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.