Venous thromboembolism (VTE) is a multifactorial disease arising from a complex interplay
between acquired clinical risk factors and inherited genetic predispositions. VTE
is a common condition and occurs in 1 to 2 per 1,000 people every year in Western
countries.[1]
[2] Laboratory tests for inherited thrombophilia are frequently requested with the goal
to uncover the susceptibility to VTE in patients devoid of major clinical risk factors.
Conventional thrombophilia testing typically involves the determination of deficiencies
in antithrombin, protein C, or protein S, and genetic testing for the factor V Leiden
(FVL) and prothrombin G20210A variants.[3] However, despite their widespread use, these tests are critically flawed with limited
sensitivity and specificity for VTE, as well as with methodological issues. Moreover,
conventional thrombophilia tests fail to differentiate between patients at high and
low risk of VTE recurrence.[4]
[5]
[6] Additionally, thrombophilia testing introduces risks, with potential long-term personal
consequences, if the information is misinterpreted or inappropriately applied. As
a consequence, current guidelines recommend against the routine use of thrombophilia
tests.[7]
[8]
[9]
[10] Nonetheless, there is substantial nonadherence to the guidelines in clinical practice.
In a recent, large, single-center cross-sectional study, merely one-third of thrombophilia
tests were conducted according to the guidelines.[11] Furthermore, the study underscored the limited therapeutic value, with only 8.3%
of thrombophilia tests influencing anticoagulant treatment decisions.[11]
To underscore the importance of judicious use of thrombophilia tests and to highlight
their potential psychological and social consequences, we here present three unrelated
cases of genetic discrimination after testing for inherited thrombophilia. The cases
were selected from the outpatient clinic of the Thrombosis and Haemostasis Department
at the University Hospitals Leuven, Belgium. All three patients presented between
2020 and 2023 after medical disqualification by the police department based on the
results of previous thrombophilia tests. To the best of our knowledge, no additional
cases of discrimination resulting from thrombophilia testing were documented at our
institution. The retrospective study of our cases was approved by the Ethics Committee
Research UZ/KU Leuven. Informed consent for publication was obtained from all three
patients.
Case 1
A 22-year-old woman in good overall health externally underwent selective FVL testing
after her grandfather was tested heterozygous for FVL following a thrombotic event.
Her test revealed that she was also a heterozygous carrier of FVL. She switched from
the estrogen–progestogen contraceptive pill to a progestogen-only pill. She has never
experienced any thrombotic event.
Case 2
A 20-year-old man, with an unremarkable medical history besides a tonsillectomy and
a traumatic radius fracture, was selectively tested for FVL by his hematologist because
of his mother's history of a contraceptive pill-related deep vein thrombosis and positive
FVL testing. The results showed heterozygosity for FVL. No specific interventions
were undertaken.
Case 3
A 36-year-old man, with no medical history, underwent thrombophilia testing via his
general practitioner after his mother was found to have FVL heterozygosity following
an unprovoked deep vein thrombosis. The test showed normal plasma levels for antithrombin,
protein C, and protein S, but clear activated protein C (APC) resistance. Further
genetic testing verified his heterozygous FVL carriership. Genetic testing for the
prothrombin G20210A variant was not performed. He was advised to start thromboprophylaxis
in high-risk situations and to maintain increased vigilance toward VTE symptoms.
Despite their overall good medical condition, all three individuals were denied by
the medical department of the police academy based solely on their asymptomatic carriership
of FVL. The decision was grounded in the perceived higher risk of VTE associated with
the combination of FVL and their potential employment as police officers.[12]
The decision for medical disqualification is fundamentally unfair. The interpretation
of the clinical consequences of a positive thrombophilia test by the police department
was incorrect, thereby illustrating the risks and complexities of thrombophilia tests.
Moreover, these cases highlight the importance of judicious use of thrombophilia tests,
considering the absence of a proper indication for testing according to the most recent
2023 guidelines from the American Society of Hematology (ASH).[10]
Prevalence and Venous Thromboembolism Risk of Factor V Leiden
Prevalence and Venous Thromboembolism Risk of Factor V Leiden
FVL results from a single missense variant in the F5 gene (p.Arg534Gln, historically reported as p.Arg506Gln). Hence, a prothrombotic
factor V (FV) protein arises, characterized by an increased resistance to inactivation
by APC and a loss of FV's anticoagulant cofactor activity in the degradation of FVIIIa
by APC.[13] FVL is the most common genetic risk factor associated with VTE, with a prevalence
of approximately 5% among Caucasians and approximately 20% in unselected individuals
with VTE.[14]
[15]
[16] Heterozygosity for FVL is associated with a 4-fold increase in the risk of VTE,
and this risk further escalates to a factor eleven in those with homozygosity for
FVL.[17] Nevertheless, the absolute risk of VTE remains low, with an annual incidence ranging
from 0.45 to 0.67% per year in asymptomatic heterozygous carriers, compared with the
overall population incidence of approximately 0.1 to 0.2% per year.[18]
[19]
[20] In FVL carriers under 30 years of age, this incidence is even lower at 0.25% per
year.[18]
[19] Ultimately, only 11% of all FVL carriers will develop VTE during their lifetime,
with over half of these events being triggered by clinical risk factors such as recent
surgery, trauma, or pregnancy.[18]
[19]
[21] Thus, FVL should only be considered as a genetic “risk factor” as it is not at all
fully penetrant for VTE. The thrombotic risk associated with FVL carriership does
not justify routine thromboprophylaxis in asymptomatic carriers, given the increased
bleeding risk associated with anticoagulant treatment. When VTE does occur, the treatment
is generally uncomplicated, and neither the choice nor the duration of treatment is
typically influenced by the presence of FVL. Clinical decision-making regarding VTE
therefore relies on clinical factors rather than the presence of hereditary thrombophilia.
Consequently, this genetic risk factor on itself is not a reason to declare someone
unfit for a profession.
Guidelines on Thrombophilia Testing
Guidelines on Thrombophilia Testing
Thrombophilia tests may provide insights into the etiology of (unprovoked) VTE, yet
their therapeutic implications are currently limited. Current guidelines therefore
recommend against their routine use in clinical practice ([Table 1]).[7]
[8]
[9]
[10] Instead, thrombophilia tests should only be performed when results will influence
management. However, due to a lack of randomized controlled trials, the level of evidence
supporting these guidelines is weak. Moreover, guidelines are inconsistent and ambiguous,
resulting in poor adherence and misuse in clinical practice.[11] According to the guidelines, thrombophilia tests should not be performed in asymptomatic
men with known familial FVL, as in case 1 and 3.[7]
[8]
[9]
[10] Nonetheless, guidelines disagree on testing asymptomatic women with familial FVL,
as in case 2 ([Table 1]).
Table 1
Overview of guidelines for thrombophilia testing in clinical practice
|
2009 GFHT[7]
|
2016 ACF[8]
|
2022 BSH[9]
|
2023 ASH[10]
|
|
Primary prevention in patients with family history of VTE
|
|
Known familial thrombophilia
|
|
AT, PC, or
PS deficiency
|
Recommended in first-degree relatives < 60 ya
|
Only considered in first-degree related women contemplating COC/pregnancy
|
Recommended in first-degree relatives
|
Recommended in first- and second-degree relatives with minor VTE risk factors, including
postpartum and COC usec,d
|
|
Heterozygous
FVL or FII
G20210A
variant
|
Only recommended in women of childbearing age
|
Only considered in first-degree related women contemplating COC/pregnancy
|
Not recommendedb
|
Not recommendedd
|
|
Unknown familial thrombophilia
|
|
Not recommended
|
Not recommended
|
Not recommended
|
Not recommendedd
|
|
Secondary prevention following personal VTE
|
|
Provoked VTE
|
Recommended in women of childbearing age
Recommended in case of recurrent VTE < 60 y
|
Not recommended
|
Not recommended
|
Only recommended when transient nonsurgical risk factors, including postpartum and
COC usee
|
|
Unprovoked VTE
|
Recommended in anyone < 60 y
|
Only recommended if low bleeding risk and plan to stop anticoagulation
|
Only, recommended when strong personal and/or family history of thrombosis
|
Not recommended
|
Abbreviations: ASH, American Society of Hematology; AT, antithrombin; BSH, British
Society of Haematology; COC, combined oral contraceptive; FVL, factor V Leiden; PC,
protein C; PS, protein S; VTE, venous thromboembolism; ACF, anticoagulation forum;
GFHT, French Group of Hemostasis and Thrombosis.
aAlso in case of homozygous polymorphisms for FVL and FII G20210A as well as double
heterozygotes.
bPrior to COC use in women with a first-degree relative with FVL and history of thrombosis,
thrombophilia testing can be discussed case by case.
cMinor provoking risk factors: immobility, minor injury, illness, infection.
dn ambulatory patients with cancer at low or intermediate VTE risk, who have a first-degree
relative with VTE, thrombophilia testing is recommended, regardless of known familial
thrombophilia.
eNon-surgical risk factors: immobilisation > 3 days, use of COC, pregnancy, post-partum.
The most recent 2023 ASH guidelines recommend thrombophilia testing for patients with
symptomatic VTE provoked by transient nonsurgical risk factors, pregnancy, postpartum
period, or combined oral contraceptives (COC), to determine the need for lifelong
anticoagulation.[10] Indefinite anticoagulation is advised for patients with confirmed thrombophilia.
Additionally, thrombophilia testing is advised for asymptomatic individuals with a
family history of VTE and known antithrombin, protein C, or protein S deficiency,
with the recommendation for thromboprophylaxis in risk situations and avoidance of
COC in thrombophilic patients. Nevertheless, thrombophilia testing is not supported
for patients with VTE provoked by major risk factors, nor for asymptomatic individuals
with a family history of VTE whose familial thrombophilia status is unknown or who
have a known heterozygous FVL or prothrombin G20210A variant in the family.
Risk of Patient Harm by Thrombophilia Tests
Risk of Patient Harm by Thrombophilia Tests
Considering not only the clinical implications but also the potential psychological
and social ramifications arising from misuse or misinterpretation of thrombophilia
tests is paramount in the context of thrombophilia testing ([Table 2]). According to the 2023 ASH guidelines, all three case patients had no firm indication
for thrombophilia testing and would have successfully passed medical examinations
if they had not undergone such testing.[10] Nonetheless, discrimination on any grounds, including genetics, is explicitly prohibited,
as stated in Article 14 of the European Convention on Human Rights. However, genetic
discrimination persists anno 2023 and continues to impact individuals' lives. These
instances are not isolated, as evidenced in a survey by Bank et al. among healthy
FVL carriers, revealing reports of stigmatization in healthcare and discrimination
by insurance companies.[22]
Table 2
Pros and cons for thrombophilia testing
|
Pro
|
Con
|
|
May provide insights into VTE susceptibility and improve knowledge and counselling
|
Limited sensitivity and specificity for VTE
• Risk of false reassurance with negative test
• Risk of overtreatment with positive test
|
|
May prevent first VTE in asymptomatic confirmed thrombophilia cases by e.g.,
• No estrogen–progestogen contraceptive pill
• Extending postpartum thromboprophylaxis
|
Limited therapeutic implications as clinical decision-making mainly relies on clinical
risk factors
|
|
Misinterpretation and misuse
• Psychological consequences: worry
• Social consequences (discrimination): profession, insurance
|
|
High costs
|
Abbreviation: VTE, venous thromboembolism.
The emergence of multigenetic thrombophilia tests to screen for (anti-)coagulation
defects holds promise for enhancing diagnostic precision and counselling.[23] However, uncertainties persist concerning the clinical usefulness and cost-effectiveness.
Furthermore, pervasive genetic testing reveals numerous variants of unknown significance,
complicating its use and thereby increasing the risk of misinterpretation or misapplication
with potential adverse patient consequences.[24] Future studies are imperative to ascertain the precise place of both conventional
and multigenetic thrombophilia testing within clinical practice. Until then, prudence
in interpretation and rational use of thrombophilia tests are warranted to prevent
potential unnecessary harm to patients.
