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The dark side of deep venous thrombosis: the failure of anticoagulation

2001; Elsevier BV; Volume: 110; Issue: 7 Linguagem: Inglês

10.1016/s0002-9343(01)00690-8

1555-7162

McDonald K. Horne,

Atrial Fibrillation Management and Outcomes

These days the typical patient with acute deep venous thrombosis of a lower extremity is treated as an outpatient with low molecular weight heparin followed by several months of oral anticoagulation therapy. The short-term outcome, at least, is gratifying (1Levine M. Gent M. Hirsh J. et al.A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis.N Engl J Med. 1996; 334: 677-681Crossref PubMed Scopus (1252) Google Scholar, 2Columbus InvestigatorsLow-molecular-weight heparin in the treatment of patients with venous thromboembolism.N Engl J Med. 1997; 337: 657-662Crossref PubMed Scopus (849) Google Scholar). But deep venous thrombosis of the lower extremities has a dark side. Five years after an initial bout, only a quarter of the patients are asymptomatic from their thrombosis, another quarter have died of cardiovascular disease or metastatic malignancy, and the rest have had recurrent thrombosis or have a postthrombotic syndrome (3Prandoni P. Lensing A.W.A. Cogo A. et al.The long-term clinical course of acute deep venous thrombosis.Ann Intern Med. 1996; 125: 1-7Crossref PubMed Scopus (1966) Google Scholar). Therefore, for half of the patients, acute deep venous thrombosis becomes a chronic disease. In this issue of The Green Journal, Douketis et al (4Douketis JD, Crowther MA, Foster GA, Ginsberg JS. Does the location of thrombosis determine the risk of disease recurrence in patients with proximal deep vein thrombosis? Am J Med. 2001;110:515–519.Google Scholar) have reported on a subset of patients treated for lower extremity deep venous thrombosis (5.5% of their series) who quickly entered the poor prognostic categories. These were anticoagulant failures—patients whose thrombosis recurred within 3 months (most within 1 month) despite appropriate therapy with heparin and then warfarin (1Levine M. Gent M. Hirsh J. et al.A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis.N Engl J Med. 1996; 334: 677-681Crossref PubMed Scopus (1252) Google Scholar, 2Columbus InvestigatorsLow-molecular-weight heparin in the treatment of patients with venous thromboembolism.N Engl J Med. 1997; 337: 657-662Crossref PubMed Scopus (849) Google Scholar). Perhaps it is more accurate, however, to say that the patients developed “recurrent symptoms” attributable to additional thrombosis or embolism, because in most cases the “recurrence” was probably not an independent episode but rather progression of a thrombosis that had never been adequately treated. This small subset of patients is actually the tip of the iceberg of the larger group of patients whose deep venous thrombosis worsens during anticoagulation but without increasing symptoms (5Meissner M.H. Caps M.T. Bergelin R.O. et al.Propagation, rethrombosis, and new thrombus formation after acute deep venous thrombosis.J Vasc Surg. 1995; 22: 558-567Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 6Van Ramshorst B. van Bemmelen P.S. Hoeneveld H. et al.Thrombus regression in deep venous thrombosis.Circulation. 1992; 86: 414-419Crossref PubMed Scopus (104) Google Scholar). The group of progressively symptomatic anticoagulant failures is different from the much larger percentage (more than 30%) of patients whose deep venous thrombosis recurs after anticoagulation therapy has been discontinued (3Prandoni P. Lensing A.W.A. Cogo A. et al.The long-term clinical course of acute deep venous thrombosis.Ann Intern Med. 1996; 125: 1-7Crossref PubMed Scopus (1966) Google Scholar). In these patients, deep venous thrombosis is as likely to recur in the other leg as in the one originally involved (3Prandoni P. Lensing A.W.A. Cogo A. et al.The long-term clinical course of acute deep venous thrombosis.Ann Intern Med. 1996; 125: 1-7Crossref PubMed Scopus (1966) Google Scholar, 7Schulman S. Rhedin A.-S. 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: 1661-1665Crossref PubMed Scopus (967) Google Scholar); standard anticoagulation treatment suppresses the prothrombotic stimuli, at least enough to prevent new symptoms, while the affected veins slowly recanalize. In contrast, anticoagulant failure is a consequence of prothrombotic forces too strong to be suppressed by routine treatment. Failure of standard antithrombotic treatment is a recognized problem among patients with coexistent cancer (8Levitan N. Dowlati A. Remick S.C. et al.Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy.Medicine. 1999; 78: 285-291Crossref PubMed Scopus (801) Google Scholar). Douketis et al (4Douketis JD, Crowther MA, Foster GA, Ginsberg JS. Does the location of thrombosis determine the risk of disease recurrence in patients with proximal deep vein thrombosis? Am J Med. 2001;110:515–519.Google Scholar) found this to be true in their series as well. However, they also found that anticoagulant failure was twice as likely when the presenting thrombosis extended from the femoral vein into the pelvis. Iliofemoral thrombosis was documented in only 4.4% of their cases, but accounted for 9.5% of their recurrences. The converse of these numbers is that thrombosis was limited to the popliteal or popliteal-femoral vein in 96% of the cases and accounted for 90% of the anticoagulant failures. Therefore, although iliofemoral thrombosis is particularly resistant to standard treatment, it is associated with only a minority of the failures of standard treatment. How should clinicians use the new information provided by Douketis et al? Insisting on contrast or magnetic resonance venography to be certain of the proximal extent of a deep venous thrombosis, which can be difficult using standard ultrasonography (9Laissy J.-P. Cinqualbre A. Loshkajian A. et al.Assessment of deep venous thrombosis in the lower limbs and pelvis MR venography versus duplex doppler sonography.Am J Roentgenol. 1996; 167: 971-974Crossref PubMed Scopus (112) Google Scholar), makes sense only if intensified treatment is planned when iliofemoral thrombosis is documented. Unfortunately, intensified treatment comes with an increased risk of bleeding, and there is no stratification of regimens from which to chose. Furthermore, most patients who failed anticoagulation therapy did not present with thrombosis extending into the iliac vein (4Douketis JD, Crowther MA, Foster GA, Ginsberg JS. Does the location of thrombosis determine the risk of disease recurrence in patients with proximal deep vein thrombosis? Am J Med. 2001;110:515–519.Google Scholar). The paper by Douketis et al is valuable because it has identified a variable that must be considered in clinical trials testing intensified antithrombotic therapies. But until those trials are conducted, the clinician is advised to adhere to practices of proven efficacy and safety, even if they are obviously inadequate for some patients. In recent years, antithrombotic research has been focused on low-molecular-weight heparin, which has been a great boon largely because it can be administered to outpatients (1Levine M. Gent M. Hirsh J. et al.A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis.N Engl J Med. 1996; 334: 677-681Crossref PubMed Scopus (1252) Google Scholar). However, Douketis et al (4Douketis JD, Crowther MA, Foster GA, Ginsberg JS. Does the location of thrombosis determine the risk of disease recurrence in patients with proximal deep vein thrombosis? Am J Med. 2001;110:515–519.Google Scholar) found no difference in early recurrence of deep venous thrombosis between patients treated with intravenous unfractionated heparin and those treated with subcutaneous low-molecular-weight heparin. Therefore, while low-molecular-weight heparin has greatly decreased the economic burden of deep venous thrombosis, it probably has not improved prognosis. Because symptomatic recurrent thrombosis begins to occur almost immediately after warfarin is stopped, several clinical trials are under way to determine whether an extended course of oral anticoagulation reduces the long-term recurrence rate without unacceptable complications (7Schulman S. Rhedin A.-S. 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: 1661-1665Crossref PubMed Scopus (967) Google Scholar, 10Ridker P.M. Long-term, low-dose warfarin among venous thrombosis patients with and without factor V Leiden mutation rationale and design for the Prevention of Recurrent Venous Thromboembolism (PREVENT) trial.Vasc Med. 1998; 3: 67-73PubMed Google Scholar). But patients like those highlighted by Douketis et al are not being addressed in those trials, nor are the asymptomatic patients whose thrombosis progresses despite anticoagulation (5Meissner M.H. Caps M.T. Bergelin R.O. et al.Propagation, rethrombosis, and new thrombus formation after acute deep venous thrombosis.J Vasc Surg. 1995; 22: 558-567Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar). These patients need more effective initial therapy in addition to optimal chronic treatment. Different anticoagulants might be more effective in preventing recurrence. A limitation of both unfractionated and low-molecular-weight heparin is that they only weakly inhibit thrombin that is bound to fibrin (11Weitz J.I. Hudoba M. Massel D. et al.Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors.J Clin Invest. 1990; 86: 385-391Crossref PubMed Scopus (1119) Google Scholar). At the thrombus-blood interface, thrombin is still able to clot fibrinogen. The heparins primarily inhibit thrombin generated in solution. Warfarin, of course, does not inhibit thrombin at all. This may explain why deep venous thrombosis often progresses during anticoagulation treatment (5Meissner M.H. Caps M.T. Bergelin R.O. et al.Propagation, rethrombosis, and new thrombus formation after acute deep venous thrombosis.J Vasc Surg. 1995; 22: 558-567Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 6Van Ramshorst B. van Bemmelen P.S. Hoeneveld H. et al.Thrombus regression in deep venous thrombosis.Circulation. 1992; 86: 414-419Crossref PubMed Scopus (104) Google Scholar). If there is active thrombin at the thrombus-blood interface when the transition to warfarin occurs, a fire has been left smoldering that can grow into an open flame (progressive thrombosis) when the water (heparin) is turned off. Therefore, more effective thrombin inhibition during the early stage of treatment might translate into fewer warfarin failures. Two newly available anticoagulants, lepirudin and argatroban, inhibit clot-bound thrombin and are obvious candidates for research directed at reducing early rethrombosis (11Weitz J.I. Hudoba M. Massel D. et al.Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors.J Clin Invest. 1990; 86: 385-391Crossref PubMed Scopus (1119) Google Scholar, 12Schiele F. Lindgaerde F. Eriksson H. et al.Subcutaneous recombinant hirudin (HBW 023) versus intravenous sodium heparin in treatment of established acute deep vein thrombosis of the legs a multicentre prospective dose-ranging randomized trial.Thromb Haemost. 1997; 77: 834-838PubMed Google Scholar, 13Berry C.N. Girardot C. Lecoffre C. Lunven C. Effects of the synthetic thrombin inhibitor argatroban on fibrin- or clot-incorporated thrombin comparison with heparin and recombinant hirudin.Thromb Haemost. 1994; 72: 381-386PubMed Google Scholar, 14Swan S.K. St Peter J.V. Lambrecht L.J. Hursting M.J. Comparison of anticoagulant effects and safety of argatroban and heparin in healthy subjects.Pharmocotherapy. 2000; 20: 756-770Crossref PubMed Scopus (97) Google Scholar). Both early and late recurrent thrombosis may result from the inability of any anticoagulant to hasten the removal of the original venous obstruction. Venous thrombus must be dissolved by natural fibrinolytic mechanisms, which require weeks to months to recanalize a large vein (6Van Ramshorst B. van Bemmelen P.S. Hoeneveld H. et al.Thrombus regression in deep venous thrombosis.Circulation. 1992; 86: 414-419Crossref PubMed Scopus (104) Google Scholar). In the process, irreversible damage occurs to the venous valves, predisposing them to chronic stasis and venous hypertension (15Meissner M.H. Caps M.T. Zierler B.K. et al.Determinants of chronic venous disease after acute deep venous thrombosis.J Vasc Surg. 1998; 28: 826-833Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). A logical way to prevent this is by thrombolytic therapy, which can be given effectively and safely by catheter-directed techniques to patients who are at low risk for bleeding (16Grossman C. McPherson S. Safety and efficacy of catheter-directed thrombolysis for iliofemoral venous thrombosis.Am J Roentgenol. 1999; 172: 667-672Crossref PubMed Scopus (67) Google Scholar, 17Horne M.K. Mayo D.J. Cannon R.O. et al.Intraclot recombinant tissue plasminogen activator in the treatment of deep venous thrombosis of the lower and upper extremities.Am J Med. 2000; 108: 251-255Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar). But such treatment is far more expensive than outpatient low-molecular-weight heparin treatment, is riskier, and is more difficult for the patient. Furthermore, it has not been shown to be superior to anticoagulation alone, except in extreme situations (18Horne M.K. Chang R. Thrombolytic therapy for deep venous thrombosis?.JAMA. 1999; 282: 2164-2166Crossref PubMed Scopus (7) Google Scholar). The appropriate role for the new anticoagulants and thrombolytic therapy in the management of deep venous thrombosis requires clinical investigation. It is necessary to develop a staging system for acute deep venous thrombosis that predicts the degree of subsequent morbidity and is based upon clinical setting, anatomic distribution (with new data contributed by Douketis et al), the presence or absence of pulmonary emboli, and genetic risk factors. With this information, researchers could target the highest risk patients for treatment with new and more aggressive (and more expensive) treatment regimens and perhaps begin to improve the prognosis of this disease.