Blood, Vol. 94 No. 9 (November 1), 1999:
pp. 3062-3066
Coinheritance of the HR2 Haplotype in the Factor V Gene Confers an
Increased Risk of Venous Thromboembolism to Carriers of Factor V
R506Q (Factor V Leiden)
By
E.M. Faioni,
F. Franchi,
P. Bucciarelli,
M. Margaglione,
V. De
Stefano,
G. Castaman,
G. Finazzi, and
P.M. Mannucci
From the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and
Department of Internal Medicine, IRCCS Maggiore Hospital and University
of Milano, Milan, Italy; the Unità di Aterosclerosi e Trombosi,
IRCCS Casa Sollievo della Sofferenza di San Giovanni Rotondo, Foggia,
Italy; the Department of Hematology, Catholic University, Rome, Italy;
the Division of Hematology, S. Bortolo Hospital, Vicenza, Italy; and
the Division of Hematology, Ospedali Riuniti, Bergamo, Italy.
 |
ABSTRACT |
With the aim of establishing whether the HR2 haplotype in factor V
affects the risk of venous thromboembolism, a retrospective multicenter
cohort study was performed in 810 family members identified through 174 probands who suffered from at least 1 episode of deep vein thrombosis
and/or pulmonary embolism and had an inherited defect associated with
thrombophilia (antithrombin, protein C, or protein S deficiency; factor
V R506Q or prothrombin G20210A). Fifty-eight percent (468/810) of the
family members had an inherited defect and 10% (47/468) were
symptomatic. The HR2 haplotype was found in association with factor V
R506Q more frequently in family members with venous thromboembolism
(18%) than in those without (8%). Double heterozygosity for factor V
R506Q and HR2 conferred a 3- to 4-fold increase in the relative risk of
venous thromboembolism compared with factor V R506Q alone. The median
age at first event was lower when the 2 defects were associated (46 v 52 years). No increase in risk of venous thromboembolism
could be demonstrated when the HR2 haplotype was associated with
inherited thrombophilic defects other than factor V R506Q. Because both
factor V R506Q and the HR2 haplotype are very frequent, the effect of
their coinheritance on the risk of venous thromboembolism might
represent a clinically relevant issue, and screening for HR2 in
carriers of factor V R506Q should be considered.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
THROMBOPHILIA results from the
interaction of multiple genetic and environmental
factors.1,2 Patients screened for thrombophilia after an
episode of venous thromboembolism (VT) often have more than 1 genetic
defect or at least 1 genetic defect and an acquired cause, such as
cancer, antiphospholipid antibodies, or hyperhomocysteinemia, and/or
circumstantial risk factors (oral contraceptive intake, pregnancy and
puerperium, prolonged immobilization, or surgery). Some of the genetic
defects associated with thrombophilia are shown to be independent risk
factors for VT by large epidemiological studies (antithrombin
deficiency,3,4 protein C deficiency,3,4 factor
V R506Q,5 and prothrombin G20210A gene
mutation6). For others, the data available are not
conclusive, because not all studies concur (protein S
deficiency3,4,7,8 mutations in the genes coding for enzymes
that participate in the metabolism of homocysteine9). It
has been shown that the association of 2 or more defects increases the
global risk of developing VT (such is the case of factor V R506Q with
either antithrombin, protein C or protein S deficiency, or prothrombin
G20210A with any of the above10-14).
Furthermore, the interaction of 2 defects, 1 of which confers no risk
of VT when isolated, can be synergistic. An example is the association
of the 4G/5G PAI-1 polymorphism with protein S deficiency15
or of the homozygous C677T mutation in methylenetetrahydrofolate
reductase with factor V R506Q, although not all investigators agree on
the latter.9
The clinical importance of identifying all genetic defects in
thrombophilic patients rests with the possibility of counseling them
for primary prophylaxis in situations at risk for VT and of planning
adequate secondary prophylaxis after thrombotic events have occurred.
On the other hand, testing for the defects associated with
thrombophilia is costly, so that it is necessary to establish which
defects truly contribute to an increased thrombotic risk. We previously
reported that the HR2 haplotype in the factor V gene, which includes 6 base substitutions in exons 13 and 16 predicting 2 amino acid changes,
is associated with increased resistance to activated protein C (APC)
both in normal subjects and in thrombophilic patients, independently of
carriership of factor V R506Q.16 Because HR2 resides on the
allele that does not carry the R506Q mutation, patients inherit each
factor V gene defect independently.16 The coinheritance of
HR2 and factor V R506Q determines a degree of APC resistance comparable
to that observed in patients homozygous for factor V
R506Q.16,17 HR2 by itself is not associated with VT,
because a similar prevalence was found in normal individuals and in
consecutive patients referred for a venous thromboembolic event.16 The aim of this study was to establish whether HR2 increases the risk of developing VT when coinherited with a defect known to be associated with thrombophilia.
| |
PATIENTS AND METHODS |
This is a retrospective multicenter cohort study of 839 individuals who
are first and second degree family members of an index case (not
included in the study to avoid selection bias) who was identified as
follows: he/she had at least 1 episode of deep vein thrombosis or
pulmonary embolism, underwent screening for thrombophilia between
January 1994 and July 1998, and had 1 of the inherited defects
associated with thrombophilia (antithrombin, protein C, protein S
deficiency, factor V R506Q, or the G20210A mutation in the prothrombin
gene). At least 1 additional family member had the same defect as the
index case. Family members belonged to 174 unrelated kindreds (median
number of family members per kindred, 4; range, 2 to 21). Of the 839 initially enrolled family members, 29 (3.4%) were not included in the
study for various reasons (for 25, the DNA could not be amplified; for
4, the sample was not available). The final number of individuals
included in the study was 810. All individuals gave informed consent to
participate in the study.
Deep vein thrombosis was objectively diagnosed on the basis of the
results of at least 1 of these tests: venography, compression ultrasonography, color-Doppler, or plethysmography. A diagnosis of
pulmonary embolism was made on the basis of the results of ventilation-perfusion lung scan, pulmonary angiography, computerized tomography (CT) scan, or magnetic resonance imaging
(MR). Deep vein thromboses diagnosed on the basis of
clinical suspicion were considered as certain if patients subsequently
developed another VT episode diagnosed by instrumental techniques or
suffered from an objectively documented postphlebitic syndrome.
Forty-six of the 52 venous thromboembolic events (88%) that occurred
in the group of family members were objectively diagnosed or considered as certain because the aforementioned criteria were fulfilled. Only 6 of 52 VT episodes (12%) were diagnosed based on clinical suspicion
only. Of these, 1 occurred in the factor V R506Q and HR2+
group, 1 in the protein C deficiency and HR2+ group, and
the remainder in the HR2
group (1 antithrombin
deficiency, 1 protein S deficiency, and 2 factor V R506Q).
Other thrombotic events (eg, superficial thrombophlebitis and arterial
thrombosis) were not considered as an endpoint of the study.
Blood was collected from family members in sodium citrate (9 parts of
blood, 1 part of 129 mmol/L trisodium citrate) and rapidly centrifuged
at 4°C and 3,000g for 20 minutes. The plasma was separated and aliquoted for storage at 
80°C, while the cells were used for DNA extraction by standard methods. Personal and family history of
thrombosis and other pertinent information were obtained as well before
the laboratory diagnosis was known. Besides a complete screening for
thrombophilia (see below), the R2 polymorphism, which defines the HR2
haplotype, was identified. The R2 polymorphism is an A
G
transition at position 4070 of the factor V gene (exon 13). The allele
frequency has been previously estimated to be 0.08 to 0.11 in the
Italian population.16 The whole haplotype comprises other
polymorphic sites in exon 13, besides that in position 4070: 2298 C/T,
2325 T/C, 2379 A/G, and 2391 A/G. There is an additional polymorphic
site in exon 16 (5380 A/G). Linkage studies have shown the latter to be
in linkage disequilibrium with the other polymorphic sites. Because the
presence of the G 4070 allele (R2) identifies with certainty the entire
HR2 haplotype, in this study patients were screened for this
polymorphic site only by polymerase chain reaction (PCR) and enzyme
restriction analysis, as previously described.16
Thrombophilia screening was based on measurement of antithrombin
(anti-Xa or anti-IIa function), protein C (amidolytic or clotting
assay), protein S (free antigen), and search for factor V R506Q (by
restriction fragment length polymorphism [RFLP])18 and
the prothrombin G20210A mutation (by RFLP or by amplification refractory mutation system [ARMS]).19,20 When a defect
was identified, further testing was performed to define the subtype of
deficiency (antithrombin, protein C, and protein S), in accordance with
current guidelines for diagnosis.21 Positive and negative controls were introduced in all test runs. Protein S functional tests
were not run in the presence of the factor V R506Q to avoid artifacts
induced by this abnormality on currently available assays.
The incidence of VT was estimated by dividing the number of episodes in
each group by the total number of patient-years in that group. For each
individual, the follow-up started from the date of birth to the first
VT episode, if any, or to July 1998. Only the first thrombotic event of
each subject was considered. Relative risks (RR) and their 95%
confidence intervals (95% CI) were also calculated, taking the group
with no inherited defects and no HR2 haplotype as reference. Survival
analysis was performed with the Kaplan-Meier method and the log-rank
test was used for comparison between curves. P values less than
.05 were taken to indicate statistical significance. The Cox's
proportional-hazards model was also used to adjust the risk of VT for
age and sex. The final hazard ratio (and its 95% CI) reflects the
relative risk of VT for one group compared with another, adjusted for
the other variables in the model. The SPSS for Windows package (release 7.5)22 (SPSS Inc, Chicago, IL) was used for
the statistical analysis.
| |
RESULTS |
Clinical characteristics of the cohort.
The whole cohort consisted of 810 family members (445 women [55%]
and 365 men [45%]; median age, 41 years; age range, 1 to 91 years).
A total of 32,506 patient-years of follow-up were recorded. Distribution of defects is shown in Table
1. The most frequent was factor V R506Q (32%), followed by prothrombin
G20210A (15%). Among the 300 subjects with factor V R506Q, 296 (98.7%) were heterozygous and 4 (1.3%) were homozygous. Of the 156 prothrombin G20210A carriers, 151 (97%) were heterozygous and 5 (3%)
were homozygous. Including the individuals with a double defect, there
were 17 type I (94%) antithrombin deficiencies and 1 type II (6%),
whereas all of the 10 protein C deficiencies were type I and all of the
25 protein S deficiencies were type I and/or III. There were 41 double
defects (5%), the majority of which (n = 30) were factor V R506Q and
prothrombin G20210A, 5 were factor V R506Q and antithrombin deficiency,
3 were factor V R506Q and protein C deficiency, 1 was factor V R506Q and protein S deficiency, 1 was prothrombin G20210A and antithrombin deficiency, 1 was prothrombin G20210A and protein S deficiency. The HR2
haplotype was detected in 94 of the 810 relatives (12%); 92 of them
were heterozygous and 2 were homozygous. Homozygous individuals for any
defect did not carry the HR2 haplotype.
Table 1 also shows the main demographic and clinical features of the
family members divided according to the different subgroups of
coagulation defects. Overall, 52 of 810 family members (6%) had VT. If
only individuals with an inherited defect were considered, 47 of 468 (10%) had a VT episode. The lowest incidence of VT was observed in the
prothrombin G20210A subgroup (0.12% per year), and the highest
incidence of VT was observed in the protein S (0.81% per year) and
double defect (0.50% per year) subgroups.
Relative risk of VT.
Forty-two subjects carried the HR2 haplotype alone, and none of them
developed VT. Because the number of individuals in the subgroups with a
deficiency of the naturally occurring anticoagulants (antithrombin,
protein C, and protein S) was small, we chose to pool them in a single
group and to analyze them together. Table 2
shows the prevalence of the HR2 haplotype in family members with or
without VT, according to their inherited thrombophilic defect. Only in
the factor V R506Q subgroup and in that with a double defect was a
higher prevalence of HR2 found in the VT-positive (4 of 22 [18%] and
1 of 8 [13%], respectively) than in the VT-negative individuals (19 of 239 [8%] and 1 of 32 [3%], respectively).
Table 3 shows the impact of the HR2
haplotype on the risk of VT associated with factor V R506Q or a double
defect. The relative risk for factor V R506Q alone, estimated at 4.2 (95% CI, 1.6 to 11.3), increased to 10.9 (95% CI, 2.9 to 40.6) when
the HR2 haplotype was coinherited. By using Cox's proportional-hazards
model and taking the group with no inherited defects and no HR2 as
reference, after adjustment for sex and age, the hazard ratio for
individuals heterozygous for factor V R506Q not carriers of HR2 was 3.7 (95% CI, 1.4 to 10.1), whereas in the doubly heterozygous patients for
factor V R506Q and HR2 it was 14.0 (95% CI, 3.7 to 53.4).
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Table 2.
Prevalence of the HR2 Haplotype in Family Members With
(DVT+) or Without (DVT) VT, According
to Their Inherited Thrombophilic Defect
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Table 3.
Effect of the HR2 Haplotype on the Relative Risk of
Thrombosis (RR) in Patients With Factor V R506Q or a Double
Thrombophilic Defect
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Survival analysis by the Kaplan-Meier method confirmed the different
pattern between carriers of factor V R506Q with or without HR2
(P = .01 with log-rank test).
Figure 1 shows thrombosis-free survival
curves in patients with factor V R506Q with and without HR2 compared
with individuals who did not carry any defect. The curve representing
cumulative thrombosis-free survival of individuals with factor VR506Q
and HR2 falls more sharply and earlier than that representing carriers
of factor R506Q only. When homozygous individuals for factor V R506Q or
prothrombin G20210A were excluded from the analysis, no differences in
results were found (data not shown). The role of circumstantial risk
factors associated with the first episode of VT was also analyzed. The
prevalence of circumstantial risk factors (surgery,
pregnancy/puerperium, oral contraceptive use, plaster, and/or
immobilization) was similar in family members carrying
factor V R506Q with and without HR2 (2 of 3 [67%] and 10 of 16 [62%], respectively).
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| Fig 1.
Thrombosis-free survival curves (Kaplan-Meier method) of
family members without defects (dotted line), with factor V R506Q alone
(dashed line), and factor V R506Q with HR2 (continuous line). In all
curves each step represents a VT event. Differences between the curves
(factor V R506Q with HR2 v individuals with no defects or
v factor V R506Q alone) were significant by log-rank test
(P < .001 and P = .01, respectively).
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| |
DISCUSSION |
A recent study by Alhenc-Gelas et al23 has shown that the
HR2 haplotype of factor V is a mild risk factor for VT. This is in
contrast with our previous findings16 and with the results of this study, in which none of the patients with HR2 alone had a
thrombotic event. Although the different results of our previous study
and that by Alhenc-Gelas et al23 could be due to the
relatively small size of the sample originally studied by us, the
discrepancy observed with the present study is most probably related to
the different design and selection of patients (case-control, all venous thromboembolic events considered).23 However, we did find that HR2 increases the risk of VT by approximately 3-fold when
associated with factor V R506Q. In the group of patients with double
thrombophilic defects in our cohort, the majority of whom (39/41) carry
factor V R506Q, the already high relative risk of thrombosis was
approximately quadruplicated by the coexistence of HR2, bringing it to
more than 40 times that of individuals with no known inherited defects.
The coinheritance of HR2 also decreased the median age at which the
first thrombotic event occurred. Our findings are in agreement with
those of a preliminary report showing that the R2 polymorphism,
although not significantly more prevalent in patients with thrombosis
compared with patients without, increased the probability of developing
thrombosis when in association with factor V R506Q.24
The conclusions relating to the effect of the coinheritance of HR2 on
the relative risk of venous thromboembolism require a note of caution.
Although the number of patients studied was globally large, the number
of thrombotic events was low, as is generally the case in family
studies, especially considering the restrictive criteria used. This
applies especially to the double thrombophilic defect group, but it is
also true for the association between HR2 and factor V R506Q. In
addition, a possible limitation of this study is that index patients
and their families were recruited in different centers and over a
4-year period. However, having selected family members from kindreds in
whom probands had had at least 1 episode of VT makes us confident to
have reduced the possible bias owing to different selection criteria.
The design of the study (retrospective) leads also to the possibility
of recall bias for thrombotic events, but we do not think that it could
have affected our results, because most of the VT events in family
members (46 of 52 [88%]) had an objective confirmation and only 1 event in the factor V R506Q with HR2 was diagnosed based on clinical
criteria. Moreover, if the bias were present, it should be equally
represented among the different coagulation defects.
The mechanism underlying the prothrombotic effect of the haplotype
remains unclear. HR2 determines mild resistance to APC, which is
evident especially when the haplotype is in the homozygous form.16 It also increases resistance to APC of patients
that are heterozygous carriers of factor V R506Q, bringing it to a degree similar to that found in patients homozygous for factor V
R506Q.16,17 Because resistance to APC in itself seems to be
a risk factor for VT,25,26 the prothrombotic action of HR2 could be mediated through an enhancement of resistance to APC, synergistic with that determined by the factor V R506Q. However, other,
as yet undetected functional effects on factor V are possible, because multiple amino acid substitutions are determined by HR2. One or
more of these could impair, for example, the cofactor activity of
factor V to APC. However, if it were so, one would expect to see an
increased prothrombotic effect also when HR2 is associated with protein
C or protein S deficiency. Because of the rarity of the defects of the
naturally occurring anticoagulants compared with factor V R506Q and
factor II G20210A, the number of family members in this group was
small. However, the difference in number of individuals with VT in the
naturally occurring anticoagulants deficiency HR2+ group
(1/11) compared with that in the HR2 group (11/31)
is striking. The factor II G20210A group was more abundant, so that the
lack of interaction of HR2 with this thrombophilic mutation is very
evident. It seems therefore that the HR2 haplotype is preferentially
worsening the prothrombotic risk associated with factor V R506Q.
Because of the elevated allelic frequency of HR2 and factor V R506Q in
the general and thrombophilic populations, the coinheritance of the 2 genetic variations is expected to be rather frequent (1 in 400 and 3 in
100, respectively). Accordingly, the impact of HR2 on the prothrombotic
risk of factor V R506Q should be considered when evaluating the risk of
VT of each individual patient, and the benefit of screening for the R2
allele in patients with factor V R506Q should be evaluated.
| |
ACKNOWLEDGMENT |
The precious contribution of A. Cappellari and I. Casorelli is
gratefully acknowledged.
| |
FOOTNOTES |
Submitted March 22, 1999; accepted June 29, 1999.
Supported by institutional grants from the IRCCS Maggiore Hospital
(Milan, Italy).
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to E.M. Faioni, MD, Hemophilia and
Thrombosis Center, Via Pace 9, 20122 Milano, Italy; e-mail:
elena.faioni{at}unimi.it.
| |
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TOP
ABSTRACT
INTRODUCTION