D-dimer prognostic role in thromboembolism recurrence

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2]

Overview

The recurrence rate within the first few months following a first episode of venous thromboembolism (VTE) is not negligible. In fact, it is estimated to be around 6% at 6 months following the first episode. Therefore, the duration of treatment with oral anticoagulation therapy must be long enough to decrease the risk of recurrence while not too long to cause bleeding complications. The duration of the treatment of oral anticoagulation is most problematic in the category of patients suffering from their first episode of unprovoked VTE; therefore, a marker of the risk of recurrence of VTE in this population in particular is needed to tailor the duration of their treatment.

An association between changes in D-dimer levels during and following the discontinuation of oral anticoagulation and risk of recurrence of VTE was suggested more than a decade ago, and the prognostic role of D-dimer in predicting the rate of recurrence of VTE has been extensively studied. Studies have been consistent in their findings of an association between elevated D-dimer levels and higher rates of recurrence of VTE; as such, they suggest a possible role for D-dimer in predicting recurrence of thromboembolism and tailoring the duration of treatment of oral anticoagulation following VTE. Resuming oral anticoagulation treatment (OAT) in subjects with abnormal D-dimer levels following the discontinuation of the OAT reduces their risk of VTE recurrence.

Recurrence of Thromboembolism

• The predictive value of D-dimer for recurrence of VTE was investigated by Palareti and colleagues in a prospective inception-cohort study involving 396 patients (median age 67 years, 198 males) treated with oral anticoagulant therapy after a first episode of DVT and/or pulmonary embolism. The VTE were classified into three categories: idiopathic, associated with non removable factors and associated with removable factors. The D-dimer levels were measured by the VIDAS D-dimer ELISA method on the day of OAT withdrawal (T1), 3 to 4 weeks after OAT withdrawal (T2) and 3 months following OAT withdrawal (T3). Patients were followed up for 21 months after discontinuation of OAT for recurrent DVT or PE. D-dimer was elevated in 15,5%, 40.3% and 46.2% of all subjects at T1, T2 and T3 respectively. 40 subjects out of the 396 had recurrent VTE, 28 of those 40 patients had increased D-dimer beyond the cut-off point (>500ng/ml) at one of three repeated measurements. The remaining 11 patients had recurrence of VTE with normal D-dimer levels, 3 subjects had a circumstantial trigger factor and 3 others had malignancy. The hazard ratio for recurrence of VTE was significantly higher in subjects with abnormal vs normal D-dimer values at 3 months (2.45, 95% CI 1.28-4.53; P<0.01). The negative predictive value of D-dimer at T3 for VTE recurrence was reported to be 95.6% (CI=95% CI 91.6-98.1). Upon exclusion of the 6 cases where recurrence was associated with a circumstantial trigger, the NPV was found to be:
  • Total population: 96.7% (95% CI 92.9-98.8%)
  • Idiopathic cases: 96.3% (95% CI 87.2-99.5)
  • Secondary cases: 99.1% (95% CI 94.9-99.9)

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• Another team of researcher conducted a prospective cohort study of 610 patients (mean age> 18years) who suffered from their first spontaneous episode of VTE and were treated with OAT for at least 3 months. The D-dimer levels were measured by an enzyme-linked immunoassay 3 weeks after the discontinuation of their treatment with OAT. The patients were followed up for 38 months for recurrent symptomatic DVT or symptomatic PE in a way that the follow up period was done at 3 months intervals for the first year, followed by 6 months intervals for a total of 10 years. Throughout the study, 5 subjects died and 175 patients were excluded because of loss of follow up, pregnancy, new diagnosis of cancer or need for antithrombotic therapy for reasons other than VTE. The overall rate of recurrence of VTE was 13% among all patients and 7.7%, 15.6%, 14.3% and 18.6% among patients with D-dimer less than 250 ng/ml, between 250 and 499 ng/ml, between 500 and 749 ng/ml and more or equal to 750 ng/ml respectively. Patients who had a D-dimer level less than 250 ng/ml were shown to have 60% less relative risk of recurrence of VTE compared to patients having higher D-dimer levels (RR=0.4; CI=95%). The details about the relative risk of recurrence of VTE for D-dimer levels compared to the reference D-dimer level>750ng/ml after adjustment to gender, age, type of thromboembolism, factor V Leiden, factor II mutation and elevated factor VIII were as follows:
  • D-dimer<250 ng/ml: 0.3 (95% CI: 0.1-0.8)
  • D-dimer 250-499 ng/ml: 0.6 (95% CI: 0.3-1.3)
  • D-dimer 500-749 ng/ml: 0.9 (0.4-2.0)
  • D-dimer ≥ 750 ng/ml: 1.0 (reference range)

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• In addition, Palareti et al. also investigated the predictive role of D-dimer in recurrent VTE measured one month after the discontinuation of oral anticoagulant in patients with idiopathic thromboembolic events who are either carriers or not carriers of inherited thrombophilia. The study prospectively followed up 599 patients (301 males) who have been diagnosed with their first episode of VTE. Between the 21st and 37th day following the discontinuation of OAT, the patients underwent D-dimer testing by VIDAS D-dimer ELISA method and thrombophilia screening that included PT, activated PTT, fibrinogen plasma levels, antithrombin, protein C, protein S, and activated protein C resistance. The studied outcome was recurrence of symptomatic DVT, unprovoked or secondary to triggering factors, and/or fatal or non fatal PE. The results of this study revealed that 21.7% of the patients had a least one thrombophilic alterations. In addition, VTE recurrence was detected in 58 cases (9.7%) such that the recurrence rate was 4.3%, 11.7% and 23.7% among patients with transient risk factors, idiopathic cases and patients with non removable risk factors respectively. Elevated D-dimer measured one month after discontinuation of OAT was found in 37.1% cases and it was associated with significant higher rates of recurrence among all subjects, among patients with unprovoked VTE and among patients with or without thrombophilia. Adjustment was done for age, gender, duration of OAT, and presence or absence of congenital thrombophila or nature of the VTE (idiopathic or secondary). Details about the rate of recurrence of VTE are presented as follows:
  • Rate of recurrence in all patients with elevated D-dimer vs normal D-dimer levels were 16.5% and 5.8% respectively (p<0.0001).
  • Rate of recurrence in patients with unprovoked VTE with elevated D-dimer vs normal D-dimer levels were 16.5% and 5.8% respectively (p=0.0226). The hazard ration was 2.43 (95% CI, 1.18 to 4.61; P=0.0153).
  • Rate of recurrence in patients carriers of thrombophila with elevated D-dimer vs normal D-dimer levels were 27.1% and 4.2% respectively (p<0.0001). The hazard ratio was 8.34 (95% CI, 2.72 to 17.43; P<0.0001).
  • Rate of recurrence in patients not carriers of thrombophilia with elevated D-dimer vs normal D-dimer levels were 12.3% and 6.2% respectively (p=0.038). The hazard ratio was 2.04 (95% CI, 1.11 to 4.18; P=0.0232).

• The results of this study revealed that the levels of D-dimer measured one month after discontinuation of OAT had a high negative predictive value for recurrence of VTE in subjects with idiopathic VTE with and without inherited thrombophilia. The sensitivity, specificity, PPV and NPV of D-dimer (measured at 1 month following discontinuation of OAT) for recurrence of VTE are summarized in the table below:

	All Subjects	Subjects with an Unprovoked Event	Subjects with Thrombophilia
Sensitivity	62.1	69.7	84.2
Specificity	65.6	52.2	61.3
PPV	16.2	16.2	27.1
NPV	94.2	92.9	95.8

• It should be taken into consideration that hyperhomocysteinemia, elevated factor VIII and elevated factor IX were not evaluated during the thrombophilia screening. In addition, another limitation of the study is that the overall recurrence rate of VTE (9.7%) included symptomatic DVT and PE; hence, the association between D-dimer levels and recurrence of asymptomatic DVT and PE remains unclear.

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• The possible role of D-dimer in tailoring OAT treatment duration was evaluated in a study conducted by the same team, where poor anticoagulation quality, objectively assessed by an INR level less than 1.5 during the 3 months OAT treatment period following a first episode of unprovoked VTE, was associated with higher D-dimer levels after discontinuation of the oral anticoagulation and with increased risk of recurrence of VTE. This study involves 297 patients (170 males) who received a treatment with vitamin K antagonist, either warfarin or acenocoumarol for at least 3 months with a target INR of 2.5 (2.0-3.0). The INR values were reported throughout the treatment period (twice in the first week, once in the second week, and then every 2-3 weeks thereafter) and after discontinuation of the OAT. The subjects were followed up for a mean time of 21 months following the discontinuation of the treatment for any symptomatic DVT and fatal or non fatal PE. During the follow up period, D-dimer levels were measured by VIDAS D-dimer ELISA method (cut-off point for abnormal level: 500ng/ml) at the time of discontinuation of the treatment (T0), after 21-37 days (T1), after 3 months (T2) and afterwards (T3). The overall rate of recurrence of VTE was 14.1% and the rate of recurrence of VTE in patients whose duration of OAT is 3 months, 4 to 6 months, 7 to 12 months and more than 12 months were 0%, 15.2%, 15.2% and 12.2% respectively. In addition, results of the study revealed that the percentage of time spent with an INR<1.5 was significantly higher among patients who experienced VTE recurrence versus those who did not after adjustment for age, gender, duration of OAT, presence or absence of thrombophilia, D-dimer levels one month following discontinuation of OAT withdrawal, presence or absence of residual vein thrombosis at the time of OAT discontinuation. In addition, a higher hazard ratio for recurrence is reported to be associated when D-dimer levels are taken into consideration with inherited hypercoagulation disorders and not with residual venous obstruction. Shown below is a table summarizing the results of this study.

% Time Spent With INR<1.5	Number of Subjects	% of Recurrence	Adjusted RR
First 90 days of OAT treatment
≦3.1%	238	10.9%	1 (Reference)
≥ 3.1%	59	27.1%	2.70 (1.39–5.25) P=0.003
Throughout OAT treatment
≦3.1%	238	12.2%	1 (Reference)
≥ 3.1%	59	22%	1.98 (0.98–4.0) P=0.056
Additional time after the first 90 days of OAT treatment
≦3.1%	203	12.3%	1 (Reference)
≥ 3.1%	51	19.6%	1.60 (0.72–3.56) P=0.253

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• Palareti et al. further investigated the use of D-dimer to tailor the duration of OAT to minimize the risk of recurrence and at the same time minimize the risk of bleeding due to unnecessary prolonged bleeding through the PROLONG study, a multicenter prospective study that aimed to evaluate the role of D-dimer to tailor the duration of OAT following a first episode of VTE. This study involved 608 patients (age between 18 and 85 years) who had their first episode of unprovoked VTE defined as VTE occurring in the absence of puerperium, pregnancy, recent surgery requiring anesthesia for more than 30 minutes, immobilization for more than 3 days, cancer, antithrombin deficiency and antiphospholipid syndrome; however, patients with factor V Leiden and G20210A were eligible. Enrolled patients should have received a course of OAT for at least 3 months during which the INR target was around 2.5. Patients with renal insufficiency, significant liver disease, limited life span, indications for OAT other than VTE or contraindications to VTE were excluded. D-dimer levels were assessed by Clearview Simplify D-dimer assay at one month following the discontinuation of OAT: patients with normal D-dimer levels were instructed to discontinue OAT, whereas patients with abnormal D-dimer levels were either assigned to resume OAT or discontinue OAT. All patients were followed up for 18 months for any suspicion of or symptoms of DVT or PE.
• Among the 608 enrolled patients, 385 patients had normal D-dimer levels and 223 patients had abnormal D-dimer levels. Among patients with the abnormal D-dimer levels, 103 subjects were assigned to not receive further OAT while 120 subjects were assigned to resume the OAT. During the stratification of therapy choices, 9 patients declined to resume OAT. In addition, during the follow up period, 25 patients had their assigned therapy changed due to changes in their clinical conditions. The results of the study are summarized in the table below, note that the hazard ratio is calculated in comparison with the rate of recurrence of VTE in subjects with abnormal D-dimer and assigned resuming OAT. Moreover, the hazard ratio was adjusted for for age, gender, duration of OAT, and presence or absence of congenital thrombophila or nature of the VTE (idiopathic or secondary).

	Number of Subjects	% of Subjects with Recurrent VTE	Major Bleeding Episodes	Unadjusted Hazard Ratio	Adjusted Hazard Ratio
Normal D-Dimer	385	6.2%	0	2.17 (0.77-7.22) p=0.20	2.46 (0.71-8.46) p=0.15
Abnormal D-Dimer Without OAT	120	15%	0	5.36 (1.58-18.2) p=0.007	4.26 (1.23-14.6) p=0.02
Abnormal D-Dimer With OAT	103	2.9%	1	1 (Reference)	1 (Reference)

• Hence In the PROLONG study, abnormal levels of D-dimer 1 month following discontinuation of anticoagulation were associated with an elevated risk of thromboembolism recurrence, whereas normal levels of D-dimer 1 month following discontinuation of anticoagulation were associated with a lower risk of thromboembolism recurrence (4.4 events per 100 patient-years). In addition, patients with abnormal D-dimer level one month following the discontinuation of OAT and who resumed OAT are at lower risk of recurrent VTE as compared with patients with abnormal D-dimer levels and who do not resume oral anticoagulation therapy.
• The limitations of this study are:
  • This study was not blinded which makes it susceptible for bias.
  • D-dimer level was measured only one time. D-dimer were not available at the time of the discontinuation of the OAT nor during the follow up period. D-dimer levels might have changed during the follow up period in parallel to increasing risk of recurrence.
  • The population size is not large enough to assess the relative risk of bleeding associated with prolonged OAT.
  • Only unprovoked cases of VTE were included.
  • The cut-off level to define normal and abnormal levels of D-dimer was not provided. In addition, it is unclear whether the prognostic cut-off value of D-dimer used in this study is the same as the diagnostic cut-off value of D-dimer.
  • The optimal duration of the course of OAT in patients with abnormal D-dimer following discontinuation of OAT remains unclear.

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• An additional year of extended follow up in the PROLONG Study further reinforced the previous findings by reporting an adjusted hazard ratio of 2.7 (P = 0.042) for recurrence of VTE in subjects with abnormal D-dimer level compared with subjects with normal D-dimer levels. In this extended follow up, PROLONG investigators also investigated the role of comorbidities alone and in combination with D-dimer levels at one month after discontinuation of treatment as risk factors for recurrence of VTE in the context of a first episode of unprovoked VTE. Higher D-dimer levels were reported in subjects with pre-existing comorbidities; nevertheless, D-dimer was an independent risk factor for recurrence of VTE while the presence of comorbidities was not. A detailed summary on the rates of recurrences is as follows:
  • Normal D-dimer, with comorbidities: 14.3%
  • Normal D-dimer, without comorbidities: 10.8%
  • Abnormal D-dimer, with comorbidities: 24.6%
  • Abnormal D-dimer, with comorbidities: 21.3%

• Moreover, gender and age seems to influence the predictive value of D-dimer; in fact, a very low risk of VTE recurrence is reported in female subjects whose age is less than 65 years and whose D-dimer level at one month after discontinuation of therapy is normal.

• Previous studies have demonstrated the positive predictive value of D-dimer levels for recurrence of VTE after discontinuation of oral anticoagulation following the first episode of unprovoked VTE. A post-hoc analysis of the PROLONG study revealed that the predictive value of D-dimer for recurrence of VTE was only significant for subjects ≤ 70 years of age. The study investigated the use of age-specific cut-off levels of D-dimer in order to determine statistically significant hazard ratios in subjects >70 years of age. With the use of higher cut-off levels for D-dimer in the elderly, abnormal levels of D-dimer were associated with a significant increase in the risk of recurrence of VTE in subjects >70 years of age. The limitations of the study is the small population size and the post-hoc nature of the study; hence, further prospective studies are needed to investigate the findings.

• While the PROLONG Study investigated the association of abnormal D-dimer level at one month following more than one month after anticoagulation suspension for unprovoked venous thromboembolism, PROLONG-II Study investigated the course of change in D-dimer level more than a month following the discontinuation of therapy and the association between the levels of D-dimers thereafter with the risk of recurrence. The PROLONG-II Study was a prospective, multi-center cohort study that enrolled 355 patients with a first episode of VTE who were followed up for 13 months. The results of the PROLONG-II Study showed that patients who have high levels of D-dimer at 3 months after anticoagulation suspension have higher thromboembolism recurrence risk than patients who have normal levels of D-dimer. 68% of the enrolled patients had a normal D-dimer one month following discontinuation of the treatment; however, not all subjects maintained a normal level of D-dimer in the follow up period. Among subjects who initially had a normal D-dimer level one month after the discontinuation of the treatment, the risks of recurrence of VTE were 27% patient years (95% CI: 12-48) and 2.9% patient years (95% CI: 1-7) in subjects whom D-dimer became elevated at 3 months and remained abnormal and in subjects whom D-dimer remained normal throughout the follow up period, respectively. These studies suggest that the measurement of D-dimer levels at intervals of several months following anticoagulation suspension in patient suffering from a first episode of VTE might be beneficial in triaging patients and targeting their therapies. It is important to note that the predictive value of D-dimer for recurrence of thromboembolic events depends on the time of discontinuation of oral anticoagulant as the oral anticoagulant affects D-dimer by decreasing its level; hence, the prognostic role of D-dimer seems to be best at least a month following discontinuation of the oral anticoagulation therapy. For instance, in this same study the percentages of patients who had abnormal D-dimer levels were 15.6%, 40.3% and 40.6% at the time of therapy discontinuation, after one month, and after three months, respectively. In addition, the predictive value of D-dimer is valid in idiopathic cases of thromboembolism and not in the context of cancer or predisposing risk factors. As previously shown, the D-dimer level has both a positive predictive value and a negative predictive value for recurrence of VTE, and it has been suggested that D-dimer is a good tool to stratify patients who had their first episode of idiopathic VTE and tailor the duration of treatment. However, it is important to evaluate whether the predictive value of D-dimer remains the same regardless of the timing of D-dimer testing, the modality of testing and the age of the patient since the D-dimer level is known to increase with age.

• The ExACT trial, a currently ongoing trial in the U.K., is investigating extending the period of OAT based on the levels of D-dimers before the discontinuation of the OAT and its impact on the rate of recurrence of VTE.

• The previous PROLONG and PROLONG II studies investigated the prognostic role of D-dimer in subjects with their first episode of unprovoked VTE. The PROLONG PLUS study took a step further and aimed to asses the negative predictive value of D-dimer in patients with recurrent VTE in a prospective cohort study. The study was interrupted and only 75 patients were enrolled at that time. Although an association between low levels of D-dimers and and low risk of VTE recurrences is suggested by the preliminary results, more studies are needed to evaluate this association in the context of patients with recurrent VTE.

Metanalyses

• Aggregate data-based and individual patient data-based meta-analyses were performed to evaluate the predictive value of D-dimer for recurrence of VTE following discontinuation of OAT in the context of the first episode of an unprovoked VTE. Both meta-analyses confirmed the clinical significance of the predictive value of D-dimer; however, the individual patient data-based meta-analysis revealed a stronger value of the prognostic value of D-dimer.

• The annual rates of recurrence of VTE in patients treated with anticoagulant after their first episode of VTE were reported to be 3.5% (CI, 2.7% to 4.3%) and 8.9% (95% CI, 5.8% to 11.9%) in patients with negative D-dimer and patients with positive D-dimer, respectively. These results were based on a systematic analysis of 7 studies involving a total of 1888 patients who received oral anticoagualtion therapy for at least 3 months and were followed up for two years thereafter.

• Another patient-level meta-analysis involving 1881 patients with a first unprovoked VTE followed up for 26.9 months (SD=19.1) revealed that the predictive value of D-dimer is independent of the age of the patient, the timing of D-dimer testing and the cut off point of the assay used to measure D-dimer.

• A meta-analysis conducted in the Netherlands gathered data about 1539 patients from four studies and showed a significant association between elevated D-dimer after a month following the discontinuation of OAT and recurrence rates of VTE with an odds ratio of 2.36 (95% CI, 1.65 to 3.36). While 16.6% of subjects with elevated D-dimer levels suffered from recurrent VTE, 7.2% of subjects with normal D-dimer experienced VTE.

Prognostic Role of D-dimer when Compared to and Combined with Other Factors

DASH Score

• Tosetto and colleagues evaluated the use of the DASH score in predicting the rate of recurrence of VTE in patients who received at least 3 months of OATfollowing a first episode of VTE. The DASH score includes D-dimer, age and hormonal therapy. The recurrence rates were reported as follows:
  • Score ≤ 1: 3.1% (95% CI, 2.3-3.9)
  • Score=2: 6.4% (95% CI, 4.8-7.9)
  • Score ≥ 3: 12.3% (95% CI, 9.9-14.7)

D-Dimer and RVO

• A study conducted in Bologna evaluated the predictive value for recurrence of VTE of D-dimer in combination with residual venous obstruction (RVO) assessed by compression ultrasound in 400 patients 30 days (+/- 10 days) following the discontinuation of oral anticoagulation for a first idiopathic DVT. Elevated levels of D-dimer more than 500 ng/ml were found to be an independent risk factor for the recurrence of VTE. However, RVO was not proven to be an independent risk factor for recurrence of VTE regardless of D-dimer levels. The detailed results about the recurrence rates were as follows:
  • Normal D-dimer without RVO: 5.7% (95% CI:2-13%)
  • Normal D-dimer with RVO: 10.4% (95% CI:6-18%)
  • Abnormal D-dimer without RVO: 22.9% (95% CI: 14-33%)
  • Abnormal D-dimer with RVO: 25.9% (95% CI: 18-35%)

• While the previous study evaluated the predictive value for recurrence of VTE of D-dimer in combination with residual venous obstruction (RVO) following the discontinuation of oral anticoagulation for a first idiopathic DVT, another study involving 296 patients evaluated the same association in the context of a provoked DVT. When compared to normal D-dimer levels, an abnormal D-dimer level at the day of and 30 days after dicontinuation of oral anticoagulation following a first episode of provoked DVT were shown to be associated with a hazard ratio of 4.2 (95% CI:1.2-14.2; p=0.02) and 3.8 (95%CI: 1.2-12.1; p=0.02), respectively. However, the association between RVO and recurrence of VTE was not significant.

• The prognostic roles of D-dimer and RVO in predicting recurrence of VTE were also evaluated after discontinuation of OAT following a first episode of VTE in cancer patients. The study was a cohort of 88 cancer patients who were followed up for two years. In the context of malignancy, both D-dimer and RVO measured at the time of and one month after withdrawal of OAT were considered independent risk factors for the recurrence of VTE.

D-Dimer and Coagulation Factors

• Further studies evaluated the prognostic role of D-dimer and factor VIII coagulant in the recurrence of VTE. In fact, the Prevention of Recurrent Venous Thromboembolism (PREVENT) trial evaluated 508 subjects who received anticoagulation therapy for at least three months following idiopathic VTE and followed them up for any VTE recurrence for more than 2 years. The results of this study revealed an association between recurrence of VTE and elevated level of D-dimer (>500ng/ml), and not elevated levels of factor VIII coagulant (> or = 150 IU dL). The hazard ratio of recurrent VTE with elevated D-dimer was reported to be 2.0 (1.2-3.4; CI=95%). This association was significant among subjects having their first episode of VTE. The annual rates of recurrence of VTE are summarized as follows:
  • Elevated level of D-dimer: 10.9%
  • Normal level of D-dimer: 2.9%

• In a different study that also investigated the prognostic role of D-dimer and factor VIII coagulant in the recurrence of VTE, both D-dimer and factor VIII coagulant were found to be independent risk factors for recurrence of VTE after discontinuation of OAT following a first episode of idiopathic DVT.

• The risk of recurrence of VTE associated with elevated D-dimer was confirmed in a 2008 Italian prospective analysis of 295 patients with first episode VTE. They further found that elevated levels of F1+2 in addition to elevated D-dimer increases the odds ratio of recurrent VTE to 4.3 (95% CI 1.6-11.6; p = 0.003).

More Studies

• A 2008 Austrian study of 861 patients with first spontaneous VTE found that high levels of endogenous thrombin potential (ETP), defined as ≥ 100%, resulted in a 1.6-fold (95% CI: 1.1-2.3) increase in risk of recurrence of VTE. High levels of D-dimer, defined as ≥ 0.5 mg/L, were associated with a 1.8-fold (95% CI: 1.1-2.8) increase in the risk of recurrent VTE. Furthermore, patients with high ETP in addition to high levels of D-dimer had a 2.8-fold (95% CI: 1.5-5.3) compared to patients with low ETP and low levels of D-dimer.

• A study conducted in Canada also evaluated D-dimer levels in 152 patients following oral anticoagulation treatment for VTE. D-dimer levels were measured at the time of discontinuation of the treatment, after one week, after one month and after 3 months. The D-dimer levels were elevated at the time of discontinuation in 70% of the subjects, 80% of whom sustained a high D-dimer after a week. The percentage of subjects with elevated D-dimer decreased to 30% after a month and to 13% after 3 months. Seven out of the 152 subjects developed recurrent VTE and all of them has a persistently high D-dimer levels.

• Another study from China investigated the predictive value of D-dimer for recurrence of VTE by following up 204 patients diagnosed with their first episode of VTE. Follow up was done after 3 months, 6 months, 12 months and then yearly. D-dimer was found to have a high negative predictive value of 94.2% and 92.2% in all studied patients and in patients with unprovoked VTE, respectively. D-dimer was an independent predictor of recurrent VTE, especially in the population of patients with unprovoked VTE (HR=4.61; 95% CI, 1.85-11.49; p=0.001).

• In a prospective study from Italy, D-dimer levels were measured at one month following OAT in 236 patients with first episode pulmonary embolism. Again, elevated D-dimer levels were associated with recurrent VTE (p=0.003).