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Blood, Vol. 92 No. 7 (October 1), 1998:
pp. 2353-2358
Different Risks of Thrombosis in Four Coagulation Defects
Associated With Inherited Thrombophilia: A Study of 150 Families
By
Ida Martinelli,
Pier Mannuccio Mannucci,
Valerio De Stefano,
Emanuela Taioli,
Valentina Rossi,
Francesca Crosti,
Katia Paciaroni,
Giuseppe Leone, and
Elena M. Faioni
From the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and
Epidemiology Unit, IRCCS Maggiore Hospital and University of Milan,
Milan, Italy; New York University, Environmental Medicine, New York,
NY; and the Department of Hematology, Catholic University,
Rome, Italy.
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ABSTRACT |
Deficiency of the naturally occurring anticoagulant proteins, such
as antithrombin, protein C and protein S, and activated protein C
resistance due to the factor V Leiden gene mutation is associated with
inherited thrombophilia. So far, no direct comparison of the thrombotic
risk associated with these genetic defects is available. In this study,
we wish to compare the lifetime probability of developing thrombosis,
the type of thrombotic symptoms, and the role of circumstantial
triggering factors in 723 first- and second-degree relatives of 150 index patients with different thrombophilic defects. We found higher
risks for thrombosis for subjects with antithrombin (risk ratio 8.1, 95% confidence interval [CI], 3.4 to 19.6), protein C (7.3, 95% CI,
2.9 to 18.4) or protein S deficiency (8.5, 95% CI, 3.5 to 20.8), and
factor V Leiden (2.2, 95% CI, 1.1 to 4.7) than for individuals with
normal coagulation. The risk of thrombosis for subjects with factor V
Leiden was lower than that for those with all three other coagulation
defects (0.3, 95% CI, 0.1 to 1.6), even when arterial and superficial
vein thromboses were excluded and the analysis was restricted to deep
vein thrombosis (0.3, 95% CI, 0.2 to 0.5). No association between
coagulation defects and arterial thrombosis was found. The most
frequent venous thrombotic manifestation was deep vein thrombosis with
or without pulmonary embolism (90% in antithrombin, 88% in protein C,
100% in protein S deficiency, and 57% in factor V Leiden), but a
relatively mild manifestation such as superficial vein thrombosis was
common in factor V Leiden (43%). There was a predisposing factor at
the time of venous thromboembolism in approximately 50% of cases for each of the four defects. In conclusion, factor V Leiden is associated with a relatively small risk of thrombosis, lower than that for antithrombin, protein C, or protein S deficiency. In addition, individuals with factor V Leiden develop less severe thrombotic manifestations, such as superficial vein thrombosis.
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INTRODUCTION |
INHERITED THROMBOPHILIA is a genetically
determined tendency to venous thromboembolism that develops in young
patients (less than 45 years old) and tends to be recurrent. Among the
inherited defects of the hemostatic mechanisms that cause a
thrombophilic state, the most frequent is resistance to activated
protein C.1 Caused by an Arg506Gln mutation on human factor
V (factor V Leiden), this abnormality is present in up to 40% of the
patients who develop venous thromboembolism and has a high frequency in
the general population of European ancestry.2-4 Defects of
the naturally occurring anticoagulant proteins antithrombin, protein C,
and protein S account altogether for 5% to 10% of
cases.5,6 The risk of thrombosis induced by each of these
coagulation defects has been investigated by family
studies2,7-10 or case-control studies11-14 that
showed an increased thrombotic risk in carriers of the defect compared
with noncarriers.
So far, only one family study has compared deficiencies of the
naturally occurring anticoagulant proteins with respect to the lifelong
probability of affected individuals developing
thrombosis,15 but the most common defect, activated protein
C resistance due to factor V Leiden, was not considered. Because
knowledge about any difference in the thrombotic risk might have
implications in management strategies, we performed a retrospective
cohort family study of 723 affected and unaffected relatives of 150 index patients with inherited deficiency of antithrombin, protein C, protein S, or with factor V Leiden. Secondary goals of the study were
to compare the types of thrombotic manifestations and to evaluate the
role of circumstantial factors predisposing to venous thromboembolism
(such as surgery, trauma and immobilization, pregnancy or puerperium
and oral contraceptive intake) in triggering such events.
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MATERIALS AND METHODS |
Patient selection criteria.
Families were identified through index patients (probands) who between
1980 and 1995 attended two Italian Thrombosis Centers in Milan and
Rome, specialized in the management of coagulation disorders. The
selection criteria for inclusion of families in the study were the
presence of an inherited coagulation defect predisposing to thrombosis
(antithrombin, protein C, protein S deficiency, or factor V Leiden) in
at least two family members and the availability of laboratory results
for the diagnosis of the four defects in each family member.
Index patients were asked to bring to the two centers as many as
possible first- and second-degree relatives. Their personal and family
histories of thrombosis were collected with a validated structured
questionnaire.16,17 None of them had any evidence of overt
neoplastic or other systemic diseases. The date of occurrence and the
site of any episode of venous or arterial thrombosis, the presence of
other factors predisposing to venous thromboembolism in the month
preceding the event (such as surgery, trauma, prolonged immobilization,
pregnancy or puerperium, and oral contraceptive intake) were collected.
A surgical procedure was defined as one in which general anesthesia was
performed; trauma included bone fractures or the application of casts,
excluding those of the upper extremity; a period of prolonged
immobilization was defined as one in which bed rest was complete for at
least 2 weeks.
Symptomatic patients, ie, those who reported having had thrombosis in
the past, were asked to bring with them the diagnostic documentation of
thrombotic events and a copy of clinical records. The term venous
thromboembolism was used for deep vein thrombosis whether or not
complicated by pulmonary embolism; the term deep vein thrombosis was
used for venous thrombotic episodes affecting the extremities, the
portal-mesenteric circulation, or the cerebral circulation. The
diagnosis of superficial vein thrombosis was based on the description
of typical signs and symptoms, and in some cases it was confirmed by
Doppler ultrasound. Other thrombotic events had to be confirmed by
objective methods: venography or compression ultrasonography for deep
vein thrombosis; (ventilation)/perfusion lung scan for pulmonary
embolism; electrocardiography, abnormal myocardial enzymes, and chest
pain for myocardial infarction; computed tomography or magnetic
resonance imaging for ischemic strokes. The diagnosis was transient
ischemic attacks when focal neurological signs appeared de novo and
disappeared within 24 hours, whether or not abnormalities in computed
tomography or magnetic resonance imaging were detected. Five patients
who reported previous episodes of deep vein thrombosis of the lower
extremities, but were unable to provide objective documentation, were
included in the study because they had been on anticoagulant treatment and/or because a Doppler ultrasound performed at the time of
our visit showed reflux in the deep veins indicative of a postphlebitic syndrome.
Laboratory tests.
Antithrombin heparin cofactor activity was measured by an amidolytic
assay (Coamate AT; Chromogenix AB, Mölndal, Sweden); when
antithrombin levels were low, the defect was further characterized by
measuring antigen levels (immunoelectrophoresis, polyclonal antibody;
Stago, Asnieres, France), and functional activity in the absence of
heparin and by performing crossed immunoelectrophoresis with or without
heparin.18 Protein C activity was assayed in Milan by a
clotting assay (ProClot, Instrumentation Laboratory, Milan, Italy) and
in Rome by an amidolytic assay (Coamatic Protein C; Chromogenix) after
activation with a snake venom. When plasma levels of
protein C activity were low, antigen levels were also measured by
enzyme-linked immunosorbent assay (ELISA) using polyclonal antibodies
(Dako A/S, Glostrup, Denmark). The diagnosis of protein S deficiency
was based on finding low plasma levels of free protein S as measured by
ELISA after precipitation of the C4b-binding protein-protein S complex
with polyethyleneglycol 6000 (3.5% final concentration)19
or using an ELISA commercial kit based on a specific monoclonal
antibody (Asserachrom Free Protein S; Stago). Protein S activity was
not measured, because no currently available functional assay was
thought to have sufficient specificity for protein S. The Arg506Gln
mutation in the factor V gene was searched for by specific DNA
amplification and digestion, as previously published.20
Statistical analysis.
The t-test was used to compare mean age values. The Cochran-Cox
approximation for unequal variances was used when the variable was not
normally distributed. The  2 test was used to compare the
prevalence of thrombotic manifestations. The absolute annual incidence
of thrombosis was calculated for relatives with and without a
thrombophilic defect by dividing the number of relatives with
thrombosis by the total number of patient year in each group. The
thrombosis-free survival was estimated from birth to the age of the
first thrombotic event by the Kaplan-Meier method curves and the
different thrombophilic defects were compared by the Wilcoxon test,
which places more weight on early events, and the log-rank test, which
places more weight on later events. Relative risks and 95% confidence
intervals (CI) for the different defects were calculated with the PHREG
procedures of the SAS package,21 which adjusts for other
variables in the model. Variables included in the model were sex and
family status, which is a code number that identifies all of the family
members belonging to the same family.
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RESULTS |
Characteristics of index patients.
Index patients were 180 unrelated individuals who, after a first
thrombotic episode, were referred consecutively to the Thrombosis Centers and diagnosed as having a coagulation defect. Thirty index patients were excluded because no relatives were available for study.
Among the remaining 150 index patients, venous thromboembolism was the
most frequent symptom (77% of cases), followed by superficial vein
thrombosis (16%), and arterial thrombosis (7%). Twenty-five patients
(17%) had antithrombin deficiency (19 type I and 5 type II, 2 of them
with a heparin-binding site defect), 23 (15%) had protein C deficiency
(22 type I and 1 type II), 15 (10%) had protein S deficiency, and 81 (54%) had factor V Leiden. Six (4%) had double defects: 2 factor V
Leiden and antithrombin deficiency (type I), 2 factor V Leiden and
protein S, 1 factor V Leiden and protein C deficiency (type I), and 1 protein C (type I) and protein S deficiency. Six index patients with
factor V Leiden and 2 with protein C deficiency were homozygotes.
Characteristics of relatives.
The entire cohort of first- and second-degree relatives of the 150 index patients consisted of 1,213 individuals, some dead, some alive at
the time of the study. From 723 relatives, blood was obtained for
coagulation testing, and they represent the actual study group. The
average number of relatives per family was 8.1 (range, 1 to 12)
considering the entire cohort and 4.8 (range, 1 to 20) considering the
study group. For 569 of the 723 relatives, medical histories were
obtained directly during a personal interview, using the same
questionnaire administered to the index patients, while for the
remaining 154 relatives, it was obtained by interviewing the index
patients. Laboratory tests became available after the medical history
was obtained and the laboratory staff was unaware of the clinical data.
The response rate of living relatives was 72%. The coagulation status
for 490 of the entire cohort of 1,213 relatives could not be
investigated because they had died (n = 203) or refused to attend the
Thrombosis Centers (n = 287). However, for 411 of them, both
demographic data (sex and age) and information about the medical
history could be obtained from the index patients. Among dead
relatives, 31% died of unknown causes at a mean age of 66 years, 45%
died of cancer at a mean age of 63 years, and 24% died of
cardiovascular accident at a mean age of 53 years. In the
noninvestigated relatives, the prevalence of thrombosis (20%) and sex
and age distribution were similar to those of the relatives who could
be investigated (16%, see below). For the remaining 79 relatives not
investigated, only demographic information could be obtained.
Table 1 shows the main characteristics of
the study group, which did not differ for relatives recruited in Milan
or Rome. The vast majority of relatives had the same defect as the
index patient of the family to whom they belonged. There were three relatives with protein S deficiency who had an index patient with factor V Leiden and one with factor V Leiden who had an index patient
with antithrombin deficiency. A total of 327 relatives had no
coagulation defects, 396 relatives carried at least one defect. Of
these, 85 had antithrombin deficiency (62 type I and 23 type II, 10 of
them with heparin-binding site defect), 64 protein C deficiency (62 type I and 2 type II), 41 protein S deficiency, 200 had factor V Leiden
and six had double defects (2 protein C and protein S deficiencies, 2 protein C and antithrombin deficiencies, 1 factor V Leiden and
antithrombin deficiency, 1 factor V Leiden and protein C deficiency).
Homozygosity for factor V Leiden was detected in 6 of 200 relatives
with this defect.
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Table 1.
Characteristics of the Study Group of First- and
Second-Degree Relatives Screened for Coagulation Defects
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Type and age at development of thrombotic events.
A total of 116 (16%) of the 723 relatives had had at least one
thrombotic episode (35% in antithrombin deficiency, 30% in protein C,
37% in protein S, 18% in factor V Leiden, 5% in those with no
defect, and 33% in those with double defect)
(Table 2). Table 2 also shows the types of
the first thrombotic event in the relatives with different coagulation
defects. Venous thromboembolism was the most frequent thrombotic
manifestation. The sites of venous thrombosis were the lower
extremities in all except 3 cases (1 with antithrombin deficiency had
portal-mesenteric vein thrombosis, 1 with protein S deficiency had
cerebral vein thrombosis, and 1 with factor V Leiden had upper
extremity deep vein thrombosis). Deep vein thrombosis was accompanied
by pulmonary embolism in 11% of cases (3 with antithrombin, 1 with
protein C, 1 with protein S deficiency, 2 with factor V Leiden, and 1 with no defect). Superficial vein thrombosis accounted for 10% of the
thrombotic episodes in antithrombin deficiency, for 13% in protein C
deficiency, and was not seen in protein S deficiency. The prevalence of
venous thromboembolism in factor V Leiden (57%) was lower than in
antithrombin (90%, P = .007), protein C (88%, P = .05) or protein S deficiency (100%, P = .008), while that of
superficial vein thrombosis was higher (43% compared with 10%,
P = .03; 13%, P = .05 and 0%, P = .02).
Arterial thrombosis accounted for 3% to 7% of thrombotic episodes in
factor V Leiden, protein C or protein S deficiency did not occur in
antithrombin deficiency and was present in 2% of relatives with no
defects (P = .9, .8, and .8, respectively). Two
protein C-deficient and 1 protein S-deficient relatives, and 2 normal
relatives had acute myocardial infarction; 1 relative with protein C, 2 with protein S deficiency, and 2 normal relatives had stroke; the 5 activated protein C-resistant relatives with arterial thrombosis had
transient ischemic attacks.
The mean age at the occurrence of arterial thrombosis (52 ± 13 years; range, 23 to 80) was higher than that at the occurrence of
venous thrombosis (36 ± 14 years; range, 10 to 70, P = .0001). Table 2 also shows that the age at the time of the first
thrombotic episode did not differ for relatives with and without
defects, varying from 35 to 40 years. The only exception was
represented by the patients with double defects, who were younger than
those with protein C deficiency and normal relatives (P = .04).
Of the two symptomatic relatives with combined defects, one with
protein C plus antithrombin deficiency, had deep vein thrombosis and
one with factor V Leiden plus protein C deficiency had superficial vein
thrombosis.
Information about predisposing factors at the time of the first episode
of thrombosis were obtained from all of the 97 relatives with venous
thromboembolism. Thrombosis occurred spontaneously in 45 (46%), while
predisposing factors were present in 52 (54%) of them. Forty-four of
the 88 relatives with a coagulation defect (50%) had thrombosis in the
presence of predisposing factors, whose distribution was not different
in the four thrombophilic defects (not shown).
Lifetime risk of thrombosis.
Figure 1 shows the probability for the
first thrombotic episode in the four groups of relatives with
coagulation defects and in normal relatives (relatives with double
defects are not shown). A minority of relatives developed thrombosis
during childhood, whereas the risk increased after the age of 20 years.
Both Wilcoxon and log-rank tests show a significant difference in the
thrombosis-free survival for all relatives (P = .001), even
when subdivided into men (P = .008) and women (P = .004). The relative risk of thrombosis for relatives with factor V
Leiden compared with that for relatives carrying all three other
coagulation defects was 0.3 (95% CI, 0.1 to 1.6), and compared with
that for normal relatives was 2.2 (95% CI, 1.1 to 4.7). The risk ratio
in comparison to normal relatives was 8.1 (95% CI, 3.4 to 19.6) for
antithrombin, 7.3 (95% CI, 2.9 to 18.4) for protein C, and 8.5 (95%
CI, 3.5 to 20.8) for protein S deficiency. Because the thrombophilic
defects evaluated in this study are established risk factors for venous
thromboembolism, but are less well-established for arterial thrombosis
and superficial vein thrombosis, the analysis was also done after
excluding these thrombotic manifestations. The corresponding
conditional risks are summarized in Table
3. The results obtained after the exclusion of arterial thromboses did
not change appreciably. When superficial vein thromboses were also
excluded from the analysis, the risk of venous thromboembolism for
factor V Leiden was 10.1 (95% CI 2.3 to 43.7) compared with normal
relatives and 0.3 (95% CI 0.2 to 0.5) compared with relatives with all
three other coagulation defects. Because the probability to develop
thrombosis is higher in homozygous individuals than in
heterozygous6,22 and is lower for heparin-binding defects
of antithrombin,23 the analysis was repeated after
exclusion of these relatives, and the results obtained were similar to
those obtained for the whole series (data not shown). To assess the
role of familial transmission of factors predisposing to thrombosis, we
calculated the relative risk of thrombosis for relatives according to
their belonging to a thrombophilic family. The risks of thrombosis was
essentially the same for individuals belonging to an
antithrombin-deficient family (risk ratio 1.2, 95% CI, 0.8 to 1.7), a
protein C-deficient family (0.9, 95% CI, 0.6 to 1.5), or a protein
S-deficient family (1.2, 95% CI, 0.7 to 1.9) as for those belonging
to a factor V Leiden family. Table 3 also shows the absolute annual
incidence of thrombosis in relatives with and without thrombophilic
defects. The highest incidence was observed in the group with
antithrombin deficiency (1.0%/yr) and the lowest incidence in the
group of normal relatives (0.2%/yr).
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| Fig 1.
Survival was measured from birth up to each age. The
probabilities of relatives with normal laboratory tests or with
antithrombin, protein C, protein S deficiencies, or factor V Leiden
were calculated by Kaplan-Meier analysis. The total number of
events/number of subjects at risk was 14 of 258 for relatives without
defect, 29 of 85 for antithrombin, 18 of 64 for protein C, 15 of 40 for
protein S deficiency, and 35 of 197 for factor V Leiden.
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Table 3.
Relative Risk and Annual Incidence for all Thromboses
(venous and arterial), Venous Thrombosis (deep and superficial veins),
and Venous Thromboembolism Only (deep vein thrombosis with or
without pulmonary embolism) for Each Thrombophilic Defect
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DISCUSSION |
This study compared the risk for thrombosis of individuals with
inherited thrombophilia due to factor V Leiden or to antithrombin, protein C, or protein S deficiency. We found that factor V Leiden is
associated with a lower risk of thrombosis and with less severe thrombotic manifestations. The probability of developing thrombosis during the lifetime was 8.1 times higher for carriers of antithrombin deficiency, 7.3 for protein C deficiency, and 8.5 for protein S
deficiency, in agreement with previous data.15 The
thrombotic risk was also greater for factor V Leiden, the most frequent
thrombophilic defect, but its magnitude was only 2.2 times higher than
that for noncarriers. This lower thrombotic tendency in carriers of factor V Leiden than in individuals with deficiencies of the naturally occurring anticoagulant proteins is compatible with the biochemical mechanism of this thrombophilic defect (activated factor V is only
partially resistant to inactivation by activated protein C).24,25
In theory, a milder thrombophilic defect should be characterized by the
onset of thrombosis at an older age and by milder clinical
manifestations. The mean age at the occurrence of the first thrombotic
episode was similar for all of the patients with single defects,
ranging from 35 to 40 years, and was also similar for men and women,
and for heterozygotes and homozygotes with factor V Leiden. This is in
agreement with a recent observation that in heterozygous relatives with
factor V Leiden or protein C deficiency,26 differences in
age at development of symptoms mainly depend on the way the patients
are selected and not on the type of defect. Even so, the type of
thrombotic manifestation was different for factor V Leiden, with the
frequency of severe manifestations, such as deep vein thrombosis and
pulmonary embolism, being lower and that of a relatively mild
manifestation, such as superficial vein thrombosis higher than for
antithrombin, protein C, or protein S deficiency. Our observations
contrast with those reported by other investigators,27 who
have found similar clinical manifestations in factor V Leiden and in
protein C or protein S deficiency, despite later occurrence of the
first thrombotic event in factor V Leiden. The larger number of
patients tested in our study and the exclusion of index patients from
the analysis probably explain the discrepancy in results.
This study included not only individuals who had venous thrombosis, but
also those who had arterial thrombosis, because they are often referred
to our centers for thrombophilia screening, despite the fact that the
association between coagulation defects and arterial thrombosis is
still debated.28 The small proportion of index patients who
had arterial thrombosis (7%) might have led to an underestimation of
the risk of thrombosis in their relatives. However, this is unlikely
because the rate of venous thrombotic events among these relatives was
very similar to that among relatives whose proband had venous
thrombosis. The prevalence of arterial thrombosis was low and was
similar in the four groups (3% to 7%). The mean age at the time of
the first occurrence of arterial thrombosis in the relatives was higher
(52 years) than that in relatives with venous episodes, indicating that
carriers of thrombophilic defects are exposed to a lower risk of
developing arterial thrombosis than venous thrombosis at a young age.
The risk of thrombosis was evaluated only for relatives of the index
patients to avoid a selection bias that would have led to
overestimating the risk. Complete data about both coagulation tests and
clinical history were available for 723 relatives. Although for 21% of
them the clinical history was obtained by interviewing the index
patients, we are confident to have correctly evaluated the rate of
occurrence of thrombosis, as we have previously reported a nearly 100%
agreement between the information obtained from the probands and that
obtained directly from relatives.17 The demographic
characteristics of the 490 relatives with incomplete data (only
clinical or demographic information) were similar to those for
personally interviewed and screened relatives. The prevalence of
thrombosis was also similar for the two groups (20% and 16%), suggesting that a selection bias due to lack of participation in the
laboratory screening is unlikely. One possible limitation of this study
may be a recall bias, as the design was retrospective. The small rate
of nonobjectively confirmed thrombotic events (five) and our decision
to consider thrombosis as certain only when anticoagulant treatment had
been given or signs of the postphlebitic syndrome were objectively
detected should have minimized this bias. Furthermore, it is unlikely
that there were differences in reporting the events for the four
thrombophilic conditions. In addition to having excluded index patients
from the analysis, overestimation of the risk was also minimized by the
second inclusion criterion, ie, each relative had to be tested for all
four coagulation defects, because the risk for thrombosis is higher in
carriers of double defects.29-32 Because the cosegregation
of factor V Leiden with the other inherited defects is relatively rare
in Italy,33 the relatives with double defects were too few
to be included in the statistical analysis. One limitation of the study
may be the relatively young age of relatives, which may have led to
underestimation of their lifetime risk of thrombosis.
There is at present no published randomized study and hence no
established guideline on primary prophylaxis for asymptomatic individuals with factor V Leiden exposed to predisposing factors for
thrombosis.1,28 We found that the lifetime risk of
thrombosis for this defect is lower than that for the other three
thrombophilic defects (relative ratio 0.3) and thrombotic symptoms are
less severe. However, antithrombotic prophylaxis with unfractionated heparin or low molecular weight heparin at standard dosages should be
implemented at the time of exposure of these individuals to predisposing factors for thrombosis. These views are supported by our
observation that there were concurrent predisposing factors in about
half of the patients with factor V Leiden who developed venous
thromboembolism. On the other hand, lifelong anticoagulant therapy of
asymptomatic individuals with inherited thrombophilia is not justified
in the absence of prospective trials demonstrating its efficacy. This
view is supported by the risk of hemorrhage, which is higher than the
annual incidence of thrombosis,34 by the cost of laboratory
monitoring of anticoagulant therapy, and by the observation that
mortality is not increased in individuals with
antithrombin35 or protein C deficiency36 or
factor V Leiden37 in comparison to the general population.
In conclusion, this family study gives the first direct answer to the
question of the varying thrombotic risks of congenital coagulation
defects associated with thrombophilia. Factor V Leiden carries a lower
risk than antithrombin, protein C, or protein S deficiency, but the
risk is three times that for the control group of individuals with
normal coagulation. Although the age at the first thrombosis is similar
for all four inherited thrombophilic defects, less severe symptoms such
as superficial vein thrombosis are more frequent for factor V Leiden
than for the remaining defects. Obviously, our findings apply only to
families in which the hereditability of the coagulation defect has been
demonstrated and not to unselected individuals.
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FOOTNOTES |
Submitted March 31, 1998;
accepted May 19, 1998.
Supported by a grant from Istituto Superiore di Sanità, Rome,
(Progetto Sangue), by institutional grants of the IRCCS Maggiore Hospital, Milan, and by a grant from Rolo Banca 1473 Spa,
Milan.
Address reprint requests to Ida Martinelli, MD, PhD, Hemophilia and
Thrombosis Center, IRCCS Maggiore Hospital, Via Pace, 9, 20122 Milano,
Italy; e-mail: martin{at}polic.cilea.it.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
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Abstract
Introduction
Abstract