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.[1] 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,[2] and the prognostic role of D-dimer in predicting the rate of recurrence of VTE has been extensively studied.[3] 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.[4][5] Resuming oral anticoagulation treatment (OAT) in subjects with abnormal D-dimer levels following the discontinuation of the OAT reduces their risk of VTE recurrence.[6]

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)[7]


  • 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 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-month intervals for the first year, followed by 6-month 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 and 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 lever>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)[8]


  • In addition, Palareti et al. also investigated the predictive role of D-dimer in recurrent VTE after the discontinuation of oral anticoagulant in patients with idiopathic thromboembolic events and in patients with inherited thrombophilia. The results of this study revealed that the levels of D-dimer measured one month after discontinuation of OAT had a high predictive value for recurrence of VTE in subjects with and without inherited thrombophilia.[9] 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.[10]
  • Palareti et al. not only proved the role of D-dimer as a prognostic factor for recurrence of VTE, but also 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.[11][12] 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). The PROLONG Study followed up 608 patients for an average of 1.4 years and reported at the end of the follow up period an adjusted hazard ratio of 2.27 (1.15 to 4.46; CI=95%; P=0.02) for recurrence of VTE in subjects with abnormal D-dimer level compared with subjects with normal D-dimer levels.[11] This point is further emphasized in a different study conducted by the same team, where poor anticoagulation quality, objectively assessed by an INR level less than 1.5 during the 3 months treatment period, was associated with higher D-dimer levels after discontinuation of the oral anticoagulation and with increased risk of recurrence of VTE. 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.[13]
  • 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.[14] 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:[15]
    • 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%
  • 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.[16]
  • 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.[17] 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.[18] 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.[18] As previously shown, the D-dimer level has both a positive predictive value and a negative predictive value for recurrence of VTE,[7][19] 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.[20]
  • 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.[21]

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.[22]
  • 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.[23]
  • 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.[24]
  • 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.[25]

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)[26]

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%)[27]
  • 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.[28]
  • 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.[29]

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%[30]
  • 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.[31]
  • 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).[32]

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.[33]
  • 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.[34]
  • 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).[35]
  • 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).[36]

References

  1. ↑ White RH (2003). "The epidemiology of venous thromboembolism". Circulation. 107 (23 Suppl 1): I4–8. doi:10.1161/01.CIR.0000078468.11849.66. PMID 12814979.
  2. ↑ Kévorkian JP, Halimi C, Segrestaa JM, Drouet L, Soria C (1998). "Monitoring of patients with deep-vein thrombosis during and after anticoagulation with D-dimer". Lancet. 351 (9102): 571–2. doi:10.1016/S0140-6736(05)78559-7. PMID 9492784.
  3. ↑ Wu C, Bates SM (2009). "Should D-dimer testing be used to predict the risk of recurrence after discontinuation of anticoagulant therapy for a first unprovoked episode of venous thromboembolism?". Pol Arch Med Wewn. 119 (4): 225–30. PMID 19413181.
  4. ↑ Zhu T, Martinez I, Emmerich J (2009). "Venous thromboembolism: risk factors for recurrence". Arterioscler Thromb Vasc Biol. 29 (3): 298–310. doi:10.1161/ATVBAHA.108.182428. PMID 19228602.
  5. ↑ Garcia DA (2009). "Review: D-dimer concentrations predict risk of recurrent VTE after anticoagulant therapy is stopped". Evid Based Med. 14 (2): 59. doi:10.1136/ebm.14.2.59. PMID 19332615.
  6. ↑ Palareti G (2007). "[Current criteria to determine the duration of anticoagulant therapy]". Recenti Prog Med. 98 (12): 603–6. PMID 18369033.
  7. ↑ 7.0 7.1 Palareti G, Legnani C, Cosmi B, Guazzaloca G, Pancani C, Coccheri S (2002). "Risk of venous thromboembolism recurrence: high negative predictive value of D-dimer performed after oral anticoagulation is stopped". Thromb Haemost. 87 (1): 7–12. PMID 11848459.
  8. ↑ Eichinger S, Minar E, Bialonczyk C, Hirschl M, Quehenberger P, Schneider B; et al. (2003). "D-dimer levels and risk of recurrent venous thromboembolism". JAMA. 290 (8): 1071–4. doi:10.1001/jama.290.8.1071. PMID 12941680. Review in: ACP J Club. 2004 Mar-Apr;140(2):50 Review in: J Fam Pract. 2004 Jan;53(1):20, 23
  9. ↑ Palareti G, Legnani C, Cosmi B, Valdré L, Lunghi B, Bernardi F; et al. (2003). "Predictive value of D-dimer test for recurrent venous thromboembolism after anticoagulation withdrawal in subjects with a previous idiopathic event and in carriers of congenital thrombophilia". Circulation. 108 (3): 313–8. doi:10.1161/01.CIR.0000079162.69615.0F. PMID 12847064.
  10. ↑ Cosmi B, Legnani C, Tosetto A, Pengo V, Ghirarduzzi A, Testa S; et al. (2010). "Sex, age and normal post-anticoagulation D-dimer as risk factors for recurrence after idiopathic venous thromboembolism in the Prolong study extension". J Thromb Haemost. 8 (9): 1933–42. doi:10.1111/j.1538-7836.2010.03955.x. PMID 20553388.
  11. ↑ 11.0 11.1 Palareti G, Cosmi B, Legnani C, Tosetto A, Brusi C, Iorio A; et al. (2006). "D-dimer testing to determine the duration of anticoagulation therapy". N Engl J Med. 355 (17): 1780–9. doi:10.1056/NEJMoa054444. PMID 17065639. Review in: ACP J Club. 2007 Mar-Apr;146(2):29 Review in: Evid Based Med. 2007 Apr;12(2):45
  12. ↑ Palareti G, Cosmi B, Legnani C (2007). "D-dimer testing to determine the duration of anticoagulant therapy". Curr Opin Pulm Med. 13 (5): 393–7. doi:10.1097/MCP.0b013e3282058b94. PMID 17940483.
  13. ↑ Palareti G, Legnani C, Cosmi B, Guazzaloca G, Cini M, Mattarozzi S (2005). "Poor anticoagulation quality in the first 3 months after unprovoked venous thromboembolism is a risk factor for long-term recurrence". J Thromb Haemost. 3 (5): 955–61. doi:10.1111/j.1538-7836.2005.01330.x. PMID 15869591.
  14. ↑ Cosmi B, Legnani C, Tosetto A, Pengo V, Ghirarduzzi A, Alatri A; et al. (2009). "Use of D-dimer testing to determine duration of anticoagulation, risk of cardiovascular events and occult cancer after a first episode of idiopathic venous thromboembolism: the extended follow-up of the PROLONG study". J Thromb Thrombolysis. 28 (4): 381–8. doi:10.1007/s11239-009-0315-5. PMID 19288181.
  15. ↑ Cosmi B, Legnani C, Tosetto A, Pengo V, Ghirarduzzi A, Testa S; et al. (2010). "Comorbidities, alone and in combination with D-dimer, as risk factors for recurrence after a first episode of unprovoked venous thromboembolism in the extended follow-up of the PROLONG study". Thromb Haemost. 103 (6): 1152–60. doi:10.1160/TH09-11-0759. PMID 20352167.
  16. ↑ Legnani C, Palareti G, Cosmi B, Cini M, Tosetto A, Tripodi A; et al. (2008). "Different cut-off values of quantitative D-dimer methods to predict the risk of venous thromboembolism recurrence: a post-hoc analysis of the PROLONG study". Haematologica. 93 (6): 900–7. doi:10.3324/haematol.12320. PMID 18443269.
  17. ↑ Cosmi B, Legnani C, Tosetto A, Pengo V, Ghirarduzzi A, Testa S; et al. (2010). "Usefulness of repeated D-dimer testing after stopping anticoagulation for a first episode of unprovoked venous thromboembolism: the PROLONG II prospective study". Blood. 115 (3): 481–8. doi:10.1182/blood-2009-08-237354. PMID 19965693.
  18. ↑ 18.0 18.1 Stein PD, Janjua M, Matta F, Alrifai A, Jaweesh F, Chughtai HL (2011). "Prognostic value of D-dimer in stable patients with pulmonary embolism". Clin Appl Thromb Hemost. 17 (6): E183–5. doi:10.1177/1076029610395129. PMID 21288930.
  19. ↑ Fattorini A, Crippa L, Vigano' D'Angelo S, Pattarini E, D'Angelo A (2002). "Risk of deep vein thrombosis recurrence: high negative predictive value of D-dimer performed during oral anticoagulation". Thromb Haemost. 88 (1): 162–3. PMID 12152661.
  20. ↑ Tullett J, Murray E, Nichols L, Holder R, Lester W, Rose P; et al. (2013). "Trial Protocol: a randomised controlled trial of extended anticoagulation treatment versus routine anticoagulation treatment for the prevention of recurrent VTE and post thrombotic syndrome in patients being treated for a first episode of unprovoked VTE (The ExACT Study)". BMC Cardiovasc Disord. 13: 16. doi:10.1186/1471-2261-13-16. PMC 3602651. PMID 23497371.
  21. ↑ Ageno W, Cosmi B, Ghirarduzzi A, Santoro R, Bucherini E, Poli D; et al. (2012). "The negative predictive value of D-dimer on the risk of recurrent venous thromboembolism in patients with multiple previous events: a prospective cohort study (the PROLONG PLUS study)". Am J Hematol. 87 (7): 713–5. doi:10.1002/ajh.23198. PMID 22488507.
  22. ↑ Marcucci M, Smith CT, Douketis JD, Tosetto A, Baglin T, Cushman M; et al. (2013). "Patient-level compared with study-level meta-analyses demonstrate consistency of D-dimer as predictor of venous thromboembolic recurrences". J Clin Epidemiol. 66 (4): 415–25. doi:10.1016/j.jclinepi.2012.08.007. PMID 23395515.
  23. ↑ Verhovsek M, Douketis JD, Yi Q, Shrivastava S, Tait RC, Baglin T; et al. (2008). "Systematic review: D-dimer to predict recurrent disease after stopping anticoagulant therapy for unprovoked venous thromboembolism". Ann Intern Med. 149 (7): 481–90, W94. PMID 18838728. Review in: Evid Based Med. 2009 Apr;14(2):59 Review in: Ann Intern Med. 2009 Feb 17;150(4):JC2-14
  24. ↑ Douketis J, Tosetto A, Marcucci M, Baglin T, Cushman M, Eichinger S; et al. (2010). "Patient-level meta-analysis: effect of measurement timing, threshold, and patient age on ability of D-dimer testing to assess recurrence risk after unprovoked venous thromboembolism". Ann Intern Med. 153 (8): 523–31. doi:10.7326/0003-4819-153-8-201010190-00009. PMID 20956709.
  25. ↑ Bruinstroop E, Klok FA, Van De Ree MA, Oosterwijk FL, Huisman MV (2009). "Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism: a meta-analysis". J Thromb Haemost. 7 (4): 611–8. doi:10.1111/j.1538-7836.2009.03293.x. PMID 19175498.
  26. ↑ Tosetto A, Iorio A, Marcucci M, Baglin T, Cushman M, Eichinger S; et al. (2012). "Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH)". J Thromb Haemost. 10 (6): 1019–25. doi:10.1111/j.1538-7836.2012.04735.x. PMID 22489957.
  27. ↑ Cosmi B, Legnani C, Cini M, Guazzaloca G, Palareti G (2005). "D-dimer levels in combination with residual venous obstruction and the risk of recurrence after anticoagulation withdrawal for a first idiopathic deep vein thrombosis". Thromb Haemost. 94 (5): 969–74. doi:10.1160/TH05-02-0095. PMID 16363238.
  28. ↑ Cosmi B, Legnani C, Cini M, Guazzaloca G, Palareti G (2011). "D-dimer and residual vein obstruction as risk factors for recurrence during and after anticoagulation withdrawal in patients with a first episode of provoked deep-vein thrombosis". Thromb Haemost. 105 (5): 837–45. doi:10.1160/TH10-08-0559. PMID 21359409.
  29. ↑ Cosmi B, Legnani C, Cini M, Guazzaloca G, Palareti G (2005). "The role of D-dimer and residual venous obstruction in recurrence of venous thromboembolism after anticoagulation withdrawal in cancer patients". Haematologica. 90 (5): 713–5. PMID 15921399.
  30. ↑ Shrivastava S, Ridker PM, Glynn RJ, Goldhaber SZ, Moll S, Bounameaux H; et al. (2006). "D-dimer, factor VIII coagulant activity, low-intensity warfarin and the risk of recurrent venous thromboembolism". J Thromb Haemost. 4 (6): 1208–14. doi:10.1111/j.1538-7836.2006.01935.x. PMID 16706961.
  31. ↑ Cosmi B, Legnani C, Cini M, Favaretto E, Palareti G (2008). "D-dimer and factor VIII are independent risk factors for recurrence after anticoagulation withdrawal for a first idiopathic deep vein thrombosis". Thromb Res. 122 (5): 610–7. doi:10.1016/j.thromres.2007.12.024. PMID 18304616.
  32. ↑ Poli D, Antonucci E, Ciuti G, Abbate R, Prisco D (2008). "Combination of D-dimer, F1+2 and residual vein obstruction as predictors of VTE recurrence in patients with first VTE episode after OAT withdrawal". J Thromb Haemost. 6 (4): 708–10. doi:10.1111/j.1538-7836.2008.02900.x. PMID 18194414.
  33. ↑ Eichinger S, Hron G, Kollars M, Kyrle PA (2008). "Prediction of recurrent venous thromboembolism by endogenous thrombin potential and D-dimer". Clin Chem. 54 (12): 2042–8. doi:10.1373/clinchem.2008.112243. PMID 18948369.
  34. ↑ Kuruvilla J, Wells PS, Morrow B, MacKinnon K, Keeney M, Kovacs MJ (2003). "Prospective assessment of the natural history of positive D-dimer results in persons with acute venous thromboembolism (DVT or PE)". Thromb Haemost. 89 (2): 284–7. doi:10.1267/THRO03020284. PMID 12574808.
  35. ↑ Wang Y, Liu ZH, Zhang HL, Luo Q, Zhao ZH, Zhao Q (2011). "Predictive value of D-dimer test for recurrent venous thromboembolism at hospital discharge in patients with acute pulmonary embolism". J Thromb Thrombolysis. 32 (4): 410–6. doi:10.1007/s11239-011-0625-2. PMID 21847593.
  36. ↑ Poli D, Cenci C, Antonucci E, Grifoni E, Arcangeli C, Prisco D; et al. (2013). "Risk of recurrence in patients with pulmonary embolism: predictive role of D-dimer and of residual perfusion defects on lung scintigraphy". Thromb Haemost. 109 (2): 181–6. doi:10.1160/TH12-07-0534. PMID 23196319.

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