ORIGINAL ARTICLE – VASCULAR
Interactive CardioVascular and Thoracic Surgery 20 (2015) 21–23
doi:10.1093/icvts/ivu346 Advance Access publication 17 October 2014
Inherited risk factors in low-risk venous thromboembolism
in patients under 45 years
Seyhan Yilmaza,* and Serdar Gunaydinb
a
b
Department of Cardiovascular Surgery, Hittite University Corum Training and Research Hospital, Corum, Turkey
Department of Cardiovascular Surgery, Medline Hospital, Eskisehir, Turkey
̇
* Corresponding author. Dr Ilhan
Gürel cad. No: 9/4-ÇORUM, Corum, Turkey. Tel: +90-533-6838186; fax: +90-364-2230323; e-mail: [email protected] (S. Yilmaz).
Received 17 June 2014; received in revised form 4 September 2014; accepted 8 September 2014
Abstract
METHODS: Of 96 VTE patients who presented to our outpatient department between February 2012 and November 2013, 58 were considered eligible for the study. Blood samples taken for thrombophilia testing were investigated in a molecular genetics and diagnosis laboratory. These data were collected prospectively and analysed retrospectively.
RESULTS: The mean age of patients in our study was 39.12 ± 2.1 years. Of the 58 patients, 30 had factor V Leiden mutation (5 homozygous,
25 heterozygous), 16 had prothrombin gene mutation, 24 had methylenetetrahydrofolate reductase C677T mutation (5 homozygous, 19
heterozygous), 18 had protein C deficiency, 17 had protein S deficiency, 14 had antithrombin III deficiency and 13 had hyperhomocysteinaemia. We observed that at least one inherited risk factor was present in most of the patients with VTE (n = 45), a finding that was compatible with those of previous studies.
CONCLUSIONS: Inherited risk factors are common among patients who present with VTE but have no major acquired risk factors. We
conclude that these patients should be further evaluated for evidence of molecular risk factors.
Keywords: Venous thromboembolism • Genetic • Thrombophilia
INTRODUCTION
Venous thromboembolism (VTE) is an important health problem
that is associated with significant mortality and morbidity. Various
genetic and acquired risk factors have been shown to be related
with its development. Its annual incidence is reported to range
from 0.1 to 0.3%. Pulmonary embolism (PE) and deep venous
thrombosis (DVT) are the most common clinical presentations of
the disease [1–3]. It has been reported that about 40% of patients
with VTE have one of the known acquired risk factors [4].
Inherited thrombophilia is common among young patients
who have recurrent VTE. Hypercoagulability disorders should be
considered in patients with recurrent thrombosis who do not
carry the known risk factors for VTE, and also in familial thrombosis cases. Such circumstances warrant thrombophilia screening,
although this is controversial [5]. Patients who have inherited
thrombophilia are at an increased risk of recurrent VTE, and these
patients have VTE episodes before the age of 45 years. About 30%
of these patients also have a positive family history of VTE [6]. In
addition, protein S, protein C, antithrombin-III deficiency, hyperhomocysteinaemia, factor XII deficiency and increased factor VIII
are among the most common abnormalities encountered in
patients with inherited thrombotic diseases [7, 8].
The aim of the present study is to investigate the incidence of
inherited risk factors for thrombophilia in patients who presented
with VTE without having a major acquired risk factor. Our study
included VTE patients who were admitted to the tertiary hospital
serving the province and the study group included both patients
with a first episode of VTE and those who had recurrent VTE.
PATIENTS AND METHODS
The study was approved by the local ethics committee
(Gaziosmanpasa University, Date: 10 December 2013, Number:
83116987-406). All participants gave their informed consent to take
part in the research. This cross-sectional study included patients
who were admitted to our tertiary hospital between February 2012
and November 2013 with the diagnosis of VTE. The data were collected prospectively and analysed retrospectively. Patient registry
information and counselling charts were systematically reviewed for
documentation of demographic risk factors and patient characteristics. The study group consisted of patients younger than 45 years of
age who had a first or recurrent episode of VTE without having any
acquired risk factors, including pregnancy, trauma, prolonged immobilization (over 6 months), obesity (body mass index >40),
© The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
ORIGINAL ARTICLE
OBJECTIVES: Venous thromboembolism (VTE) is a complex disease and an important preventable cause of morbidity and mortality today.
Many genetic and acquired factors contribute to its aetiology. The aim of the present study is to investigate the incidence of inherited risk
factors for thrombophilia in patients under 45 years of age who presented with VTE without having a major acquired risk factor.
S. Yilmaz and S. Gunaydin / Interactive CardioVascular and Thoracic Surgery
22
Table 1: Patient demographics
Variable
n (%)
Age
Male patients
Patients with familial predisposition
Patients with recurrent VTE
Patients who had VTE at a younger age
Smokers
39.12 ± 2.10
26 (45)
21 (36)
27 (47)
39 (67)
9 (16)
VTE: venous thromboembolism.
malignancy, major surgery and use of oral contraceptives. We have
chosen a younger generation with low risk to demonstrate the clear
impact of inherited risk factors [2]. Care was taken for the ethnicity
of the patients to be similar origin. Patients who had acquired risk
factors for VTE and those who had previous thrombophilia testing
and had been diagnosed with any type of inherited gene disorder
were excluded from the study. Patients who were on anticoagulation treatment were also excluded from the study.
Of 96 VTE patients who presented to our outpatient department
between the dates given, 58 were considered eligible for the study.
Routine laboratory investigation included total blood count, renal
and liver function tests, d-dimers, venous duplex scanning of both
lower limbs and chest X-ray. Patients who had a history of PE and
those who had symptoms possibly indicating PE were evaluated
with contrast computed tomography. Blood samples taken for
thrombophilia testing were investigated in the molecular genetics
and diagnosis laboratory of another university hospital serving a
neighbouring province. Thrombophilia testing included DNA isolation, gel electrophoresis, multiplex polymerase chain reaction and
stipple mutation analyses; protein C, S and antithrombin-III activities were also detected.
All patients were started on oral warfarin and subcutaneous
low-molecular weight heparin (1.5 mg/kg/day) immediately after
the blood samples were drawn. A pair of 30–40 mmHg compression stockings was given to all patients and they were encouraged
to walk during their hospital stay.
Descriptive data were given in number of patients without
defining as percentages since the total number of patients was
below a hundred. This descriptive study did not include any further
statistical analysis.
RESULTS
Patient demographics are given in Table 1. One patient had VTE in
both legs, 18 patients had right leg involvement and 38 had left
leg involvement. Five patients had a previous history of PE. None
of the patients with PE had severe chronic thromboembolic pulmonary hypertension. The distributions of thrombophilia markers
and risk factors are given in Fig. 1. The results of the genetic analysis in our patients are given in Figs 2 and 3.
Of the 58 patients, 30 had factor V Leiden (FVL) mutation
(5 homozygous, 25 heterozygous), 16 had prothrombin (PT)
gene mutation and 24 had methylenetetrahydrofolate reductase
(MTHFR) C677T mutation (5 homozygous, 19 heterozygous).
Twelve of the 30 patients with FVL mutation also had PT gene mutation and 11 of those 30 patients also had MTHFR C677T gene
Figure 1: Venn diagram showing the number of patients testing positive for
each of the thrombophilia markers.
Figure 2: Venn diagram showing number of patients having mutations in each
gene category.
Figure 3: Results of genetic analysis. FV Leiden: factor V Leiden; MTHFR: methylenetetrahydrofolate reductase.
mutation. A total of 45 patients were diagnosed to have at least one
hereditary risk factor, whereas 13 patients had none of the risk
factors we investigated.
DISCUSSION
Inherited mutations of genes encoding coagulation factors show
important differences within the general population and this variation may also be encountered across different regions of the
same country. The increasing incidence of the inherited tendency
to PE is remarkable. We consider that VTE patients who do not
carry acquired risk factors should be further evaluated for evidence of molecular risk factors [1]. Therefore, the present study
S. Yilmaz and S. Gunaydin / Interactive CardioVascular and Thoracic Surgery
heterozygous PT gene mutation [10]. In our study, 45 patients
(77%) had one or more inherited risk factors for VTE and 13
patients (22%) had no genetic risk factors.
Our observation that at least one inherited risk factor was
present in the majority of VTE patients is consistent with previous
studies. We observed that the presence of at least one inherited
risk factor in an individual patient increased the risk of VTE; this is
consistent with previous studies. Simioni et al. reported that APC
resistance was more frequent than all other inherited mutations in
patients with recurrent VTEs [11]. In our study, FVL resistance was
the most common inherited disorder among all other mutations
we investigated.
It is still controversial whether asymptomatic relatives who have
an inherited risk for VTE should receive anticoagulation, or not.
However, it has been proposed that these patients be given anticoagulation in risky periods [8]. Because FVL and PT gene mutation positivity was higher in our series, we suggest that VTE
patients of younger age should undergo thrombophilia testing if
they do not carry any of the known acquired risk factors for development or recurrence of VTE. As a first step, these patients may
be tested for protein C, protein S and PT gene mutations; further
molecular assessment is warranted in patients who show suspicious findings.
Conflict of interest: none declared.
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ORIGINAL ARTICLE
was performed to reveal the incidence of inherited disorders in
patients of younger age who presented with a first or a recurrent
episode of VTE.
FVL mutation is reported to be the most commonly observed
inherited risk factor in the European population, with a prevalence
rate ranging from 4 to 15%. Its occurrence has also been associated with an increased risk of VTE recurrence. Heterozygous
mutations of FVL were observed in 12–20% of patients with incidental VTE and in 40–50% of patients with familial predisposition
[1]. Homozygous FVL mutations are less frequent, with an incidence rate of 0.02%. Abughoush et al. reported in their study of
unexplained VTE cases that 33.6% of the patients had activated
protein C (APC) resistance, and this condition was associated with
an increased risk of venous thrombosis [9]. The prevalence of FVL
mutation was reported to be 9–10% in Turkey, and various reports
from Turkey found the mutation in 20% of patients with VTE [1]. In
our patients, FVL mutation was much more common than in the
normal population, and also more common than previously
reported in patients with VTE. This may be attributed to the fact
that our study population consisted of patients who did not carry
major acquired risk factors for VTE. Furthermore, the FVL frequency in our patients was close to that reported in patients with
familial predisposition and recurrent disease.
About 10% of patients who have heterozygous FVL mutation
and almost all who have homozygous FVL mutation are at an
increased risk for development of VTE during their lifespan [1].
The incidence rate of homozygous FVL mutation has been
reported to be 0.02% and patients with homozygous mutations
have a higher risk of developing VTE than those who have heterozygous mutations. The reason for this is that heterozygous individuals have normal factor V circulating within the bloodstream.
Simkova et al. reported in their study of a Slovak population that
37% of all VTE patients had an FVL mutation and 8% of these were
homozygous mutations [3]. In our study, 9% of FVL mutations
were homozygous; this rate was higher than that reported in the
general population and in VTE patients.
The second most common genetic risk factor for VTE is PT gene
mutation, which is present in 6% of Caucasians. It has been
reported to increase the risk of VTE by 2.7–3.8% [1, 10]. The prevalence rate of this mutation is 2.3% in healthy individuals and
6–18% in patients who have various diseases. The heterozygous
form of this mutation increases the risk of VTE by 3-to 9-fold. Its
incidence rate was reported to be 2.6% in a healthy Turkish population. In different studies, its incidence rate has been reported to
range 6.3–7.7% in patients with PE and 6–16% in patients with
DVT [1]. As with our findings regarding the FVL gene mutation, the
PT gene mutation was also more common than previously
reported.
Although point mutation in the MTHFR gene has been reported
to be associated with an increased risk of venous and arterial
thrombosis, a recent study found no relationship between this
mutation and increased VTE risk. In the Turkish population, the incidence rate of MTHFR C677T gene mutation was reported to
range 20.0–34.9% [1]. Our finding that the MTHFR gene mutation
rate was high in VTE patients is consistent with the literature.
Stefano et al. reported that 45% of their patients had no mutations, whereas 21% of patients had heterozygous FVL and 3% had
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