pros and cons of thrombophilia testing: cons
TRANSCRIPT
DEBATE
Pros and cons of thrombophilia testing: cons
S . J . M A C H I N
Department of Haematology, University College London, UK
Thrombophilia is generally defined as an inherited disorder of
the hemostatic system that results in an increased risk of venous
thromboembolism (VTE). There are several well characterized
and accepted inherited thrombophilia conditions that predis-
pose to venous thrombosis. The most important ones are the
factor (F)V Leiden mutation, the prothrombin gene mutation,
protein C, protein S and antithrombin deficiency, high levels of
FVIIIc and hyper-homocystinemia [1]. Generally speaking
these inherited thrombophilias are present in about 10–15%
of the Caucasian Western European population (their frequen-
cies vary in other well defined racial groups) but in patients with
recurrent episodes of VTE the incidence of such disorders in-
creases to about 50%. However, there is a paucity of evidence-
based medicine regarding how, if at all, the clinical management
of patients with thrombophilia and VTE differs from those
individuals who do not have a specific inherited thrombophilia.
It is not clear whether or not these individuals should be treated
differently and risk stratification of the thrombophilia condi-
tions does not change clinical recommendations for specific
treatment regimes [2].
So as not to be condemned as adopting a nihilistic approach
in this discussion, thrombophilia testing for research projects,
particularly prospective randomized clinical trials and the dev-
elopment of new diagnostic laboratory methodology, is not at
issue. The main argument that needs to be considered is whether
indiscriminate generalized screening and the routine clinical
practice of testing is necessary or helpful, particularly also
focusing on cost effectiveness and the financial waste of wide-
spread testing diverting scarce health care resources from other
areas of clinical medicine. Widespread thrombophilia screening
has been advocated in many clinical situations but particularly
in women prior to starting a combined oral contraceptive pill or
hormone replacement therapy and also during pregnancy. Other
areas of consideration are prior to long haul air travel particu-
larly in the cramped economy section, prior to high risk surgical
procedures, in patients after a first proven episode of VTE for
which there was no obvious predisposing condition and also to
assess the risk of developing pulmonary embolism after an
episode of deep vein thrombosis (DVT).
The rate of VTE according to combined oral contraceptive
usage is now well defined and it is useful to compare this to
similar aged women who are not receiving any form of hormone
preparation and also to similar aged women during pregnancy. It
is generally accepted that the rate of VTE per 100 000 women
per year is approximately five in women who are not pregnant
or taking oral contraceptives and increases to a rate of about 15
in women taking a second generation combined oral contra-
ceptive pill and to about 60 for women during pregnancy. If one
assesses the rate of VTE when associated with specific throm-
bophilias, there is an increase in patients on the combined pill
with the heterozygous form of the FV Leiden mutation to about
25.5 per 10 000 persons per year. In patients with antithrombin
deficiency, the rate has been reported to be as high as 27.5% per
year compared with 12% per year with protein C deficiency and
no difference in patients with protein S deficiency compared
with an annual control rate of between 3.4 and 6.9% [3]. The
simple question resulting from these epidemiological incidence
figures is – should women receive some form of thrombophilia
screening prior to starting the combined oral contraceptive
pill? It has been estimated that overall, one would need to
screen 2 000 000 women to prevent one death from pulmonary
embolism [4]. Although 100 episodes of DVT could be pre-
vented, they cause little long-term morbidity in otherwise young
healthy women who receive the appropriate treatment. The
downside obviously is that contraceptive failure rate by other
methods is considerably higher which would reverse even fur-
ther any benefits from screening. Even focused screening of
patients with a proven personal or family history of VTE would
require testing of between 5000 and 10 000 women to prevent
one death from PE. We know that approximately 40% of
European women who test thrombophilia positive will never
develop a VTE event and one can always get false reassurance
through inappropriate interpretation of negative laboratory tests
[5]. A similar argument can be made against thrombophilia
screening in pregnancy. We know that the overall incidence for
VTE is about 0.67 per 1000 pregnant women with about one in
500 for the FV Leiden mutation, one in 200 for the prothrombin
gene mutation and 4.6 in 100 for the combination of the FV
Leiden and prothrombin gene mutation [6]. Again these figures
do not support the concept of overall general screening as the
potential overall predictive value is relatively low.
The risks of venous thrombosis associated with long haul air
travel has recently been widely recognized. A prospective
randomized study has shown that symptomless calf DVT may
occur in up to 10% of long haul travelers over the age of 50 and
that this incidence is considerably reduced by wearing below
Journal of Thrombosis and Haemostasis, 1: 412–413
# 2003 International Society on Thrombosis and Haemostasis
Correspondence: S. J. Machin, Department of Haematology, University
College London Hospitals, 3rd Floor A & E Building, 25 Grafton Way,
London WC1E 6DB, UK.
Tel.: þ44 207 3809884; fax: þ44 207 3809886; e-mail: samuel.machin@
ucl.ac.uk
knee fitted compression stockings [7]. Although 7% of travelers
had either the FV Leiden or prothrombin gene mutation, these
defects were of no predictive value for the development of
symptomless DVT in the group of travelers who were not
wearing prophylactic compression hosiery.
Recently it has been claimed that a DVT associated with the
FV Leiden mutation is more stable and adherent to the vessel
wall. This is presumed to be due to the fact that the FV Leiden
mutation enhances local thrombin generation, intensifies the
local inflammatory process and impairs the pro-fibrinolytic
response to activated protein C [8]. A phlebography study of
the location and extension of acute DVT has shown that in the
presence of the FV Leiden mutation a DVT is less likely to
extend into the ileo-femoral veins compared with a group of
patients with acute DVT who do not have the FV Leiden
mutation [9]. They reported an odds ratio of 0.5 (0.06–3.9)
for extension of a DVT into the ileo-femoral veins when the FV
Leiden was present compared with control subjects. Indeed the
prevalence of the FV Leiden mutation in patients with isolated
pulmonary embolus without DVT seems to be about half of that
in patients with isolated DVT alone [10].
The standard approach to the anti-thrombotic regime after a
first DVT is to continue oral anticoagulation for the first
6 months. A frequent question is, if thrombophilia screening
of such individuals after their first proven episode of VTE is
positive, would extension of warfarin therapy for say a 1–5-year
further period reduce the recurrence rate of further VTEs after
this initial 6 months treatment period for those individuals with
an inherited thrombophilia? Using a Markov decision analysis
model, which takes into account the yearly risk of major
bleeding, the high rate of clinical PE and a maximum efficiency
of warfarin of approximately 90%, they concluded that the
number of major hemorrhages induced would significantly
exceed the number of clinical pulmonary embolic events pre-
vented over the entire 5-year period [11]. They concluded
therefore that the decision to promote widespread thrombophi-
lia screening after a first episode of VTE was not justified and
the decision to extend oral anticoagulant therapy in such
individuals did not lead to any improved clinical outcome.
Whenever one is considering thrombophilia screening, one
has to take into account the local availability of laboratory
methodology. For each thrombotic condition, each laboratory
must establish its own age, sex and racial group reference
ranges. In some conditions, particularly protein S deficiency,
there is considerable overlap between some heterozygous de-
fects and the lower limit of the normal range and this can be
particularly affected by the age of the individual, their contra-
ceptive status and also during pregnancy. Some tests are affect-
ed by the acute post thrombotic state, any acute phase response
and also obviously by anticoagulant use. The individual level of
any heterozygous specific inherited thrombophilic defect does
not affect the management of any acute or indeed long-term
thrombotic event. In the United Kingdom, with a population of
about 55 million, one can estimate from national quality control
exercises that there are about 30 000 inherited thrombophilia
screens performed per year. Using in-house University College
Hospital prices, a complete thrombophilia screen in real terms
costs approximately 500 Euros with an estimated total UK cost
to the National Health Service budget of about 15 000 000 Euros
per year. Thrombophilia testing is therefore a very expensive
exercise, inappropriate laboratory testing is poor clinical prac-
tice and diverts scarce resources from other areas of healthcare.
To conclude, identification of a non-modifiable contributory
factor (i.e. an inherited thrombophilic condition) is not a
worthwhile end in its own right [12]. Testing of any patient
or their relatives generates needless anxiety or indeed promotes
false reassurance in those who are reported as being negative
for the various tests performed. Indiscriminate thrombophilia
screening cannot be justified. There is no evidence, particularly
in the areas discussed above, that thrombophilia testing affects
the overall standard clinical management of patients.
References
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# 2003 International Society on Thrombosis and Haemostasis
Debate 413