Thrombophilia Due To Activated Protein C Resistance

A number sign (#) is used with this entry because of evidence that the disorder is caused by heterozygous mutation in the gene that encodes factor V (F5; 612309) on chromosome 1q24.

Description

Thrombophilia due to activated protein C resistance is due to a mutation in the F5 gene that renders factor V resistant to cleavage and inactivation by activated protein C (PROC; 612283) and results in a tendency to thrombosis.

See also factor V deficiency (227400), an allelic disorder resulting in a hemorrhagic diathesis due to lack of factor V.

The most common mutation that causes this disorder is referred to as factor V Leiden (R506Q; 612309.0001), named after the town in the Netherlands where Bertina et al. (1994) discovered the defect. Homozygosity increases the risk of thrombotic complications to a greater extent than heterozygosity. However, heterozygous presence of the mutation may be combined with defects in other genes in the clotting pathway to contribute to the disorder. Expressivity is variable and influenced by environment.

Clinical Features

Dahlback et al. (1993) reported a family in which 5 individuals spanning 3 generations had adult-onset thromboembolic disease, most often deep venous thrombosis of the legs, inherited in an autosomal dominant pattern. Laboratory studies of patients' plasma demonstrated a poor anticoagulant response upon the addition of activated protein C (APC; 612283), as measured by the lack of prolongation of clotting time in an activated partial thromboplastin time (aPTT) assay. In addition, 14 of 19 tested family members showed a similar defect in this assay. Known coagulation defects and serum autoantibodies or inhibitors to APC were excluded. Two additional unrelated patients with thrombophilia and inherited poor response to APC were identified using this novel assay. The thromboembolic events occurred during pregnancy or in the postpartum period in the 2 additional families. Dahlback et al. (1993) concluded that these individuals were lacking a previously unrecognized cofactor for APC that was responsible for the subnormal APC effects in the degradation of factors Va and VIIIa (300841).

Greengard et al. (1994) reported variability of thrombosis in a family in which 4 sibs were homozygous for the R560Q mutation. The oldest son, who was homozygous, developed deep vein thrombosis (DVT) of the leg after an injury to that extremity at age 18 years. Two weeks later, during treatment with warfarin, he developed a DVT of the other leg. A clip was placed on the inferior vena cava and warfarin therapy was continued for 2 years. He later developed severe bilateral postphlebitic syndrome with chronic leg ulcers. Another son, who was heterozygous, developed a spontaneous DVT of the leg at age 23 years. The youngest son, who was homozygous, had a spontaneous pulmonary embolus confirmed by pulmonary angiography at the age of 16 years. This recurred 1 year later after the discontinuation of warfarin treatment. At the age of 24, he had a DVT of the right leg when he was not receiving warfarin; he was treated for 6 months. Four months after the discontinuation of treatment, he had a recurrent DVT in the right leg. The heterozygous mother developed a DVT of the left leg during her most recent pregnancy at the age of 37. Two daughters, aged 28 and 33 years, who were homozygous for the mutation, and the father, who was heterozygous, had not developed thrombosis. Greengard et al. (1994) noted that the daughters had not been exposed to risk factors, such as major surgical procedures, the use of oral contraceptives, or pregnancy.

Zoller and Dahlback (1994) studied a large kindred in which familial thrombophilia and APC resistance was inherited as an autosomal dominant trait, and all affected individuals had the R506Q mutation.

Among 47 Swedish families with APC resistance and the R506Q mutation, Zoller et al. (1994) observed that by age 33 years, 8% of normals, 20% of heterozygotes, and 40% of homozygotes had had manifestations of venous thrombosis. In a majority of both heterozygous and homozygous individuals, thrombosis was associated with risk factors, most commonly pregnancy, oral contraceptives, trauma, and surgery.

Pipe et al. (1996) reported a patient with neonatal purpura fulminans associated with heterozygosity for the R506Q mutation. At 8 hours of age, the neonate had progressive purpuric skin lesions and later had evidence of microvascular hemorrhagic thrombosis in the brain. The infant was treated with fresh frozen plasma infusions and had complete resolution of the skin lesions and no apparent long-term complications.

Simioni et al. (1997) found heterozygosity for factor V Leiden in 41 (16.3%) of 251 unselected patients with a first episode of symptomatic deep vein thrombosis diagnosed by venography. The cumulative incidence of recurrent venous thromboembolism after follow-up of up to 8 years was 39.7% among carriers of the mutation, as compared with 18.3% among patients without the mutation.

Jackson and Luplow (1998) described 2 adults with purpura fulminans related to sepsis who were found to be heterozygous for the factor V Leiden mutation. Each patient survived disseminated intravascular coagulation, shock, and digital necrosis, but eventually required digit amputations. The first patient was a 42-year-old man with Streptococcus pneumoniae. Acrocyanosis progressed to dry gangrene of all the fingers and toes; however, the skin of the forehead, ears, and nose recovered without scarring. The second patient was a 40-year-old woman with septicemia due to Bacteroides fragilis and Fusobacterium species.

In a male neonate with inferior vena cava thrombosis, complicated by bilateral adrenal hemorrhage and left renal vein thrombosis Gorbe et al. (1999) identified a homozygous factor V Leiden mutation. The infant improved with intravenous administration of dopamine-dobutamine and low doses of heparin. An associated persistent ductus arteriosus detected by echocardiography was ligated during hospitalization.

In a population-based cohort study of 9,253 Danish adults, Juul et al. (2004) found that heterozygotes and homozygotes for factor V Leiden had 2.7 and 18 times higher risk for venous thromboembolism, respectively, than noncarriers. Absolute 10-year risks for thromboembolism among heterozygote and homozygote nonsmokers younger than age 40 years who were not overweight were 0.7% and 3%, respectively. The 10-year risks in heterozygotes and homozygotes older than age 60 years who smoked and were overweight were 10% and 51%, respectively.

Other Features

Role in Pregnancy Complications

Brenner et al. (1996) observed 2 patients with the HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count) who were heterozygous for the R506Q mutation. The HELLP syndrome is a severe presentation of preeclampsia (see 189800). The finding of the R506Q mutation suggested that the pathogenesis of HELLP syndrome may be associated with a thrombotic process.

Among 122 pregnant women with preeclampsia or intrauterine growth retardation, Lindqvist et al. (1998) found a significantly reduced risk of intrapartum bleeding complications in the APC-resistant subgroup compared to non-APC-resistant subgroup, as indicated by reduced intrapartum blood loss and pre- and postpartum hemoglobin measurements. However, there was no difference between the 2 groups regarding preeclampsia or intrauterine growth retardation. Lindqvist et al. (1998) speculated that the remarkably high prevalence of a potentially harmful factor V gene mutation in the general population may be the result of an evolutionary selection mechanism conferring such survival advantages as reduction in the risk of intrapartum bleeding.

Kupferminc et al. (1999) identified the factor V R506Q mutation in 22 of 110 women with obstetrical complications, including severe preeclampsia, abruptio placentae, fetal growth retardation, and stillbirth, and in 7 of 110 women with normal pregnancies (p = 0.003). In 24 of the women with complications, as compared with 9 women without complications, homozygosity for the 677C-T polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR; 607093.0003) was also found. Overall, 57 women with obstetrical complications had a thrombophilic mutation, as compared with 19 women with normal pregnancies (p less than 0.001). Anticardiolipin antibodies or deficiency of protein S, protein C, or antithrombin III were detected in an additional 14 women with complications, as compared with 1 woman with a normal pregnancy (p less than 0.001). Kupferminc et al. (1999) recommended that women with such obstetrical complications should be tested for genetic and acquired markers of thrombophilia because these complications tend to recur in subsequent pregnancies.

Faisel et al. (2004) analyzed the allele and genotype frequencies of 2 F5 polymorphisms, M385T, R485K, and the R506Q Leiden mutation in 133 Finnish women with preeclampsia (189800) and 112 controls. There were statistically significant differences in R485K allele (p = 0.003) and genotype (p = 0.03) frequencies between patients and controls. The A allele of R485K was overrepresented among the patients (12%) compared to the controls (4%), with an odds ratio of 2.8 (95% CI, 1.2-6.2) for combined A genotypes. Faisel et al. (2004) concluded that genetic variations in the factor V gene other than the Leiden mutation may play a role in disease susceptibility.

Role in Other Diseases

Heresbach et al. (1997) added small bowel infarctions to the many thrombotic states in which the factor V Leiden mutation plays a role. They observed the R506Q mutation in 2 cases of arterial and 2 cases of venous small bowel infarction. Two patients were heterozygous and 2 were homozygous. Three of the patients were in their mid-thirties and the fourth was a 45-year-old man.

Mahmoud et al. (1997) reported the incidence of the factor V Leiden mutation in Budd-Chiari syndrome (600880) and portal vein thrombosis. The R506Q mutation was seen in 7 (23%) of 30 patients with Budd-Chiari syndrome (6 heterozygotes and 1 homozygote), 3 of whom had coexistent myeloproliferative disease. Only 1 (3%) of 32 patients with portal vein thrombosis was found to have the R506Q mutation. The mutation was found in 3 (6%) of the 54 controls, who had liver disease but no history of thrombophilia. Mahmoud et al. (1997) concluded that the R506Q mutation may be an important factor in the pathogenesis of Budd-Chiari syndrome but not of portal vein thrombosis.

Leebeek et al. (1998) described a 27-year-old female homozygous for factor V Leiden with Budd-Chiari syndrome caused by hepatic vein thrombosis in association with portal and mesenteric vein thrombosis. She was treated by transjugular intrahepatic portosystemic stent placement followed by local thrombolytic therapy. Venous outflow from the liver was established and the thrombi in the portal and mesenteric veins were lysed completely. Gurakan et al. (1999) described a child with Budd-Chiari syndrome who was homozygous for the factor V Leiden mutation. The authors noted that Budd-Chiari syndrome is rare in children.

De Bruijn et al. (1998) studied risk factors in cerebral venous sinus thrombosis in women. They found a clear and significant excess of both hereditary prothrombotic conditions, including factor V Leiden, and oral contraceptive use in 40 prospectively ascertained patients compared to 2,248 randomly sampled controls. The authors concluded that the presence of prothrombotic conditions like the factor V Leiden mutation and the use of oral contraceptives increase the risk of this rare condition in a multiplicative fashion.

Chung et al. (2006) described Budd-Chiari syndrome in a 46-year-old woman who developed rapidly increasing abdominal girth over a period of several days with accumulation of ascites. The disorder was found to be associated with a mutation in JAK2 (V617F; 147796.0001) and the factor V Leiden mutation. As many as 50% of patients with Budd-Chiari syndrome have a myeloproliferative disorder, either preexisting or diagnosed at the time of the syndrome. However, some patients with the Budd-Chiari syndrome may have a latent myeloproliferative disorder without elevated blood counts. The V617F mutation of the JAK2 gene has been detected in a high proportion of patients with the Budd-Chiari syndrome, providing evidence that these patients have a latent myeloproliferative disorder (Patel et al., 2006).

Debus et al. (1998) found that 6 of 24 children with porencephaly (175780) were heterozygous for the factor V Leiden mutation. Two of these also had familial raised Lp(a) levels (152200) and 1 child also had protein S deficiency (612336). An additional 10 children had protein C deficiency, protein S deficiency, or familial raised Lp(a) levels. Five of the 24 children had a positive family history of thrombosis. Debus et al. (1998) suggested that hereditary thrombophilic states may predispose to perinatal cerebroarterial occlusion and porencephaly. The authors commented that other interacting prenatal factors, such as infection, placental dysfunction, or fetal cardiac arrhythmias, should also be considered as causative factors. Debus et al. (2004) found a higher prevalence of the R506Q mutation among 76 patients with porencephaly compared to controls. Eighteen patients were heterozygous and 1 infant was homozygous; 4 controls carried the mutation. The authors suggested that patients with porencephaly have certain prothrombotic risk factors which may contribute to the development of the disorder.

Kerlin et al. (2003) found that 4.1% of 65 patients with sepsis were heterozygous carriers of the factor V Leiden mutation. The 28-day mortality was lower in heterozygous carriers (13.9%) compared to those without the mutation (27.9%, p = 0.013). The mortality benefit of recombinant human activated protein C treatment was similar in both groups. Kerlin et al. (2003) suggested that F5 Leiden constitutes a rare example of a balanced gene polymorphism that maintains the F5 Leiden mutation in the general gene pool due to a survival advantage of heterozygotes in severe sepsis.

In a comprehensive metaanalysis of 26 case-control studies including 4,588 white adult patients, Casas et al. (2004) found a statistically significant association between ischemic stroke (601367) and the R506Q substitution (odds ratio of 1.33).

Diagnosis

Meyer et al. (1999) described a method for simultaneously genotyping for factor V Leiden and the prothrombin 20210G-A variant (176930.0009) by a multiplex PCR-SSCP assay on whole blood.

Greer (2000) stated that there is no evidence to support general screening of pregnant women for thrombophilia; however, all pregnant women with a personal or family history of venous thromboembolism should be screened. Drug prophylaxis against venous thromboembolism is warranted for pregnant women with thrombophilia who have had a previous thromboembolic event. Women with thrombophilia who have not had venous thromboembolism require individualized assessment of the defect and of additional risk factors. Screening should be extended to women with a history of second-trimester pregnancy loss (see 614389), severe or recurrent preeclampsia, or intrauterine growth restriction, although whether antithrombotic therapy will prevent these complications in women with congenital thrombophilia was not known.

Krawczak et al. (2001) described a strategy called 'cascade genetic screening' whereby screening for genetic variants is targeted at the relatives of previously identified carriers rather than being performed at the general population level. They estimated that some 80% of all carriers of the factor V Leiden mutation would be detected if screening were to be targeted specifically at first- to third-degree relatives of patients with venous thrombosis.

Segal et al. (2009) provided a metaanalysis of the predictive value of factor V Leiden for the development of venous thromboembolism using a literature review of 13 relevant articles. Heterozygosity and homozygosity for the mutation in probands were predictive of recurrent venous thromboembolism (OR of 1.56 and 2.65, respectively) compared to individuals without the mutation. In relatives of probands, heterozygosity and homozygosity also predicted venous thromboembolism (OR of 3.5 and 18.0, respectively) compared to family members without the mutation. It remained unknown whether testing for the mutation improved clinical outcome.

Clinical Management

Sarasin and Bounameaux (1998) used a Markov decision analysis model that incorporated all current data concerning recurrent venous thromboembolism and long-term anticoagulation. The model suggested that the benefits of prolonged oral anticoagulant treatment in factor V Leiden heterozygotes after a first episode of deep vein thrombosis were usually overwhelmed by its risks. Sarasin and Bounameaux (1998) concluded that any decision to promote widespread screening programs to detect factor V Leiden heterozygotes should be questioned in the absence of a clinical benefit provided by extended use of oral anticoagulants.

Heterogeneity

Zoller et al. (1994) identified the R506Q mutation in 47 of 50 Swedish families with inherited APC resistance. There was perfect cosegregation between a low APC ratio and the presence of the mutation in 40 families. However, the cosegregation was not perfect in 7 families, as 12 of 57 APC-resistant family members did not have the mutation. Moreover, in 3 families with APC resistance, the specific R506Q mutation was not found, suggesting another still unidentified cause of inherited APC resistance.

Pathogenesis

Dahlback and Hildebrand (1994) discovered that the APC cofactor deficient in this disorder was identical to factor V. An affinity-purified factor V corrected the poor anticoagulant response to APC of APC-resistant plasma in a dose-dependent manner. Because the APC-resistant plasma contained normal levels of factor V procoagulant activity, the results indicated that APC resistance was due to a selective defect in the anticoagulant function of factor V. The findings suggested that factor V not only has procoagulant properties after its activation by thrombin, but may also play an important role in the anticoagulant system as cofactor to activated protein C. Dahlback and Hildebrand (1994) commented on this appropriate, unique, and ingenious means of regulating blood coagulation.

Sun et al. (1994) stated that APC resistance was 'currently the most common laboratory finding among venous thrombophilic patients.' They presented findings indicating that APC resistance is due to abnormality in factor V and not abnormality in factor VIII, which is also inactivated by APC, and that half of the patients' factor Va is resistant to APC, consistent with dominant inheritance.

Molecular Genetics

In affected members of a family with thrombophilia due to APC resistance, Bertina et al. (1994) identified a heterozygous R506Q mutation in the F5 gene. Of note, this family came to attention because of symptomatic protein C deficiency. The authors identified the mutation in 56 of 64 patients with APC-resistant thrombosis from a larger cohort of 301 consecutive patients with a first episode of deep vein thrombosis. The mutation was homozygous in 6 patients.

Voorberg et al. (1994) found the R506Q mutation in 10 of 27 consecutive patients with recurrent thromboembolism.

In a patient with thrombophilia due to APC resistance, Williamson et al. (1998) identified a heterozygous R306T mutation in the F5 gene (612309.0003). The mutation was also present in a first-degree relative with APC resistance.

In 2 Caucasian brothers with thrombophilia due to APC resistance, Mumford et al. (2003) identified compound heterozygosity for 2 mutations in the F5 gene: a missense mutation (I359T; 612309.0013) and a nonsense mutation (E119X; 612309.0014). Both brothers developed spontaneous venous thromboses in the second decade of life. One presented at the age of 14 years with thrombosis of the right femoral vein and inferior vena cava; an older brother suffered recurrent episodes of femoral vein thrombosis from the age of 18 years and was managed with long-term warfarin therapy. Heterozygous family members were asymptomatic. The I359T allele was predicted to create an additional consensus site for N-linked glycosylation in factor V, which may have resulted in abnormal N-linked glycosylation within the factor V A2 domain and and reduced susceptibility of factor Va to proteolysis. Mumford et al. (2003) suggested that the E119X mutation resulted in an mRNA that was recognized and degraded by the cell via a process termed nonsense-mediated decay. Thus, the authors concluded that hemizygosity for the I359T variant was the cause of severe early-onset thrombophilia in these sibs.

Pseudohomozygosity for Factor V Leiden

Castaman et al. (1997) and Castoldi et al. (1998) described patients with thrombosis who were compound heterozygous for factor V Leiden and a factor V deficiency allele. The patients are referred to as having 'pseudohomozygosity' for factor V Leiden, since they present with venous thromboembolic events. Those with factor V null mutations show only factor V Leiden molecules, and those with deficiency mutations show decreased levels of factor V that are insufficient to protect against thrombosis. Zehnder et al. (1999) identified a man with thrombophilia who was compound heterozygous for factor V Leiden and a null allele of the F5 gene (612309.0005). The patient had 50% of normal levels of F5, all of which was of the Leiden type; hence he was pseudohomozygous for factor V Leiden. Castaman et al. (1999) referred to pseudohomozygosity for activated protein C resistance due to the association of heterozygous factor V Leiden mutation and factor V deficiency. Among 7 families with 11 pseudohomozygotes and 45 relatives, 16 relatives were heterozygous factor V Leiden carriers, 9 showed partial factor V deficiency, and 20 had no abnormalities. Deep vein thrombosis occurred in 4 (36.3%) of 11 pseudohomozygous patients versus 6 (37.4%) of 16 factor V Leiden carriers and 1 (5%) of 20 normal relatives.

Modifier Genes

Kemkes-Matthes et al. (2005) found that the presence of a heterozygous or homozygous arg225-to-his (R225H) substitution in exon 8 of the protein Z gene (PROZ; 176895) was associated with a higher frequency of thromboembolic complications in patients carrying the factor V Leiden mutation, although plasma levels of protein Z were not different between those with or without the R225H substitution. In a study of 134 carriers of factor V Leiden, the R225H mutation was found in 11 (14.4%) of 76 patients with thromboembolic events and in only 3 (5.1%) of 58 patients who did not have thromboembolic events.

Genotype/Phenotype Correlations

Koeleman et al. (1994) found that heterozygous carriers of both the factor V Leiden mutation and a mutation in the protein C gene were at higher risk of thrombosis compared to patients with either defect alone.

Gandrille et al. (1995) detected the R506Q mutation in 15 (14%) of 113 patients with protein C deficiency and in 1 (1%) of 113 healthy controls. There was a significant difference in the allele frequency of the R506Q mutation between heterozygous protein C-deficient patients and protein C-deficient patients with no identified mutation in the PROC gene. The results demonstrated that a significant subset of thrombophilic patients have multiple genetic risk factors, although additional secondary genetic risk factors remained to be identified in a majority of symptomatic protein C-deficient patients.

Talmon et al. (1997) described retinal arterial occlusion in a child heterozygous for the factor V R506Q mutation and homozygous for the thermolabile variant of methylene tetrahydrofolate reductase (607093.0003). Thus, the coexistence of 2 mild hereditary thrombophilic states can result in severe thrombotic manifestations in young people. Although factor V Leiden had been associated clearly with venous thrombosis, most studies had failed to demonstrate an association between isolated factor V Leiden and arterial thrombosis.

De Stefano et al. (1999) examined the relative risk of recurrent deep venous thrombosis using a proportional-hazards model. The authors found that whereas patients who were heterozygous for factor V Leiden alone had a risk of recurrent deep venous thrombosis that was similar to that among patients who had neither mutation, patients who were heterozygous for both factor V Leiden and prothrombin 20210G-A (176930.0009) had a 2.6-fold higher risk of recurrent thrombosis than did carriers of factor V Leiden alone.

Meinardi et al. (1999) described double homozygosity for factor V Leiden and prothrombin 20210G-A in a 34-year-old man with idiopathic venous thrombosis.

Among 119 women with a history of venous thromboembolism during pregnancy, Gerhardt et al. (2000) found a prevalence of 43.7% for factor V Leiden, as compared with 7.7% among controls (relative risk of venous thromboembolism was 9.3). The prevalence of the 20210G-A prothrombin mutation (176930.0009) was 16.9% in the thromboembolism group as compared with 1.3% in the control group. The frequency of both factor V Leiden and the 20210G-A prothrombin mutation was 9.3% in the thromboembolism group as compared with 0 in the control group (estimated odds ratio, 107). Assuming an overall risk of 1 in 1,500 pregnancies, the risk of thrombosis among carriers of factor V Leiden was 0.2%, among carriers of the 20210G-A prothrombin mutation, 0.5%, and among carriers of both defects, 4.6%, as calculated in a multivariate analysis. Thus, the risk among women with both mutations was disproportionately higher than that among women with only 1 mutation.

Martinelli et al. (2000) found that both factor V Leiden and the 20210G-A prothrombin mutation were associated with an approximate tripling of the risk of late fetal loss.

Population Genetics

Koster et al. (1993) detected a poor anticoagulant response to activated protein C in 64 (21%) of 301 unselected consecutive patients younger than 70 years with a first episode of deep vein thrombosis unassociated with malignant disease. The frequency of the defect was 5% among 301 healthy controls. An autosomal dominant mode of transmission of the abnormality was confirmed in families of the probands with the defect. Both parents of a probable homozygote, with an extremely poor response to activated protein C, were found to have the abnormality.

In a study of 104 consecutive patients with venous thrombosis and 211 members of 34 families of affected probands, Svensson and Dahlback (1994) determined that the prevalence of APC resistance was as much as 40% in patients with thrombosis. The anticoagulant response to APC was measured with a modified version of the aPTT test and the results were expressed as APC ratios. Thirty-three percent of patients showed an APC ratio below the 5th percentile of the control values. Thrombosis-free survival of APC-resistant family members was significantly less than that of non-APC-resistant family members.

Majerus (1994) quoted estimates that 2 to 4% of the Dutch population and 7% of the Swedish population carried the factor V Leiden mutation. The high frequency of a single factor V mutation in diverse groups of people raised the question of whether positive selection pressure was involved in maintaining it in the population. Majerus (1994) suggested that a slight thrombotic tendency may confer some advantage in fetal implantation.

Greengard et al. (1994) identified a heterozygous R506Q mutation in 8 patients with APC resistance; 2 were Ashkenazi Jews, 5 were Europeans of varying origins, and 1 was African American.

Beauchamp et al. (1994) identified the R506Q mutation in all affected members of 2 families with inherited APC resistance associated with thrombosis studied in England. The molecular studies confirmed suspected homozygosity in 2 individuals. The mutation in heterozygous form was also found in approximately 3.5% of the normal population.

Among 14,916 apparently healthy men in the Physicians' Health Study, including 121 with deep venous thrombosis, Ridker et al. (1995) found that the R506Q mutation of the F5 gene was present in 25.8% of men over the age of 60 in whom primary venous thrombosis developed. There was no increased risk for secondary venous thrombosis. The presence of the mutation was not associated with an increased risk of myocardial infarction or stroke. In a follow-up study, of 77 study participants who had a first idiopathic venous thromboembolism, Ridker et al. (1995) found that factor V Leiden was associated with a 4- to 5-fold increased risk of recurrent thrombosis. The data raised the possibility that patients with idiopathic venous thromboembolism and factor V Leiden may require more prolonged anticoagulation to prevent recurrent disease compared to those without the mutation.

In a population study in southern Germany, Braun et al. (1996) found that 7.8% of 180 unrelated individuals were heterozygous for the factor V Leiden mutation.

In a multiethnic survey of 602 Americans, Gregg et al. (1997) found that Hispanic Americans had the highest frequency of the Leiden mutant allele, 1.65%, while African Americans had a somewhat lower frequency, 0.87%. No instances of the Leiden mutation were found in 191 Asian Americans or 54 Native Americans tested. These results indicated that the Leiden mutation segregates in populations with significant Caucasian admixture and is rare in genetically distant non-European groups.

The factor V Leiden mutation (612309.0001) and the 20210G-A mutation in the prothrombin gene (176930.0009) are the most frequent abnormalities associated with venous thromboembolism. Martinelli et al. (2000) compared the prevalence and incidence rate of venous thromboembolism in relatives with either of these 2 mutations or both. The study population included 1,076 relatives of probands with the prothrombin gene mutation, factor V Leiden, or both, who underwent screening for inherited thrombophilia and were found to be carriers of single mutations or double mutations or who were noncarriers. The prevalence of venous thromboembolism was 5.7% in relatives with the prothrombin gene mutation, 7.8% in those with factor V Leiden, 17.1% in those with both mutations, and 2.5% in noncarriers. Annual incidences of thrombosis were 0.13%, 0.19%, 0.42%, and 0.066%, respectively. The relative risk of thrombosis was 2 times higher in carriers of the prothrombin gene mutation, 3 times higher in those with factor V Leiden, and 6 times higher in double carriers than in noncarriers. The incidence of venous thromboembolism in carriers of the prothrombin gene mutation was slightly lower than that observed in carriers of factor V Leiden, whereas in carriers of both mutations it was 2 or 3 times higher. From these findings, Martinelli et al. (2000) concluded that lifelong primary anticoagulant prophylaxis of venous thromboembolism is not needed in asymptomatic carriers of single or double mutations. Anticoagulant prophylaxis seems to be indicated only when transient risk factors for thrombosis coexist with mutations.

Zivelin et al. (2006) estimated the age of the factor V Leiden mutation to be 21,340 years. Like the prothrombin 20210G-A mutation, factor V Leiden occurred in whites toward the end of the last glaciation and their wide distribution in whites suggested selective evolutionary advantages. A selective disadvantage, i.e., thrombosis, was unlikely because until recent centuries humans did not live long enough to manifest a meaningful incidence of thrombosis. On the other hand, augmented hemostasis conceivably conferred a selective advantage by reducing mortality from postpartum hemorrhage, hemorrhagia associated with severe iron deficiency anemia, and posttraumatic bleeding. For example, Lindqvist et al. (1998) found that the amount of blood lost during labor was significantly smaller in heterozygotes with factor V Leiden than in women not carrying the mutation. Lindqvist et al. (2001) found that profuse menstrual bleeding was significantly less common in factor V heterozygotes.

Nomenclature

Greengard et al. (1994) proposed that thrombophilia associated with APC resistance caused by factor V mutations be designated 'thrombophilia V.'

Animal Model

Cui et al. (2000) generated mice carrying the R504Q mutation, homologous to human R506Q, inserted into the endogenous murine factor V gene. Adult heterozygous and homozygous mice were viable and fertile and exhibited normal survival. Compared with wildtype mice, adult homozygous mice demonstrated a marked increase in spontaneous tissue fibrin deposition. On a mixed genetic background, homozygous mice developed disseminated intravascular thrombosis in the perinatal period, resulting in significant mortality shortly after birth. Cui et al. (2000) suggested that these results may explain the high degree of conservation of the R504/R506 activated protein C cleavage site within factor V among mammalian species.