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Blood, Vol. 94 No. 8 (October 15), 1999:
pp. 2590-2594
Gene-Gene and Gene-Environment Interactions Determine Risk of
Thrombosis in Families With Inherited Antithrombin Deficiency
By
H.H. van Boven,
J.P. Vandenbroucke,
E. Briët, and
F.R. Rosendaal
From the Department of Clinical Epidemiology and Hemostasis and
Thrombosis Research Center, Leiden University Medical Center, Leiden,
The Netherlands; and the Department of Internal Medicine, Academic
Medical Center, Amsterdam, The Netherlands.
 |
ABSTRACT |
To analyze inherited antithrombin deficiency as a risk factor for
venous thromboembolism in various conditions with regard to the
presence or absence of additional genetic or acquired risk factors, we
compared 48 antithrombin-deficient individuals with 44 nondeficient
individuals of 14 selected families with inherited antithrombin
deficiency. The incidence of venous thromboembolism for antithrombin
deficient individuals was 20 times higher than among nondeficient
individuals (1.1% v 0.05% per year). At the age of 50 years,
greater than 50% of antithrombin-deficient individuals had experienced
thrombosis compared with 5% of nondeficient individuals. Additional
genetic risk factors, Factor V Leiden and PT20210A, were found in more
than half of these selected families. The effect of exposure to 2 genetic defects was a 5-fold increased incidence (4.6% per year; 95%
confidence interval [CI], 1.9% to 11.1%). Acquired risk factors
were often present, determining the onset of thrombosis. The incidence
among those with exposure to antithrombin deficiency and an acquired
risk factor was increased 20-fold (20.3% per year; 95% CI, 12.0% to
34.3%). In conclusion, in these thrombophilia families, the genetic
and environmental factors interact to bring about venous thrombosis.
Inherited antithrombin deficiency proves to be a prominent risk factor
for venous thromboembolism. The increased risks among those with
exposure to acquired risk factors should be considered and adequate
prophylactic anticoagulant therapy in high-risk situations seems
indicated in selected families with inherited antithrombin deficiency.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
SINCE THE ASSOCIATION of familial
antithrombin deficiency and venous thromboembolism was described by
Egeberg in 1965,1 many single cases and families have been
reported in the literature. Based on these reports, the clinical
manifestations of inherited antithrombin deficiency have been assessed
in reviews.2-5 The frequency of a history of venous
thromboembolism was estimated to be 51% among deficient individuals in
one of these reviews.5 This risk of venous thrombosis
should be viewed as that among highly thrombosis- prone families, ie,
families who were diagnosed and selected to be reported.
An extensive study of one very large family was performed by Demers et
al.5 The risk of venous thromboembolism in this selected
family was less than 20% (6/31) in deficient family members; 0 of 36 nondeficient family members had had a thrombotic event.5 In
a population-based case control study, the association of antithrombin deficiency and venous thromboembolism was assessed in unselected outpatients with venous thrombosis. Because of the rarity of the defect, only a small number of 5 patients and 1 control with
antithrombin deficiency were diagnosed in this study (Leiden
Thrombophilia Study).6 In this setting, the relative risk
for thrombosis was 5.0 (95% confidence interval [CI], 0.7 to
34).6 The only family study of pedigrees not selected on a
high frequency of venous thromboembolism has been performed among
healthy blood donors.7 In blood donors diagnosed with an
inherited deficiency of antithrombin or protein C and their relatives,
the thrombosis rate was low. Only 4% (2/51) of individuals with
antithrombin deficiency had experienced venous thrombosis and 1 subject
experienced a recurrence.7 One might argue that here there
is some selection on absence of disease.
Apparently, differences in selection lead to very different risks
between relatives of healthy carriers, relatives of consecutive outpatients, and relatives of selected families with familial thrombophilia (the latter display the highest risk).8 These differences are likely not just to be stochastic phenomena, but to have
a biological basis and to be the result of the simultaneous presence,
or absence, of other risk factors. It is becoming increasingly clear
that thrombosis is a multicausal disease and that several factors,
acquired and genetic, interact to bring about
thrombosis.9-12
Because clinicians will have to offer guidelines to individuals from
families with thrombophilia, in which the risk appears highest,
knowledge of factors contributing to the risk is essential. To date, no
risk estimates for thrombosis in antithrombin deficiency based on a
large number of families were available. Therefore, we set out to
determine the risk of thrombosis in families with thrombophilia and
antithrombin deficiency to assess the interaction with other risk
factors, genetic and acquired.
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MATERIALS AND METHODS |
Participants of this family study were identified through family trees
of 15 probands diagnosed with type I antithrombin deficiency. The
parents, siblings, and children of the proband were invited to
participate, as well as siblings of the affected parent and the
children of affected siblings. Ten of the 15 probands had been referred
for tests because of unexplained thrombosis and recurrent thrombosis,
thrombosis occurring at a relatively young age, or a family history for
thrombosis. Three probands were registered in our hospital with
familial thrombophilia due to antithrombin deficiency. We included 1 proband referred because of high doses of heparin for treatment of
recurrent thrombotic episodes and therefore screened. One proband had
been referred to our center because of a positive family history;
simultaneously, he participated and was identified again,
independently, in a population-based patient control study, the Leiden
Thrombophilia Study (LETS).6 Two probands were found to
have a common ancestor.
Each family member was interviewed, and a detailed history of
thromboembolic diseases was obtained by the same physician (H.H.v.B.) using a standardized questionnaire. Family members were questioned specifically about history of venous thromboembolism, ie, deep venous
thrombosis and pulmonary embolism. If an individual reported such a
problem, information about the method of diagnosis was obtained as well
as clinical risk factors for thrombosis at the time of or preceding the
event. Risk factors were defined a priori as surgery, hospitalization,
immobilization, major trauma, plaster casts, pregnancy, postpartum
state, and use of oral contraceptives. The criteria used for the
diagnosis of previous venous thromboembolism were hospitalization or
treatment. The clinical diagnosis of the physician was confirmed with
objective diagnostic techniques in 71% of the first venous
thromboembolic event of the relatives.
Venepuncture was performed in each participant. Blood samples were
collected from the antecubital vein in 1/10 vol of 0.11 mmol/L
trisodium citrate. Plasma was prepared by centrifugation for 10 minutes
at 2,000g at 10°C and stored at  70°C until use. Antithrombin antigen concentration was measured by
immunoelectropheresis according to the method of Laurell.13
Amidolytic heparin cofactor assays (Chromogenix, Mölndal, Sweden)
were used for antithrombin activity measurement. Genomic DNA was
isolated from blood leukocytes by standard methods. DNA analysis in 9 of the 14 families had elucidated different defects in the antithrombin
gene in 7 families.14 Genetic analysis for the prothrombin
20210 A allele (PT20210A) and Factor V Leiden (FVL) was performed as
described previously.15,16 Available DNA samples of 12 families had been screened in a collaborate study described
elsewhere.12
The occurrence of venous thrombosis was assessed for
antithrombin-deficient subjects and nondeficient subjects. In all
analyses of relative risks and risk factors for thrombosis, the
probands were excluded to eliminate bias. Median age of onset and
thrombosis-free survival curves were constructed according to the
Kaplan and Meier method. To compare the 2 curves, we used the logrank
rest, resulting in a  2 distribution with 1 degree of
freedom. Confidence intervals for the thrombosis-free survival rates
were calculated based on a binomial distribution.
The incidence of first thrombotic events in antithrombin-deficient
subjects and nondeficient subjects was calculated by counting patient-years of observation and dividing the number of events in each
group by the sum of observation-years of all the individuals in the
group. Similarly, incidence rates were calculated as the number of
thromboses in the years that surgery, immobilization (including
hospital admissions, plaster casts, and immobilization longer than 2 weeks), pregnancy, and the postpartum period took place. The time
window was 1 year, and incidence rate ratios were calculated as the
incidence rate in 1 year over the incidence rate in all other years.
CIs for incidences and incidence rate ratios were calculated by the
assumption of a Poisson distribution. Multivariate analysis was
performed using the Poisson method for aggregate data. With
multivariate analysis, it is possible to determine the effect of one
variable, while the other variables are adjusted for.
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RESULTS |
Diagnosis and thrombotic events (relatives only).
In all 14 families affected, individuals had antithrombin activity and
antigen levels less than 80 U/mL (type I antithrombin deficiency). Of
107 eligible family members, 90 individuals (84%) participated: 5 nonrespondents lived abroad and 3 subjects were in poor health; 6 asymptomatic individuals, of whom 4 had been tested as nondeficient
before, were not interested in further investigations and 3 family
members could not be contacted because the proband had no contacts. In
total, 46 individuals proved to be antithrombin-deficient (19 men and
27 women; average age, 43 years; age range, 15 to 88 years); 44 individuals were normal (23 men and 21 women; average age, 44 years;
age range, 18 to 86 years). Before this study, the diagnosis of
antithrombin deficiency was known to 67% of all participants.
Of 46 antithrombin-deficient individuals, 18 subjects had experienced 1 or more venous thromboembolic events. The first clinical manifestation
was mostly deep venous thrombosis of the legs (12/18); 1 individual
presented with symptoms of pulmonary embolism, whereas 5 individuals
presented with manifestations of pulmonary embolism and deep venous
thrombosis. One of 44 nondeficient individuals had experienced venous thromboembolism.
Precipitating risk factors.
Only 2 first episodes (2/18) occurred apparently spontaneously. Before
16 first thromboembolic episodes, 1 or 2 of the following risk factors
were present: postpartum period (n = 4), surgery (n = 4),
immobilization (n = 1), plaster cast (n = 2), hospital admission (n = 1), oral contraceptive use (n = 2), long travel by air
(n = 3), and FVL or PT20210A (n = 5). The 1 nondeficient individual who
had experienced venous thrombosis had had recent surgery and proved to
be a carrier of FVL.
Overall, there were no differences in exposure to predisposing acquired
risk factors between antithrombin-deficient individuals and normal
individuals (surgery/trauma, immobilization and for women oral
contraceptive use, pregnancy, and childbirth). Additional genetic
factors, FVL and PT20210A, were found in 7 of the 14 families.
Risk of venous thromboembolism.
The median age of onset was 27 years (range, 16 to 68 years) for
antithrombin-deficient individuals (the age of onset was 42 years of
age for the symptomatic individual without antithrombin deficiency).
Notably, the median age of onset for carriers of 2 defects was 17 years
(range, 16 to 25 years). According to Kaplan and Meier survival
analysis, the median thrombosis-free survival for
antithrombin-deficient individuals was 48 years
(Fig 1). Overall, men more often
experienced venous thromboembolism than women: 9 of 19 men (47%;
median age of onset, 27 years; range, 16 to 48 years), whereas 9 of 27 women were symptomatic (33%; median age of onset, 26 years; range, 16 to 68 years).
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| Fig 1.
Venous thrombosis-free survival curve in
antithrombin-deficient individuals and nondeficient individuals
(probands excluded). Probability of freedom from venous thrombotic
events is presented. Steps in curves indicate events; short vertical
lines indicate censoring.
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The incidence of (first) thrombotic event was 1.1% per year (95% CI,
0.7% to 1.8%) in the antithrombin-deficient individuals, which is
more than 20 times greater than among nondeficient individuals (0.05%
per year; 95% CI, 0.01% to 0.4%). The incidence of first thrombotic
events was equal in men and women up to 25 years of age (0.7% per year
in men v 0.6% per year in women); after 25 years of age,
incidence was twice as high in men as in women (at 26 to 45 years of
age, 3.0% per year in men v 1.7% per year in women; at >46
years of age, 2.2% per year in men v 1.4% per year in women).
Interaction with other risk factors.
We compared the annual incidence of venous thromboembolism in relatives
with exposure to other genetic and acquired risk factors. The risk
among antithrombin-deficient subjects exposed to surgery (12.7% per
year; 95% CI, 5.7% to 28.4%) was much larger than the increased risk
of antithrombin deficiency (0.8% per year; 95% CI, 0.4% to 1.4%) or
surgery (1.6% per year; 95% CI, 0.2% to 11.3%) separately.
Table 1 shows that, overall, the incidence
rates were less than 1% per year for individuals exposed to inherited antithrombin deficiency only. Among those with exposure to 2 genetic defects, the incidence rate increased to 4.6% per year (95% CI, 1.9%
to 11.1%). Combined exposure to antithrombin deficiency and an
acquired risk situation led to even higher incidence rates of 20.3% in
the year of the risk event (95% CI, 12.0% to 34.3%).
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Table 1.
Incidences of Venous Thromboembolism: Exposure to
Inherited Antithrombin Deficiency and the Effect of Acquired or
Genetic Risk Factors (Men and Women, Univariate)
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For women, exposure to pregnancy, the postpartum period, and use of
oral contraceptives were analyzed separately (women only). Use of oral
contraceptives by antithrombin-deficient women was associated with an
incidence rate of 4.1% per year (95% CI, 1.0% to 16.3%); the
postpartum period conferred the highest risk for women (incidence rate
of 14.3% per year; 95% CI, 1.0% to 16.3%). When we looked at
pregnancies and postpartum periods in hitherto asymptomatic women
without anticoagulation prophylaxis, no pregnancies (0/28) but 15% of
postpartum periods (4/27) were complicated by venous thromboembolism
(Table 2). During pregnancy, only 1 antithrombin-deficient woman developed recurrences of venous thrombosis
(twice, in 2 pregnancies). Pregnancies and postpartum periods of
symptomatic antithrombin-deficient women, without anticoagulant
prophylaxis, were complicated frequently by venous thromboembolism, ie,
20% (2/10 pregnancies) and 50% (4/8 postpartum periods), respectively (Table 2).
Multivariate analysis.
The incidence rate ratios computed with multivariate analysis by
Poisson analysis are listed in Table 3. For
each factor, the relative risk is shown compared with the absence of
that factor, which is adjusted for all other variables. In these
families, the most prominent risk factor is antithrombin deficiency,
increasing the incidence 26-fold in multivariate analysis. Other
genetic risk factors (FVL and PT20210A) were strong risk factors, too, with relative risks of 5 to 7. Well-established acquired risk factors,
such as surgery and immobilization, were associated with a relative
risk of 10. For women, the postpartum state accounted for the highest
relative risk when recalculated to an annual risk (Table 3). These
results were almost comparable to our univariate analysis; due to small
numbers, unfortunately, the estimates for interaction between risk
factors could not be calculated.
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Table 3.
Adjusted Incidence Rate Ratios for Potential Genetic and
Acquired Risk Factors (Multivariate by Poisson Analysis)
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Thrombotic disease in the probands.
In all prior analyses, the probands were excluded to avoid
ascertainment bias. In probands, severity of disease was indeed impressive: the 14 probands of these families, 9 men and 5 women (average age, 51 years; age range, 24 to 77 years) had all suffered recurrent thromboembolism. The median age of onset was 33 years of age
(age range, 19 to 55 years). One proband presented spontaneously with
mesenterial thrombosis, and 1 proband developed mesenterial thrombosis
as a recurrence after surgery. The most frequent clinical presentation
was deep venous thrombosis of the leg with pulmonary embolism.
Six of 14 episodes of onset (43%) and 9 of 19 recurrences (47%) had
occurred in the absence of an additional precipitating risk factor. An
additional genetic defect, FVL, was identified in 1 female proband
only. Acquired risk factors such as surgery and immobilization were the
precipitating risk factor in men. Among the female probands, pregnancy,
postpartum period, and oral contraceptive use were present before two
thirds of all episodes (onset and recurrences). Four female probands
had developed venous thromboembolism within 3 months after first
prescription of oral contraceptives.
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DISCUSSION |
Venous thromboembolism is a multicausal disorder. Age, surgery,
immobilization, oral contraceptive use, and postpartum state are
well-known predisposing factors for venous thromboembolism. In
thrombophilia families, the genetic and environmental factors interact
to bring about venous thrombosis. This family study showed a 20-fold
increased risk for venous thromboembolism in antithrombin-deficient individuals versus nondeficient individuals. The risks became extremely
high in the simultaneous presence of other genetic or environmental
risk factors.
Acquired and genetic risk factors were often present simultaneously at
the onset of thrombosis. The annual incidence increased 10- to 20-fold
among individuals who had been exposed to an acquired risk factor and
inherited antithrombin. The incidence rate was less than 1% per year
among individuals exposed to inherited antithrombin deficiency only.
Thus, environmental risk factors lead to interaction as the effect of
antithrombin deficiency and environmental risk factors together was
greater than the sum of the effect of each of these risk factors
separately (Table 1). Similarly, a 5-fold increase of the annual
incidence was found due to gene-gene interactions. Summarized, both
gene-environmental interactions and gene-gene interactions play an
important role in the onset of venous thromboembolism in inherited
antithrombin deficiency.
Most families in this study were referred to our center, therefore
representing high-risk families. Overall, our risk estimates should be
viewed as the risks for antithrombin-deficient individuals, who are
thrombosis-prone and referred for thrombophilia work-up. Families with
inherited antithrombin deficiency selected differently may very well
display different, ie, lower, risks.
When thrombophilia is viewed as a multicausal disorder, highly
thrombosis-prone families are identified, because common genetic defects are present simultaneously in those families. In this study,
DNA analysis showed the presence of 2 common genetic factors in 7 of
the 14 families with inherited antithrombin deficiency. When thrombosis
occurred in a patient at a young age, an additional genetic defect, the
FVL or PT20210A, was most often present. In the other individuals,
interaction with environmental risk factors had led to high risks.
Although these risk factors are not genetic, they may, even when
present coincidentally, make a family stand out that is then recognized
as thrombophilic.
It is believed that antithrombin deficiency confers a higher risk than
protein C, protein S, and FVL. Again, a comparison between families
seems only justified when the investigated families are selected under
similar criteria. Lensen et al8 showed that, when uniform
selection criteria were applied, no differences in median age of onset
were observed between selected families with protein C deficiency or
activated protein C (APC) resistance. The selection criteria used in
the study by Lensen et al8 were similar to the criteria of
our selection of families with inherited antithrombin deficiency. After
making a comparison, the median ages of onset in our
antithrombin-deficient families approximated the median ages of onset
of families with protein C deficiency and APC resistance. The median
age of onset was 26 years (range, 16 to 50 years) for probands and 35 years (range, 17 to 65 years) for relatives with protein C deficiency;
in high-risk families with APC resistance, the median age of onset was,
respectively, 29.5 years (range, 21 to 46 years) and 29 years (range,
16 to 63 years); in our families, the median age of onset was,
respectively, 33 years (range, 19 to 55 years) and 27 years (range, 16 to 68 years). The median ages of onset in protein C deficiency, APC resistance, and antithrombin deficiency suggest that differences between thrombophilia disorders may be minor compared with the effect
of selection.
We also compared our data with a study of families with protein C
deficiency, in which the applied selection criteria were again quite
similar.17 The risk estimates comprised a 9 times higher
incidence of venous thrombosis among protein C-deficient individuals
than among nondeficient individuals (crude odds ratio, 9.2; 95% CI, 5 to 16.8); the age-related incidence rates were a little lower, but the
incidence rates after surgery (incidence rate ratio, 9.2; 95% CI, 3.5 to 24.9) differed little from the incidence rates in the
antithrombin-deficient families. We suggest that antithrombin
deficiency is not different from protein C deficiency or other
thrombophilia disorders: the risk of antithrombin deficiency is often
enhanced simultaneously by other factors, both environmental and
genetic. For that reason too, the risk of inherited antithrombin deficiency is unlikely to be much higher than for the other
deficiencies, because, in that case, there would be no or less need for
additional enhancing risk factors.
For this study, we only included the thromboembolic episodes that
required hospitalization and treatment with anticoagulant therapy. The
detailed history of thromboembolic diseases was obtained using a
standardized questionnaire, which was proven to be a valuable tool for
the diagnosis of personal past episodes of venous
thromboembolism.18 The majority of the clinically suspected
first episodes of venous thromboembolism (71%) were confirmed by
reliable objective tests. It seems likely therefore that our data are
accurate and not overestimated. The probands were rightly excluded from
the analysis because of ascertainment bias. Their clinical
manifestations pointed to a higher (recurrence) risk of venous
thromboembolism. It was remarkable that we observed almost no
additional genetic defects in the probands. Given their impressive
thrombotic histories, additional yet unknown factors seem likely.
We studied the highly thrombosis-prone and referred families. The
heterogeneity of the molecular basis of antithrombin deficiency in
these families was in accordance with reported mutations in other
families.14 In the absence of other risk factors, we found that the annual incidence was less than 1% per year. This implies that, even in the worst case, lifelong prophylactic therapy cannot be
justified, because higher annual risks of bleeding complications have
been consistently reported.19,20 In contrast, with
gene-environmental interaction, incidence rates in high-risk situations
exceeded the reported risks of bleeding complications. The use of
prophylaxis has to be considered carefully but seems indicated as
short-term prophylactic anticoagulant therapy in all high-risk
situations. The postpartum period showed to be the most prominent
acquired risk factor for onset of venous thromboembolism in women. The risk was also greater in the puerperium than during pregnancy (Table
3). Based on these data, adequate prophylactic anticoagulant therapy
for asymptomatic pregnant women may be confined to the postpartum state only.
In conclusion, venous thromboembolism in inherited antithrombin
deficiency proved to be multicausal. Inherited antithrombin deficiency
was a strong risk factor. In the presence of other precipitating risk
factors, interactive effects strongly determined the risk of thrombosis
for an individual. In selected families with young symptomatic family
members, additional genetic factors should be assessed. The risks of
acquired risk factors should be considered and adequate prophylactic
anticoagulant therapy seems indicated only during high-risk situations.
Further study is needed to assess whether similar risks are found in
unselected families.
| |
ACKNOWLEDGMENT |
The authors are grateful to Dr H.R. Büller, Dr J.W. ten Cate, and
Dr M.V. Huisman for permitting us to study a family with inherited
antithrombin deficiency. We thank E.W.M. Vogels and S.R. Poort, who
performed the DNA analysis.
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FOOTNOTES |
Submitted January 27, 1999; accepted June 10, 1999.
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 F.R. Rosendaal, MD, Department of Clinical
Epidemiology, University Hospital, Bldg 1, CO-P45, PO Box 9600, 2300 RC
Leiden, The Netherlands.
| |
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F. R. Rosendaal
Venous Thrombosis: The Role of Genes, Environment, and Behavior
Hematology,
January 1, 2005;
2005(1):
1 - 12.
[Abstract]
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V. Picard, M.-D. Dautzenberg, B. O. Villoutreix, G. Orliaguet, M. Alhenc-Gelas, and M. Aiach
Antithrombin Phe229Leu: a new homozygous variant leading to spontaneous antithrombin polymerization in vivo associated with severe childhood thrombosis
Blood,
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[Abstract]
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S. M. Raja, N. Chhablani, R. Swanson, E. Thompson, M. Laffan, D. A. Lane, and S. T. Olson
Deletion of P1 Arginine in a Novel Antithrombin Variant (Antithrombin London) Abolishes Inhibitory Activity but Enhances Heparin Affinity and Is Associated with Early Onset Thrombosis
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A. I. Schafer, M. N. Levine, B. A. Konkle, and C. Kearon
Thrombotic Disorders: Diagnosis and Treatment
Hematology,
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[Abstract]
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W. Burke, D. Atkins, M. Gwinn, A. Guttmacher, J. Haddow, J. Lau, G. Palomaki, N. Press, C. S. Richards, L. Wideroff, et al.
Genetic Test Evaluation: Information Needs of Clinicians, Policy Makers, and the Public
Am. J. Epidemiol.,
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[Abstract]
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K. Laczika, I. M. Lang, P. Quehenberger, C. Mannhalter, M. Muhm, W. Klepetko, and P. A. Kyrle
Unilateral Chronic Thromboembolic Pulmonary Disease Associated With Combined Inherited Thrombophilia
Chest,
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[Abstract]
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K. A. Bauer, F. R. Rosendaal, and J. A. Heit
Hypercoagulability: Too Many Tests, Too Much Conflicting Data
Hematology,
January 1, 2002;
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[Abstract]
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U. Seligsohn and A. Lubetsky
Genetic Susceptibility to Venous Thrombosis
N. Engl. J. Med.,
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T. K. Giri, T. Yamazaki, N. Sala, B. Dahlback, and P. G. de Frutos
Deficient APC-cofactor activity of protein S Heerlen in degradation of factor Va Leiden: a possible mechanism of synergism between thrombophilic risk factors
Blood,
July 15, 2000;
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[Abstract]
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TOP
ABSTRACT
INTRODUCTION