1. Top of page
  2. Abstract
  3. Introduction
  4. Factor V variations and venous thrombosis
  5. Haplotypes
  6. A link between Factor V variability and protein function?
  7. Acknowledgements
  8. References

Summary.  DNA variations in the Factor V gene have played a major role in thrombosis research ever since the discovery of Factor V Leiden. Here, all relatively common DNA variations in the coding regions of the Factor V gene are discussed. Many of them have been associated with venous thrombosis or related diseases. However, most variations have been studied separately, without taking the presence of other variations in the same gene into account. This means that their association with disease should be interpreted with caution, as it may reflect linkage with another variation. An approach in which a haplotype-based analysis of the Factor V gene is combined with in vitro assays of recombinant proteins is advocated. Finally, a possible reason for the relatively polymorphic nature of the Factor V protein is discussed.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Factor V variations and venous thrombosis
  5. Haplotypes
  6. A link between Factor V variability and protein function?
  7. Acknowledgements
  8. References

Coagulation Factor V (FV) is a cofactor that plays an important role in the coagulation cascade. Its active form, Factor Va (FVa), participates in the conversion of prothrombin into thrombin by correctly positioning enzyme (Factor Xa) and substrate (prothrombin) relative to each other. FVa is inactivated by site-specific cleavage by Activated Protein C (APC), an anti-coagulant protein that acts in conjunction with Protein S. FV structure and function have been intensely investigated following the description of APC resistance as an important clinical phenotype [1,2] and the subsequent demonstration that this was the result of an Arg->Gln variation in one of the APC cleavage sites in FVa [3]. This APC-resistant form of FV is now generally known as FV Leiden. In the heterozygous state, it is associated with a five- to sevenfold increased risk of venous thromboembolism. The risk is even higher in homozygous carriers. FV Leiden is present in several percent of the white population and is one of the most important genetic risk factors for venous thrombosis in Caucasians. This important gene variation and several general aspects of FV biology have previously been reviewed in detail [4–6].

In this review, only some of the more recent developments with respect to FV Leiden will be discussed. The focus will mainly be on additional single nucleotide polymorphisms (SNPs) in the FV gene that cause an amino acid alteration, but do not lead to loss-of-function. Deficiency-causing mutations are discussed in the accompanying review by Asselta et al. [7]. Here, all known FV missense variations will be described that have a frequency of more than one percent in any of the three major human populations: Africans, Caucasians and Orientals/East-Asians (Table 1). Most of these variations have already been investigated in case-control populations and have been associated with thrombotic risk or changes in FV plasma levels. In addition, some of the more rare variants with a clear effect on FV biology will also be discussed.

Table 1.  Data on frequent missense variations in the Factor V cDNA
NameChimp sequenceDomainExoncDNAdbSNP rs-numberMAF AfricaMAF Cauc.MAF Orient.
  1. List of missense variations in the Factor V protein with a population frequency >1% in any of the three major populations. The common allele is given before the coordinate, the rare allele after the coordinate. Numbering is according to Jenny et al. [8]. The chimpanzee sequence is derived from the WGS-section of GenBank and is expected to be identical to the ancestral human allele. MAF = Minor Allele Frequency. Population frequency data are from the HapMap project (, in which Africans, Caucasians, Han Chinese and Japanese were typed. The Oriental MAF represents the average from the Chinese and Japanese data. If the HapMap data are not available, data from Seattle SNPs ( have been used (indicated by an asterisk (*)). The Seattle data are from AfroAmericans and Caucasians. If neither the HapMap nor the Seattle SNPs data are available, a question marks has been entered. Because of its presence in a repeated region, the H1299R-variant has not been typed in any of the projects.

G-14SGsign. pept.1 G133Ars9332485700
D79HDA13 G409C   rs60193950
M385TMA28T1328C   rs6033063
R455KRA210G1628A   rs602032070
R506QRA210G1691A   rs6025010
P781SPB13C2515T   rs6031900
N789TNB13A2540C   rs6018640
K830RKB13A2663G   rs4524172617
H837RHB13A2684G   rs45252021*27*
K897EE!B13A2863G   rs6032172617
H1118QHB13C3528G   rs6005800
E1502AEB13A4679C   rs6007021
L1721VLA316C5335G   rs6034010
M1736VV!A316A5380G   rs6030193222
M1792IMA317G5550A   rs6026200
D2194GDC225A6755G   rs6027075

In the following paragraphs, the common variants are shown before, and the minor alleles after the amino acid position, using both the one- and three-letter codes. The standard FV amino acid numbering starts at the first residue of the mature protein, with negative numbering for the 28 amino acids long signal peptide [8]. The nucleotide numbering is that of the cDNA reported by Jenny et al. [8].

Factor V variations and venous thrombosis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Factor V variations and venous thrombosis
  5. Haplotypes
  6. A link between Factor V variability and protein function?
  7. Acknowledgements
  8. References

G-14S, Gly-14Ser, G133A

This change is present in the signal peptide (hence the negative position number) and only has been detected in Africans. The effect of this change on FV is not yet known. The scores of the variant signal peptide with Ser are better than those of the wild-type Gly-allele, as assessed by the SignalP3.0 program [9], indicating that this variant will probably not hamper correct processing of the signal peptide. Interestingly, the same Gly-14 residue is changed to Asp in a FV deficient patient described by Montefusco et al. [10]. This change significantly lowers the score of the signal peptide, however, suggesting that this is a true mutation that negatively affects the function of the protein.

D79H, Asp79His, G409C

The D79H polymorphism is an example of a change with strongly different population frequencies across the world (Table 1). Bossone et al [11] reported that it was associated with low FV levels and that it contributed to APC resistance, if FV Leiden was present on the other chromosome. Others did not observe decreased FV plasma levels [12,13] and could not find an associated risk of thrombosis [13]. Lunghi et al. [14] observed a modulation of the effect of D79H on FV levels by the G/A polymorphism at position –426 in the promoter of the FV gene. The 79H-allele destroys the epitope of the V-23 monoclonal antibody [13]. This epitope does not seem to be centered at the Asp-to-His change, however, as the V-23 antibody did not bind to a peptide spanning this region. This suggests that the 79His-variant results in a conformational change affecting a somewhat larger region of the FV molecule. Such a change would be compatible with a decreased stability, but this was not observed when specifically tested in recombinant molecules, in which the polymorphism was the sole variation present [13].

M385T, Met385Thr, T1328C

The M385T polymorphism is nearly always present in carriers of the HR2 haplotype (see below), but it may also occur independently [15]. The 385Thr-variant has been associated with the risk of placental abruption in a Finnish population [16]. The HR2 haplotype-status of the subjects was not reported, however.

R455K, Arg455Lys, G1628A

The R455K polymorphism is not very well characterized, although it has frequently been associated with risk of arterial or venous disease in Oriental populations, in which the 455Lys-allele is the most common allele. In these populations, the 455Lys-alelle has been associated with venous thrombosis [17], with heart disease and a reduced normalized APC sensitivity [18] and with pre-eclampsia [19]. The latter disease association was also reported in a Finnish population [20]. Further research on this variation will be required, which should also consider the possible presence of another SNP in (a subgroup of) the 455Lys-carriers.

R506Q, Arg506Gln, G1691A

FV Leiden is well known for its APC-resistant properties, which result in a strongly pro-thrombotic effect [1–3]. More recently, it has been shown that FV also has anti-coagulant properties in that it participates in the degradation of Factor VIIIa (FVIIIa) by APC and Protein S [4,6]. Cleavage of FV, and not FVa, by APC at position 506 is essential for the function of FV as a cofactor in this process. As a result, FV Leiden, which lacks the APC-cleavage site at position 506, is defective in the FVIIIa inactivating activity, making FV Leiden pro-thrombotic by two different mechanisms; it is more pro-coagulant and less anti-coagulant. The APC cofactor function of FV, in addition to the FXa cofactor role of FVa, implies that FV-derived proteins may participate in two opposing functions, which probably make different demands on the amino acid sequence. This may have some repercussions on the role of various FV missense variations. This will be discussed at the end of this review.

A rather surprising observation regarding FV Leiden was recently made in that heterozygous carriers were protected against death from sepsis, an effect that could be repeated in controlled experiments with mice heterozygous for the same amino acid change [21]. Homozygous FV Leiden carriers were at a similar risk as homozygous carriers of the wild-type allele. An explanatory mechanism has not yet been described and more recent results suggest that the protection in both humans and mice is not as strong as initially reported [22,23]. Clearly, the effect of FV Leiden on sepsis survival needs to be independently confirmed. A protective effect in heterozygotes against a life-threatening disease would constitute an additional explanation for the relatively high frequency of FV Leiden mutation among Caucasians. The initial, plausible, explanation involved a protection against life-threatening hemorrhages [24].

B-domain polymorphisms

The B-domain of FV is poorly conserved among mammalian species, although some short amino acid motifs show a good similarity (unpublished results). The overall poor conservation suggests that the function of this domain does not strongly depend on its amino acid sequence, a view that is corroborated by the fact that so far no missense mutations leading to Factor V deficiency have been found in the B-domain [7]. Probably as a result of this low functionality, many missense variants are present in the B-domain of FV. Some of these are always co-inherited in Caucasians, leading Kostka et al [25] to define an A- and a G-allele. The common A-allele is characterized by A-variants at nucleotides 2391, 2663, 2684 and 2863, whereas the rare G-allele contains Gs at these positions (Fig. 1). The last three changes lead to amino acid alterations (Table 1). Not much is known about the functional effects of most of the B-domain variants. Because of their presence in a domain that is removed upon activation of FV, an effect on the activity of FVa seems unlikely, but an effect on FV as a cofactor of APC, when the B-domain is retained, can not be excluded. A modifying role of some of the B-domain variants is also suggested by a significantly different APC response of the A- and the G-allele in a test that measures FVIIIa inactivation [25].


Figure 1. Some haplotypes of the Factor V cDNA. Haplotypes of a white population were predicted using the PHASE-program (version 2.0.2) [39] from the genotyping data from Seattle SNPs ( and the Perlegen Genotype Browser ( [40]. These institutes have sequenced or genotyped the same 23 subjects allowing pooling of their data. The haplotypes have been ordered based on similarity. Individual number and haplotype number are shown on the left and the position of the SNP in an exon and in the cDNA is shown at the top (using the numbering of Jenny et al., [8]). The latter two numbers should be read vertically. Numbers of individuals refer to those used by the Coriell Cell Repositories ( The common allele of each variant is indicated by a grey block and the rare allele by a white block. Some well-known haplotypes have been indicated on the right. The arrow indicates the position of the major recombination site in intron 6. As a result, haplotypes at the left of this site are almost independent from those at the right. Note that the SNPs at positions 4185 and 5380 are part of several haplotypes, indicating the necessity of doing haplotype-based analyses. Also note that some well-known polymorphisms (e.g. the 2391-TaqI polymorphism that is part of the G-allele and the SNP at 4070 that is part of the HR2-allele) have not been found or typed by any of the institutes.

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The HR2 allele [26] was initially characterized by the His1299Arg conversion, but the Asp2194Gly change is the most important. The HR2-allele will be discussed in more detail below, therefore.

M1736V, Met1736Val, A5380G

This change is very frequent in several populations and it is present in several haplotypes (Fig. 1). Relatively little is known of its in vivo effects. It was expressed in isolation as a recombinant Factor V molecule by Yamazaki et al. [27], who showed that it had no effects on FV levels. No reports have so far been published on two other A3 domain variations, L1721V and M1792I (Table 1).

M2120T, Met2120Thr, T6533C

Scanavini et al [12] showed that this variant leads to lower FV levels both in vivo and in in vitro experiments using recombinant FV. The effect was similar in magnitude to that of the HR2 allele. This allele appears to be restricted to the white population, in which it occurs in a few percent of the alleles (Table 1).

D2194G, Asp2194Gly, A6755G

This change is located only three amino acids from the end of the FV molecule, directly adjacent to the cysteine residue that participates in the only disulfide bridge of the C2 domain. This domain is essential to the membrane binding of FV. The 2194Gly-variant is part of the HR2 allele and is probably responsible for most of the in vivo properties of the FV molecule encoded by this allele [12]. Although the effects of HR2 on the level and properties of FV in plasma are still being debated, recombinant FV molecules carrying the D2194G change are characterized by lower Factor V levels [27,28], something that was also observed in vivo by de Visser et al [15]. Miteva et al [29] showed that the 2194Gly-allele has a less stable C2-domain as a result of the loss of a salt bridge network between Asp2194 and Lys-residues at 2101 and 2103. In heterozygous carriers of Factor V Leiden, a lower contribution of normal FV is expected to lead to increased APC resistance and lower cofactor activity in FVIIIa inactivation and hence to a more strongly pro-thrombotic phenotype. This has indeed been observed in compound heterozygous carriers of FV Leiden and the HR2-allele. An observation made in vivo that FV-HR2 is associated with higher glycosylation levels at Asn2194 [30], a residue that is normally only partially glycosylated, could not be confirmed using recombinant Factor V molecules [28]. The combined results can only be explained if the non-glycosylated 2194Gly-variant is less stable in the circulation, for instance due to accelerated clearance of the non-glycosylated form.

Other rare polymorphisms with thrombotic phenotypes:

Ever since the discovery of FV Leiden at Arg506, researchers have anticipated the presence of similar variations at Arg306, the other major APC cleavage site in FV. Two such variants were indeed found: FV HongKong (R306G, Arg306Gly, A1090G) and FV Cambridge (R306T, Arg306Thr, G1091C) [31,32]. Both variants appear to be rare and both show an unexpectedly mild form of APC resistance when expressed in vitro [33,34]. This may be caused by the presence of alternative APC cleavage sites around Arg306 that become relevant in the absence of the normal cleavage site in this region [35].

FV Liverpool is an interesting variant that also displays APC resistance [36], but by a mechanism not involving the arginine residues of the APC cleavage sites. As a result of an Ile359Thr change, it contains an additional glycosylation side chain at Asn357 that interferes with the action of APC by steric hindrance [37].


  1. Top of page
  2. Abstract
  3. Introduction
  4. Factor V variations and venous thrombosis
  5. Haplotypes
  6. A link between Factor V variability and protein function?
  7. Acknowledgements
  8. References

In the past, the genetic variants in the FV gene have mainly been investigated in isolation, with the clear exception of the HR2-allele. This means that many of the published in vivo data on FV polymorphisms are mere associations, because they were often obtained without sufficient knowledge of the presence of additional SNPs physically and genetically linked to the variant under investigation, in other words in which haplotype the variant resides. It is possible that another variant within the same or a similar haplotype is actually responsible for the effect now attributed to a given variant. The HR2 haplotype is a case in point. This haplotype is characterized by four amino acid changes relative to the consensus sequence, of which H1299R was initially thought to be responsible for the observed effect. Only by realizing that several missense variations are co-inherited with the H1299R change and by subsequently expressing each variant in isolation using recombinant DNA techniques, it was possible to dissect this haplotype and to identify the main functional variant [27]. This is not an easy undertaking. An approach using recombinant molecules is already complex if a missense variation is deemed to be responsible for an observed qualitative property, but it may become a daunting task if a quantitative effect is to be studied. Variants that alter protein levels may be located nearly everywhere in and around a gene, not just in the coding parts of the gene. In such a case, as many as twenty SNPs may initially be candidates for the observed effect, especially if the gene is as large as the FV gene. There is therefore an urgent need for rapid assay systems that will help us to evaluate the functionality of SNPs of any kind relatively quickly. Doing such assays is highly relevant, because identification of the causal variant contributing to disease (or to an intermediate phenotype) is absolutely required to understand the biochemical mechanisms behind a haplotype-disease association.

A simplified haplotype-structure of the FV gene made up of only the SNPs present in exons is shown in Fig. 1. It shows the consistent co-occurrence of some variants in the same haplotype and the presence of some variants (e.g. A5380G) in multiple haplotypes. An important feature of the FV gene is the presence of a major recombination hot spot in intron 6. As a result, linkage between SNPs in the first six exons and those more downstream is rather weak. The regions on both sides of a recombination hot spot are therefore best considered as separate haplotype blocks. The presence of the hot spot is especially relevant for the D79H variation. Any effect attributed to this variation is unlikely to be caused by variants located downstream from exon 6, because of their poor linkage with the variant at position 79. The promoter variation at position –426 reported by Lunghi et al. [14] is, however, in the same haplotype block.

A link between Factor V variability and protein function?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Factor V variations and venous thrombosis
  5. Haplotypes
  6. A link between Factor V variability and protein function?
  7. Acknowledgements
  8. References

The large number of relevant missense polymorphisms in the FV gene is intriguing, even if one discounts the variants in the B-domain, because of its limited functionality and poor conservation. The highly comparable FVIII gene does not nearly show as many polymorphisms. Despite the fact that the latter gene is located on the X-chromosome, which has a lower SNP density than autosomes, the difference still is remarkable. Can an explanation for this phenomenon be provided? The combined procoagulant and anticoagulant nature of FV might offer a clue. These two functions are likely to have different sequence requirements [6]. Balancing the two opposing functions of FV in times of continuously shifting evolutionary constraints, as a result of changing living conditions of the human species, may have resulted in the positive selection of certain variants of the FV gene that may be especially advantageous in heterozygous carriers. Some changes may have been beneficial to the function of the prothrombinase complex, others may have improved the Factor VIIIa inactivating complex. This could explain the large number of missense changes in the FV gene. In this way, FV may act as a paradigm for the coagulation process as a whole. Coagulation is an extremely fine-tuned mechanism that needs to balance two opposing functions; prevention of haemorrhages and of thromboses. Over time, however, this may have required the equilibrium point to shift more toward the haemorrhagic or thrombotic side, depending on the nature, severity and frequency of the risks posed by the environment. Such shifts can be obtained by small variations in the quality (the sequence) or the quantity (the level) of a number of coagulation proteins, both of which can be brought about by genetic variation in the genes encoding them. The double functionality of coagulation proteins in the prevention of both haemorrhages and thromboses could well be the reason why genetic variation plays such an important role in the etiology of venous thrombosis. The presence of so many missense variants in FV, which has both been described as a Janus-faced protein [4] and as the Dr. Jekyll and Mr. Hyde of coagulation [5], could indicate that this protein is an important target for shifting the balance. In addition, because FV levels may vary over a large range without appreciably affecting the risk of either haemorrhages or thromboses [7,38], relevant changes in the FV gene would need to be qualitative in nature. Such changes will almost invariably be present in the coding domain of the gene. This also leads to the suggestion that at least some of the frequent missense changes in the FV gene should have a detectable functional effect on one of the two functions of the FV protein. In summary, the dual function of FV might make it the polymorphic protein that it is. This assertion is far from proven, however. Right now, it only provides the FV community with yet another good reason to continue investigating the structure and function of this extremely interesting, but very complex protein. We are not yet done!


  1. Top of page
  2. Abstract
  3. Introduction
  4. Factor V variations and venous thrombosis
  5. Haplotypes
  6. A link between Factor V variability and protein function?
  7. Acknowledgements
  8. References

The author apologize to all authors whose work could not be cited due to lack of space. The critical comments of R.M. Bertina and S. Duga are gratefully acknowledged.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Factor V variations and venous thrombosis
  5. Haplotypes
  6. A link between Factor V variability and protein function?
  7. Acknowledgements
  8. References
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