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Dorit Blickstein, MD 1
Thrombophilia assessment: what should the
guidelines look like ?
Dorit Blickstein, MD
Hemato-gynecology service, Institute of Hematology, Rabin Medical Center, Campus
Beilinson, and the Sackler School of Medicine, Tel Aviv University
Guidelines, as opposed to protocols, are important in providing reliable tools
that bridge between evidence-based medicine and clinical practice. Protocols are used
as strict schemes for practice whereas guidelines are inherently more flexible. [1]
Inevitably, guidelines change from one nationality to another primarily because of
differences in disease prevalence and, secondarily, because of difference in resources
available for screening, diagnosis, and treatment of a given disease state.
Information about the association between thrombophilia and adverse
outcomes related to women’s health appeared in the scientific literature only in the
last decade. It is now clear that women face situations of increased risk of venous
thromboembolism (VTE) during hormone therapy or pregnancy. These risks are
increased by inherited and acquired factors, collectively named thrombophilia. In
recent years, various adverse pregnancy outcomes have been suspected to have
inherited thrombophilic background. As a result, treatment modalities for VTE were
recommended also to treat several pregnancy complications.[2, 3]
This chapter will discuss what is expected from guidelines related to
thrombophilia assessment.
Dorit Blickstein, MD 2
The common denominator
The culprit in all VTE cases is a thrombothic event. This can manifest
generally as deep vein thrombosis (DVT) and/or pulmonary embolism (PE) or locally
as impaired circulatory function of the uteroplacental unit. This view suggests that
there is a common denominator and a cause and effect relationship between various
manifestations of thrombophilia and adverse perinatal outcomes.[2]
If one accepts this view, pregnancy complications associated with frequent
thrombotic changes in placental vessels, should be considered in the same terms of
VTE phenomena. Thus, guidelines for assessment and treatment are basically related
to the general risks of VTE.
The limitations of guidelines
Guidelines are not without limitations. First, they might be totally inaccurate
because the scientific evidence is either not available or its interpretation is
misleading. Second, guidelines are prone to be influenced by those who sponsored or
conducted the research. Finally, guidelines may not be implemented because of
limited resources and differing opinions of the decision-makers. A special teamwork
is often necessary to develop evidence-based clinical-practice guidelines. This may
include epidemiological reviewing of the published literature and careful statistical
analysis of the data. Thereafter, experts from various related disciplines should
interpret the findings and appropriately define the required guidelines. However,
because of profound national differences in epidemiology as well as in resources,
guidelines suitable for one country may be entirely unsuitable for another one.
What should the guidelines related to thrombophilia look like ?
Dorit Blickstein, MD 3
Most clinicians in need for guidelines related to thrombophilia and women’s
health are concerned with two main issues.
(1) Who should be screened for thrombophilia ?
Currently there is no evidence to support routine screening of women for
congenital thrombophilia. This is true for pregnancy as well as different sex-hormone
treatments. The basic argument is the extremely poor cost-effectiveness of routine
screening. For example, to test for the most common thrombophilic defect (Factor V
Leiden mutation, APCR) in order to avoid one fatality due to VTE in a healthy
woman without any known risk factor, one should invest about 12 million USD. [4]
As a result, physicians should perform a thrombophilia screen in women with a
personal or family history of VTE. There is still an ongoing controversy related to the
association between pregnancy complications and various thrombophilias, although
there is an increasing body of evidence that links between inherited thrombophilia and
gestational vascular complication. [5,6]
(2) The extent of the thrombophilia screening
The most economical way to screen patients for thrombophilia is by dividing
them into three groups, according to the frequency of the defect in the population. [3]
(Table 1) One should remember that thrombophilic defect(s) may vary between
various populations, and therefore the guidelines in table 1 may not be entirely
suitable for every nation. For instance, the frequency of APCR in Afro-Americans is
significantly lower than in Caucasians.
In addition, one should acknowledge that even a negative workup in a patient
with a personal or family history of VTE, the risk of having an as yet unidentified
thrombophilia, is significant. These false-negative results are estimated to be about
Dorit Blickstein, MD 4
30-50%. It follows that a negative workup may erroneously give the woman a
misconception that there is no risk. [4]
Available guidelines
To date, there are several available international guidelines published by a
group of European experts – the so-called International Consensus Statements (ICS)
and by the American College of Chest Physicians (ACCP). Some national guidelines
(Scotland and Belgium) were also published. These guidelines are primarily
concerned with the diagnosis, prophylaxis, and treatment of VTE in general. The
ACCP guidelines, however, include specific recommendations related to women’s
In the process of selecting individuals for screening according to the ACCP
guidelines, one should obtain a detailed clinical and familial history of VTE, exclude
acquired causes, pay attention to recurrent thrombosis or to thrombosis in unusual
sites (including neonatal thrombosis), and assess hormonal/pregnancy related
Why should we do thrombophilia workup to index case ?
There are at least three good arguments why should we perform an extensive
thrombophilia workup in a patient who had a thrombotic event.
First, it is known that some thrombophilias are more risky than others. In
terms of pregnancy complications, antithrombin deficiency and the acquired lupus
anticoagulant (LAC) are notoriously putative. [5,8,9] Second, combinations of
thrombophilias carry a more significant risk for VTE and pregnancy
complications.[5,8,9] Finally, the risk related to the specific defect(s) determines the
Dorit Blickstein, MD 5
duration and dosage of anticoagulation. For example, LAC associated VTE needs a
high dose of anticoagulants, and a prolonged therapy period (sometimes for life).
Why should we screen family members of an index case ?
An important public health issue is screening of family members of index
cases who exhibited thrombophilia related VTE. This screen may have a major
preventive role for the family members at high-risk situations. For instance, a young
woman should be screened and appropriately consulted if her mother had a
thrombotic event under hormonal replacement therapy. Additionally, information
about the occurrence of thrombophilia is important for epidemiological research.
Dorit Blickstein, MD 6
1. Woolf SH, Grol R, Hutchinson A, Eccles M, Grimshaw J. Clinical guidelines:
potential benefits, limitations, and harms of clinical guidelines. BMJ 1999; 318:52730.
2. Brenner B, Conard J. Women’s issues in thrombophilia. Semin Thromb Hemost
2003; 29.
3. The sixth (2000) ACCP guidelines for antithrombotic therapy for prevention and
treatment of thrombosis. American College of Chest Physicians. Chest 2001; 119
4. Schulman S. Inherited thrombophilia. In: Brenner B, Marder VJ, Conard J (eds)
Women’s issues in thrmbosis and hemostasis. Martin Dunitz, London, UK, 2002.
5. Brenner B. Thrombophilia and fetal loss. Semin Thromb Hemost 2003; 29: 165-70.
6. Kupferminc M, Eldor A. Inherited thrombophilia and gestational vascular
complications. Semin Thromb Hemost 2003; 29: 185-93.
7. Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Eng J
Med 2001; 344:122-31.
8. Blickstein D, Blickstein I. Fetal consequences of maternal inherited
hypercoagulable states (thrombophilia). In: Fetal medicine: The clinical care of the
fetus as a patient. Chervenak FA, Kurjak A, (eds), Parthenon Publishing, Lancs, 1999.
9. Preston FE, Rosendaal FR, Walker ID, Briet E, Berntorp E, Conard J, Fontcuberta
J, Makris M, Mariani G, Noteboom W, Pabinger I, Legnani C, Scharrer I, Schulman
S, van der Meer FJ. Increased fetal loss in women with heritable thrombophilia.
Lancet. 1996;348:913-6
Dorit Blickstein, MD 7
Table 1. Screening by priority
High priority
Intermediate priority
Low priority
Protein C deficiency
FV Leiden
Protein S deficiency
Elevated fibrinogen
Prothrombin gene
AT III deficiency
Elevated F IX
Elevated F XI
Increased homocystein
Increased F VIII
MTHFR homozygote
F XIII deficiency