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After a first episode of venous thromboembolism (VTE) oral anticoagulant treatment (OAT) is able to prevent most episodes of recurrence, but is associated with a significant risk of major bleeding [1,2]. Therefore the evaluation of possible predictors of VTE recurrence at the time of OAT withdrawal is of clinical relevance, in order to better define the optimal duration of therapy. Several parameters have been evaluated as contributing factors to recurrence: the presence of thrombophilia, the plasma concentration of clotting activation markers and the entity of venous recanalization assessed by compression ultrasonography (CUS). Nevertheless, none of these parameters shows a predictive value for recurrence high enough to give a clear indication on OAT optimal duration [3,4]. Few studies have evaluated the role of the combination of these parameters as predictors of recurrence [5,6], and in each study only some of them have been considered. The purpose of our study was to assess if the risk of VTE recurrence could be better predicted by the association of several parameters: the levels of D-dimer, prothrombin fragment 1 + 2 (F1+2), residual vein obstruction (RVO) and thrombophilia, alone or in combination.

We prospectively investigated a cohort of consecutive patients who had suffered from a first episode of VTE and were referred to our Centre, from June 1996 to June 2006. All were on warfarin, therapeutic range INR 2-3 [7,8]. The treatment duration was at least 3 months in the case of VTE associated with transient risk factors and at least 6 months in the case of idiopathic VTE. The follow-up started after OAT withdrawal.

One month after stopping OAT all patients were screened for common thrombophilia markers (antithrombin III, protein C and protein S deficiency, factor V Leiden mutation, G20210A prothrombin gene variant), for antiphospholipid antibodies, D-dimer and F1+2 plasma levels. Laboratory tests to screen thrombophilia were performed as previously reported [9,10], except for protein S which was measured as free antigen (Instrumentation Laboratory, Milan, Italy). Exclusion criteria were the presence of antiphospholipid antibody syndrome and active cancer. D-dimer testing was measured by IL-Test (Instrumentation Laboratory, Milan, Italy); normal values <250 μg L−1. F1+2 was assayed by Enzygnost F1+2 (Behring Institute, Marburg, Germany); normal values <1.4 nmol L−1 [11]. Patients who suffered from deep vein thrombosis (DVT) underwent CUS examination of the common femoral and popliteal veins of lower limbs at OAT withdrawal. RVO was defined as present when the vein transverse diameter was greater than 2 mm or when residual thrombus occupied more than 40% of the vein area at maximum compressibility [12,13].

All patients had periodical examinations (twice in the first year and once thereafter) and were contacted by phone if they missed the appointment. Moreover, they were instructed to contact the Anticoagulation Clinic at the occurrence of symptoms and/or signs suggesting VTE recurrence.

Recurrent DVT was diagnosed in the presence of high clinical likelihood for DVT confirmed by a new CUS, compared with that customarily performed at the time of OAT interruption. The diagnosis of pulmonary embolism (PE) recurrence was based on the combination of clinical probability, chest radiography and perfusion lung scanning [14].

The SPSS statistical software package (Statistical Package for Social Sciences, Chicago, USA, software for Windows; version 11.0) was used for data processing. Data are expressed as median and range due to their skewed distribution. Preliminary statistical analysis was performed using Wilcoxon’s signed rank test and χ2 test (categorical data). The nonparametric Mann-Whitney test was used for comparison between individual groups. Multiple logistic regression analysis was used to ascertain which factors were significantly associated with the risk of VTE recurrence during follow-up. All odds ratios (OR) are given with their 95% confidence intervals (CI) and a two-sided value of < 0.05 was chosen for statistical significance. The two-way and three-way interaction hypotheses between OR for recurrence related to elevated D-Dimer and elevated D-dimer associated with elevated F1+2 were ascertained by the likelihood ratio testing (LRT).

The analysis was conducted on 295 patients (157 males and 138 females; median age 62 (12–92) years; 183 with unprovoked VTE and 112 with removable risk factors), followed up for a median time of 25 months (1–120 months) after OAT withdrawal. The median OAT duration was 9 (3–72) months. During follow-up three patients died from cancer. Six patients restarted OAT because of atrial fibrillation (five cases) and stroke (one case).

VTE recurrence was recorded in 37 patients (12.5%) after a median time of 6 (1–75) months. Recurrences were more frequent among males (26/157) compared with females (11/138) (= 0.034). One or more thrombophilic alterations were detected in 23% of patients and no relationship was found between thrombophilia and VTE recurrence (= 0.5).

When we compared patients with PE with those with DVT as index event, no difference was found either in recurrence rate or in the different laboratory parameters investigated.

After OAT withdrawal, elevated D-dimer and F1+2 levels were associated with a significantly higher rate of VTE recurrence (Table 1a). A CUS study for detection of RVO was obtained in 256 patients (this parameter was not considered in patients with isolated PE). The presence of RVO was not related to VTE recurrence (Table 1a).

Table 1.   Clotting activation and residual vein obstruction (a); odds ratios for venous thromboembolism (VTE) recurrence (b)
  All patients (%)Patients without recurrence (%)Patients with recurrence (%)P
  1. *Adjusted for age and sex. RVO, residual vein obstruction; LRT, likelihood ratio testing.

(a)
Elevated D-dimer99/280 (35)78/245 (32)21/35 (60)0.02
Elevated F1 + 255/269 (20)43/236 (18)12/33 (36)0.02
Presence of RVO105/258 (41)91/226 (40)14/32 (44)0.7
(b)
 Unadjusted analysisOR95% CIP 
  Male sex2.31.1–4.80.04 
  Elevated D-dimer3.21.5–6.60.002 
  Elevated F1 + 22.61.2–5.60.02 
  Presence of RVO1.10.5–2.40.7 
  Common thrombophilia0.60.2–1.60.3 
  Combination of elevated D-dimer and F1 + 24.01.6–10.30.003 
 Adjusted analysis   P value (LRT)
  Elevated D-dimer*3.11.5–6.70.003Reference
  Elevated F1 + 2*2.41.1–5.50.030.91
  Combination of elevated D-dimer and F1 + 2*4.31.6–11.60.0030.24

Univariate analysis showed that elevated D-dimer, elevated F1+2 levels, and male sex were significantly associated with recurrence (Table 1b).

Multiple logistic regression analysis adjusted for sex and age confirmed that elevated D-dimer and elevated F1+2 are independently associated with recurrence (Table 1b). Higher ORs for recurrence were found when we combined elevated D-dimer and F1+2. The analysis of the contemporary presence of two parameters shows an increase of the ORs for recurrence, but this is not statistically significant (Table 1b).

We confirmed that elevated D-dimer levels detected 4 weeks after OAT withdrawal are significantly associated with recurrence [5–15]. We have also studied F1+2 levels, and we have confirmed a similar role for this parameter as a risk factor for recurrence after OAT withdrawal [11]. In our patients, hereditary thrombophilia was not able to predict recurrence, in agreement with other studies [3–16]. Also, the presence of RVO was not related to recurrence. RVO was previously reported as a risk factor for recurrence [12,13], but others [6] did not confirm these data. The absence of a standardized method to define RVO and the different designs of the studies, in particular in relation to the timing of CUS and the characteristics of patients enrolled, might in part account for these different findings. When we analyzed the combination of elevated D-dimer levels with elevated F1+2 levels, we found a non-significant increase in the OR for recurrence (Table 1b). Nevertheless, the progressive increase in ORs related to the risk of recurrence suggests that the combination of the studied parameters should help to identify patients at high risk, who request a careful evaluation for tailoring the better duration of OAT.

Limitations of our study are the single centre design and the definition of RVO. However, CUS is a technique difficult to standardize in routine clinical practice, and with a high inter-operator variability. It should be noted that the percentage of patients with RVO in our series is not different from that found by others [6–13].

In conclusion, we have confirmed that the risk of recurrence after a first VTE episode is associated with elevated D-dimer, and that the evaluation of F1+2 levels could add information to better define this risk. The stratification of the risk of recurrence after a first episode of OAT still remains an unresolved issue. The detection of other clinical and laboratory characteristics and the definition of the weight of each of them, might give the framework for stratifying patients who would require prolonged anticoagulation.

Disclosure of Conflict of Interests

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  2. Disclosure of Conflict of Interests
  3. References

The authors state that they have no conflict of interest.

References

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  2. Disclosure of Conflict of Interests
  3. References
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