|Year : 2011 | Volume
| Issue : 1 | Page : 15-21
Optimal duration of anticoagulation in patients with venous thromboembolism
Paolo Prandoni, Chiara Piovella, Luca Spiezia, Fabio Dalla Valle, Raffaele Pesavento
Department of Cardiothoracic & Vascular Sciences, Clinica Medica II & Thromboembolism Unit, University of Padua, Italy
|Date of Web Publication||29-Jul-2011|
Department of Cardiothoracic & Vascular Sciences, Thromboembolism Unit, University of Padua, Via Giustiniani 2, 35128 - Padua
| Abstract|| |
The risk of recurrent venous thromboembolism (VTE) approaches 40 per cent of all patients after 10 yr of follow up. This risk is higher in patients with permanent risk factors of thrombosis such as active cancer, prolonged immobilization from medical diseases, and antiphospholipid syndrome; in carriers of several thrombophilic abnormalities, including deficiencies of natural anticoagulants; and in patients with unprovoked presentation. Patients with permanent risk factors of thrombosis should receive indefinite anticoagulation, consisting of subtherapeutic doses of low molecular weight heparin in cancer patients, and oral anticoagulants in all other conditions. Patients whose VTE is triggered by major surgery or trauma should be offered three months of anticoagulation. Patients with unprovoked VTE, including carriers of thrombophilia, and those whose thrombotic event is associated with minor risk factors (such as hormonal treatment, minor injuries, long travel) should receive at least three months of anticoagulation. The decision as to go on or discontinue anticoagulation after this period should be individually tailored and balanced against the haemorrhagic risk. Post-baseline variables, such as the D-dimer determination and the ultrasound assessment of residual thrombosis can help identify those patients in whom anticoagulation can be safely discontinued. As a few emerging anti-Xa and anti-IIa compounds seem to induce fewer haemorrhagic complications than conventional anticoagulation, while preserving at least the same effectiveness, these have the potential to open new scenarios for decisions regarding the duration of anticoagulation in patients with VTE.
Keywords: Anticoagulation - deep venous thrombosis - pulmonary embolism - thrombophilia - venous thromboembolism
|How to cite this article:|
Prandoni P, Piovella C, Spiezia L, Valle FD, Pesavento R. Optimal duration of anticoagulation in patients with venous thromboembolism. Indian J Med Res 2011;134:15-21
|How to cite this URL:|
Prandoni P, Piovella C, Spiezia L, Valle FD, Pesavento R. Optimal duration of anticoagulation in patients with venous thromboembolism. Indian J Med Res [serial online] 2011 [cited 2014 Mar 11];134:15-21. Available from: http://www.ijmr.org.in/text.asp?2011/134/1/15/83319
| Introduction|| |
After discontinuing anticoagulation a substantial proportion of patients with deep venous thrombosis (DVT) and/or pulmonary embolism (PE) will develop recurrent venous thromboembolic (VTE) events. According to the findings from prospective cohort studies conducted at our Institution , and elsewhere ,,,,, , recurrent events are expected to develop in up to 40 per cent of all patients, this figure being considerably higher in patients with unprovoked than in those with provoked VTE, provided that factors accounting for the first episode are transitory.
| Risk factors of recurrent thromboembolism|| |
1. Persistent acquired risk factors
After stopping anticoagulation patients with active cancer, especially those with metastatic malignancy and those undergoing chemotherapy, carry a particularly high risk of recurrent VTE  , and so do patients with chronic medical diseases requiring prolonged immobilization , . Although there is no conclusive evidence coming from randomized clinical trials, all such patient should be treated with long-term anticoagulation unless they have contraindications. According to the results of recent randomized clinical trials, low molecular weight heparins (LMWH) in full doses for the first month followed by approximately 75 per cent of the initial dosage for another 5 month period has the potential to halve the rate of recurrent events while not increasing the haemorrhagic risk  . Conventional oral anticoagulants still represent the treatment of choice in medical conditions other than neoplastic diseases  .
Indefinite treatment should also be considered in patients with multiple (especially if unprovoked) VTE episodes  , the insertion of a permanent vena caval filter (whenever anticoagulation is not contraindicated)  and the antiphospholipid antibody syndrome  . Whether these subjects require anticoagulation regimens that are more intense than usual has long been debated. Based on the results of recent randomized studies , , the latest international guidelines recommend also for these patients the adoption of conventional regimens  .
2. Transient risk factors
Patients whose thrombosis is provoked by a major reversible risk factor, such as surgery or major trauma, have a low risk of recurrence, whereas this risk becomes higher when thrombosis is provoked by a minor reversible risk factor, such as minor leg trauma, estrogen therapy, pregnancy or puerperium, or prolonged air travel  .
Accordingly, patients with major transient risk factors, such as major trauma or surgery, should be given 12 wk of anticoagulation , . This period can be halved in those patients in whom DVT is confined to the calf vein system , . In patients with minor transient risk factors, such as minor trauma, long air travel, hormonal therapy, a longer duration may be considered according to each individual case, after carefully considering the haemorrhagic risk and patients' preferences  .
When a thrombotic episode arises during pregnancy, it should be managed with LMWHs in full doses for at least three months, bearing in mind that the treatment should not be discontinued before the end of pregnancy, and should always be extended to cover the first six weeks after delivery.
3. Unprovoked VTE
After discontinuing anticoagulation, patients with the first episode of unprovoked VTE have a risk of recurrences that approaches 50 per cent of all such patients after 8-10 yr , . This figure will not change after prolonging anticoagulation up to 6 or 12 months ,,, . Patients presenting with a first episode of unprovoked VTE should be offered at least 3 months of oral anticoagulant therapy, targeting an (INR) between 2,0 and 3.0  . The decision as to go on or discontinue anticoagulation after this period should be individually tailored and balanced against the haemorrhagic risk  . Indeed, the annual incidence of major bleeding from long-term anticoagulation is 1.5-2.0 per cent, and the 'case-fatality rate' of an episode of major bleeding is considerably higher that that of an episode of recurrent VTE ,, .
Whether low-dose warfarin, that is a dose that produces a targeted INR between 1.5 and 2.0, may offer a suitable option for patients requiring longer periods of anticoagulation has long been debated , . We believe that conventional warfarin regimen should be regarded as the first choice. However, a low-intensity regimen can be considered in particular situations depending on individual judgment, for example, in patients reputed to be at a higher haemorrhagic risk.
Several post-baseline parameters have the potential to identify subgroups of patients with unprovoked VTE in whom anticoagulation can be safely discontinued. In a few cohort studies, the ultrasound persistence of residual thrombosis after an episode of proximal DVT was found to be an independent risk factor for recurrent thromboembolism , . In subsequent randomized clinical trials and systematic reviews of available studies it has been shown that adjusting the duration of anticoagulation according to the persistence of residual thrombosis reduces the risk of recurrent VTE by 40 per cent ,, .
Following the demonstration that a marker of a thrombotic tendency (D-dimer) can be helpful in the risk stratification, and thus ultimately therapeutic guidance, of individual patients with DVT ,,, , a randomized clinical trial showed that in patients who are left without anticoagulation as a consequence of a negative D-dimer - assessed one month after warfarin discontinuation - the rate of recurrent events is only slightly higher than in patients with positive D-dimer who continue anticoagulation  . In addition, repeating D-dimer testing after anticoagulation suspension has the potential to identify a number of individuals in whom D-dimer reverts to be positive and are, therefore, candidate to resume anticoagulation in order to prevent VTE recurrences  .
Another post-baseline factor potentially associated with an increased risk of recurrent VTE is the early development of post-thrombotic manifestations  . In this regard, an example of how useful a few post-baseline parameters can be, alone or in combination with baseline variables, for the identification of patients at low risk of recurrent VTE, has recently been offered by the prospective study by Rodger et al . Indeed, women with unprovoked VTE and none or 1 of a number of parameters (early post-thrombotic manifestations, D-dimer positivity at time of discontinuing anticoagulation, obesity, and age older than 65) were found to exhibit a considerably lower risk of recurrent VTE than the remaining patients.
An interesting prediction model for the development of recurrent VTE has recently been published by a group of Austrian investigators, which enables identification of the recurrence risk based on the combination of two baseline factors (sex and type of clinical presentation) and one post-baseline factor (D-dimer)  . This observation is interesting, but requires confirmation in settings other than that where the model has been developed.
4. Inherited thrombophilia
While inherited thrombophilia does not increase the risk of recurrent thromboembolism while on warfarin  , whether and to which extent carriers of inherited thrombophilia exhibit a higher risk of recurrent VTE after discontinuing anticoagulation is controversial. It is generally accepted, although not conclusively demonstrated, that carriers of antithrombin (AT), protein C and S  , carriers of hyperhomocysteinemia  and carriers of increased levels of factor VIII or IX ,, , have a recurrence risk that is higher than that of control subjects.
Whether carriers factor V Leiden or prothrombin G20210A variant - including homozygous carriers and carriers of double heterozygosity have a higher risk of recurrence as well is controversial, as there are data in favour and against this association , . Discrepancies among studies may be related to different selection of inception cohort, length of follow up, initial treatment of the acute thrombotic disorder, duration of treatment, and changes in general management of thrombotic patients. As a consequence, whether detection of these abnormalities, which are highly prevalent in western countries, has the potential to identify a subgroup of patients who might benefit from the adoption of individually adjusted prevention strategies following their first thrombotic episode, is virtually unknown. Recent studies suggest that prolonging anticoagulation for one year following the qualifying episode of VTE has the potential to reduce the risk of recurrent events in comparison to conventional 3-month anticoagulation , .
According to the results of a controlled, randomized clinical trial, homocysteine lowering by B-vitamin supplementation does not help prevent recurrent venous thrombosis  .
5. Other factors
Following the observation that males exhibit a higher recurrence risk than females  , a few meta-analyses of several studies confirmed the somewhat unexpected association between male sex and recurrent VTE , . Whether this finding is accounted for by sex-specific risk factors at time of first venous thrombosis is controversial ,, .
Patients with a first symptomatic unprovoked DVT are at higher risk of recurrent VTE than patients with a first unprovoked PE , . In addition, patients with clinically symptomatic PE have consistently been found to be at a higher risk of recurrent PE than those with DVT alone. These findings have recently been confirmed by a patient-level meta-analysis  .
Old age, which has long been regarded as a risk factor of venous thrombosis, has recently been identified as a predictive factor of recurrent VTE  . Thus, the common practice of administering old patients lower regimens or shorter periods of anticoagulation because of the fear of haemorrhagic complications should be reconsidered  . Likewise, excess body weight was recently found to be a powerful and independent risk factor of recurrent VTE  . Obese patients should therefore, be carefully educated, as decrease in body weight is likely to play a key role in reducing the risk of recurrent events.
Finally, it has recently been reported that a number of simple laboratory tests, such as the activated partial thromboplastin time and global coagulation assays measuring thrombin generation can help identify patients at a lower or higher risk of recurrent VTE ,,, . These observations show potential, but need confirmation.
| Recurrent VTE in the fertile age|| |
Women who had their first episode in fertile age are at a higher risk of experiencing recurrent thromboembolism when they are given hormonal treatment or become pregnant. This risk is particularly high in women in whom the first episode had been triggered by hormonal compounds or had developed during pregnancy ,,, . Accordingly, hormonal treatment should be strongly discouraged in women with previous VTE. Whenever hormonal treatment is reputed to be necessary, the contemporary administration of oral anticoagulants should be considered. Postpartum anticoagulation is recommended in all women with previous VTE  .
While the systematical adoption of compression elastic stockings is recommended in all women with previous VTE throughout pregnancy, antenatal thromboprophylaxis with LMWH should be offered whenever the previous episode was unprovoked or was pregnancy- or estrogen-related, in carriers of thrombophilia, if there is a family history of thrombosis, if there are additional risk factors (such as obesity), and in women with multiple previous VTE episodes  .
| New perspectives for the long-term treatment of patients with VTE|| |
Finally, new categories of oral antithrombotic drugs are emerging, which have the potential to simplify the long-term treatment of patients with VTE by obviating the need for periodic laboratory monitoring, while being associated with a favourable benefit-to-risk ratio. They include compounds that inhibit factor Xa, such as rivaroxaban, and compounds that inhibit thrombin, such as dabigatran etexilate. Recently, the results of the Recover  and those of the Einstein  randomized clinical trials, dealing with the initial and long-term treatment of VTE patients with dabigatran etexilate and rivaroxaban, respectively, have been reported. In the former study, the administration of dabigatran etexilate at the dose of 150 mg twice daily for 6 months in patients with acute VTE was found to be as effective as warfarin in patients who had all been treated with heparins or fondaparinux for the initial 7 to 10 days, and was associated with a statistically significant reduction in the incidence of major or clinically relevant bleeding complications  . In the latter, the administration of rivaroxaban from the beginning at the dose of 15 mg twice daily for three weeks followed by 20 mg once daily for 3 to 12 months in patients with acute DVT was found to be at least as effective and safe as conventional enoxaparin-warfarin treatment  . Of interest, rivaroxaban was found to be significantly more effective than comparators for the achievement of the combined end-point recurrent VTE plus major bleeding. In addition, prolonging rivaroxaban at the dose of 20 mg once daily for an additional 6 to 12-month period in patients who had received at least three months of rivaroxaban or warfarin achieved an 82 per cent reduction in the risk of recurrent events over placebo while being associated with less than 1 per cent of major bleeding complications  .
| References|| |
|1.||Prandoni P, Lensing AWA, Cogo A, Cuppini S, Villalta S, Carta M, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996; 125 : 1-7. |
|2.||Prandoni P, Noventa F, Ghirarduzzi A, Pengo V, Bernardi E, Pesavento R, 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 1626 patients. Haematologica 2007; 91 : 199-205. |
|3.||Schulman S, Rhedin AS, Lindmarker P, Carlsson A, Lärfars G, Nicol P, et al, and the Duration of Anticoagulation Trial Study Group. 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 : 1661-5. |
|4.||Hansson PO, Sorbo J, Eriksson H. Recurrent venous thromboembolism after deep vein thrombosis. Incidence and risk factors. Arch Intern Med 2000; 1260 : 769-74. |
|5.||Baglin T, Luddington R, Brown K, Baglin C. Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. Lancet 2003; 362 : 523-6. |
|6.||Palareti G, Legnani C. Cosmi B, Valdré L, Lunghi B, Bernardi F, et al. Predictive value of D-Dimer test for recurrent venous thromboembolism after anticoagulation withdrawal in subjects with a previous idioipathic event and in carriers of congenital thrombophilia. Circulation 2003; 108 : 313-8. |
|7.||Christiansen SC, Cannegieter SC, Koster T, Vandenbroucke JP, Rosendaal FR. Thrombophilia, clinical factors, and recurrent venous thrombotic events. JAMA 2005; 293 : 2352-61. |
|8.||Prandoni P, Falanga A, Piccioli A. Cancer and venous thromboembolism. Lancet Oncol 2005; 6 : 401-10. |
|9.||Kearon C. Long-term management of patients after venous thromboembolism. Circulation 2004; 110 (Suppl 1) : 10-8. |
|10.||Prandoni P, Villalta S, Tormene D, Spiezia L, Pesavento R. Immobilization resulting from chronic medical diseases: a new risk factor for recurrent venous thromboembolism in anticoagulated patients. J Thromb Haemost 2007; 5 : 1786-7. |
|11.||Lee AY, Levine MN, Baker RI, Levine MN, Baker RI, Bowden C, et al, for the Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003; 349 : 146-53. |
|12.||Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (6 Suppl) : 454S-545S. |
|13.||Schulman S, Granqvist S, Holmstrom M, Carlsson A, Lindmarker P, Nicol P, et al, and the Duration of Anticoagulation Trial Study Group. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med 1997; 336 : 393-8. |
|14.||Decousus H, Leizorovicz A, Parent F, Page Y, Tardy B, Girard P, et al. A clinical trial of vena cava filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. N Engl J Med 1998; 338 : 409-15. |
|15.||Schulman S, Svenungsson E, Granqvist S. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Am J Med 1998; 104 : 332-8. |
|16.||Crowther MA, Ginsberg JS, Julian J, Denburg J, Hirsh J, Douketis J, et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med 2003; 349 : 1133-8. |
|17.||Finazzi G, Marchioli R, Brancaccio V, Schinco P, Wisloff F, Musial J, et al. A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome. J Thromb Haemost 2005; 3 : 848-53. |
|18.||Kearon C, Ginsberg JS, Anderson DR, Kovacs MJ, Wells P, Julian JA, et al. Comparison of 1 month with 3 months of anticoagulation for a first episode of venous thromboembolism associated with a transient risk factor. J Thromb Haemost 2004; 2 : 743-9. |
|19.||Pinede L, Ninet J, Duhaut P, Chabaud S, Demolombe-Rague S, Durieu I, et al. Investigators of the "Durée Optimale du Traitement AntiVitamines K" (DOTAVK) Study. 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 deep vein thrombosis. Circulation 2001; 103 : 2453-60. |
|20.||Kearon C, Gent M, Hirsh J, Weitz J, Kovacs MJ, Anderson DR, 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 : 901-7. |
|21.||Agnelli G, Prandoni P, Santamaria MG, Bagatella P, Iorio A, Bazzan M, et al. Warfarin Optimal Duration Italian Trial Investigators. Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. N Engl J Med 2001; 345 : 165-9. |
|22.||Agnelli G, Prandoni P, Becattini C, Silingardi M, Taliani MR, Miccio M, et al. Warfarin Optimal Duration Italian Trial Investigators. Extended oral anticoagulant therapy after a first episode of pulmonary embolism. Ann Intern Med 2003; 139 : 19-25. |
|23.||Douketis JD, Shu Gu C, Schulman S, Ghirarduzzi A, Pengo V, Prandoni P. The risk for fatal pulmonary embolism after discontinuing anticoagulant therapy for venous thromboembolism. Ann Intern Med 2007; 147 : 766-74. |
|24.||Linkins LA, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism. A meta-analysis. Ann Intern Med 2003; 139 : 893-900. |
|25.||Carrier M, Le Gal G, Wells PS, Rodger MA. Systematic review: case-fatality rates of recurrent venous thromboembolism and major bleeding events among patients treated for venous thromboembolism. Ann Intern Med 2010; 152 : 578-89. |
|26.||Ridker PM, Goldhaber SZ, Danielson E, Rosenberg Y, Eby CS, Deitcher SR, et al. PREVENT Investigators. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med 2003; 348 : 1425-34. |
|27.||Kearon C, Ginsberg JS, Kovacs MJ, Anderson DR, Wells P, Julian JA, et al. Extended Low-Intensity Anticoagulation for Thrombo-Embolism Investigators. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med 2003; 349 : 631-9. |
|28.||Prandoni P, Lensing AW, Prins MH, Bernardi E, Marchiori A, Bagatella P, et al. Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism. Ann Intern Med 2002; 137 : 955-60. |
|29.||Piovella F, Crippa L, Barone M, Viganò D'Angelo S, Serafini S, Galli L, et al. Normalization rates of compression ultrasonography in patients with a first episode of deep vein thrombosis of the lower limbs: association with recurrence and new thrombosis. Haematologica 2002; 87 : 515-22. |
|30.||Prandoni P, Prins MH, Lensing AW, Ghirarduzzi A, Ageno W, Imberti D, 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 : 577-85. |
|31.||Siragusa S, Malato A, Anastasio R, Cigna V, Milio G, Amato C, et al. Residual vein thrombosis to establish duration of anticoagulation after a first episode of deep vein thrombosis: the "DACUS" study. Blood 2008; 112 : 511-5. |
|32.||Tan M, Mos ICM, Klok FA, Huisman MV. Residual venous thrombosis as predictive factor for recurrent venous thromboembolim in patients with proximal deep vein thrombosis: a sytematic review. Br J Haematol; 2011; 1111 : 1365-2141. |
|33.||Palareti G, Legnani C, Cosmi B, Guazzaloca G, Pancani C, Coccheri S. Risk of venous thromboembolism recurrence: high negative predictive value of D-dimer performed after oral anticoagulation is stopped. Thromb Haemost 2002; 87 : 7-12. |
|34.||Eichinger S, Minar E, Bialonczyk C, Hirschl M, Quehenberger P, Schneider B, et al. D-dimer levels and risk of recurrent venous thromboembolism. JAMA 2003; 290 : 1071-4. |
|35.||Verhovsek M, Douketis JD, Yi Q, Shrivastava S, Tait RC, Baglin T, et al. Systematic review: D-dimer to predict recurrent disease after stopping anticoagulant therapy for unprovoked venous thromboembolism. Ann Intern Med 2008; 149 : 481-90. |
|36.||Palareti G, Cosmi B, Legnani C, Tosetto A, Brusi C, Iorio A, et al. PROLONG Investigators. D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med 2006; 355 : 1780-9. |
|37.||Cosmi B, Legnani C, Tosetto A, Pengo V, Ghirarduzzi A, Testa S, 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 : 481-8. |
|38.||Stain M, Schönauer V, Minar E, Bialonczyk C, Hirschl M, Weltermann A, et al. The post-thrombotic syndrome: risk factors and impact on the course of thrombotic disease. J Thromb Haemost 2005; 3 : 2671-6. |
|39.||Rodger MA, Kahn SR, Wells PS, Anderson DA, Chagnon I, Le Gal G, et al. Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ 2008; 179 : 417-26. |
|40.||Eichinger S, Heinze G, Jandeck LM, Kyrle PA. Risk assessment of recurrence in patients with unprovoked deep vein thrombosis or pulmonary embolism. The Vienna Prediction Model. Circulation 2010; 121 : 1630-6. |
|41.||Kearon C, Julian JA, Kovacs MJ, Anderson DR, Wells P, Mackinnon B, et al. ELATE Investigators. Influence of thrombophilia on risk of recurrent venous thromboembolism while on warfarin: Results from a randomized trial. Blood 2008; 112 : 4432-6. |
|42.||De Stefano V, Simioni P, Rossi E, Tormene D, Za T, Pagnan A, et al. The risk of recurrent venous thromboembolism in patients with inherited deficiency of natural anticoagulants antithrombin, protein C and protein S. Haematologica 2006; 91 : 695-8. |
|43.||Eichinger S, Stümpflen A, Hirschl M, Bialonczyk C, Herkner K, Stain M, et al. Hyperhomocysteinemia is a risk factor of recurrent venous thromboembolism. Thromb Haemost 1998; 80 : 566-9. |
|44.||Kyrle PA, Minar E, Hirschl M, Bialonczyk C, Stain M, Schneider B, et al. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med 2000; 343 : 457-62. |
|45.||Eischer L, Gartner V, Schulman S, Kyrle PA, Eichinger S. 6 versus 30 months anticoagulation for recurrent venous thrombosis in patients with high factor VIII. Ann Hematol 2008; 88 : 485-90. |
|46.||Weltermann A, Eichinger S, Bialonczyk C, Minar E, Hirschl M, Quehenberger P, et al. The risks of recurrent venous thromboembolism among patients with high factor IX levels. J Thromb Haemost 2003; 1 : 28-32. |
|47.||Segal JB, Brotman DJ, Necochea AJ, Emadi A, Samal L, Wilson LM, et al. Predictive value of factor V Leiden and prothrombin G20210A in adults with venous thromboembolism and in family members of those with a mutation: a systematic review. JAMA 2009; 301 : 2472-85. |
|48.||Lijfering WM, Middeldorp S, Veeger NJ, Hamulyák K, Prins MH, Büller HR, et al. Risk of recurrent venous thrombosis in homozygous carriers and double heterozygous carriers of factor V Leiden and prothrombin G20210A. Circulation 2010; 121 : 1706-12. |
|49.||Taliani MR, Becattini C, Agnelli G, Prandoni P, Moia M, Bazzan M, et al. Warfarin Optimal Duration Italian Trial (WODIT) Investigators. Duration of anticoagulant treatment and recurrence of venous thromboembolism in patients with and without thrombophilic abnormalities. Thromb Haemost 2009; 101 : 596-8. |
|50.||Prandoni P, Tormene D, Spiezia L, Pesavento R, Simioni P. Duration of anticoagulation and risk of recurrent thromboembolism in carriers of factor V Leiden or prothrombin mutation. J Thromb Haemost 2008; 6 : 2223-4. |
|51.||den Heijer M, Willems HP, Blom HJ, Gerrits WB, Cattaneo M, Eichinger S, et al. Homocysteine lowering by B vitamins and the secondary prevention of deep-vein thrombosis and pulmonary embolism. A randomized, placebo-controlled, double blind trial. Blood 2007; 109 : 139-44. |
|52.||Eichinger S, Weltermann A, Minar E, Stain M, Schönauer V, Schneider B, et al. Symptomatic pulmonary embolism and the risk of recurrent venous thromboembolism. Arch Intern Med 2004; 164 : 92-6. |
|53.||McRae S, Tran H, Schulman S, Ginsberg J, Kearon C. Effect of patient's sex on risk of recurrent venous thromboembolism: a meta-analysis. Lancet 2006; 368 : 371-8. |
|54.||Douketis J, Tosetto A, Marcucci M, Baglin T, Cosmi B, Cushman M, et al. Risk of recurrence after venous thromboembolism in men and women: patient level meta-analysis: BMJ 2011; 342 : d813. |
|55.||Lijfering WM, Veeger NJ, Middeldorp S, Hamulyák K, Prins MH, Büller HR, et al. A lower risk of recurrent venous thrombosis in women compared to men is explained by sex-specific risk factors at time of first venous thrombosis in thrombophilic families. Blood 2009; 114 : 2031-6. |
|56.||Le Gal G, Kovacs MJ, Carrier M, Do K, Kahn SR, Wells PS, et al. Risk of recurrent venous thromboembolism after a first oestrogen-associated episode. Data from the REVERSE cohort study. Thromb Haemost 2010; 104 : 498-503. |
|57.||Kovacs MJ, Kahn SR, Wells PS, Anderson DA, Chagnon I, LE Gal G, et al. Patients with a first symptomatic unprovoked DVT are at higher risk of recurrent VTE than patients with a first unprovoked PE. J Thromb Haemost 2010; 8 : 1926-32. |
|58.||Baglin T, Douketis J, Tosetto A, Marcucci M, Cushman M, Kyrle P, et al. Does the clinical presentation and extent of venous thrombosis predict likelihood and type of recurrence? A patient level meta-analysis. J Thromb Haemost 2010; 8 : 2436-42. |
|59.||Eischer L, Eichinger S, Kyrle PA. Age at first venous thromboembolism and risk of recurrence: a prospective cohort study. Medicine (Baltimore) 2009; 88 : 366-70. |
|60.||López-Jiménez L, Montero M, González-Fajardo JA, Arcelus JI, Suárez C, Lobo JL, et al. RIETE Investigators. Venous thromboembolism in very elderly patients: findings from a prospective registry. Haematologica 2006; 91 : 1046-51. |
|61.||Eichinger S, Hron G, Bialonczyk C, Hirschl M, Minar E, Wagner O, et al, Overweight obesity, and the risk of recurrent venous thromboembolism. Arch Intern Med 2008; 68 : 1678-83. |
|62.||Grand'maison A, Bates SM, Johnston M, McRae S, Ginsberg JS. "ProC Global": A functional screening test that predicts recurrent venous thromboembolism. Thromb Haemost 2005; 93 : 600-4. |
|63.||Hron G, Kollars M, Binder BR, Eichinger S, Kyrle PA. Identification of patients at low risk for recurrent venous thromboembolism by measuring thrombin generation. JAMA 2006; 296 : 397-402. |
|64.||Hron G, Eichinger S, Weltermann A, Quehenberger P, Halbmayer WM, Kyrle PA. Prediction of recurrent venous thromboembolism by the activated partial thromboplastin time. J Thromb Haemost 2006; 4 : 752-6. |
|65.||Besser M, Baglin C, Luddington R, van Hylckama Vlieg A, Baglin TJ. High rate of unprovoked recurrent venous thrombosis is associated with high thrombin-generating potential in a prospective cohort study. J Thromb Haemost 2008; 6 : 1720-5. |
|66.||Hoibraaten E, Qvigstad E, Arnesen H, Larsen S, Wickstrom E, Sandset PM. Increased risk of recurrent venous thromboembolism during hormone replacement therapy--results of the randomized, double-blind, placebo-controlled estrogen in venous thromboembolism trial. Thromb Haemost 2000; 84 : 961-7. |
|67.||Pabinger I, Grafenhofer H, Kaider A, Kyrle PA, Quehenberger P, Mannhalter C, et al. Risk of pregnancy-associated recurrent venous thromboembolism in women with a history of venous thrombosis. J Thromb Haemost 2005; 3 : 949-54. |
|68.||De Stefano V, Martinelli I, Rossi E, Battaglioli T, Za T, Mannuccio Mannucci P, et al. The risk of recurrent venous thromboembolism in pregnancy and puerperium without antithrombotic prophylaxis. Br J Haematol 2006; 135 : 386-91. |
|69.||White RH, Chan WS, Zhou H, Ginsberg JS. Recurrent venous thromboembolism after pregnancy-associated versus unprovoked thromboembolism. Thromb Haemost 2008; 100 : 246-52. |
|70.||Bates SM, Greer IA, Pabinger I, Sofaer S, Hirsh H. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (6 Suppl); 844-86S. |
|71.||Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361 : 2342-52. |
|72.||The Einstein Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363 : 2499-510. |