Discussion:
This study showed the following results: firstly, IT did not influence
the decision to pursuit or to stop anticoagulation. In patients who
stopped anticoagulation, IT was not associated with longer treatment
duration. However patients with idiopathic VTE and IT received
anticoagulation for a period of time longer than those with provoked VTE
and IT. Secondly IT did not increase the risk of VTE recurrence. In
univariate analysis, male gender, smoking, history of previous VTE or
cardiovascular events, proximal localization, persistent risk factor,
idiopathic thrombosis and post phlebitic syndrome significantly
increased the risk of recurrence. This retrospective study provided a
real life vision of clinical decisions regarding VTE treatment duration
in response to a tedious laboratory workup results. However it had some
limitations, mainly the monocentric and retrospective character of the
study as well as the small cohort. Thus, results could not be
generalized. We mentioned also as a limitation the non availability of
factor V Leiden and prothrombin gene mutation results that are included
in the IT workup as well as the absence of a control group of patients
with VTE who were not tested for IT.
Therapeutic implications of IT: This study showed that
anticoagulation was pursued in half the patients with IT. Patients with
both IT and idiopathic VTE received a longer course of anticoagulation
comparing to patient with IT and provoked VTE. So far, there is no
prospective study assessing the benefice of prolonged anticoagulation
versus routine duration in patients testing positive for IT [10]. In
the MEGA study [11], which is the largest case controlled study, the
authors have evaluated the influence of treatment decisions taken after
obtaining IT screening results. Testing was performed in 35% of
patients who had had recurrence versus 30% of patients without
recurrence. Testing for IT did not reduce the risk of recurrence.
Similarly, data from literature stipulate that IT seems to have a minor
role in determining the duration of anticoagulant treatment after a VTE
[12]. The evaluation of real professional practices showed that IT
testing was frequently realized after an episode of VTE but rarely
considered in deciding treatment duration [5,13].
Regarding the available recommendations [6,8,14,15], there is no
clear consensus concerning patients’ management according to the results
of IT testing which led to heterogeneity in therapeutic attitude among
clinicians. Nevertheless, it is obvious that IT screening is no longer a
determinant factor in treatment decisions. Deconstructing the actual
recommendations, IT screening still has a minor therapeutic implication
in specific situations essentially after an unprovoked first proximal
VTE in patients without a high hemorrhagic risk and desiring to
interrupt anticoagulation [8,16]. In addition, some experts tend to
restrict more the indication of a prolonged anticoagulation and reserve
it to patients with proximal first VTE and deficiency of AT or
deficiencies of PC and PS less than 30% [17]. On the topic of VTE
at unusual site, the optimal duration of anticoagulation is still
unknown due to the lack of solid evidence [18]. According to recent
recommendations [18,19], the duration of treatment depends
essentially on the site of thrombosis and the presence of an eventual
underlying condition. Nevertheless, some authors enhance a prolonged
anticoagulation in patients with cerebral venous thrombosis, portal vein
or supra hepatic thrombosis and major thrombophilia [18,19].
Risk of VTE recurrence: In this study, the recurrence rate
after treatment withdrawal was 21%. This rate varies from one study to
another (7.75-23.9%) [20,21]. This variation is essentially due to
differences in inclusion criteria of patients and duration of follow up.
In Satpanish et al [22] study including 198 patients with either
first or recurrent VTE from 2004 to 2014 followed up during a mean
period of 52 months, the recurrence rate was 11%.
In the present study, male sex, smoking, personal history of venous
thrombosis or cardiovascular events, persistent trigger, unprovoked VTE
and post phelebitic syndrome were predictors of recurrence in the
univariate study. Compared to distal VTE, proximal VTE were not
associated with a high risk of recurrence. This observation may be
explained, at least partially, by the duration of anticoagulation which
was significantly longer in proximal VTE than in distal thrombosis.
Nevertheless, and comparing to other localizations, proximal deep venous
thrombosis was a risk factor of recurrence. Predictors of the risk of
recurrence are not formally established. This is due to the
multifactorial character of the VTE, the complexity of interactions
between the risk factors and the differences in study methodologies.
Nevertheless, available data from literature showed that the following
factors were predictive, regularly or not, of a high risk of recurrence:
young age [23], male sex [24], obesity [25], dyslipidemia
[26], family history of thrombosis [27], personal history of
thrombosis [20], proximal VTE [28], unprovoked VTE [29],
persistent risk factor [30] and post phlebitic syndrome [31]. In
fact, it is proved that the main clinical characteristic considered as
determinant in estimating the risk of recurrence is the idiopathic type
of VTE [6,8,14,15].
Regarding the impact of IT on the risk of recurrence, it did not affect
the risk of recurrence in the present study. In the absence of a
methodologically powerful study, it is still controversial whether IT
confers a greater risk of recurrence. Such study would have as
intervention thrombophilia testing and as result the occurrence of a
recurrent thrombotic event [32]. A study following this model was
initiated but was early interrupted because of a low inclusion rate
[32]. Nevertheless, several studies with heterogeneous methodologies
have assessed the role of IT on the risk of recurrences. Some
investigators did not find an increased risk of recurrence associated
with the presence of IT regardless of the idiopathic or provoked type of
VTE [13,24,33]. On the other hand, several retrospective and
prospective studies have shown that IT significantly impacted the risk
of recurrence after anticoagulation withdrawal [21,22,34].
Concerning the deficiencies of natural inhibitors, the study of their
impact on the risk of recurrence is difficult due to their low
prevalence and the lack of prospective studies [35]. Available data
demonstrated that the risk of recurrence conferred by these deficiencies
was at best moderately elevated and seemed to be highest in patients
with AT deficiency [33,36]. Three systematic reviews have
demonstrated that the risk of recurrence in carriers of an heterozygous
factor V Leiden mutation was modesty increased with a relative risk
varying from 1.36 to 1.56 [37-39]. Concerning the heterozygous
prothrombin gene mutation, data diverged between the absence of an
increased risk to a modest significant increase. Uncertainty remains
also with homozygous mutations and compound heterozygosity for both
mutations [11].
Conclusion: Despite the small cohort and the non exhaustivity
of thrombophilia testing, we could draw some conclusions: Practically,
the value of screening in patients with VTE is limited. Results did not
alter initial management in real practice. Decisions usually depend on
clinician judgment and sometimes the patient preferences. IT testing
should be performed only in the case the result influences patient
management. Prospective studies determining the situations where
changing management in response to thrombophilia testing results is of
clear clinical benefit are warranted.