The Thrombophilic Pattern of Different Clinical Manifestations of Venous Thromboembolism: A Survey of 443 Cases of Venous Thromboembolism

Abstract

Although pulmonary embolism (PE) and deep vein thrombosis (DVT) share many risk factors, it is uncertain whether thrombophilic abnormalities may impact differently on the development of these two clinical manifestations of venous thromboembolism (VTE). To give further insight into this issue, we estimated the association of PE with different types of thrombophilia and evaluated whether these abnormalities have a different prevalence in patients presenting with PE, alone or associated with DVT, as compared with those with isolated DVT. In this study 443 consecutive patients with a first episode of VTE and 304 matched healthy controls underwent laboratory screening for thrombophilia, including natural anticoagulants, factor V Leiden and prothrombin G20210A polymorphisms, antiphospholipid antibodies, homocysteine, factor VIII, and lipoprotein(a). Of the 443 patients, 224 patients had isolated DVT, 144 had combined DVT/PE, and 75 had isolated PE. At least one thrombophilic abnormality was detected in 72.8% of DVT, 66% of DVT/EP, and 60% of isolated PE patients. A high prevalence of hyperhomocysteinemia and elevated lipoprotein(a) levels was found in all patients with no significant differences among the three groups. The prevalence of prothrombin G20210A polymorphism and of elevated factor VIII levels was significantly higher in patients with DVT and DVT/PE than in controls, but not in those with isolated PE, whereas factor V Leiden polymorphism was associated with isolated DVT but not with DVT/PE or isolated PE. In conclusion, the thrombophilic burden seems different in isolated PE versus DVT with or without PE, suggesting that PE may encompass a different pathophysiological process of thrombosis to DVT.

Full text

The Thrombophilic Pattern of Different Clinical
Manifestations of Venous Thromboembolism: A
Survey of 443 Cases of Venous Thromboembolism
Elisa Grifoni, M.D.1Rossella Marcucci, M.D.1, 2 Gabriele Ciuti, M.D.1Caterina Cenci, M.D.1, 2
Daniela Poli, M.D.2Lucia Mannini, M.D.2Agatina Alessandrello Liotta, B.S.2Massimo Miniati, M.D.1
Rosanna Abbate, M.D. 1, 2 Domenico Prisco, M.D.1
1Department of Medical and Surgical Critical Care, University of
Florence, Florence, Italy
2Department of Heart and Vessels, Thrombosis Centre, Azienda
Ospedaliero-Universitaria Careggi, Florence, Italy
Semin Thromb Hemost 2012;38:230–234.
Address for correspondence and reprint requests Rossella Marcucci,
M.D., Department of Medical and Surgical Critical Care, Center of
Atherothrombotic Disease, University of Florence, Largo Brambilla,
3–50134 Florence, Italy (e-mail: rossella.marcucci@unifi.it).
Pulmonary embolism (PE) and deep vein thrombosis (DVT)
are typically cons idered a single disea se entity termed venous
thromboembolism (VTE). Although they share many risk
factors, it is unclear whether thrombophilic abnormalities
may impact differently on the development of the two clini cal
manifestations of VTE. Inherited thrombophilia is detectable
in at least 30 to 40% of patients with DVT,1whereas contro-
versial data are available about its prevalence in patients with
PE. Several authors reported a lower prevalence of factor V
(FV) Leiden among patients with PE than among those with
Keywords
►venous
thromboembolism
►pulmonary embolism
►thrombophilia
Abstract Although pulmonary embolism (PE) and deep vein thrombosis (DVT) share many risk
factors, it is uncertain whether thrombophilic abnormalities may impact differently on
the development of these two clinical manifestations of venous thromboembolism
(VTE). To give further insight into this issue, we estimated the association of PE with
different types of thrombophilia and evaluated whether these abnormalities have a
different prevalence in patients presenting with PE, alone or associated with DVT, as
compared with those with isolated DVT. In this study 443 consecutive patients with a
first episode of VTE and 304 matched healthy controls underwent laboratory
screening for thrombophilia, including natural anticoagulants, factor V Leiden and
prothrombin G20210A polymorphisms, antiphospholipid antibodies, homocysteine,
factor VIII, and lipoprotein(a). Of the 443 patients, 224 patients had isolated DVT, 144
had combined DVT/PE, and 75 had isolated PE. At least one thrombophilic abnormality
was detected in 72.8% of DVT, 66% of DVT/EP, and 60% of isolated PE patients. A high
prevalence of hyperhomocysteinemia and elevated lipoprotein(a) levels was found in
all patients with no significant differences among the three groups. The prevalence of
prothrombin G20210A polymorphism and of elevated factor VIII levels was signifi-
cantly higher in patients with DVT and DVT/PE than in controls, but not in those with
isolated PE, whereas factor V Leiden polymorphism was associated with isolated DVT
but not with DVT/PE or isolated PE. In conclusion, the thrombophilic burden seems
different in isolated PE versus DVT with or without PE, suggesting that PE may
encompass a different pathophysiological process of thrombosis to DVT.
Issue Theme Coagulopathies and
Thrombosis: Usual and Unusual Causes
and Associations. Part VI; Guest Editors,
Giuseppe Lippi, M.D., and Emmanuel J.
Favaloro, Ph.D., M.A.I.M.S., F.F.Sc.
(RCPA).
Copyright © 2012 by Thieme Medical
Publishers, Inc., 333 Seventh Avenue,
New York, NY 10001, USA.
Tel: +1(212) 584-4662.
DOI http://dx.doi.org/
10.1055/s-0032-1301420.
ISSN 0094-6176.
230
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DVT—the so-called “FV Leiden paradox.”2–17 Asimilarfinding
was reported for prothrombin (PT) G20210A polymorphism
by some authors,10,11 but was not confirmed by
others.8,12,13,16,17 Recently, in a large series of patients with
afirst episode of proximal DVT, Rossi et al18 found that the
risk of symptomatic PE was increased in patients with anti-
thrombin (AT) deficiency or PT G20210A polymorphism and
decreased in those with FV Leiden in comparison to patients
without inherited thrombophilic defects. Less data are avail-
able about the role of other thrombophilic abnormalities,
such as the presence of antiphospholipid antibodies (aPL),
elevated levels of homocysteine (Hcy), factor VIII (FVIII), or
lipoprotein(a) (Lp[a]), in determining the risk of PE.10,19 This
study was designed to estimate the association of PE with
different types of thrombophilia and to evaluate whether
these abnormalities have a different prevalence in patients
presenting with PE, alone or associated with DVT, as com-
pared with those with isolated DVT.
Methods
Subjects Investigated
We studied 443 consecutive patients (229 men and 214
women, median age 57 [18 to 88] years) with a first episode
of V TE (DVT of the lower limbs and/or PE) who were referred
to our Thrombosis Center from January 2006 to Septem-
ber 2008. History was taken to assess the presence of circum-
stantial risk factors at the time of the episode of V TE, such as
surgery, trauma, prolonged immobilization, use of oral con-
traceptives or hormone replacement therapy, pregnancy, and
puerperium. In the absence of the aforementioned risk
factors, VTE was labeled as “unprovoked.”Diagnosis of DVT
or PE was accepted only when objectively confirmed by
standard imaging methods, such as compression ultrasonog-
raphy, perfusion lung scanning, and spiral computed tomog-
raphy. All patients with PE at presentation underwent an
ultrasonographic study of lower limbs and abdomen for DVT
within 5 days. Patients with known active cancer, or known
aPL syndrome were excluded.
The patients of control group (304 healthy subjects; 159
men [52.3%] and 145 women [47.7%]; median age 55, range
19 to 75 years) were recruited from blood donors and
partners or friends of the patients from the same geographi-
cal area. We excluded controls with a history of cardiovascu-
lar disease (coronary artery disease, cerebrovascular disease,
and peripheral artery disease) or VTE events.
Experimental Procedures
After giving informed consent, all patients and controls
underwent laborator y screening for thrombophilia, including
AT, protein C (PC) and free protein S (PS), FV Leiden and PT
G20210A polymorphisms, lupus anticoagulant (LA) and anti-
cardiolipin antibodies (aCL), fasting Hcy, and FVIII and Lp(a)
plasma levels. Patients were studied 6 months to 1 year after
the acute event, at least 1 month after having stopped
treatment wi th vitamin K antagonists, and also in the absence
of any severe inflammatory disease for at least 6 months.
Laboratory tests to screen thrombophilia were performed as
previously reported,20 except for PS, which was measured as
free antigen (Instrumentation Laboratory, Milan, Italy), and
FVIII levels, which were determined by a clotting method
(Siemens, Milan, Italy). AT, PC, and free PS deficiencies were
diagnosed in the presence of values <80% (AT), <65% (PC), and
<65% in females and 75% in males (free PS), respectively.
aPL positivity (LA or aCL) was defined according to the
revised Sydney (Miyakis et al) criteria.21 Fasting hyper-
homocysteinemia (HHcy) and high levels of FVIII were
diagnosed when plasma levels exceeded the 95th perce ntile
of distribution of values obtained in controls (17 and 13
μmol/L in males and females, respectively, for Hcy; 188% for
FVIII). A Lp(a) level >300 mg/L, which is widely accepted as
the cutoff for increased vascular risk,22,23 was considered as
elevated.
Statistical Analysis
Statistical analysis was performed using the Statistical Pack-
age for the Social Sciences (SPSS) software version 11.5 for
Windows (Chicago, IL). Unless otherwise indicated, the re-
sults are given as median (range). Di fferences between groups
were estimated by the Fisher exact test or the Mann-Whitney
test, used when appropriate. Logistic regression analysis was
used to describe the association between VTE and the pres-
ence of a thrombophilic risk factor. All odds ratios (OR) are
given with their 95% confidence inter val (CI). All probability
values are two-tailed, with pvalues <0.05 considered sta-
tistically significant.
Results
Clinical Characteristics of Patients
In this study, 224 patients (121 males and 103 females,
median age 60, range 18 to 88 years) had isolated DVT (Group
A) and 219 patients (108 males and 111 females, median age
55, range 18 to 87 years) had PE. Of these 219 patients, 144
patients’PE was a complication of a DVT (Group B), whereas
in 75 there was not objective evidence of an associated DVT
(viz, isolated PE group; Group C). In 242 patients (54.6%) VTE
occurred in th e absence of circumstantial risk fac tors. The rate
of unprovoked events was higher in Group A than in Group B
and C (p¼0.01 and p¼0.08, respectively). The prevalence of
circumstantial risk factors according to the type of VTE event
is reported in ►Table 1. A family history of VTE was recorded
in 104 patients (23.5%), with no significant differences among
the groups (►Table 1).
Inherited and Acquired Thrombophilic Abnormalities
The prevalence of thrombophilic abnormalities in patients
and in controls is reported in ►Table 2. The presence of at
least one thrombophilic abnormality was detected in 163
patients (72.8%) of Group A, in 95 patients (66%) of Group B, in
45 patients (60%) of Group C, and in 88 patients (28.9%) of
controls.
The frequency of natural anticoagulant deficiencies was
not significantly different between patients and controls,
except for PC deficiency found only in one control and in
six patients with isolated DVT (p¼0.04).
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Thrombophilic Pattern of Different Clinical Manifestations of VTE Grifoni et al. 231
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The prevalence of FV Leiden polymorphism was signifi-
cantly higher in Group A than in controls (OR 4.4; 95% CI, 2.3–
8.6; p<0.001), whereas no significant difference was ob-
served between control s and Group B (OR 1.9; 95% CI, 0.8–4.2;
p¼0.20) or Group C (OR 1.6; 95% CI, 0.6–4.6; p¼0.40).
Furthermore, patients with isolated DVT showed a signifi-
cantly higher frequency of FV Leiden in comparison to both
patients of Group B (OR 2.4; 95% CI, 1.2–4.9; p¼0.02) and C
(OR 2.8; 95% CI, 1.05–7.3; p¼0.03).
The prevalence of PT G20210A polymorphism was signifi-
cantly higher in Group A (OR 3.9; 95% CI, 1.6–9.5; p¼0.002)
and in Group B (OR 7.2; 95% CI, 3.0–17.5; p<0.001) than in
Table 1 Main Clinical Characteristics of Patients According to the Type of VTE Event
Characteristics Group A (DVT)
n¼224
Group B (DVT/PE)
n¼144
Group C (PE)
n¼75
Age at VTE median range (years) 60 (18–88) 55 (18–83) 58 (18–87)
Sex
Males n(%) 121 (54) 80 (55.6) 28 (37.3)
Females n(%) 103 (46) 64 (44.4) 47 (62.7)
Unprovoked VTE event n(%) 137 (61.2)
a
68 (47.2) 37 (49.3)
Provoked VTE event n(%) 87 (38.8)
a
76 (52.8) 38 (50.7)
Surgery n(%) 30 (13.4) 32 (22.2) 16 (21.3)
Tra uma n(%) 18 (8) 17 (11.8) 5 (6.7)
Immobilization n(%) 9 (4) 7 (4.9) 3 (4)
Oral contraceptives/hormone
replacement therapy
b
n(%)
26 (25.2) 20 (31.2) 10 (21.3)
Pregnancy/puerperium
b
n(%) 4 (3.9) 0 4 (8.5)
Family history of VTE n(%) 52 (23.2) 34 (23.6) 18 (24)
a
p¼0.01 versus Group B.
b
Percentage calculated on the number of female patients.
VTE, venous thromboembolism; DVT, deep vein thrombosis; PE, pulmonary embolism.
Table 2 Prevalence of Thrombophilic Abnormalities in Patients and in Controls
Condition Group A (DVT)
n¼224
Group B (DVT/PE)
n¼144
Group C (PE)
n¼75
Controls
n¼304
No abnormalities n(%) 61 (27.2)
a
49 (34)
a
30 (40)
a
216 (71.1)
AT deficiency
b
n(%) 3 (1.3) 2 (1.4) 0 1 (0.3)
PC deficiency
b
n(%) 6 (2.7)
c
0 0 1 (0.3)
PS deficiency n(%) 9 (4) 2 (1.4) 1 (1.3) 4 (1.3)
FV Leiden
b
n(%) 37 (16.5)
a
11 (7.6)
d
5 (6.7)
d
13 (4.3)
PT G20210A polymorphism
b
n(%) 19 (8.5)
e
21 (14.6)
a
4 (5.3)
f
7 (2.3)
aPL n(%) 7 (3.1) 1 (0.7) 2 (2.7) 5 (1.6)
Elevated FVIII levels n(%) 34 (15.2)
a
24 (16.7)
a
6(8)
f
13 (4.3)
HHcy n(%) 65 (29)
a
38 (26.4)a 23 (30.7)
a
10 (3.3)
Elevated Lp(a) levels n(%) 70 (31.3)
a
43 (29.9)
a
26 (34.7)
a
45 (14.8)
Multiple abnormalities n(%) 72 (32.1)
a
40 (27.8)
a
18 (24)
a
10 (3.3)
a
p<0.001 versus controls.
b
Combined heterozygosity for FV Leiden and PT G20210A polymorphisms in one patient with isolated DVT, one with DV T/PE,a ndo ne with isolated PE.
Combined AT deficiency and FV Leiden polymorphism in one patient with isolated DVT. Combined AT deficiency and PT G20210A polymorphism in
one patient with DVT/PE. Combined PC deficiency and FV Leiden polymorphism in one patient with isolated DVT. Homozygosity for FV Leiden
polymorphism in two patients with isolated DVT. Homozygosity for PTG20210A polymorphism in one patient with isolated DVT.
c
p<0.05 versus controls.
d
p<0.05 versus Group A.
e
p<0.01 versus controls.
f
p<0.05 versus Group B.
DVT, deep vein thrombosis; PE, pulmonary embolism; AT, antithrombin; PC, protein C; PS, protein S; FV, factor V; PT, prothrombin; aPL,
antiphospholipid antibodies; HHcy, hyperhomocysteinemia; Lp(a), lipoprotein(a).
Seminars in Thrombosis & Hemostasis Vol. 38 No. 2/2012
Thrombophilic Pattern of Different Clinical Manifestations of VTE Grifoni et al.232
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controls, whereas no significant difference was detected
between Group C and controls (OR 2.4; 95% CI, 0.7–8.4; p¼
0.20). Group B showed a higher frequency of PT G20210A
polymorphism in compar ison to both Group A (OR 1.8; 95% CI,
0.9–3.6; p¼0.085) and Group C (OR 3.0; 95% CI, 1.0–9.2; p¼
0.045).
As regards aPL positivity (LA and/or aCL), no significant
difference was observed between patients and controls.
Elevated FVIII levels were detected in a significantly higher
proportion of patients in Groups A and B (OR 4.0; 95% CI, 2.1–
7.8; p<0.001 and OR 4.5; 95% CI, 2.2–9.1; p<0.001, respec-
tively) than in controls, whereas the prevalence in patients
with isolated PE was not different from controls (OR 1.9; 95%
CI, 0.7–5.3; p¼0.20). The prevalence of elevated FVIII levels
was significantly higher in Group B than in Group C (OR 2.6;
95% CI, 1.1–5.9; p¼0.03).
The prevalence of HHcy and elevated Lp(a) levels was
significantly higher in patients than in controls (Group A
OR 12.0; 95% CI, 6.0–24.0; p<0.001 and OR 2.6; 95% CI, 1.7–
4.0, p<0.001, respectively; Group B OR 10.5; 95% CI, 5.1–
21.9; p<0.001 and OR 2.4; 95% CI, 1.5–3.9; p<0.001, respec-
tively; Group C OR 13.0; 95% CI, 5.8–28.9; p<0.001 and OR
3.1; 95% CI, 1.7–5.4; p<0.001, respectively), with no signifi-
cant differences among the three groups of patients.
Discussion
In this study we have performed an extensive analysis of
inherited and acquired thrombophilic abnormalities in a
series of patients with VTE referred to an Italian Thrombo-
sis Centre. Several studies are available on different throm-
bophilicmarkersinpatientswithisolatedPE,butthisisthe
first that has extensively evaluated parameters related to
thrombophilia in patients with different clinical manifes-
tations of VTE. Among metabolic markers associated with a
thrombotic risk, we found that HHcy and elevated Lp(a)
levels are the only ones significantly associated with iso-
lated PE.
Interestingly, the prevalence of PT G20210A polymor-
phism and of elevated FVIII levels was significantly higher
in patients with DVT and DVT/PE, but not with isolated PE
versus controls, whereas FV Leiden polymorphism was asso-
ciated with isolated DVT but not with DVT/PE or isolated PE.
Finally, the prevalence of natural anticoagulant deficiencies
and aPL was very low.
Previous data on the risk of PE associated with the pres-
ence of PT G20210A polymorphism were controversial.8,10–12
In our study the prevalence of PT G20210A polymorphism
was not significantly higher in isolated PE with respect to
controls. We found a significant association between this
polymorphism and DVT wit h or wi thout PE, with the highest
prevalence in DVT complicated by PE.
As regards FVIII levels, in a small study on 38 patients
with isolated PE and 26 with DVT/PE, Erkekol et al reported
an increased prevalence of high FVIII levels in patients with
isolated PE.19 Onthecontrary,wefoundthatelevatedFVIII
levels were not significantly associated with isolated PE. It
should be noted that FVIII may act as an acute phase
reactant, so that the time between the acute event and
blood sampling may affect the results. Erkekol et al re-
ported that FVIII was measured at least 4 months after the
index episode, whereas our patients were evaluated after a
significantly longer time, at least 1 month after warfarin
withdrawal with a minimum anticoagulation duration of
6months.
No data are available in the literature on the prevalence of
HHcy and elevated Lp(a) levels in the different clinical man-
ifestations of VTE. HHcy is a marker associated with an
increased risk of venous and arterial thrombotic events.
Lp(a) is a marker of arterial thrombotic risk. More
recently, we and others have demonstrated in a large
number of cases the significant association between ele-
vated Lp(a) levels and the risk of VTE.22,23 This study has
confirmed the higher prevalence of elevated Lp(a) levels in
patients with VTE and has found that is the only marker
associated with isolated PE.
It is, however, not surprising that hyperlipoproteinemia
(a) might be more strongly associated with isolated PE rather
than with DVT or secondary PE. The conformation of Lp(a) in
vivo is highly sensitive to the environmental conditions.
When exposed to strong shearing forces, such as those
present in the pulmonary arteries, Lp(a) undergoes a shift
from a close conformation to a fully extended chain, whereby
its thrombogenic potential is dramatically amplified.24 This
structural modification is instead less unlikely to occur in the
veins, where the blood flow is less perturbed.
Finally, as regards FV Leiden, several investigations
reported a lower prevalence of FV Leiden in PE in compari-
sontopatientswithDVT.
2–17 In our study, the prevalence
of this polymorphism in patients with PE, both with and
withoutDVT,wasnotsignificantly different from controls.
Moreover, in agreement with previous reports,3,4,7,8,10,12
the lowest prevalence of FV Leiden was found in patients
with isolated PE. Therefore, our results strengthen the so-
called “FV Leiden paradox.”As a possible explanation of the
weak association between FV Leiden and PE it has been
suggested that carriers of this polymorphism develop a
thrombus which is more stable and more adherent to the
vessel wall and so less likely to embolize.9This hypothesis
is supported by the knowledge that activated PC has
profibrinolytic effects, but activated PC-resistance due to
FV Leiden produces an increased thrombin formation,
which leads to an increased rate of activation of thrombin
activatable fibrinolysis inhibitor and to a downregulation
of fibrinolysis.25–27
Conclusion
Our data indicate that the prothrombotic pattern is different
in isolated PE from that observed in DVT with or without PE.
Thus, PT G20210A polymorphism and elevated FVIII are
associated with DVT but not with isolated PE and HHcy
and elevated Lp(a) levels represent the only risk markers
found in isolated PE. This supports the concept that isolated
PE may have a different pathophysiology of thrombosis from
DVT.
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Thrombophilic Pattern of Different Clinical Manifestations of VTE Grifoni et al. 233
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