Gregory Piazza

Thrombophilia Testing, Recurrent Thrombosis, and Women's Health

Print ISSN: 0009-7322. Online ISSN: 1524-4539
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is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Circulation
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2014;130:283-287 Circulation.
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283
C
ase Presentation 1: A 33-year-old
previously healthy man presented
with sudden-onset dyspnea and sharp
right-sided chest pain. He had noted
right leg edema and calf discomfort a
week earlier. He denied recent trauma,
surgery, or immobility. His mother
had a history of postpartum deep vein
thrombosis (DVT). On physical exami-
nation, he was tachycardic with a heart
rate of 114 bpm, normotensive with
a blood pressure of 102/76 mm Hg,
and hypoxemic to 88% on room air.
Contrast-enhanced chest computed
tomogram demonstrated bilateral seg-
mental pulmonary embolism. Right
lower-extremity venous ultrasound
documented femoral and popliteal
DVT.
Case Presentation 2: A 78-year-old
woman with hypertension and obesity
developed acute left leg edema and
pain 2 days after open reduction and
internal xation of a right hip fracture.
On physical examination, the patient
had severe edema and tenderness of
the left lower leg and thigh. Left lower-
extremity venous ultrasound docu-
mented left common femoral, distal
femoral, and popliteal DVT.
Overview
Thrombophilias describe inherited
and acquired hypercoagulable states
that increase the risk of venous and, in
some cases, arterial thrombosis. The
prevalence of thrombophilias varies
according to the population studied. In
the general population, thrombophil-
ias are less frequent than traditional
venous thromboembolism (VTE) risk
factors such as cancer, immobility, and
obesity. However, in patients who have
experienced an initial episode of VTE
or have a family history of VTE, the
prevalence of thrombophilia increases.
In a European registry of 21 367
consecutive patients with symptom-
atic VTE, thrombophilia testing was
performed in 21%.
1
Thrombophilia
was detected in 32% of those in whom
testing was performed. The most fre-
quently detected thrombophilias were
factor V Leiden (26%), antiphospho-
lipid antibodies (20%), and prothrom-
bin gene mutation (18%). The rate of
thrombophilia detection was similar in
patients with idiopathic (unprovoked)
and provoked VTE.
Thrombophilias may be classied
according to their diagnostic yield.
High-yield thrombophilia testing
includes evaluation for factor V Leiden,
prothrombin gene mutation, and
antiphospholipid antibodies. Lower-
yield thrombophilia testing focuses
on deciency of protein C, protein S,
or antithrombin; homocysteine levels,
methylenetetrahydrofolate reductase
gene mutations; plasminogen activa-
tor inhibitor-1 levels; plasminogen
activator inhibitor-1 gene mutation;
and levels of factors VIII, IX, XI, and
brinogen. Importantly, the yield of
particular thrombophilia tests may vary
according to patient demographics.
Thrombophilias may also be cat-
egorized on the basis of whether the
hypercoagulable condition is inherited
or acquired and according to the risk
of initial thrombosis (Table 1). High-
risk thrombophilias include deciency
of protein C, protein S, or antithrom-
bin; homozygosity for factor V Leiden
or the prothrombin gene mutation;
compound heterozygosity for factor
V Leiden and the prothrombin gene
mutation; and elevated antiphospho-
lipid antibodies. Although quite rare
(0.2%), severe hyperhomocysteinemia
(>100 mol/L) is a high-risk thrombo-
philia associated with recurrent throm-
bosis in 42% of cases.
2
(Circulation. 2014;130:283-287.)
2014 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.113.007664
From the Cardiovascular Division, Department of Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, MA.
Correspondence to Gregory Piazza, MD, MS, Cardiovascular Division, Brigham and Womens Hospital, 75 Francis St, Boston, MA 02115. E-mail
gpiazza@partners.org
Thrombophilia Testing, Recurrent
Thrombosis, and Womens Health
Gregory Piazza, MD, MS
CLINICIAN UPDATE
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284 Circulation July 15, 2014
Major Thrombophilias
Factor V Leiden
The factor V Leiden mutation describes
a guanine-to-adenine substitution at
nucleotide 1691 that results in a gluta-
mine instead of arginine at amino acid
residue 506. Factor V becomes resis-
tant to cleavage by activated protein C
because of this mutation. The preva-
lence of factor V Leiden is greatest
among white patients (5%), especially
those of Northern European descent.
Factor V Leiden results in an almost
3-fold increase in the risk of a rst epi-
sode of VTE. Although factor V Leiden
increases the frequency of VTE at any
age, the mutation results in the great-
est increase in risk among patients 70
years of age.
3
Factor V Leiden testing
usually begins with a screening assay
for activated protein C resistance, fol-
lowed by direct DNA-based genotyp-
ing for positive screens.
Prothrombin Gene Mutation
The prothrombin gene mutation most
commonly describes a guanine-to-ade-
nine substitution at nucleotide 20210
in the 3 untranslated region of the pro-
thrombin gene. However, other poly-
morphisms of the prothrombin gene
have been reported. Heterozygotes for
the prothrombin gene mutation have
30% higher plasma prothrombin levels
than normal. Heterozygosity for the
prothrombin gene mutation confers a
4-fold increased risk of VTE.
4
Testing
for prothrombin gene mutation requires
direct DNA-based genotyping.
Antiphospholipid Antibodies
Antiphospholipid antibodies are
a class of autoantibodies directed
against epitopes on plasma proteins
that are exposed when these proteins
bind phospholipids on plasma mem-
branes. Antiphospholipid antibodies
may increase the risk of arterial and
venous thrombosis through a variety
of proposed mechanisms, resulting in
endothelial injury and coagulation acti-
vation.
5
DVT, pulmonary embolism,
and stroke are the most common com-
plications of antiphospholipid antibod-
ies, although any segment of the arterial
or venous circulation may be affected.
A small subset of patients will develop
catastrophic antiphospholipid antibody
syndrome, characterized by thrombo-
sis in multiple vascular beds culmi-
nating in multisystem organ failure.
Testing for antiphospholipid antibodies
includes lupus anticoagulant assays to
detect autoantibodies that prolong in
vitro clotting times and enzyme-linked
immunosorbent assay for anti-cardio-
lipin antibodies, anti
2
-glycoprotein I
antibodies, and anti-prothrombin anti-
bodies. Because antiphospholipid anti-
bodies may be transiently present in
the setting of an acute thrombotic event
or infection, testing should be repeated
at least 12 weeks after an initial posi-
tive test to document the persistence of
the antiphospholipid antibody.
Impact on Recurrent VTE
Thrombophilia testing is often per-
formed to assess the risk of recurrent
VTE in a patient with an initial event.
However, only a subset of thrombo-
philias have been documented to sig-
nicantly increase the risk of VTE
recurrence. Although antiphospholipid
antibodies and deciency of protein
C, protein S, or antithrombin consis-
tently increase the risk of recurrent
VTE, more commonly diagnosed
thrombophilias such as factor V Leiden
and the prothrombin gene mutation
do not appear to increase the risk of
recurrence.
In the Leiden Thrombophilia Study,
474 patients with an initial VTE event
underwent extensive thrombophilia
testing, including evaluation for factor
V Leiden and levels of homocysteine,
brinogen, factor VIII, factor IX, factor
XI, protein C, protein S, and antithrom-
bin.
6
The cumulative rate of recurrent
VTE was similar in patients with and
without thrombophilia (adjusted haz-
ard ratio, 1.4; 95% condence interval,
0.92.2). With the exception of patients
with hyperbrinogenemia, none of the
tested thrombophilias were associated
with an increased risk of recurrent
VTE.
A subsequent study evaluated the
impact of factor V Leiden and the
prothrombin gene mutation on VTE
recurrence.
7
Heterozygosity for either
factor V Leiden or the prothrombin
gene mutation was not associated with
an increased risk of VTE recurrence.
Furthermore, compound heterozygos-
ity and homozygosity for either factor
V Leiden or prothrombin gene muta-
tion did not increase the risk of recur-
rent VTE.
Determining whether a VTE event
was provoked or unprovoked (idio-
pathic) appears to have greater impli-
cations for the prevention of VTE
recurrence than the results of throm-
bophilia testing. In an analysis of 1626
patients with an initial VTE, unpro-
voked VTE (adjusted hazard ratio, 2.3;
95% condence interval, 1.822.9) was
a more powerful predictor of recur-
rent VTE than thrombophilia status
(adjusted hazard ratio, 1.44; 95% con-
dence interval, 1.032.03) and increas-
ing age (adjusted hazard ratio, 1.14;
Table 1. Thrombophilia Classication
Thrombophilia
Arterial/Venous
Thrombosis Inherited/Acquired
Relative Risk of Initial
Thrombosis
Factor V Leiden Venous Inherited Heterozygous
Homozygous
Prothrombin gene
mutation
Venous Inherited Heterozygous
Homozygous
Protein C deciency Venous Inherited
Protein S deciency Venous Inherited
Antithrombin deciency Venous Inherited
Hyperhomocysteinemia Arterial/venous Rarely inherited/most
often acquired
If mild to moderate
If severe
Antiphospholipid
antibodies
Arterial/venous Acquired
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Piazza Thrombophilia Testing 285
95% condence interval, 1.061.12).
8

Extending anticoagulation with either
warfarin
9,10
or a direct oral anticoagu-
lant
1113
reduces the risk of recurrent
VTE by 60% to 90% over placebo in
patients with unprovoked VTE who
have completed limited-duration antico-
agulation. Low-dose aspirin in patients
with unprovoked VTE who have com-
pleted limited-duration anticoagula-
tion also reduces the risk of recurrent
VTE.
14,15
Persistently elevated D-dimer
levels at 1 month after the completion
of limited-duration anticoagulation in
patients with an initial unprovoked VTE
may identify some patients at increased
risk for VTE recurrence.
Impact on Womens Health
Thrombophilia has important implica-
tions for womens health, particularly
contraceptive therapy, fertility, and
pregnancy.
Hormonal Contraceptive/
Replacement Therapy
Use of combination oral contraceptive
pills, especially those containing third-
generation progestins, has been asso-
ciated with at least a 3-fold increased
risk of VTE.
16
Use of combination
oral contraceptive pills in patients
with thrombophilia such as factor V
Leiden heterozygosity is associated
with at least a 30-fold increase in risk
of VTE.
16
The increased risk of VTE
appears to be highest around the time
of oral contraceptive pill initiation and
within the rst 6 months.
Infertility
In a subset of women, thrombophilia
results in infertility, which may mani-
fest as difculty with conception,
recurrent pregnancy loss, or both. The
mechanism by which thrombophilia
causes infertility does not appear to
be limited to a hypercoagulable state
but may also include abnormalities of
trophoblast differentiation and placen-
tation. Thrombophilias are associated
with both early and late pregnancy loss.
Thrombophilia and Pregnancy
Thrombophilias also increase the risk
of pregnancy-related complications,
including VTE. For example, the rela-
tive risk increase for VTE ranges from
9-fold in women with heterozygosity
for factor V Leiden to 34-fold in those
with homozygosity for the mutation.
17

However, the absolute risk increase in
pregnant women with factor V Leiden
is 0.2%.
18
Therefore, although the rela-
tive risk of VTE resulting from throm-
bophilia in pregnancy is high, the
absolute risk is low.
18
The risk of other pregnancy-related
complications such as preeclampsia and
placental abruption is also increased in
the presence of thrombophilia.
Thrombophilia Testing
Thrombophilia testing is often consid-
ered in patients with VTE at a young
age, recurrent VTE, thrombosis in
unusual sites, a strong family his-
tory of VTE, and recurrent pregnancy
loss. Rationales for performing throm-
bophilia evaluations include select-
ing the optimal agent and duration of
anticoagulation, predicting the risk of
VTE recurrence, determining the opti-
mal intensity of thromboprophylaxis,
assessing VTE risk with pregnancy or
hormonal contraceptive or replacement
therapy, and identifying family mem-
bers at risk for thrombosis. Patients
seeking an explanation for an arte-
rial or venous thrombosis, especially
if unprovoked or expected, will fre-
quently request thrombophilia testing.
Strategies for Thrombophilia
Testing and Cost Implications
Various strategies for thrombophilia
testing have been proposed. The
kitchen sink approach runs all avail-
able tests. A selective strategy performs
the highest-yield tests rst and focuses
on those tests that will affect therapy or
for which there is an intellectual curios-
ity, for example, if a patient has a com-
pelling family history. Finally, a no
testing approach is to defer all testing
because the results are not expected to
affect disease management.
Selection of an approach to throm-
bophilia testing must take into account
cost implications. A kitchen sink
approach, if applied broadly, would
result in a considerable cost to health-
care systems with limited yield, given
the low prevalence of thrombophilia
in the general population. Although
saving on laboratory costs, a no test-
ing approach would fail to identify
patients with high-risk thrombophilias
who would benet from extended-
duration anticoagulation and may incur
the expense of potentially preventable
recurrent VTE.
The cost-effectiveness of throm-
bophilia testing for patients with an
initial VTE has been the focus of a
number of decision analysis studies. In
a Markov model, strategies of throm-
bophilia testing or no testing followed
by anticoagulation for 6 to 36 months
were compared in a cohort of patients
with idiopathic DVT.
19
Thrombophilia
testing followed by 24 months of anti-
coagulation in patients with a hyper-
coagulable state proved to be more
cost-effective than 6 months of antico-
agulation without testing.
A subsequent modeling study
assessed the cost-effectiveness of
changing standard 3-month warfarin-
based anticoagulation for acute VTE
to 10-year, 20-year, or lifelong therapy
on the basis of the results of thrombo-
philia testing.
20
Thrombophilia test-
ing in patients with acute pulmonary
embolism was cost-effective regardless
of sex or age. For patients with acute
DVT, thrombophilia testing was cost-
effective in men <70 years of age and
women <50 years of age.
A Stepwise Approach to
Thrombophilia Testing
A stepwise strategy for thrombophilia
testing considers the clinical scenario
(when to test), the implications of test-
ing (why to test), and then the overall
approach to testing (how to test). A
selective strategy begins with an ini-
tial thrombophilia evaluation focused
on the highest-yield testing, factor
V Leiden, prothrombin gene muta-
tion, and antiphospholipid antibodies
(Figure). Although antiphospholipid
antibodies require conrmation 12
weeks after an initial positive, poly-
morphisms detected on genetic testing
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286 Circulation July 15, 2014
for factor V Leiden or prothrombin
gene mutation represent true posi-
tives, regardless of when the testing
is performed. A secondary evaluation
for less common thrombophilias such
as deciencies of protein C, protein S,
and antithrombin may be performed
after completion of anticoagulation if
a high clinical suspicion for throm-
bophilia exists and the initial evalua-
tion is negative. Because low levels of
protein C, protein S, and antithrombin
may be observed in the setting of acute
thrombosis and anticoagulation and do
not necessarily indicate true thrombo-
philia, testing for these thrombophilias
should be deferred for the short term
(Table 2).
Although the desire to perform
thrombophilia testing during the
patients hospitalization for VTE is
frequently high, a strong case can be
made to defer evaluation to the follow-
up outpatient visit. Clinicians often
have very limited time and resources
during the hectic hospitalization for a
thrombotic event to explain the impli-
cations of a thrombophilia diagnosis on
management and to answer questions.
Furthermore, the psychological shock
of suffering thrombosis may hinder a
patients ability to absorb the implica-
tions of a discussion on thrombophilia
testing and its ramications.
Case Presentation 1: Given the
patients youth, family history of VTE,
and unprovoked event, thrombophilia
testing was performed after discharge
from the hospital. A lupus anticoagu-
lant was detected and subsequently
conrmed on a second test 6 weeks
later. Because of a high risk of VTE
recurrence in the setting of a lupus anti-
coagulant and an unprovoked event, the
patient was maintained indenitely on
warfarin anticoagulation with an inter-
national normalized ratio of 2 to 3. At
the 1-year follow-up, he had recovered
fully and had not experienced another
pulmonary embolism or DVT.
Case Presentation 2: Given the
patients age and the provoked nature
of her DVT, thrombophilia testing was
not performed. She was treated with 6
months of anticoagulation with riva-
roxaban. At the 1-year follow-up, she
had recovered fully and had not suf-
fered a VTE recurrence.
Disclosures
None.
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Table 2. Tips for Thrombophilia Testing
Follow a stepwise strategy for thrombophilia testing that considers the clinical scenario (when to test), the
implications of testing (why to test), and then the overall approach to testing (how to test).
Use a selective strategy that focuses on the highest-yield thrombophilia testing rst.
Defer testing for deciencies of protein C, protein S, and antithrombin because low levels do not necessarily
indicate true thrombophilia in the setting of acute thrombosis and anticoagulation.
Remind patients that a negative thrombophilia evaluation does not exclude thrombophilia because there are
many hypercoagulable conditions that have yet to be identied and for which testing does not exist.
Consider deferring thrombophilia testing to the follow-up outpatient visit when there will be more time for
discussion and when the patient will have recovered psychologically from the acute thrombotic event.
Figure. A stepwise approach to thrombophilia testing.
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