVL testing in individuals with non-VTE conditions for which an association with FVL has been proposed, such as those with osteonecrosis or Legg-Calvé-Perthes disease, unless they also have a strong personal or family history of VTE. This is because a finding that the individual carries the FVL variant would not alter management, which would be based on the VTE history.

Indications for testing pregnant women for FVL (and other inherited thrombophilias) is discussed separately. (See "Inherited thrombophilias in pregnancy", section on 'Selection of patients for testing'.)

With the increasing use of genomic sequencing tests (including direct-to-consumer testing), increasing numbers of FVL heterozygotes with neither a family history nor a personal history of VTE are being identified. It is not clear that individuals diagnosed with FVL from random population screening or genomic sequencing of healthy individuals without a clinical suspicion of thrombophilia should be managed any differently than the general population. (See 'Asymptomatic individuals' below.)

Diagnostic tests

Choice between genetic testing or functional assay — FVL can be detected by genetic testing (DNA testing) or a functional coagulation test for aPC resistance using a "second generation" aPC resistance assay. Either of these approaches will generally give an accurate diagnosis of FVL, and the choice of diagnostic test can be based on cost and institutional availability.

For individuals with a family history of FVL who require testing, genetic testing is preferable because it provides definitive evidence of the variant.

For individuals with antiphospholipid syndrome (APS) or those who require testing while receiving an anticoagulant that might interfere with the results (eg, direct thrombin inhibitor, direct factor Xa inhibitor), genetic testing will circumvent these potential sources of test interference.

For individuals with a family history of thrombophilia for whom a genetic cause has not yet been identified, it is appropriate to test clinically affected members first, to identify the variant(s), followed by testing of unaffected family members (if clinically indicated) for the specific variant(s).

For individuals who have a positive functional assay for aPC resistance, genetic testing should be performed to confirm the diagnosis, to allow family screening if appropriate, and to determine if the patient is homozygous or heterozygous.

A negative result from genetic testing or a second or third-generation functional assay is good evidence that the individual does not have FVL [107]. However, testing errors may occur with either type of test, and there may be cases in which repeat testing using the other platform is appropriate, such as individuals with a strongly positive personal or family history of thrombosis.

Genetic testing — FVL can be detected directly by analyzing genomic DNA from nucleated cells (eg, from peripheral blood). Since only a single gene variant is involved, this testing is straightforward and relatively inexpensive to perform. Information about how to review the genetic test report is presented separately. (See "Gene test interpretation: Factor V Leiden".)

Polymerase chain reaction (PCR) methods for detecting the FVL variant have been implemented in most laboratories and have taken the place of earlier assays that took advantage of the FVL sequence that eliminated a restriction enzyme site. In these earlier assays, DNA from individuals without the variant was cut by a restriction enzyme, whereas DNA with the FVL variant would not be cut, leading to a different banding pattern on a DNA gel [108].

Genetic testing is unaffected by anticoagulants and other drugs because it detects the FVL variant directly. However, genetic testing for FVL will not detect other hereditary causes of aPC resistance, which are rare, or acquired causes of aPC resistance. (See 'Other causes of aPC resistance' above.)

Functional aPC resistance assays — The initial activated partial thromboplastin time (aPTT) assays used to detect aPC resistance used unaltered ("neat") plasma ("first generation assays"); some versions of the assay were neither sensitive nor specific for FVL. Modifications in which diluted patient plasma is mixed with factor V-deficient plasma have resulted in "second generation" functional assays that correlate extremely well with the presence of FVL [109,110]. If a functional assay is used to test for FVL, it is almost always a "second generation" assay. These tests generally cost less than genetic tests, although the cost of genetic testing continues to decline.

In rare cases, functional assays for aPC resistance can give misleading results. As an example, the presence of a lupus anticoagulant can cause falsely abnormal results in some assays, and therapy with a direct thrombin inhibitor (argatroban, dabigatran) or oral factor Xa inhibitor (eg, apixaban, edoxaban, rivaroxaban) can cause falsely normal results [111].

DIFFERENTIAL DIAGNOSIS — The differential diagnoses of risk factors for venous thromboembolism and causes of pregnancy loss are presented separately. (See "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors" and "Inherited thrombophilias in pregnancy".)

POST-DIAGNOSIS TESTING AND TESTING OF FIRST-DEGREE RELATIVES — We generally do not perform additional testing in individuals with FVL who have not had a thromboembolic event.

Routine testing of first-degree relatives of an individual with FVL is controversial and may not be indicated, especially in cases in which the information will not alter management. Prior to testing individuals for FVL, issues regarding testing should be discussed with the patient, including an increased likelihood for the variant being present in first-degree relatives in the event of a positive test. Situations in which testing of relatives may be appropriate include:

First-degree relatives of affected individuals in families with FVL and a strong history of thrombophilia including VTE in individuals <50 years of age; individuals with VTE in an unusual location, or individuals with severe, life-threatening VTE. (See "Hereditary thrombophilia testing in adults without VTE".)

Female first-degree relatives of individuals with FVL who are considering use of an estrogen-containing contraceptive or who are likely to become pregnant in the future. (See "Contraception: Counseling for women with inherited thrombophilias".)

Siblings of individuals who are homozygous for FVL or double heterozygous for FVL and another inherited thrombophilia. In these cases, parents and children may only inherit a single gene defect, whereas siblings are at risk to inherit two variants (one from each parent).

MANAGEMENT

Patients with VTE — The presence of FVL does not influence the initial treatment of venous thromboembolism (VTE) (algorithm 1).

Hence, the presence of FVL also does not influence the decision of whether to use warfarin or a direct oral anticoagulant (DOAC). This choice is based on a number of factors including the severity of thrombosis, patient preference, adherence to therapy, and potential drug and dietary interactions.

Advantages and disadvantages are discussed in more detail separately. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Comparison with heparin and warfarin'.)

The duration of anticoagulation depends on the risk of recurrent VTE, which is 1.4 fold higher in FVL heterozygotes as compared to patients with VTE without FVL (see 'Risk of recurrent VTE' above). As in all patients with VTE, the duration of anticoagulation is an individualized decision. Similar to the general population, we are more likely to advise indefinite anticoagulation in those whose VTE is unprovoked, life-threatening, at an unusual site such as the mesenteric or portal vein, or with more than one episode of VTE. For individuals with heterozygous FVL and a single episode of VTE provoked by a major transient risk factor, indefinite anticoagulation generally is not required after an initial three to six months of treatment. After a first episode of VTE provoked by a hormonal risk factor such as oral contraceptives, pregnancy, or the postpartum period, presence of FVL may justify considering indefinite duration anticoagulation. Factors to be incorporated into the decision regarding the duration of anticoagulation are discussed in more detail separately. (See "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation".)

Additional information regarding the anticoagulants, and their dosing and monitoring, is presented separately. (See "Venous thromboembolism: Initiation of anticoagulation" and "Venous thromboembolism: Anticoagulation after initial management" and "Heparin and LMW heparin: Dosing and adverse effects".)

Recommendations specific to the site of thromboembolism are also presented in separate topic reviews:

Pulmonary embolism (PE) – (See "Venous thromboembolism: Initiation of anticoagulation".)

Deep vein thrombosis (DVT) – (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)".)

Portal vein thrombosis (PVT) – (See "Acute portal vein thrombosis in adults: Clinical manifestations, diagnosis, and management" and "Chronic portal vein thrombosis in adults: Clinical manifestations, diagnosis, and management".)

Cerebral vein thrombosis (CVT) – (See "Cerebral venous thrombosis: Treatment and prognosis" and "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".)

Asymptomatic individuals

FVL heterozygous carriers — Most individuals who are heterozygous for FVL and who do not have a personal or family history of thrombosis are unlikely to be aware they have a genetic variation. However, some individuals may be tested inadvertently or become aware of their FVL status from genome sequencing or direct-to-consumer testing.

Heterozygous carriers of FVL generally do not require prophylactic anticoagulants or antiplatelet agents unless there is a clinical indication such as an acute medical illness or surgery for which routine thromboprophylaxis is indicated. However, unlike the general population, we are more likely to use anticoagulation for certain surgeries (see 'Surgery' below); when contraception is appropriate, we advise to consider non-estrogen-containing methods when possible (eg, when these methods are available) (see "Contraception: Counseling for women with inherited thrombophilias"); and we are more likely to anticoagulate during pregnancy and postpartum if other risk factors are present. (See 'Obstetric issues' below.)

A common question that arises is the prevention of VTE during airline travel or other situations with prolonged sitting. We generally suggest ambulating and performing leg exercises while seated. Compression stockings may be appropriate for individuals with leg edema. There are no high-quality data that aspirin or an anticoagulant reduces the risk of VTE; however, we do not object to the administration of low-dose aspirin as long as the individual is aware that it is not supported by high-quality evidence. (See "Prevention of venous thromboembolism in adult travelers".)

We also do not perform screening for other inherited thrombophilias in these asymptomatic individuals as a way to estimate their risk of VTE, because there are no data to support this practice. (See "Hereditary thrombophilia testing in adults without VTE", section on 'General risks and benefits of testing'.)

Potential settings in which anticoagulation may be appropriate are described in the following sections. (See 'FVL homozygous carriers' below and 'Surgery' below and 'Obstetric issues' below.)

In addition, asymptomatic individuals who are heterozygous for FVL may benefit from counseling about the following issues:

Awareness of signs and symptoms of VTE requiring prompt medical attention. (See "Epidemiology and pathogenesis of acute pulmonary embolism in adults".)

Obtaining a complete family history of VTE, both to clarify individual risk and to counsel regarding testing or not testing relatives. Individuals with FVL and a positive family history for VTE are at greater personal risk of VTE than those identified by general population screening. For these individuals, we feel more strongly about avoiding estrogen-containing contraceptives and limiting other exposures that could provoke VTE. (See "Hereditary thrombophilia testing in adults without VTE", section on 'Deciding whether to test'.)

FVL homozygous carriers — As noted above, individuals who are homozygous or pseudo-homozygous for FVL, as well as those who are heterozygous for FVL and another thrombophilic variant, are at greater risk for VTE than those with FVL heterozygosity. There are no data that show a benefit of long-term anticoagulation in asymptomatic individuals who are homozygous for FVL, and we generally do not anticoagulate them in the absence of VTE. However, anticoagulation might be appropriate for those individuals who place an especially high value on preventing thrombosis (eg, due to massive, unprovoked pulmonary embolism in a family member).

Surgery — Individuals with FVL who undergo surgery should generally be treated as a high-risk group and receive prophylactic anticoagulation to reduce the risk of VTE (eg, with low molecular weight heparin, fondaparinux, or unfractionated heparin); this is especially true for patients with a prior personal history of VTE (algorithm 1). FVL homozygous individuals undergoing surgery should be managed as a higher risk group in the perioperative setting, even in the absence of a personal thrombosis history. (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients", section on 'Assess risk for thrombosis' and "Prevention of venous thromboembolism in adults undergoing hip fracture repair or hip or knee replacement", section on 'Risk assessment' and "Heparin and LMW heparin: Dosing and adverse effects".)

Obstetric issues — The two major issues that arise related to pregnancy are whether to intervene to reduce the risk of pregnancy complications (miscarriage, preeclampsia) and whether to intervene to reduce the risk of pregnancy-related VTE. Despite the relatively high frequency of FVL in the general population, there are no randomized trials or other high-quality evidence to guide management of individuals with FVL before, during, and after pregnancy.

Pregnancy complications – FVL is not associated with an increased risk of unsuccessful in vitro fertilization (IVF). Information on early pregnancy loss is mixed, but if an association exists it is likely to be modest at best. Approaches to management of individuals with FVL who are concerned about possible pregnancy complications or who have experienced these complications are presented separately. (See "Inherited thrombophilias in pregnancy", section on 'Adverse pregnancy outcome risk' and "Recurrent pregnancy loss: Management", section on 'Thrombophilia' and "Recurrent pregnancy loss: Evaluation".)

VTE prophylaxis – For VTE prophylaxis, anticoagulation during pregnancy and/or postpartum may be appropriate, depending on the woman's personal and family history of VTE, method of delivery, and other VTE risk factors (table 3). (See "Inherited thrombophilias in pregnancy", section on 'Prevention of VTE'.)

The choice of anticoagulant, dosing, timing, and issues related to delivery and breast feeding in women receiving an anticoagulant are discussed separately. (See "Use of anticoagulants during pregnancy and postpartum".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anticoagulation".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Factor V Leiden (The Basics)")

SUMMARY AND RECOMMENDATIONS

Biology – Factor V Leiden (FVL) is a point mutation in the F5 gene that eliminates a cleavage site in factor V and factor Va (figure 3), rendering activated FVL relatively resistant to inactivation by aPC. Unactivated FVL is less effective as a cofactor for activated protein C (aPC) cleavage of FVa and FVIIIa. These mechanisms contribute to the increased risk of thrombosis in individuals who are heterozygous for FVL. This risk may be further increased by homozygosity or pseudo-homozygosity for FVL or other inherited or acquired thrombophilias. (See 'Physiology' above.)

Prevalence – Heterozygosity for FVL is the most common inherited thrombophilia in unselected White populations (prevalence, approximately 5 percent) and the most common inherited thrombophilia in individuals with venous thromboembolism (VTE; prevalence, approximately 10 to 20 percent) (table 2). (See 'Epidemiology' above.)

VTE risk – The major manifestation of FVL is VTE. However, only a small percentage of individuals who are heterozygous for FVL will develop VTE in their lifetime (approximate risk, 5 to 10 percent or up to 20 percent in thrombophilic families). Risk is greater with homozygosity for FVL or compound heterozygosity for FVL and another inherited thrombophilia. The most common site of VTE is deep vein thrombosis and pulmonary embolism. Other possible sites include superficial leg veins and cerebral, portal, and hepatic veins. (See 'Venous thromboembolism' above.)

Arterial events – The relationship of FVL with arterial thromboembolism (myocardial infarction, stroke) or pregnancy complications (late fetal loss) is controversial; the magnitude of the effect is likely to be small relative to other risk factors. (See 'Arterial thromboembolism' above and 'Fetal loss and obstetric complications' above.)

Diagnosis – FVL may be suspected in a member of a thrombophilic kindred or an individual with VTE, especially at a young age (<50 years) or in an unusual location (portal vein, cerebral vein), or recurrent VTE. Diagnosis can be made using genetic testing or a functional test ("second generation" aPC resistance assay). (See 'Diagnosis' above and "Gene test interpretation: Factor V Leiden".)

Differential diagnosis – The differential diagnoses of risk factors for VTE and pregnancy loss are presented separately. (See "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors" and "Inherited thrombophilias in pregnancy".)

Management

Other testing and counseling – We generally do not test for other thrombophilias in individuals with FVL who have not had a thromboembolic event. It may be appropriate to test first-degree relatives in some settings (strong family history of VTE, contraceptive counseling for female first-degree relatives, siblings of homozygous patients with VTE). (See 'Post-diagnosis testing and testing of first-degree relatives' above.)

VTE treatment – FVL does not influence the initial treatment of VTE (algorithm 1). We individualize the duration of anticoagulation according to features such as whether the VTE was provoked, life-threatening, or at an unusual site, as done for the general population, rather than a more aggressive approach. After a first episode of VTE provoked by a hormonal risk factor such as oral contraceptives, pregnancy, or the postpartum period, the presence of FVL may justify considering indefinite duration anticoagulation. (See 'Patients with VTE' above and "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation".)

VTE prevention – For asymptomatic individuals who are heterozygous for FVL, we suggest not treating routinely with anticoagulation (Grade 2B), with the exception of certain high-risk situations such as surgery, pregnancy or the postpartum period, or additional thrombophilic variants. Possible avoidance of estrogen-containing contraceptives and counseling about VTE risk are discussed above. (See 'Asymptomatic individuals' above and 'Obstetric issues' above and "Contraception: Counseling for women with inherited thrombophilias".)

Population screening – Screening for FVL in asymptomatic individuals is discouraged. Population screening is discussed separately. (See "Thrombophilia testing in children and adolescents" and "Hereditary thrombophilia testing in adults without VTE" and "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors" and "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis" and "Overview of the evaluation of stroke" and "Inherited thrombophilias in pregnancy", section on 'Selection of patients for testing'.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Lawrence LK Leung, MD, who contributed to earlier versions of this topic review.

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Topic 1355 Version 62.0

References

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