Thrombolytic Therapy

Anthony J. Comerota, MD, FACS
Director, Jobst Vascular Center
Toledo, OH
Clinical Professor of Surgery
University of Michigan
Ann Arbor, MI

The underlying pathophysiology of the postthrombotic syndrome is ambulatory venous hypertension.12   During exercise (walking) the venous pressure in the lower extremity should drop to less than 50% of the standing venous pressure.  In patients with the postthrombotic syndrome the ambulatory pressure drops very little, and in those with persistent proximal venous occlusion the ambulatory pressures may increase compared to the standing pressure, resulting in the debilitating symptom of venous claudication.  The pathologic components leading to ambulatory venous hypertension are venous obstruction and/or venous valve incompetence.  Shull and colleagues13 and Johnson and colleagues14 have confirmed that following acute DVT, patients with combined obstruction and valvular incompetence suffer the most severe postthrombotic morbidity.
One reason that anticoagulation is often ineffective with large clots associated with iliofemoral venous disease is because anticoagulation has no chemical thrombolytic activity.  Anticoagulants do not dissolve existing clots, they simply prevent the body from making more clots.  Therefore, with current anticoagulation regimes, especially for extensive DVT, intrinsic thrombolysis occurs slowly, is often incomplete and highly variable.  This inadequate intrinsic thrombolysis results in significant residual clot causing persistent venous obstruction and remains a nidus for rethrombosis and recurrent PE.

Basic Science and Natural History Studies
There is increasing evidence supporting the concept that early thrombus resolution after acute DVT is associated with improved outcome.  This evidence includes experimental data, natural history studies of acute DVT treated with anticoagulation, venous thrombectomy data and observations regarding catheter-directed thrombolysis. Cho and colleagues 15 and Rhodes and colleagues 16 have used a canine experimental model of acute DVT to evaluate the results of urokinase infusion versus placebo versus mechanical thrombectomy.  They demonstrated that thrombolysis with urokinase preserves valve function and endothelium-dependent relaxation acutely and at 4 weeks.  There was less residual thrombus in veins treated with urokinase, thereby maintaining the structural and functional integrity of the vein.

A number of excellent observations have been published by the vascular investigators at the University of Washington regarding the natural history of acute DVT treated with anticoagulation.17-20   They observed that persistent obstruction of proximal veins was associated with distal valve incompetence.  As mentioned, the postthrombotic combination of venous obstruction and valve incompetence is associated with severe postthromboic morbidity.  Another important observation by this group was that early spontaneous lysis preserves valve function and of course restores patency to the thrombosed vein.   While most would consider “early lysis” as clot dissolving in days to a couple of weeks, it was interesting to note that the timeframe for early lysis in this study was defined as up to 60-90 days for the various vein segments.

The Historical Approach to Thrombus Removal
Early trials of systemic thrombolytic therapy for proximal DVT demonstrated that only 45% of patients had significant or complete lysis.  Those whose clot was successfully lysed had a significant reduction in postthrombotic morbidity and preservation of venous valve function.21 Scandinavian investigators randomized patients with iliofemoral DVT to venous thrombectomy plus temporary arteriovenous fistula and anticoagulation versus anticoagulation alone.  Follow-up reports at 6 months,22  5 years23 and 10 years24 demonstrated clear benefit to patients randomized to venous thrombectomy.  Early thrombus removal resulted in improved patency of the iliofemoral venous system, lower venous pressures, less edema, and fewer postthrombotic symptoms.

The aggregate of the above observations lend consistent support to the concept that thrombus removal in patients with acute iliofemoral DVT results in significantly less postthrombotic morbidity.  Unfortunately, systemically delivered thrombolytic therapy is associated with a less than acceptable chance of success and a higher than acceptable risk of bleeding.  And, despite the favorable results of contemporary venous thrombectomy, few vascular surgeons in the United States are willing to perform a venous thrombectomy.

Catheter-Directed (Intrathrombus) Thrombolysis
Catheter-based techniques which deliver thrombolytic agents into the thrombus can accelerate thrombolysis, increasing the likelihood of a successful outcome while decreasing bleeding complications.  The basic mechanism of thrombolysis is activation of fibrin-bound plasminogen.25  When circulating Glu-plasminogen binds to fibrin, it is modified to Lys-plasminogen, which has greater affinity for plasminogen activators.  When delivered intrathrombus, plasminogen activators efficiently activate Lys-plasminogen.  There is less neutralization of the delivered plasminogen activator by circulating plasminogen activator inhibitors and less neutralization of plasmin by circulating α2-antiplasmins.

A large number of reports have emerged supporting favorable outcomes with catheter-directed thrombolysis.  Three of the larger reports by Bjarnason and colleagues,26 Mewissen and colleagues 27 and Comerota and colleagues 28 demonstrate an 80-85% success rate (Table 1).  Initial success rates might have been higher if treatment was restricted to only patients with acute iliofemoral DVT.  However, a desire to help patients with more chronic venous thrombosis leads to a higher failure rate and a lower overall success rate, which is reflected in the data.  A total of 422 patients were treated in these 3 studies with remarkably consistent success and complication rates.  Catheter-directed urokinase was used in each of these studies.  Underlying iliac vein stenoses were treated with balloon angioplasty and/or stenting to achieve unobstructed drainage into the vena cava and reduce the risk of recurrent thrombosis.

Major bleeding occurred in 5-10% of patients with the majority being manageable puncture site bleeding.  Fortunately, intracranial bleeding was rare, occurring only in 3 patients in the National Venous Registry and resulting in only one death.  Pulmonary embolism occurred in 1% of the patients in Bjarnason’s series and the National Venous Registry.  Fatal pulmonary embolism occurred in only 1 patient out of the 422.  Therefore, death as a result of catheter-directed thrombolysis was rare.

It is revealing to take a closer look at the efficacy results reported in the National Venous Registry,27 as they represent a cross-sectional experience from centers in the United States.  Of the 287 patients treated within the 63 academic and community centers contributing to the registry, 66% had acute DVT, 16% were chronic, and 19% had an acute episode superimposed on a chronic condition.  Seventy-one percent of the patients presented with iliofemoral DVT and 25% with femoral-popliteal DVT.

Catheter-directed thrombolysis with intrathrombus infusion of urokinase resulted in better outcomes than systemic or regional techniques which did not deliver the plasminogen activator into the clot.  Phlebographic results demonstrated that 31% of patients had 100% lytic success, 52% had 50-99% lytic success and 17% had < 50% of their thrombus dissolved.  Interestingly, analyzing the subgroup of patients with acute, first-time iliofemoral DVT, 65% of the patients had 100% clot lysis.

Overall, thrombosis-free survival was observed in 65% of patients at 6 months and 60% at 12 months.  There was a significant correlation (P < 0.001) of thrombosis-free survival with the results of initial therapy.  Seventy-eight percent of patients who had complete clot resolution had patent veins at 1 year compared to 37% who had < 50% of their clot dissolved.  Notably, in the subgroup of patients with acute, first-time iliofemoral DVT who had successful thrombolysis, 96% remained patent at 1 year.  In addition to sustained patency, early success directly correlated with valve function at 6 months.  Sixty-two percent of patients with < 50% lysis had venous valvular incompetence, whereas 72% of patients who had complete lysis had normal valve function.

These objectively documented treatment outcomes provided an opportunity to evaluate whether catheter-directed thrombolysis improved the quality-of-life over the long-term compared to patients treated with anticoagulation alone.

After constructing and validating a quality-of-life questionnaire,29 68 patients treated with catheter-directed urokinase for iliofemoral DVT were compared with 30 patients who were treated with anticoagulation alone because of physician preference.30  All patients were candidates for thrombolytic therapy.  Patients were queried at 16 and 22 months following treatment.  Patients treated with catheter-directed urokinase enjoyed a significantly better quality of life compared to patients treated with anticoagulation alone.  Not surprisingly, the quality-of-life results were directly related to the initial success of thrombolysis.   Patients who had a successful lytic outcome (≥ 50% lysis) reported a significantly better health utilities index, better physical functioning, less stigma of chronic venous disease, less health distress and fewer overall postthrombotic symptoms. (Table 2)  Patients failing catheter-directed thrombolysis had similar outcomes to patients treated with anticoagulation alone.  These data offer a compelling argument for a prospective randomized trial of catheter-directed thrombolysis compared to anticoagulation alone for patients with acute iliofemoral DVT.

Indeed, a prospective randomized trial comparing catheter-directed intrathrombus urokinase versus anticoagulation has just been initiated.  The TOLEDO trial (Thrombolysis Of Lower Extremity Deep vein thrombosis Oral anticoagulation) was recently approved by the FDA.  The hypothesis of the study is that catheter-directed intrathrombus infusion of urokinase will be associated with significantly better early clot lysis than anticoagulation alone, and that early clot lysis is associated with a significantly improved quality-of-life at 1 year. This Phase IV multicenter, open label trial will randomize 150 patients in a 2:1 ratio, with two patients receiving catheter-directed intrathrombus urokinase for each one receiving standard anticoagulation. It is likely that the results of this trial will show that catheter-directed thrombolysis for acute iliofemoral DVT in patients who have no contraindication to thrombolytic therapy is the preferred treatment.  However, until the trial is completed, the available data strongly support a strategy of catheter-directed thrombolysis for acute iliofemoral DVT.  Sixty-five to 80% of patients will have complete clot lysis.  Following lysis and correction of an underlying iliac vein stenosis, unobstructed venous drainage into the vena cava is restored, avoiding post-thrombotic symptoms and improving quality of life.  If a contraindication to lytic therapy exists, a contemporary venous thrombectomy followed by long-term anticoagulation should be considered. 

1. Comerota AJ. Venous thromboembolism.  In: Rutherford RB, ed. Vascular Surgery, 4th ed. Philadelphia, PA: WB Saunders; 1995: 1785-1814.

2. Hyers TM, Agnelli G, Hull RD, et al.  Antithrombotic therapy for venous thromboembolic disease. Sixth ACCP Consensus Conference on Antithrombotic Therapy. Chest. 2001; 119(suppl 1):176S-193S.

3. Lensing AWA, Prins MH, Davidson BL, et al. Treatment of deep venous thrombosis with low molecular weight heparins: a meta analysis.  Arch Intern Med. 1995;
155:601-607.

4. Ridker PM, Goldhaber SZ, Danielson E, et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med. 2003;348:1425-1434.

5. Kearon C, Ginsberg JS, Kovacs MJ, et al. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med. 2003;349:631-639.

6. Turpie AGG, Bauer KA, Eriksson BI, et al.  The Steering Committees of the Pentasaccharide Orthopedic Prophylaxis Studies. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies.  Arch Intern Med. 2002;162:1833-1840.

7. Heit JA, Colwell CWJ, Francis CW, et al. Comparison of the oral direct thrombin inhibitor with enoxaparin as prophylaxis against venous thromboembolism after total knee replacement: a phase 2 dose-finding study.  Arch Intern Med. 2001;161:2215-2222.

8. Lagerstedt CI, Olsson CG, Fagher BO, et al. Need for long term anticoagulant treatment in symptomatic calf-vein thrombosis. Lancet. 1985;2:515-518.

9. Akesson H, Brudin L, Dahlstron JA, et al. Venous function assessed during a 5-year period after acute ilio-femoral venous thrombosis treated with anticoagulation. Eur J Vasc Surg. 1990;4(1):43-48.

10. O’Donnell TF, Browse NL, Burnand KG, et al. The socioeconomic effects of an iliofemoral venous thrombosis. J Surg Res. 1977;22:483-488.

11. Hill SL, Martin D, Evans P. Massive vein thrombosis of the extremities. Am J Surg. 1989;158:131-135.

12. Nicolaides AN, Schull K, Fernandes E, et al. Ambulatory venous pressures: new information. In: Nicolaides AN and Yao JST, eds.  Investigation of Vascular Disorders, New York, NY: Churchill Livingstone; 1981: 488-494.

13. Shull KC, Nicolaides AN, Fernandes E, et al. Significance of popliteal reflux in relation to ambulatory venous pressure and ulceration. Arch Surg. 1979;114:1304-1306.

14. Johnson BF, Manzo RA, Bergelin RO, et al. Relationship between changes in the deep venous system and the development of the postthrombotic syndrome after an acute episode of lower limb deep vein thrombosis: a one-to-six year follow-up. J Vasc Surg/ 1995;21:307-313.

15. Cho JS, Martelli E, Mozes G, et al. Acute effects of thrombolysis and thrombectomy on valvular competence, thrombogenicity, morphology and function of canine veins. J Vasc Surg. 1998;28:787-799.

16. Rhodes JM, Cho JS, Gloviczki P, et al. Thrombolysis for experimental deep venous thrombosis maintains valvular competence and vasoreactivity. J Vasc Surg. 2000;31:1193-1205.

17. Killewich LA, Bedford GE, Beach KW, et al. Spontaneous lysis of deep venous thrombi: rate and outcome. J Vasc Surg. 1989;9:89-97.

18. Markel A, Manzo R, Bergelin R, et al. Valvular reflux after deep vein thrombosis: incidence and time of occurrence. J Vasc Surg. 1992;15:377-384.

19. Meissner MH, Manzo RA, Bergelin RO, et al. Deep venous insufficiency: the relationship between lysis and subsequent reflux. J Vasc Surg. 1993;18:596-605.

20. Caps MT, Manzo RA, Bergelin RO, et al. Venous valvular reflux in veins not involved at the time of acute deep vein thrombosis. J Vasc Surg. 1995;22:524-531.

21. Comerota AJ, Aldridge SA. Thrombolytic therapy for acute deep vein thrombosis. Semin Vasc Surg. 1992;5(2):76-84.

22. Plate G, Einarsson E, Ohlin P, et al. Thrombectomy with temporary arteriovenous fistula: the treatment of choice in acute iliofemoral venous thrombosis. J Vasc Surg. 1984;1:867-876.

23. Plate G, Akesson H, Einarsson E, et al. Long-term results of venous thrombectomy combined with a temporary arterio-venous fistula. Eur J Vasc Sur. 1990;4:483-489.

24. Plate G, Eklof B, Norgren L, et al. Venous thrombectomy for iliofemoral vein thrombosis—10-year results of a prospective randomized study. Eur J Vasc Endovasc Surg. 1997;14:367-374.

25. Alkjaersig N, Fletcher AP, Sherry S. The mechanism of clot dissolution by plasmin. J Clin Invest. 1959;38:1086.

26. Bjarnason H, Kruse JR, Asinger DA, et al. Iliofemoral deep venous thrombosis: safety and efficacy outcome during 5 years of catheter-directed thrombolytic therapy. J Vasc Interv Radiol. 1997;8:405-418.

27. Mewissen MW, Seabrook GR, Meissner MH, et al. Catheter-directed thrombolysis for lower extremity deep venous thrombosis: report of a national multicenter registry. Radiology. 1999;211:39-49.

28. Comerota AJ, Kagan SA. Catheter-directed thrombolysis for the treatment of acute iliofemoral deep venous thrombosis. Phlebology. 2001;15:149-155.

29. Mathias SD, Prebil LA, Patterman CG, et al. A health related quality-of-life measure in patients with deep vein thrombosis: a validation study. Drug Info J. 1999;33:1173-1187.

30. Comerota AJ, Thromb RC, Mathias S, et al. Catheter-directed thrombolysis for iliofemoral deep venous thrombosis improves health-related quality of life. J Vasc Surg. 2000;32:130-137.
 

Table 1