D-Dimer, Oral Anticoagulation, and Venous Thromboembolism Recurrence

ABSTRACT

Venous thromboembolism (VTE) requires prolonged treatment to prevent late recurrences. However, the optimal duration of vitamin K antagonist (VKA) therapy is still controversial. More recently, D-dimer (D-d) has emerged as a predictive factor for recurrences. D-d has been evaluated both during and after VKA treatment. Some patients with DVT of the lower limbs have persistently high D-d during anticoagulation and this could reflect insufficient anticoagulation despite apparently adequate antithrombotic treatment. Altered D-d during anticoagulation is more frequent in patients with idiopathic or cancer-associated VTE than in those with secondary VTE. In subjects with an unprovoked VTE event, the time spent at near normal international normalization ratio (INR) values (< 1.5) during the first 3 months of treatment is associated with higher D-d during and after VKA treatment and with a higher risk for late recurrences. Moreover, the combination of altered D-d and inherited thrombophilia, and not residual venous obstruction, is associated with a significantly higher hazard ratio for recurrence. Preliminary results of a management study, the PROLONG study, indicate that subjects with normal D-d at 1 month after VKA withdrawal have a low risk of recurrence, and those with altered D-d have a significantly higher risk and deserve prolonged treatment.

KEYWORDS

Warfarin - venous thromboembolism - recurrence - thrombosis - fibrin degradation products

REFERENCES

• 1 Büller H R, Agnelli G, Hull R D et al.. Antithrombotic therapy for venous thromboembolic disease. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.  Chest. 2004;  126 401S-428S
• 2 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
• 3 Agnelli G, Prandoni P, Santamaria M G et al.. Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis.  N Engl J Med. 2001;  345 165-169
• 4 Agnelli G, Prandoni P, Becattini C For the Warfarin Optimal Duration Italian Trial Investigators et al.. Extended oral anticoagulant therapy after a first episode of pulmonary embolism.  Ann Intern Med. 2003;  139 19-25
• 5 Pinede L, Ninet J, Duhaut P et al.. Comparison of 3 and 6 months of oral anticoagulant therapy after a first episode of proximal deep vein thrombosis or pulmonary embolism and comparison of 6 and 12 weeks of therapy after isolated calf-vein thrombosis.  Circulation. 2001;  103 2453-2460
• 6 The DVTENOX study . Markers of hemostatic system activation in acute deep venous thrombosis-evolution during the first days of heparin treatment.  Thromb Haemost. 1993;  70 909-914
• 7 Speiser W, Mallek R, Koppensteiner R et al.. D-dimer and TAT measurement in patients with deep venous thrombosis: utility in diagnosis and judgement of anticoagulation treatment effectiveness.  Thromb Haemost. 1990;  64 196-201
• 8 Kakkar V V, Hoppenstead D, Fareed J et al.. Randomized trial of different regimens of heparin and in vivo thrombin generation in acute deep vein thrombosis.  Blood. 2002;  99 1965-1970
• 9 Estivals M, Pelzer H, Sie P et al.. Prothrombin fragment 1 + 2, thrombin-antithrombin III complexes and D-dimers in acute deep vein thrombosis: effects of heparin treatment.  Br J Haematol. 1991;  78 421-424
• 10 Kévorkian J P, Halimi C, Segrestaa J M, Drouet L, Soria C. Monitoring of patients with deep-vein thrombosis during and after anticoagulation with D-dimer.  Lancet. 1998;  351 571-572
• 11 Fattorini A, Crippa L, Viganò D'Angelo S, Pattarini E, D'Angelo A. Risk of deep vein thrombosis recurrence: high negative predictive value of D-dimer performed during oral anticoagulation.  Thromb Haemost. 2002;  88 162-163
• 12 Palareti G, Legnani C, Cosmi B, Guazzaloca G, Pancani C, Coccheri S. Risk of venous thromboembolic recurrence: high negative predictive value of D-dimer performed after oral anticoagulation is stopped.  Thromb Haemost. 2002;  87 7-12
• 13 Kuruvilla J, Wells P, Morrow B, MacKinnon K, Keeney M, Kovacs M J. Prospective assessment of the natural history of positive D-dimer results in persons with acute venous thromboembolism (DVT or PE).  Thromb Haemost. 2003;  89 284-287
• 14 Eichinger S, Minar E, Bialonczyk C et al.. D-dimer levels and risk of recurrent venous thromboembolism.  JAMA. 2003;  290 1071-1074
• 15 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
• 16 Palareti G, Legnani C, Cosmi B, Guazzaloca G, Cini M, Mattarozzi S. Poor anticoagulation quality in the first three months after unprovoked venous thromboembolism is a risk factor for long term recurrence.  J Thromb Haemost. 2005;  3 955-961
• 17 Piovella F, Crippa L, Barone M et al.. Normalization rates of compression ultrasonography in patients with a first episode of deep vein thrombosis of the lower limbs: association with DVT recurrence and new thrombosis.  Haematologica. 2002;  87 515-522
• 18 Prandoni P, Lensing AWA, Prins M H et al.. Residual vein thrombosis as a predictive factor of recurrent venous thromboembolism.  Ann Intern Med. 2002;  137 955-960
• 19 Cosmi B, Legnani C, Cini M, Guazzaloca G, Palareti G. The effect of D-dimer and residual venous obstruction on the risk of recurrence after anticoagulation withdrawal for a first idiopathic deep vein thrombosis.  Thromb Haemost. 2005;  90 , In press
• 20 Palareti G, Tosetto A, Cosmi B et al.. The D-dimer Test to establish the duration of anticoagulation after a first unprovoked episode of venous thromboembolism (VTE); the prospective randomized “Prolong” Study. Presented at the XXth Congress of the International Society on Thrombosis and Haemostasis (ISTH) Sydney, Australia; August 6-12, 2005