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

Benilde Cosmi; Cristina Legnani; Michela Cini; Giuliana Guazzaloca; Gualtiero Palareti

doi:10.1160/TH10-08-0559

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2011; 105(05): 837-845
DOI: 10.1160/TH10-08-0559

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

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

Benilde Cosmi

¹Division of Angiology and Blood Coagulation “M. Golinelli”; S. Orsola-Malpighi University Hospital, Bologna, Italy

,

Cristina Legnani

¹Division of Angiology and Blood Coagulation “M. Golinelli”; S. Orsola-Malpighi University Hospital, Bologna, Italy

,

Michela Cini

¹Division of Angiology and Blood Coagulation “M. Golinelli”; S. Orsola-Malpighi University Hospital, Bologna, Italy

,

Giuliana Guazzaloca

¹Division of Angiology and Blood Coagulation “M. Golinelli”; S. Orsola-Malpighi University Hospital, Bologna, Italy

,

Gualtiero Palareti

¹Division of Angiology and Blood Coagulation “M. Golinelli”; S. Orsola-Malpighi University Hospital, Bologna, Italy

› Author Affiliations

Abstract

Summary

D-dimer and residual venous obstruction (RVO) have been separately shown to be risk factors for recurrent venous thromboembolism (VTE) after a first episode of unprovoked proximal deep-vein thrombosis (DVT). It was the objective of this study to assess the predictive value of D-dimer and residual vein obstruction (RVO), alone and in combination, for recurrence after provoked DVT of the lower limbs. A total of 296 consecutive patients with a first episode of symptomatic provoked proximal DVT were evaluated at a university hospital in Bologna, Italy. On the day of anticoagulation withdrawal (T0), RVO was determined by compression ultrasonography. D-dimer levels (cut-off: 500 ng/ml) were measured at T0 and after 30 ±10 days (T1). The main outcome was recurrent VTE during a two-year follow-up. D-dimer was abnormal in 11.6% (32/276) and 31% (85/276) of subjects at T0 and at T1, respectively. RVO was present in 44.8% (132/294) of patients. Recurrence rate was 5.1% (15/296; 95% confidence interval [CI]: 3–8%; 3% patient-years; 95% CI: 2–5 %). An abnormal D-dimer either at T0 or at T1 was associated with an adjusted hazard ratio (HR) for recurrence 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, when compared with normal D-dimer. The HR for recurrence associated with RVO was not significant, and RVO did not increase the recurrence risk associated with an abnormal D-dimer either at T0 or T1. In conclusion, an abnormal D-dimer during vitamin K antagonist (VKA) treatment or at one month after VKA withdrawal is a risk factor for recurrence in patients with provoked DVT, while RVO at the time of anticoagulation withdrawal is not.

Keywords

Venous thromboembolism - D-dimer - recurrence - thrombophilia - vitamin K antagonists

Full Text

References

References
1 Schulman S, Rhedin AS, Lindmarker P. et al. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med 1995; 332: 1661-1665.
2 Kearon C, Gent M, Hirsh J. et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999; 340: 901-907.
3 Hirsh J, Kearon C, Ginsberg J. Duration of anticoagulant therapy after first episode of venous thrombosis in patients with inherited thrombophilia. Arch Intern Med 1997; 157: 2174-2177.
4 Hull R, Delmore T, Genton E. et al. Warfarin sodium versus low dose heparin in the long term treatment of venous thrombosis. N Engl J Med 1979; 301: 855-858.
5 Kearon C, Kahn SR, Agnelli G. et al. Antithrombotic Therapy for Venous Thromboembolic Disease. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chest 2008; 133: 454S-545S.
6 Schulman S, Rhedin AS, Lindmarker P. et al. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med 1995; 332: 1661-1665.
7 Hansson PO, Sorbo J, Eriksson H. Recurrent venous thromboembolism after deep vein thrombosis. Incidence and risk factors. Arch Intern Med 2000; 1260: 769-774.
8 Heit JA, Mohr DN, Silverstein MD. et al. Predictors of recurrence after deep vein thrombosis and pulmonary embolism. A population based cohort study. Arch Intern Med 2000; 160: 761-768.
9 Baglin T, Luddington R, Brown K. et al. Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. Lancet 2003; 362: 523-526.
10 Christiansen SC, Cannegieter SC, Koster T. et al. Thrombophilia, clinical factors, and recurrent venous thrombotic events. J Am Med Assoc 2005; 293: 2352-2361.
11 Baglin T, Palmer CR, Luddington R. et al. Unprovoked recurrent venous thrombosis: prediction by D-dimer and clinical risk factors. J Thromb Haemost 2008; 6: 577-582.
12 Prandoni P, Noventa F, Ghirarduzzi A. et al. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica. 2007; 92: 199-205.
13 White RH, Murin S, Wun T. et al. Recurrent venous thromboembolism after surgery-provoked versus unprovoked thromboembolism. J Thromb Haemost 2010; 8: 987-997.
14 Palareti G, Legnani C, Cosmi B. et al. Risk of venous thromboembolism recurrence: high negative predictive value of D-Dimer performed after oral anticoagulation is stopped. Thromb Haemost 2002; 87: 7-1219.
15 Palareti G, Cosmi B, Legnani C. et al. PROLONG Investigators. D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med 2006; 355: 1780–1789. Erratum in: N Engl J Med 2006; 355: 2797.
16 Cosmi B, Legnani C, Tosetto A. et al. 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 2009; 28: 381-388.
17 Cosmi B, Legnani C, Tosetto A. et al. PROLONG Investigators (on behalf of Italian Federation of Anticoagulation Clinics). Usefulness of repeated D-dimer testing after stopping anticoagulation for a first episode of unprovoked venous thromboembolism: the PROLONG II prospective study. Blood 2010; 115: 481-488.
18 Pengo V, Palareti G, Cosmi B. et al. D-dimer testing and recurrent venous thrombo-embolism after unprovoked pulmonary embolism: A post-hoc analysis of the Prolong extension study. Thromb Haemost 2008; 100: 718-721.
19 Cosmi B, Legnani C, Tosetto A. et al. 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 2010; 103: 1152-1160.
20 Siragusa S, Malato A, Anastasio R. et al. Residual vein thrombosis to establish duration of anticoagulation after a first episode of deep vein thrombosis: the Duration of Anticoagulation based on Compression UltraSonography (DACUS) study. Blood 2008; 112: 511-515.
21 Prandoni P, Prins MH, Lensing AW. et al. AESOPUS Investigators. Residual thrombosis on ultrasonography to guide the duration of anticoagulation in patients with deep venous thrombosis: a randomized trial. Ann Intern Med 2009; 150: 577-585.
22 Palareti G, Legnani C, Cosmi B. et al. 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 2003; 108: 313-318.
23 Prandoni P, Lensing AWA, Bernardi E. et al. The diagnostic value of compression ultrasonography in patients with suspected recurrent deep vein thrombosis. Thromb Haemost 2002; 88: 402-406.
24 Prandoni P, Lensing AWA, Prins MH. et al. Residual vein thrombosis as a predictive factor of recurrent venous thromboembolism. Ann Intern Med 2002; 137: 955-960.
25 Kearon C. Diagnosis of pulmonary embolism. Can Med Assoc J 2003; 168: 183-194.
26 Fedullo PF, Tapson VF. The evaluation of suspected pulmonary embolism. N Engl J Med 2003; 349: 1247-1256.
27 Agnelli G, Prandoni P, Santamaria MG. et al. Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. N Eng J Med 2001; 345: 165-169.
28 Iorio A, Kearon C, Filippucci E. et al. Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor. A systematic review. Arch Intern Med 2010; 170: 1710-1716.
29 Linkins LA, Stretton R, Probyn L. et al. Interobserver agreement on ultrasound measurements of residual vein diameter,thrombus echogenicity and Doppler venous flow in patients with previous venous thrombosis. Thromb Res 2006; 117: 241-247.