The influence of factor V Leiden and G20210A prothrombin mutation on the presence of residual vein obstruction after idiopathic deep-vein thrombosis of the lower limbs

Summary

It was our aim to assess whether factor V Leiden (FVL) and G20210A prothrombin (FII) mutation are associated with the presence of residual vein obstruction (RVO) after a standard course of anticoagulation for a first episode of idiopathic proximal deep-vein thrombosis (DVT) of the lower limbs, with or without symptomatic pulmonary embolism (PE). Patients were enrolled in two prospective multicentre studies: PROLONG and PROLONG II. RVO was detected by compression ultra-sonography according to the method of Prandoni on the day of anticoagulation withdrawal. Patients were also screened for FVL and FII mutation. The presence of FVL and/or FII mutation was determined in 872/963 (90.5%) patients, in 753 of whom RVO was assessed. FVL was significantly less frequent among subjects with isolated PE (7/176:4%) than among patients with either DVT and PE (15/133:11.3%; p=0.0018) or isolated DVT (89/563:15.8%; p<0.0001), confirming the FVL paradox. The rate of FII mutation was similar among patients with isolated PE (11/176:6.2%) and patients with either DVT and PE (12/133:9%) or isolated DVT (52/563:9.2%). FVL and FII mutation were not significantly associated with RVO at the multivariate analysis in all patients, although data suggest that FVL and FII mutation may have a differential effect on RVO in the subgroups of patients with DVT and DVT plus PE patients. Male sex and isolated DVT were significantly associated with RVO in all patients. In conclusion, male sex and isolated DVT are associated with RVO, while FVL and FII mutations are not significantly associated with RVO in this study.

Keywords

Deep-vein thrombosis - pulmonary embolism - thrombophilia - venous thrombosis - residual vein obstruction

^* The PROLONG and Prolong II investigators are listed in Appendix ClinicalTrials.gov number NCT00264277 and NCT00266045.

• References

• 1 Prandoni P, Lensing AWA, Prins MH. et al. Residual vein thrombosis as a predictive factor of recurrent venous thromboembolism. Ann Intern Med 2002; 137: 955-956.
• 2 Cosmi B, Legnani C, Cini M. et al. 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 2005; 94: 969-964.
• 3 Prandoni P, Frulla M, Sartor D. et al. Venous abnormalities and the post- thrombotic syndrome. J Thromb Haemost 2005; 3: 401-402.
• 4 Roumen-Klappe EM, den Heijer M, Janssen M. et al. The post-thrombotic syndrome: incidence and prognostic value of non-invasive venous examinations in a six-year follow-up study. Thromb Haemost 2005; 94: 825-830.
• 5 Kahn S. Post-thrombotic syndrome. Thromb Res 2011; 127 (Suppl. 03) S89-S92.
• 6 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.
• 7 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.
• 8 Poli D, Antonucci E, Ciuti G. et al. 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 2008; 6: 708-710.
• 9 Cosmi B, Legnani C. Iorio A et al PROLONG Investigators (on behalf of FCSA, Italian Federation of Anticoagulation Clinics).. Residual venous obstruction, alone and in combination with D-dimer, as a risk factor for recurrence after anticoagulation withdrawal following a first idiopathic deep vein thrombosis in the Prolong study. Eur J Vasc Endovasc Surg 2010; 39: 356-65.
• 10 Carrier M, Rodger MA, Wells PS. et al. Residual vein obstruction to predict the risk of recurrent venous thromboembolism in patients with deep vein thrombosis: a systematic review and meta-analysis. J Thromb Haemost 2011; 9: 1119-1125.
• 11 Bank I, Tick LW, Hutten BA. et al. Acquired and inherited thrombophilic factors and the risk for residual venous thrombosis. Pathophysiol Haemost Thromb 2003; 33: 192-196.
• 12 Spiezia L, Tormene D, Pesavento R. et al. Thrombophilia as a predictor of persistent residual vein thrombosis. Haematologica 2008; 93: 479-480.
• 13 Desmarais S, de Moerloose P, Reber G. et al. Resistance to activated protein C in an un selected population of patients with pulmonary embolism. Lancet 1996; 347: 1374-1375.
• 14 Bounameaux H. Factor V Leiden paradox: risk of deep-vein thrombosis but not of pulmonary embolism. Lancet 2000; 356: 182-183.
• 15 Martinelli I, Cattaneo M, Panzeri D. et al. Low prevalence of factor V: Q506 in 41 patients with isolated pulmonary embolism. Thromb Haemost 1997; 77: 440-443.
• 16 Martinelli I, Battaglioli T, Razzari C. et al. Type and location of venous thromboembolism in patients with factor V Leiden or prothrombin G20210A and in those with no thrombophilia. J Thromb Haemost 2007; 5: 98-101.
• 17 van Stralen KJ, Doggen CJM, Bezemer ID. et al. Mechanisms of the Factor V Leiden Paradox. Arterioscler Thromb Vasc Biol 2008; 28: 1872-1877.
• 18 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.
• 19 Cosmi B, Legnani C, Tosetto A. et al. 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.
• 20 Cini M, Legnani C, Cavallaroni K. et al. A new rapid bedside assay for D-dimer measurement (Simplify D-dimer) in the diagnostic work-up for deep vein thrombosis. J Thromb Haemost 2003; 1: 2681-2683.
• 21 Holm S. A simple sequentially rejective multiple test procedure. Scand J Stat 1979; 6: 65-70.
• 22 Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Series B 1995; 57: 289-300.
• 23 Kyrle PA, Minar E, Bialonczyk C. et al. The risk of recurrent venous thromboembolism in men and women. N Engl J Med 2004; 350: 2558-2563.
• 24 McRae S, Tran H, Schulman S. et al. Effect of patient’s sex on risk of recurrent venous thromboembolism: a meta-analysis. Lancet 2006; 368: 371-378.