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Blood, 1 July 2001, Vol. 98, No. 1, pp. 21-22
PERSPECTIVE
Genetic hypercoagulability: prevention suggests testing family
members
Pier Mannuccio Mannucci
From the Angelo Bianchi Bonomi Hemophilia and
Thrombosis Center, and Fondazione Luigi Villa, Istituto di Ricovero e
Cura a Carattere Scientifico Maggiore Hospital and University of Milan,
Italy.
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Article |
Dahlback in 1993 and Bertina in 1994 made the
landmark discovery that resistance to activated protein C due to a
point mutation in the factor V gene (G1691A in exon 10, leading to
Arg506Gln) is associated with a 6- to 8-fold increased risk of venous
thrombosis.1,2 The importance of these findings, which
have since been confirmed and cited more than 2000 times in the medical
literature, is due to the fact that heterozygosity for factor V
Arg506Gln (generally known as factor V Leiden) is present in
approximately 20% of unselected patients who present with a first
episode of venous thrombosis3 and, most important, in
approximately 4% of general white populations.4 Another
piece of evidence supporting the importance of genetic risk factors in
causing venous thrombosis was added in 1996, when again Bertina and his
colleagues found that the prothrombin G20210A polymorphism has a
frequency of 6% in patients with a first episode of venous thrombosis,
contrasting with approximately 2% in the general white
population.5 Adding to factor V Leiden and prothrombin G20210A the rarer deficiencies of the naturally occurring anticoagulant proteins antithrombin, protein C, and protein S, the proportion of
venous thromboses attributable to genetic factors is 25% to 30%, at
least as large as that attributable to well-established acquired risk
factors such as surgery, trauma, prolonged immobilization in bed (more
than 7 days), pregnancy and puerperium, estrogen use, and cancer. With these genetic risk factors of venous thrombosis having such a
weight and prevalence in the general population, the first obvious
question is whether they should be looked for in healthy individuals
with no personal or family history of thrombosis, particularly when
they are exposed to acquired factors that may interact with genetic
factors to increase the risk of venous thrombosis. The magnitude of the
interaction between genetic and acquired factors can be exemplified by
one of the most frequently occurring interactions, that is, that
between heterozygosity for factor V Leiden and oral contraceptive
intake. Given that oral contraceptives alone increase from 4- to 6-fold
the relative risk of venous thrombosis, the concomitant presence of
factor V Leiden brings the relative risk up to 30-fold or
more.6 Despite this impressive increase in the relative
risk, one must consider that the annual incidence of venous thrombosis
in women of childbearing age is approximately 1 in 10 000.
Hence, more than 20 000 women should be tested and counseled to
prevent one episode of venous thrombosis, and more than 2 million
tested and counseled to prevent one death from pulmonary
embolism.7 These figures clearly indicate that it is
hardly justified to screen for thrombophilia all women who are
considering oral contraceptive intake. By analogy, the same negative
consideration applies to pregnant women and to individuals of both
sexes exposed to major surgery, immobilization, cancer, and hormone
replacement therapy, because there is no evidence that the interaction
among these risk factors and heterozygosity for factor V Leiden is more
thrombogenic than that between the latter and oral contraceptive intake. A special situation is that of asymptomatic relatives of index patients
with a thrombophilic defect diagnosed after an episode of venous
thrombosis. In these individuals, screening is obviously more focused
and potentially more fruitful than in the general population because
all the genetic risk factors are transmitted as autosomal dominant
traits. The first issue is whether the results of screening would be
advantageous for family members. In principle, screening entails the possibility of giving advice for
antithrombotic prophylaxis to these individuals. There is no evidence
that their lifelong risk of thrombosis justifies exposure to the risks
associated with primary prophylaxis with oral anticoagulants, because
many individuals with a genetic thrombophilic abnormality never develop
thrombotic symptoms, nor do these defects increase
mortality.8,9 However, when asymptomatic
thrombophilic individuals are exposed to acquired risk factors, the
increased risk of thrombosis might in principle be reduced with
relatively little risk and cost by adopting short-term prophylaxis with
low-dose unfractionated or low-molecular-weight heparin. What is the evidence in favor of this diagnostic strategy and of the
ensuing prophylaxis strategy? In a retrospective study conducted in
Italy in 1994, 238 patients with antithrombin, protein C
deficiency, or protein S deficiency were analyzed for the
incidence of thrombotic events prediagnosis and postdiagnosis of the
thrombophilic abnormality.10 In the prediagnosis period,
antithrombotic prophylaxis was not implemented at the time of exposure
to acquired thrombosis risk factors. However, after diagnosis,
short-term prophylaxis with heparin was usually implemented. This
approach reduced the incidence of both first (0.7/100 patient-years
postdiagnosis vs 1.7 prediagnosis) and recurrent (1.3/100 vs 4.8/100
patient-years) thrombotic episodes.10 Among the
limitations of this study are its retrospective design and the fact
that factor V Leiden and prothrombin G20210A were not known as risk
factors at the time of the study and so they were not considered in the
analysis.10 Another piece of evidence in favor of the usefulness of screening and
of antithrombotic prophylaxis during risk periods stems from a
prospective cohort study carried out in Europe and Canada in 208 affected but asymptomatic family members of 94 symptomatic antithrombin, protein C-, and protein S-deficient patients who had a
venous thrombotic event.11 During 40 periods of exposure of these individuals to acquired risk factors, the decision to use
antithrombotic prophylaxis and the regimens used were left to the
choice of the treating physicians. The incidence of risk period-related, objectively documented, first venous thromboembolic episodes was 4.5% in the individuals who received prophylaxis, as
compared with 16.7% in those who did not receive prophylaxis. Limitations of this study are the very small number of periods of
exposure to transient risk factors, the nonuniform and nonrandom approach to antithrombotic prophylaxis, and, as for the retrospective Italian study, the fact that the factor V and prothrombin mutations were not known when the study was carried out. These genetic risk factors carry a smaller risk of thromboembolism than
antithrombin, protein C deficiency, and protein S
deficiency.12,13 We recognize that several arguments can be made against the adoption of
screening and prophylaxis in members of thrombophilic families. The
cost of screening, particularly of DNA testing, is not negligible and
cost effectiveness remains to be demonstrated. There is also the risk
of labeling individuals with a genetic "disease" who in many
instances will never have thrombotic disease. Besides generating
anxiety, this situation might create problems in obtaining insurance in
some schemes of health care delivery, particularly in the United
States. These limits notwithstanding, we advise thrombophilia screening
in asymptomatic relatives of symptomatic patients carrying genetic
abnormalities such as factor V Leiden, prothrombin G20210A,
antithrombin, protein C deficiency, or protein S deficiency. When women
found to carry one of these abnormalities consider taking oral
contraceptives, we try to give them a balanced view of the absolute and
relative risk of thrombosis associated with the drug use, taking into
account the age of the woman and her general health condition. The same
approach is adopted for women who consider hormone replacement therapy,
informing them that the background annual incidence of venous
thrombosis at their age is higher than that in women of childbearing
age (between 1 in 1000 and 1 in 5000). When men and women with
thrombophilic abnormalities, even if asymptomatic, undergo procedures
of major surgery, we advise the same regimen of short-term
antithrombotic prophylaxis with low-dose unfractionated or
low-molecular-weight heparin that is routine for all individuals older
than 40 years of age. We recognize that this diagnostic and prophylactic approach is not
supported by evidence stemming from prospective clinical studies, but
the corresponding risks and costs are considered acceptable in a
country that, like Italy, traditionally has a system of health care
delivery focused on prevention. In the United Kingdom, a country with a
similar system, Greaves and Baglin14 think that suitable
studies should first demonstrate that the expenses and risks involved
in screening and prophylaxis are justified by improved patient care. We
appreciate their position, but because such studies would require
extremely large sample sizes to be definitive, we doubt they will ever
be undertaken, or if begun, we will have to consider the issues of
hypercoagulability in asymptomatic family members of thrombophilic
patients for a considerable time until the studies are completed.
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Footnotes |
Submitted February 15, 2001; accepted March 1, 2001.
Reprints: P. M. Mannucci, Via Pace 9, 20122 Milano, Italy; e-mail: piermannuccio.mannucci{at}unimi.it.
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