© 1999 American Heart Association, Inc.
Original Contributions |
Study of the Prothrombin Gene 20201 GA Variant in FV:Q506 Carriers in Relationship to the Presence or Absence of Juvenile Venous Thromboembolism
From the Department of Internal Medicine, University Hospital, Frankfurt am Main (S.E., E.A-P., I.S.); the Department of Internal Medicine, Medical School, Hannover (M. von D.P., A.G.); and the Department of Pediatrics, University Hospital, Münster (U.N-G.), Germany.
Correspondence to Dr S. Ehrenforth, Department of Internal Medicine I, HS 13A, J.W. Goethe University Hospital, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany. E-mail ehrenforth{at}em.uni-frankfurt.de
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Abstract—The G20210A transition of the prothrombin gene has been identified as a common but probably mild hereditary risk factor for venous thromboembolism (VTE). However, the prothrombin gene variant might contribute to the penetrance of thromboembolic disease in many patients with other prothrombotic defects, such as the FV:R506Q mutation. In this investigation, the A20210 allele was found in 9 of 450 healthy controls (2%). Among 89 asymptomatic FV:Q506 carriers, 3 subjects were doubly affected (3.4%). In contrast, of 263 unrelated carriers of the FV:Q506 mutant with a history of juvenile VTE, 30 also had the prothrombin gene G20210A variant (11.4%), including 25 of 220 patients who were heterozygous (11.4%) and 5 of 43 homozygous (11.6%) for FV:Q506. Thus, the A20210 allele of the prothrombin gene is significantly overrepresented in symptomatic FV:Q506 carriers compared with healthy controls (P<0.0001) and asymptomatic relatives carrying the FV mutant (P=0.02). Persons homozygous for the 20210A allele were not found. A statistically significant increase in the prevalence of more unusual sites of venous thrombosis at clinical onset was found in doubly affected patients (9 of 30; 30%) compared with patients without the prothrombin gene variant (26 of 233; 11.1%) (P=0.004). First VTE occurred spontaneously in 53.3% of all doubly affected patients (16 of 30) and in 28.3% of all simply affected patients (66 of 233) (P=0.005). Among patients with VTE preceded by circumstantial risk factors, the A20210 allele was found in 7.7% (14 of 181). We conclude that the A20210 allele of the prothrombin gene is frequently coinherited in symptomatic FV:Q506 carriers and possibly influences age, site, and type of thrombotic onset manifestation in these patients.
Key Words: genes • variation (genetics) • prothrombin • factor V • mutation • thrombosis, venous
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Introduction |
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Within the last decade, several variant alleles of the genes encoding proteins regulating blood coagulation, such as protein C, protein S, antithrombin, and fibrinogen, have been shown to be relatively strong but uncommon risk factors for thrombosis.1 2 3 4 Resistance to activated protein C due to the factor (F) V Arg 506 to Gln mutation (FV:R506Q)5 6 7 is the most common inherited risk factor for venous thromboembolism (VTE) and has been found at an average prevalence of 22% (range, 20% to 52%) in patients with primary VTE.1 8 9 10 11 Furthermore, a novel sequence variation in the prothrombin (factor II) gene, which is encoded by a 21-kb-pair-long gene localized on chromosome 1112 has recently been identified as another common risk factor for VTE. The genetic variation is located at nucleotide position 20210 in the 3'-untranslated region of the prothrombin gene at which 1 nucleotide is changed (G to A transition.13 Carriers of the A20210 allele were found in 0% to 4% of healthy controls and in 5% to 19% of patients with VTE.13 14 15 16 17 18
Whereas the cosegregation of the FV:R506Q mutation and other well-established thrombotic risk factors has been investigated in greater detail, scant information is available concerning the coexistence of both of the most common prothrombotic gene variants, FII 20210 GA and FV 1691 GA. This prompted us to evaluate the prevalence of the prothrombin gene variant G20210A among patients with juvenile VTE and to assess its importance as an additional prothrombotic risk allele in patients carrying the FV:R506Q mutation.
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Methods |
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Subjects
A total of 352 subjects carrying the FV:R506Q mutation were screened for the prothrombin gene A20210 allele. Two hundred sixty-three unrelated subjects (163 females and 100 males) had experienced an objectively confirmed first VTE
45 years of age
episode (juvenile VTE). Forty-three (28 females and 15 males) were
known homozygous carriers of the FV:Q506 mutant, whereas
220 (135 females and 85 males) carried the FV mutation in a
heterozygous form. Eighty-nine patients were asymptomatic
relatives (56 females and 33 males; median age, 33 years; range, 16 to
74 years), carrying the FV:R506Q mutation in a heterozygous (n=79) or
homozygous form (n=10). For controls, we screened 450 healthy persons
(212 females and 238 males; age, 18 to 72 years; median age, 30 years)
from the same geographic region for the presence of the prothrombin
gene A20210 allele. The criterion for recruitment of control
subjects was the lack of any history of a thromboembolic disorder. In all of the symptomatic subjects enrolled, coexisting deficiencies of antithrombin, protein C, protein S, plasminogen, or antiphospholipid antibodies had been previously excluded by using conventional functional and immunological tests. From the medical records and the personal interview, information was obtained on characteristics of the thrombotic event, such as site, age at onset, and presence or absence of circumstantial risk factors known to be associated with an increased risk for venous thrombosis (recent surgery, trauma or immobilization, oral contraceptive intake, and pregnancy or postpartum period).
Blood Sampling
After subjects gave informed consent, venous blood was collected
in EDTA-treated sample tubes (Sarstedt), from which cells were
separated by centrifugation at 300g for 15
minutes. The buffy-coat layer was then removed and stored at -70°C
until DNA extraction was performed by standard techniques.
DNA Analysis
The presence or absence of the 1691 G to A transition in the FV
gene was determined by polymerase chain reaction and MnlI
restriction analysis of PCR-amplified genomic FV DNA
fragments.6 7 Screening of the G to A transition at
nucleotide 20210 in the 3'-untranslated region of the
prothrombin gene was carried out by HindIII cleavage of a
345-bp fragment amplified by polymerase chain reaction using a
mutagenic primer, as described by Poort et al.13
Statistical Analysis
The Pearson-Mantel-Haenszel 
2 test was used for
group comparison of carrier frequency. P values and 95%
confidence intervals (95% CI) were calculated. A P value
<0.05 was considered significant. Statistical analysis was
performed with BiAS software by Dr H. Ackermann, Department of
Medical Statistics, University Frankfurt.
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Results |
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Prevalence of the Prothrombin Gene 20210 GA Variant
In the group of 450 healthy controls, 9 (2%) were heterozygous carriers of the A20210 allele (95% CI, 0.9% to 3.7%), of whom 1 had also the FV:R506Q mutation, corresponding to a prevalence of 0.2% for the combined defect.
Of 43 symptomatic patients carrying the FV:R506Q mutation in a homozygous form, a coexistence of the prothrombin gene 20210 GA variant was detected in 5 subjects, corresponding to a prevalence of 11.6% (95% CI, 3.9% to 25.1%). In contrast, the G20210A transition of the prothrombin gene could not be detected in any of the 10 asymptomatic homozygotes for FV:Q506.
In subjects affected by the heterozygous FV:R506Q mutation, the frequency of the prothrombin gene 20210 GA variant was increased by 3-fold in symptomatic patients compared with asymptomatic relatives (P=0.04); of 220 symptomatic FV:Q506 carriers, 25 (11.4%) had also the A20210 allele (95% CI, 7.5% to 16.3%), whereas among 79 asymptomatic FV:Q506 heterozygotes, the prothrombin variant was detected in only 3 cases (3.8%; 95% CI, 0.8% to 10.7%). Persons homozygous for the A20210 allele were not found among the study group presented in this article.
Taken together, the A20210 allele of the prothrombin gene was
significantly overrepresented in symptomatic
carriers of the FV:Q506 mutant compared with healthy
controls (P<0.0001) and asymptomatic relatives
(P=0.02). The FII 20210 genotyping results are summarized in
Table 1
.
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Age at Onset of VTE in Relation to the Genotype
In subjects carrying both FII 20210 GA and FV:R506Q, first VTE
occurs at a younger age than simply affected patients, but the
difference was not statistically significant (Table 2). The median age at clinical onset was
32 years of age for patients simply heterozygous for
FV:Q506 (range, 18 to 45), 28 for double heterozygotes
(range, 18 to 45), 28 for simply homozygous carriers of the FV:R506Q
mutation (range, 18 to 41), and 25 for patients homozygous for
FV:Q506 and heterozygous for FII A20210 (range, 18 to
43).
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Site of First Clinical Manifestation
The onset manifestation in 263 symptomatic patients is
shown in Table 2
. It consisted of lower-extremity deep-vein thrombosis
(DVT) (n=214) and unusual sites of venous thrombosis (VT): subclavian
or axillar (n=13), central nervous (n=7), mesenteric (n=8), portal
(n=3), Budd-Chiari syndrome (n=1), inferior caval (n=2),
and renal (n=1) VT. No differences in site of VT was observed with
respect to sex or age at onset. However, as shown in Table 2, a
significant increase in the prevalence of more unusual sites of VT at
clinical onset was observed in doubly affected patients (9 of 30; 30%)
compared with patients without the prothrombin gene variant (26 of 233;
11.1%) (P=0.004), including 4 of 38 homozygotes (10.5%)
and 22 of 195 heterozygotes (11.3%) for FV:Q506.
Conversely, we found a statistically significant increase in the
prevalence of the A20210 allele in those subjects who had a more
unusual manifestation of first VT (9 of 35; 25.7%) compared with
subjects who had DVT (21/214; 9.8%) at clinical onset
(P=0.007).
Pulmonary embolism (PE) was detected in 48 cases: in 14 of these 48 cases, it occurred as an isolated event (29.2%), whereas in the remaining 34 cases, it was associated with DVT (70.8%). Patients homozygous for FV:Q506 had a significantly higher rate of concomitant PE (13 of 43; 30.2%) compared with heterozygotes (21 of 220; 9.5%) (P<0.001). Among patients with symptoms of only PE, none had the A20210 allele of the prothrombin gene, whereas in patients with concomitant PE, the A20210 allele was found in 11.8% (4 of 34).
Type of First Clinical Manifestation
At clinical onset, circumstantial risk factors known to be
associated with an increased risk of VTE were found in 181 patients
(68.8%), whereas spontaneous VTE (ie, with no apparent triggering
factor other than the congenital deficiency) occurred in the remaining
82 subjects (31.2%). In 44 patients (16.7%; 29 females and 15 males)
the first thromboembolic event occurred in conjunction with recent
surgery and in 55 patients (20.9%; 22 females and 33 males), with
trauma and/or immobilization. Fifty-five of 163 female patients
(33.7%) had taken oral contraceptives before first VTE. In 25.1% of
females (n=41), the first thromboembolic event was associated with
pregnancy or the postpartum period. Fourteen women had more than 1
single risk factor. The events with a triggering factor were
significantly more frequent than the spontaneous episodes in the female
subjects versus the males (133 of 163 [81.6%] of females versus 48
of 100 [48%] of males; P<0.001). When study was confined
to all patients with spontaneous VTE (n=82), the A20210 allele was
present in 19.5% (n=16), whereas among patients with VTE preceded
by a triggering factor it was found in 14 of 181 (7.7%)
(P=0.005).
Furthermore, homozygous FV:Q506 carriers experienced
significantly more of the spontaneous VTE at onset (20 of 43; 46.5%)
than patients heterozygous for FV:Q506 (62 of 220; 28.2%)
(P=0.01). Among heterozygotes, the type of first
thromboembolic event clearly differed between patients carrying the
single FV:Q506 and those who were double heterozygotes
(P=0.005). In the latter patient group, VTE occurred
spontaneously in 52% of cases (13 of 25) compared with 25.1% of
patients simply heterozygous for FV:Q506 (49 of 195). In
homozygotes of FV:Q506, the rate of spontaneous VTE did not
differ significantly in relation to the FII 20210 genotype.
Site and type of first thromboembolic event in relation to the
genotype are listed in Table 2.
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Discussion |
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Very recently, increased risk of venous thrombosis has been associated with a variation in the prothrombin gene due to a G to A transition at nucleotide 20210.13 As the precursor of thrombin that is known to exert procoagulant, anticoagulant, and antifibrinolytic activities,19 20 the zymogen prothrombin possesses an important role in the balance between procoagulation and anticoagulation.21 Due to the central role of prothrombin in the hemostatic system, it is obvious that variations in the prothrombin gene might predispose to thrombosis. Accordingly, heterozygosity for the prothrombin gene variant 20210 GA has been identified in
18% of selected patients with a personal and
family history of VTE and in 5% to 7.1% of unselected patients with
VTE.13 14 15 16 17 For heterozygous carriers of the FII A20210
allele, odds ratios for thrombosis of 
3 to 4 have been
reported.13 14 15 16 In comparison, the odds ratio for
thrombosis has been calculated to be 3- to 8-fold for those carrying
the FV mutation in a heterozygous form and 30- to 140-fold in
homozygous individuals.5 6 9 10 22 23 24 Therefore,
we might assume that the 20210 A allele of the prothrombin gene is
a common but probably mild risk factor of venous thrombosis. However,
since the discovery of the FV:R506Q mutation and its apparent
cosegregation in 15% to 25% of patients with heterozygous
deficiencies for antithrombin,25 protein
C,26 27 28 29 or protein S,30 31 32 33 evidence is
accumulating that the association of multiple hemostatic defects
greatly increases the penetrance of the thrombotic disease.
Accordingly, patients affected by double or multiple heterozygous
defects presented with thrombosis at a younger age and had a
substantially higher frequency of VTE compared with patients suffering
from a single heterozygous defect.25 26 27 28 30 33 This
finding raises the question of whether the prothrombin 20210 A
allele may also cosegregate with the common FV:R506Q mutation and
contribute to the thrombotic manifestation in subjects affected by
inherited APC resistance. Because of the relatively high prevalence of
either the FV:R506Q mutation or the FII 20210 A allele in
thrombophilic patients as well as in the general population, however,
either FV:Q506 or FII 20210 A is likely to be frequently
identified as an additional risk factor predisposing for thrombosis in
carriers of the other mutant. This prompted us to assess the
coexistence of the prothrombin 20210 G to A variant in
symptomatic and asymptomatic carriers of
FV:Q506. The most marked finding of our investigation is
that the prevalence of the A20210 allele of the prothrombin gene
was significantly higher among FV:Q506 carriers with a
history of juvenile VTE (11.4%) compared with a group of healthy
individuals (2%) and asymptomatic relatives (3.4%). With
respect to the coexistence of the prothrombin gene variant 20210 GA in
carriers of the FV:R506Q mutation, the rate observed in the present
investigation of relatively young thrombophilic patients was clearly
higher compared with results recently published for other
populations.15 16 34 35 However, when it is assumed that a
high proportion of combined inherited hemostatic abnormalities already
predisposes for thrombophilia in young persons, the significance of the
uncommon coinheritance of both FV:Q506 mutant and FII 20210
GA observed in previous studies is difficult to assess; either the age
was not mentioned at all34 or the majority of patients
investigated were >60 years of age,15 much older than our
patient population.14 16 Additionally, since both FII
20210 A and particularly FV:R506Q are shown to be highly prevalent
hereditary risk factors for VTE in Germans,22 our findings
are not surprising for our geographic region. The 20210 A allele of
the prothrombin gene possibly has a similar distinctive racial and/or
geographic distribution as has been described for the FV
mutant.36 These observations need to be kept in mind for
prediction of the risk of VTE emanating in different populations from
either FV:R506Q mutation or FII 20210 GA variant or their
coinheritance. Similar to our findings, Ferraresi et al17 found a significant increase in the frequency of the 20210 GA genotype in thrombophilic patients doubly heterozygous for other known thrombophilic defects (14%), including FV Leiden, but not in their asymptomatic relatives (3%). Zöller et al37 reported that none of 78 thrombotic protein S–deficient patients carried the FII 20210 GA variant, whereas of 29 FV:R506Q-positive index cases, 3 (10%) were carriers of the 20210 A allele in heterozygous form. They calculated that the combined heterozygosity for the latter 2 gene defects led to earlier onset of thrombosis and tended to be more severe than single gene defects. In addition, we have observed a statistically significant increase in the prevalence of spontaneous events and more unusual sites of venous thrombosis at clinical onset among patients carrying both FV:Q506 and FII A20210 compared with patients simply affected by the FV mutation.
In summary, the data from our investigation as well as from previous studies13 17 37 underline the importance of the prothrombin 20210 GA variant as a common additional risk factor for venous thrombosis in carriers of the FV:Q506 mutant. The high frequency of double carriership for FV:Q506 and FII 20210 GA found in our patients who experienced juvenile VTE supports the hypothesis that the presence of 2 inherited prothrombotic risk factors might lead to thromboembolic manifestations at young ages with an increasing rate of spontaneous onset manifestations. Thus, comprehensive investigations of the prothrombin 20210 A allele are important for interpretation of the additional thrombotic risk in patients with other genetic defects predisposing for thrombosis.
Received May 5, 1998; accepted June 23, 1998.
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M. D. Smirnov, O. Safa, N. L. Esmon, and C. T. Esmon Inhibition of Activated Protein C Anticoagulant Activity by Prothrombin Blood, December 1, 1999; 94(11): 3839 - 3846. [Abstract] [Full Text] [PDF]
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R. Junker, H.-G. Koch, K. Auberger, N. Munchow, S. Ehrenforth, and U. Nowak-Gottl Prothrombin G20210A Gene Mutation and Further Prothrombotic Risk Factors in Childhood Thrombophilia Arterioscler Thromb Vasc Biol, October 1, 1999; 19(10): 2568 - 2572. [Abstract] [Full Text] [PDF]
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G. A.F. Nicolaes and B. Dahlback Factor V and Thrombotic Disease: Description of a Janus-Faced Protein Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 530 - 538. [Abstract] [Full Text] [PDF]
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