© 1999 American Heart Association, Inc.
Original Contributions |
Risk of Venous Thromboembolism and Clinical Manifestations in Carriers of Antithrombin, Protein C, Protein S Deficiency, or Activated Protein C Resistance
A Multicenter Collaborative Family Study
From the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center (P.B., A.T., P.M.M.), IRCCS Maggiore Hospital and University of Milan, Italy; the Department of Clinical Epidemiology and Hemostasis and Thrombosis Research Center (F.R.R.), Leiden University Medical Center, The Netherlands; the Department of Hematology (V.D.S.), Catholic University of Rome, Italy; the Department of Angiology and Coagulation (G.P.), S Orsola Hospital, Bologna, Italy; the Department of Hematology (G.F.), Riuniti Hospital, Bergamo, Italy; the Hematology Department (F.B.), Niguarda Cà Granda Hospital, Milan, Italy; and the Hemostasis Center (R.Q.), V Medical Department, Regional Hospital, Parma, Italy.
Correspondence to Paolo Bucciarelli Hemophilia and Thrombosis Center, IRCCS Maggiore Hospital, Via Pace 9, 20122 Milano, Italy. E-mail bucciare{at}imiucca.csi.unimi.it
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Abstract |
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Abstract—Deficiencies of antithrombin (AT), protein C (PC) or protein S (PS), and activated protein C resistance (APCR) are very well-established coagulation defects predisposing to venous thromboembolism (VTE). We performed a retrospective cohort family study to assess the risk for VTE in individuals with AT, PC, or PS deficiency, or APCR. Five hundred thirteen relatives from 9 Italian centers were selected from 233 families in which the proband had had at least 1 episode of VTE. We calculated the incidence of VTE in the whole cohort and in the subgroups after stratification by age, sex, and defect. The overall incidence of VTE (per 100 patient-years) in the group of relatives was 0.52. It was 1.07 for AT, 0.54 for PC, 0.50 for PS, 0.30 for APCR, and 0.67 in the group with a double defect. The incidence was associated with age, but not with sex. The mean age at onset was between 30 and 40 years for all the coagulation defects. Women had the peak of incidence in the age range of 21 to 40 years, earlier than men. The lifetime risk for VTE was 4.4 for AT versus APCR, 2.6 for AT versus PS, 2.2 for AT versus PC, 1.9 for PC versus APCR, and 1.6 for PS versus APCR. AT deficiency seems to have a higher risk for VTE than the other genetic defects. There is a relation between age and occurrence of thrombosis for both men and women. The latter had the peak of incidence earlier than the former.
Key Words: venous thromboembolism • antithrombin • protein C • protein S • activated protein C resistance
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Introduction |
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Inherited thrombophilia is defined as a genetically determined tendency to venous thromboembolism (VTE). It is characterized by onset at an early age, a frequent recurrence, and a family history (each one present in different combination with the others).1 It has been known for several decades that deficiencies of the natural coagulation inhibitors, such as antithrombin (AT), protein C (PC), and protein S (PS), are associated with inherited thrombophilia.2 Several studies have demonstrated that mutations in the genes encoding AT, PC, and PS are strong risk factors for thrombosis, but their prevalence in patients with venous thrombosis is low (3% to 10%).2 3 4 5 6 Recently, a poor anticoagulant response to activated PC has been described in patients with inherited thrombophilia and is as yet the most common inherited risk factor for thrombosis known (20% to 40% prevalence among patients with venous thrombosis).7 8 Activated protein C resistance (APCR) is caused by the presence of a mutant factor V molecule (factor V:Q506) in which a single point mutation leads to a substitution of Arg506 by Gln in 1 of the APC cleavage sites.9 Its relatively high frequency in populations of white origin (3% to 13%), and the fact that some homozygotes for APCR remain asymptomatic for a long time led to the conclusion that this coagulation defect is mild in comparison with the inherited deficiencies of the coagulation inhibitors. To date, only 1 clinical study on unselected cases of VTE (Leiden Thrombophilia Study)8 10 is available comparing directly APCR and the other coagulation inhibitor deficiencies. In this population-based case–control study, the risk for VTE was increased 7-fold in both PC deficiency and APCR carriers, and increased 2-fold in AT deficiency carriers, but no association between PS deficiency and VTE was demonstrated. The limit of this study is the small size of AT, PC, and PS carriers. A cohort study might assure a sufficient number of subjects also for rare defects, such as those of coagulation inhibitors. For these reasons, the Italian Research Group on Inherited Thrombophilia (GIRTE) has been recently constituted among clinical centers known to have interest and expertise in the diagnosis and management of inherited coagulation disorders, to form a national register for the study of inherited thrombophilia. Until now, 9 centers have taken part in this project. We performed a retrospective cohort family study of 513 relatives from 233 kindreds with inherited deficiency of AT, PC, or PS, or with APCR, in which the proband had had at least 1 episode of VTE. The main objectives were (1) to assess the lifetime risk for VTE in subjects with inherited thrombophilia, (2) to describe the clinical manifestations in these thrombophilic subjects, and (3) to evaluate the importance of triggering factors for the development of thrombosis.
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Methods |
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Data Collection
After several meetings about the aims of the study, each center received a floppy disk with a database (made by using the program Clinix 3.1, Softwarehouse of Maggiore Hospital) to fill in with all the information about thrombophilic subjects, ie, subjects with 1 of the congenital deficiencies well established to be associated with VTE (AT, PC, PS, or APCR). The file was divided into the following 5 main parts: patient identification (coded name, age, sex, whether proband or relative, and type[s] of coagulation defect), pedigree (number of family members studied, number of subjects with deficiency, and number of members with thrombosis), history of thrombosis (type of event[s], age at each event, diagnostic methods used to detect thrombosis, and risk factor[s] for each event), history of exposure to risk factors, and laboratory results. All computerized data were returned to the coordinating center (Angelo Bianchi Bonomi Hemophilia and Thrombosis Center of Milan) and entered in a single file.
Study Design
Families were selected based on the probands who came to each
participating center between January 1978 and March 1996 with at least
1 episode of VTE. We selected only families for which the inheritance
of the coagulation defect was demonstrated (at least 2 family members,
including the proband, had to be carriers of the defect). In all cases,
history of thrombosis and of exposure to risk factors was recorded
before the laboratory diagnosis was made. As VTE, we referred to any
episode of deep vein thrombosis (ie, thrombosis affecting the deep
veins of the lower and upper extremities, the superior and
inferior cava vein, the cerebral veins, and the
portal-mesenteric circulation) and/or pulmonary embolism. As
instrumental diagnosis of VTE, we accepted all diagnoses made by
venography, compression ultrasound, color Doppler, impedance
plethysmography, ventilation–perfusion lung scan, pulmonary
angiography, CT scan, and MRI scan. Diagnosis made without using these
tests was classified as clinical. However, clinically diagnosed VTE was
considered "certain" if at least 1 of the following conditions was
satisfied: (1) the patient had a recurrence of VTE, diagnosed
instrumentally, or (2) there was an objective demonstration of a
postphlebitic syndrome after that episode. Diagnosis of superficial
vein thrombosis (SVT) was based on clinical symptoms.
Arterial thrombosis was diagnosed by clinical signs and
objective methods, ie, chest pain, high levels of myocardial enzymes
and electrocardiography for myocardial
infarction, CT scan or MRI for ischemic strokes, and focal
neurological signs during <24 hours for transient ischemic
attack.
As risk factors for VTE, we considered surgery (only when total anesthesia was administered), pregnancy, puerperium, oral contraceptives intake, plaster casts (excluding those of the upper extremities), trauma, and immobilization in bed for >10 days. When a thrombosis was not associated with a triggering factor, the episode was classified as "idiopathic."
After a descriptive analysis of our population in toto, we started a retrospective cohort study, considering VTE as the end point. To avoid bias, we focused our attention only on the group of relatives. For all centers the follow-up extended from the date of birth of subjects to either the date of the first episode of VTE, if any, or April 1996.
Patients
We received information on 1143 subjects from the 9 Italian
centers; 178 probands (16 AT, 29 PC, 29 PS, 93 APCR, 1 heparin
cofactor II, and 10 with double defect) were excluded because the
defect was not demonstrated in other family members; ie, in 124 cases
the proband was the only family member studied, whereas in 54 cases at
least 1 relative other than the index case was studied, but the
inheritance of the defect was not confirmed. Nineteen patients (1
proband and 18 relatives) were excluded because no complete information
about history of thrombosis was available. Fifty-six probands and their
144 relatives were not considered in the analysis because the
index patient had no episodes of VTE. At the end, 746 eligible subjects
with demonstrated inherited thrombophilia were available, ie, 233
probands (31%) and 513 relatives (69%). The average number of study
subjects per family was 3.2 (range, 2 to 11 subjects). Total
patient-years were 26 151 (6609 for probands and 19 542 for
relatives). The number of subjects per type of defect was 129 with AT,
145 PC, 138 PS, 309 APCR, and 25 with a double defect. Of the 513
relatives, 95 had AT, 102 PC, 93 PS, 209 APCR, and 14 had a double
defect. Type I deficiency was represented in the 81% of
AT, 95% of PC, and 100% of PS, whereas type II deficiency was found
in 19% of AT and 5% of PC. Homozygosity was found in 3 patients with
PC deficiency (2 probands and 1 relative, all symptomatic),
whereas no patient with AT or PS was homozygous. Among the 306 carriers
of factor V:Q506 mutation, 295 (96%) were
heterozygous and 11 (4%) homozygous. Of the latter, 5 were probands
(all symptomatic) and 6 were relatives (1
symptomatic and 5 asymptomatic). In 76% of
families with AT, 67% with PC, 82% with PS, 75% with APCR, and 82%
with double defect, 1 or >1 family member was affected, other than
the proband.
In 8% of all subjects with a first episode of VTE, no information was available about the type of diagnosis. In the other cases, the diagnosis was instrumental in 76% and clinical in 24% of VTE. Considering only relatives with at least 1 episode of VTE (n=106), 64 (60%) received instrumental diagnosis and 42 (40%) clinical diagnosis. For 15 of the latter, VTE was in any case considered certain with reference to the inclusion criteria mentioned above. So, for 79 of 106 subjects (75%) VTE was confirmed, and for 27 of 106 (25%) it was uncertain.
Blood Collection and Laboratory Methods
All the study subjects (both probands and relatives) received a
complete screening for all the coagulation defects that we studied.
Also, those patients receiving a diagnosis before 1993 (the year in
which APCR was discovered) were contacted again to obtain blood samples
and complete the screening. Because of the nature of the study
(multicenter retrospective), assays for AT, PC, PS, and APCR changed
during the years and in the different centers. However, all the
participating centers are expert in the diagnosis of congenital
coagulation disorders and participate with proficiency at least
annually in quality control laboratory exercises. The
diagnostic approach to detect a deficiency of anticoagulant
proteins (AT, PC, and PS) followed guidelines previously published in
detail.11 In brief, a functional assay was first made and
then, if the results of this assay were low, the antigenic
concentration of the protein was determined by either enzyme
immunoassay or radioimmunoassay, to differentiate type I
(quantitative) from type II (qualitative) deficiency. The only
exception was for PS deficiency, which was diagnosed based on low
levels of free PS antigen. APCR was measured by using an APTT-based
clotting method as previously described.12 In 306 (94%)
of the 327 total subjects with APCR the defect was confirmed with a
genetic test for demonstration of factor V:Q506
mutation,9 and in 21 (6%) only the functional test was
performed.
Statistical Analysis
The incidence of VTE was estimated by dividing the number of
episodes in each group by the total number of patient-years in that
group. Only the first thrombotic event of each subject has been
considered. In the calculation of relative risk (RR), we used 95%
confidence interval (CI) according to Woolf.13 Survival
analysis was performed by the Kaplan–Meier method and with the
Cox proportional-hazards model, which yields a hazard ratio (and its
95% CI) for VTE, adjusted for age, sex (0 for male and 1 for female),
and age of proband at the first episode of VTE (0 for 
20 years, 1 for
21 to 45 years, and 2 for >45 years). The hazard ratio reflects the
relative risk of thrombosis for one defect compared with another one,
adjusted for the other variables in the model. Patients with a
double defect were excluded from survival analysis.
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Results |
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Clinical Manifestations
Three hundred eighty-two of the 746 subjects of the whole cohort were symptomatic (51%), ie, 233 probands (99 males and 134 females) and 149 relatives (65 males and 84 females). Table 1
shows the main characteristics of the
study population of relatives. The prevalence of thrombosis was 29%
(149/513). For AT-deficient relatives, VTE occurred most frequently as
the first thrombotic event (35 of 38 subjects, 92%), compared with SVT
(3 of 38 subjects, 8%), and arterial thrombosis (0 of 38
subjects). For the other groups this difference was less evident; in
particular, in APCR relatives 21 of the 42 first episodes (50%) were
VTE, 11 of 42 (26%) were SVT, and 10 of 42 (24%) were
arterial thromboses. The prevalence of pulmonary
embolism at the first episode was 17% for AT, 7% for PC, 10% for PS,
and 7% for APCR. No episode of pulmonary embolism was found in
the 4 cases with a double defect.
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Incidence of VTE
The overall incidence of VTE (per 100 patient-years) was 3.4 for
probands and 0.52 for relatives. The mean age at the onset of VTE was
29.4 years (range, 0 to 71 years) for probands and 35.8 years (range, 8
to 81 years) for relatives. Table 2 shows
that the age of probands and the age of relatives at the first episode
of VTE are positively related, whereas the incidence of VTE in the
relatives group is negatively related to the age of probands; the
relation is more evident in the last age group of probands (>45
years). Table 3 gives the incidences of
VTE for the strata of defects in the population of relatives. It shows
the highest incidence in the AT group (1.07%/y) and the lowest
incidence in the APCR group (0.30%/y). The mean age at the onset was
similar for all groups, ranging from 33 to 39 years, except for the
group with a double defect, in which it was the lowest (25 years;
range, 15 to 41 years). The stratification by sex did not show
differences between men and women (incidence, 0.52%/y for both). The
mean age at the first episode was 36.5 years (median 36; range, 10 to
69 years) for men and 35.1 years (median 30; range, 8 to 81 years) for
women. Table 4 shows incidences of VTE
for strata of ages and RR of VTE for each stratum compared with the
first age range (20 years). There was an increased risk for VTE in
the second age group (21 to 40 years), and afterward the risk became
more or less constant. Table 5
represents the same data after stratification by sex. Women had
peak of incidence at a younger age than men (age range, 21 to 40 years
versus 41 to 60 years). Differences were found in the age ranges of 21
to 40 for women versus men (0.96%/y versus 0.63%/y; RR=1.5 [95% CI,
0.9 to 2.7]) and 41 to 60 for men versus women (1.1%/y versus
0.63%/y; RR=1.7 [95% CI, 0.85 to 3.4]).
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Survival analysis confirmed these data. The risk for VTE in the
AT group, adjusted for age, sex, and age of proband at the time of the
first VTE, was 4-fold greater than that in the APCR group (hazard
ratio, 4.4 [95% CI, 2.5 to 7.7]; P<0.0001), 3-fold than
in the PS group (hazard ratio, 2.6 [1.4 to 4.6]; P=0.002),
and 2-fold than in the PC group (hazard ratio, 2.2 [1.2 to 4.0];
P=0.01). The risk was 2 times higher in the PC group than in
the APCR group (hazard ratio, 1.9 [1.1 to 3.4]; P=0.03).
No difference was found between the PS group and the APCR group (hazard
ratio, 1.6 [0.86 to 3.0]; P=0.14). The
Figure shows thrombosis-free survival
curves for carriers of inhibitor deficiencies or APCR.
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Considering only relatives with a certain first episode of VTE (n=79), the total incidence became 0.41 per 100 patient-years (0.84 for AT, 0.46 for PC, 0.40 for PS, and 0.24 for APCR). Results of survival analysis did not change substantially (data not shown).
Arterial Thromboses
A total of 26 first episodes of arterial thrombosis
were recorded in the population of relatives (4 in the AT group, 6
in the PC group, 5 in the PS group, 10 in the APCR group, and 1 in the
group with a double defect). The types of clinical manifestation were
acute myocardial infarction (n=10; 2 AT, 3 PC, 2 PS, and 3 APCR),
stroke (n=8; 2 AT, 2 PS, and 4 APCR), transient ischemic attack
(n=3; 1 PC and 2 APCR), peripheral artery occlusion (n=3; 1
PC, 1 APCR, and 1 double defect), and bowels infarction (n=2; 1 PC and
1 PS). The overall incidence of arterial thrombosis was
0.12%/y. It was 0.09%/y for AT, 0.13%/y for PC, 0.12%/y for PS,
0.11%/y for APCR, and 0.20%/y for the group with a double defect. We
found a positive relation between age and incidence of
arterial thrombosis (0% for age 20 years, 0.08%/y for
the age range of 21 to 40 years, 0.27%/y for the age range of 41 to 60
years, and 0.78%/y for age >60 years), but the number of cases was
too small to draw any firm conclusion (0, 6, 11, and 9, respectively,
in the 4 age groups). We obtained similar numbers for both men and
women (data not shown).
Risk of Thrombosis in High-Risk Situations
Information about risk factors at the time of the first
episode of VTE was obtained from 95 of 106 symptomatic
relatives (90%). Idiopathic thrombosis occurred in 30 of the 95 cases
(32%) (12 of 32 AT [38%], 6 of 20 PC [30%], 3 of 15 PS [20%],
8 of 25 APCR [32%], and 1 of 3 double defect [33%]), and a
triggering factor was associated with 65 of the 95 cases of
thromboembolic events (68%) (20 of 32 AT [62%], 14 of 20 PC
[70%], 12 of 15 PS [80%], 17 of 25 APCR [68%], and 2 of 3
double defect [67%]). Surgery preceded VTE in 28 of 95 cases (29%),
puerperium in 12 of 56 (21%), pregnancy in 10 of 56 (18%), whereas
immobilization was found in 10 of 95 cases (11%), oral contraceptives
in 6 of 56 (11%), and plaster in 6 of 95 (6%). Table 6 shows the distribution of risk factors
among the different groups of inherited defects. In most cases of
secondary VTE, the event was associated with 1 risk factor only. A
concomitant association with 2 risk factors was found in 1 patient with
AT (oral contraceptives and plaster), 2 patients with PC (puerperium
and gynecologic surgery), 1 patient with PS (orthopedic surgery and
immobilization), 1 patient with APCR (general surgery and
immobilization), and 1 patient with a double defect (general surgery
and immobilization). In 1 subject with PC deficiency, a concomitant
association with 3 risk factors was present (orthopedic surgery,
immobilization, and oral contraceptives).
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Discussion |
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One of the main objectives of this study was to establish the lifetime risk for VTE in subjects with 1 of the 4 main coagulation defects related to inherited thrombophilia (AT, PC, PS, and APCR) and to compare the clinical features of the different defects. Particular attention was taken to include only families with documented inherited defects and to avoid selection bias, by considering only relatives. Of the 1143 subjects of whom we received data, 746, from 233 kindreds, fulfilled the inclusion criteria. The 513 relatives were included in the study.
The lifetime risk for VTE in the AT group was 4-fold greater than
in the APCR group, 3-fold than in the PS group, and 2-fold than in the
PC group. It was 2-fold greater in PC than in APCR, whereas no
difference was found between the PS and APCR groups. The probability
that a subject with APCR will be free of thrombosis at the age of 45 is
0.88, compared with 0.59 for AT, 0.74 for PC, and 0.79 for PS. This
finding is in agreement with the study of Svensson and
Dahlbäck,7 who found a probability of 
0.89 to be
free of VTE at age 45 in his APCR relatives group. A similar result was
obtained recently in a retrospective family study,14 in
which the estimated annual incidence of VTE in APCR carriers was
0.45%, near that found in our study (0.30%). These figures may
explain previous observations15 that homozygosity for APCR
gives a lower risk of thrombosis than homozygosity for PC and PS, which
frequently causes severe neonatal thrombosis.16 17 Also in
our study, all 3 homozygous patients with PC deficiency were
symptomatic, and 1 of them had deep vein thrombosis at
birth; of the 11 homozygous patients with APCR, 6 were
symptomatic and 5 were still asymptomatic (2 of
them were >60 years old), despite their exposure to many risk factors.
A higher risk for VTE in AT carriers than in subjects with PC and PS
deficiency was also reported in previous studies,18 19 as
well as in a recent single-center prospective study but with a small
number of cases.20
One possible limitation in our study is that cases were not consecutive, and selection criteria could have been different over the years for each single center and in different centers. This implies that the apparent severity of thrombophilia depends on how families were selected. Carriers of common inherited defects (eg, APCR) are easier to find than those with rare defects (eg, AT, PC, and PS) and selection on severity may be less strong; then they will appear less severely affected. Evidence that selection is crucial comes from the reported absence of thrombosis in blood donors with PC deficiency and their relatives,21 from the different age at onset because of patient selection,22 from some case reports about homozygous PC-deficient carriers with absence or moderately severe clinical symptoms,23 24 and from those studies that report a different risk of thrombosis in patients with an association of 2 inherited coagulation abnormalities.25 26 27 28 29 In our study this problem has been reduced by focusing our attention only on families in which the proband had had at least 1 episode of VTE. The results might be different if we consider unselected cases, as reported in previous studies.8 10 But the main disadvantage of selecting consecutive cases is the time demanded if an appropriate number of subjects with rare defects must be selected.
Another possible limitation is the nature of this study (multicenter retrospective). This design could have influenced our conclusions in 2 ways, ie, (1) the laboratory diagnosis has been made by using different assays during different periods of time and in different centers, and (2) there could be a possible recall bias for thrombotic events, if they are not objectively documented, and for exposure to risk factors. The inclusion criterion of at least 2 family members with the coagulation defect suggests that we avoided possible acquired defects, also in those situations in which we did not have confirmation by genetic tests. Furthermore, all centers are proficient in laboratory quality control exercises in which they regularly participate. Recall bias should be equally represented in all the genetic defects for cases of thrombosis and exposure to risk factors. In fact, selection of only relatives with a "certain" episode of VTE (79 of 106) did not affect substantially the results.
We did not contemplate a parallel study of VTE incidence in
individuals without genetic defects. To get a general idea of the
different risk for VTE between subjects with a genetic defect and the
general population, we considered the study by Nordström et
al,30 which showed in a community-wide study that the
annual incidence of first VTE is 1.0 per 1000. Taking this example
as a baseline risk, the risk for VTE for AT deficiency carriers would
be 11-fold greater than this, whereas it would be 5-fold for
PC and PS deficiency carriers and 3-fold for APCR carriers.
The incidence rate of VTE could be underestimated because some asymptomatic subjects might have had subclinical thrombosis that no one was able to diagnose. This problem has also been postulated by Anderson et al,31 but there is no particular reason to think that it is represented more in one inherited defect than in the others.
The mean age of relatives at the time of the first episode of VTE
was similar in all the groups of coagulation defects, excluding that
with a double defect. This is in agreement with recent reports
regarding the age at onset in relatives with APCR and
PC.22 In most of the other studies the age at onset of VTE
was lower than the age in our study, and the prevalence of
symptomatic subjects was higher, perhaps because both
probands and relatives were considered in the analysis, leading
to a selection bias.18 19 32 33 Moreover, the age of
relatives at the time of the first episode of VTE and the incidence of
thrombosis can change according to the age of the probands at the first
VTE event (Table 2
). This could be because a selection of
subjects from families with a different risk for VTE (higher in
families in which the proband had had the thrombosis at a younger age),
probably because there is a co-segregation of other unknown inherited
defects.
This study gives a clear demonstration that the risk for VTE increases with age after age 20, but it becomes constant after age 40. This is in agreement with the finding that the mean age at onset of VTE is in the fourth decade. Ridker et al34 also demonstrated an increased risk for VTE with age in factor V:Q506 carriers. Women had the peak of risk earlier than men (age range, 21 to 40 years versus 41 to 60 years); pregnancy/puerperium and oral contraceptives play an important role in the earlier onset of VTE for women.
The type of first thrombotic manifestation was different among the groups of inherited defects. In the AT group, VTE was mostly represented, SVT was rare, and arterial thrombosis absent, whereas in PC and PS groups the prevalence of SVT and arterial thrombosis was higher, as described in previous studies.18 19 32 In patients with APCR, the prevalence of VTE and that of SVT were near those in PC- and PS-deficient patients (50% and 26%, respectively), in agreement with a recent study35 that showed similar clinical manifestations in APCR, PC, and PS deficiency, despite a later occurrence of the first event in APCR.
We conclude that the risk for VTE in carriers of inherited AT, PC, and PS deficiencies or APCR is related to age. The age at onset is earlier in women than in men. The risk seems to be higher in AT deficiency than in the other inherited coagulation abnormalities. Selection of families in which probands have different ages at onset of VTE can affect the age at onset and the incidence of thrombosis of relatives coming from those different families. Recruiting relatives from kindreds with inherited thrombophilic defects can lead to an overestimation of the thrombotic risk because of such mutations, as further unknown genetic defects may co-segregate in these families. In our study we considered family members of patients with at least 1 episode of VTE; 90% of the first events in the index cases occurred before age 45. Therefore, it should be emphasized that these findings must be applied only to familial thrombophilia, but for consecutive cases the results might be different. Because in our study the follow-up ended in April 1996, we could not consider the other common genetic determinant of VTE, the novel G20210A prothrombin gene mutation.36 In the near future we will evaluate in a family study the importance of this mutation, alone and in combination with the other defects, as a cause of VTE.
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List of Participants
Coordinating Center: Paolo Bucciarelli, Armando Tripodi, Pier Mannuccio Mannucci (A Bianchi Bonomi Hemophilia and Thrombosis Center, IRCCS Maggiore Hospital and University of Milan); Valerio De Stefano, Katia Paciaroni, Giuseppe Leone (Hematology Department, Catholic University, Rome); Gualtiero Palareti, Cristina Legnani (Angiology and Coagulation Diseases Division, S Orsola Hospital, Bologna).
Guido Finazzi, Stefana Marziali (Hematology Department, Riuniti Hospitals, Bergamo); Francesco Baudo, Rosaria Redaelli (Hematology Department, Niguarda Cà Granda Hospital, Milan); Roberto Quintavalla (Hemostasis Center, V Medical Department, Regional Hospital, Parma); Mauro Berrettini, Alessandra Bura (Internal and Vascular Medicine, University of Perugia); Pier Luigi Antignani, Anna Rita Todini (Angiology Department, S Camillo Hospital, Rome); Nicola Ciavarella, Loredana Mendolicchio (Coagulation Department, Policlinico Hospital, Bari).
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Acknowledgments |
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This study was supported by a grant from Istituto Superiore di Sanità (Progetto Sangue). We thank all the participating GIRTE Centers for their cooperation in this study. We are also very grateful to Dr Eugenia Biguzzi from the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Maggiore Hospital, Milan, and to Drs Luca Pizzocaro and Rosalba Donato from the Softwarehouse of Maggiore Hospital, Milan, for their help with the computerization of the data.
Received September 21, 1998; accepted September 29, 1998.
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References |
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