pros and cons of thrombophilia testing: pros
TRANSCRIPT
DEBATE
Pros and cons of thrombophilia testing: pros
I . M A R T I N E L L I
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, IRCCS Maggiore Hospital and Department of Internal Medicine,
University of Milan, Italy
Unlike the deficiencies of the anticoagulant proteins antithrom-
bin, protein C and S, rare in patients with venous thromboem-
bolism (VTE; 5% altogether) and in the general population (less
than 1%), both the gain-of-function mutations of the factor (F)V
and prothrombin genes are common in patients with VTE
(around 25 and 10%, respectively) and in the general population
(3–7% and 3%) [1]. The high prevalence of these mutations has
prompted a wider application of thrombophilia screening, not
always appropriately. Who should to be screened, and what are
the benefits of screening?
As inherited thrombophilia predisposes to VTE, the first
category of individuals who might benefit from screening are
those who developed an episode of VTE. To establish whether
or not thrombophilia screening is worthwhile in these patients
one should first know whether or not results would influence
treatment, and particularly the duration of anticoagulants. If
patients with thrombophilia had a higher risk of recurrence after
discontinuation of anticoagulants, a more prolonged period of
treatment would be recommended. Unfortunately, data on the
comparative risk of recurrent VTE in patients with or without
thrombophilia are conflicting [2]. This issue has been tackled by
means of several prospective studies in heterozygous carriers of
FVor prothrombin mutations, some providing evidence in favor
of an increased recurrence rate [3–6], others not [7–10].
Whether or not a longer duration of anticoagulant treatment
is more efficacious than the conventional period of 3–6 months
is still a matter of debate. Longer or indefinite anticoagulant
treatment should perhaps be reserved for patients with ‘severe’
thrombophilia associated with a very high risk of VTE, like
carriers of homozygous or double heterozygous gain-of-func-
tion mutations and those with quantitative (type I) antithrombin
deficiency, particularly if VTE occurred in the absence of
transient risk factors. This approach is biologically plausible,
even though it is not evidence based.
I purport that thrombophilia screening helps to decide on the
usefulness of primary prophylaxis in the presence of transient
risk factors in asymptomatic relatives of thrombosis patients
diagnosed with thrombophilia [11,12]. Prophylaxis with un-
fractionated or low molecular weight heparin is commonly
given to all individuals older than 40–45 years during surgery,
trauma or prolonged immobilization, since the risk of VTE
increases with these conditions and age [1]. When these con-
ditions occur in individuals younger than 40–45 years diag-
nosed with thrombophilia in the frame of family screening, they
should be recommended primary antithrombotic prophylaxis
after the age of 15 years [13,14]. Knowledge of the existence of
thrombophilia is also likely to benefit women during the post-
partum period, when the risk of VTE is 10–15 times higher than
during the whole period of pregnancy [15]. Antithrombotic
prophylaxis should be given during puerperium in asympto-
matic women with thrombophilia [16], and should perhaps be
given during the whole gestational period in carriers of ‘severe’
thrombophilic states (see above) [17]. In addition, women
diagnosed with thrombophilia during family testing could be
counseled on whether or not they can be safely put on oral
contraceptives or hormone replacement therapy. Apart from
asymptomatic women with ‘severe’ thrombophilia, who should
be discouraged to use oral contraceptives, those with other
causes of thrombophilia should be informed of the relative risk
of VTE due to the type of abnormality (e.g. sevenfold increased
for FV Leiden), the risk due to the use of the pill (fivefold) and
to the multiplicative effect due to the presence of both (20- to
30-fold) [18,19]. The relative risk of VTE is also increased two-
to threefold by hormone replacement therapy [20], and the older
age and greater absolute risk of VTE of postmenopausal women
has to be considered when this therapy is prescribed, especially
in carriers of thrombophilia. It is up to the physician’s com-
munication skills to impart information in a clear, balanced,
comprehensive and accessible form, without creating undue
anxiety.
What definitely happened after the discovery of the common
polymorphisms in FV and prothrombin genes is an inappropri-
ate request of thrombophilia screening in healthy individuals
with no personal or family history of VTE. A typical example of
such unjustified testing is the screening of healthy women
before the prescription of oral contraceptives. It has been
calculated that to prevent one episode per year of VTE, oral
contraceptives should be withdrawn from 400 asymptomatic
carriers of FV Leiden; to find them, approximately 10 000
asymptomatic women should be tested, and this is obviously
not cost-effective [21]. Indiscriminate screening for FV Leiden
in pregnant women is also not cost-effective [22]. As to
hormone replacement therapy, this does increase not only the
relative risk of VTE but also that of a second non-fatal myo-
cardial infarction [20]. The presence of the prothrombin muta-
tion, but not of FV Leiden, increases the risk of a second
myocardial infarction in women with hypertension [23]. These
Journal of Thrombosis and Haemostasis, 1: 410–411
# 2003 International Society on Thrombosis and Haemostasis
Correspondence: I. Martinelli, Angelo Bianchi Bonomi Hemophilia and
Thrombosis Center, IRCCS Maggiore Hospital and Department of Internal
Medicine, University of Milan, Italy.
Tel.: þ39 02 55035468; fax: þ39 02 50320723; e.mail: martin@policli-
nico.mi.it
findings should be confirmed before recommending screening
for the prothrombin mutation.
In conclusion, thrombophilia screening is likely to be useful
in patients carrying a very high risk of VTE (such as homo-
zygous carriers of FV Leiden or prothrombin mutation, and type
I antithrombin deficiency), as it may improve clinical outcome
through changes in the duration of anticoagulant therapy. In
addition, family screening performed when thrombophilia is
diagnosed in thrombosis patients allows for optimization of
primary prophylaxis in asymptomatic carriers during high-risk
situations. Moreover, counseling can be more focused in these
women when oral contraceptives or hormone replacement
therapy are considered. In other situations, screening is not
useful and represents a waste of resources.
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# 2003 International Society on Thrombosis and Haemostasis
Debate 411