Introduction

The majority of physicians treat patients with iliofemoral deep venous thrombosis (DVT) with anticoagulation alone, despite a growing body of evidence that these patients suffer more severe postthrombotic morbidity and higher recurrence rates than patients with infrainguinal DVT. Although there have been enormous advances in anticoagulation therapy (e.g., low-molecular-weight heparins, pentasaccharides, and direct thrombin inhibitors), these agents serve to limit the progression of thrombosis and, with proper duration of therapy, reduce recurrence. However, anticoagulants are not designed to remove existing thrombus from the deep venous system.

Acute iliofemoral DVT is associated with significant postthrombotic morbidity.1–3 Treatment that removes the thrombus from the iliofemoral venous system and restores patency appears to improve the patient’s clinical condition and reduces long-term postthrombotic morbidity.4–7 Treatment methods have evolved over time from systemic anticoagulation alone to catheter-directed thrombolysis to pharmacomechanical thrombolytic therapy. With each advance in treatment, there appears to be more effective thrombus resolution, reduction of postthrombotic morbidity, and overall improvement in the health of patients following acute DVT.

The latest American College of Chest Physicians (ACCP) evidenced-based clinical practice guidelines echo the importance of treatment designed to eliminate the thrombus in patients with extensive acute proximal DVT. Kearon et al4 state that “in selected patients with extensive acute proximal DVT (iliofemoral DVT, symptoms for < 14 days, good functional status, life expectancy of ≥ 1 year) with low risk of bleeding, catheter-directed thrombolysis may be used to reduce acute symptoms and postthrombotic morbidity if appropriate expertise and resources are available (Grade 2B).” They also added that “pharmacomechanical thrombolysis in preference to CDT alone may be performed to shorten treatment time (Grade 2C).”

Understanding Postthrombotic Venous Disease

The pathophysiology of primary versus postthrombotic venous disease is often unappreciated by many physicians. Consequently, the importance of thrombus removal for the prevention of postthrombotic morbidity, especially in patients with iliofemoral DVT, has been undervalued. The pathophysiology of chronic venous disease (CVD) is ambulatory venous hypertension, which is defined as an elevated venous pressure during exercise.5 Shull et al measured ambulatory venous pressures in a cohort of patients who had iliofemoral DVT 3–5 years earlier. Using a threshold of ≤ 30 mmHg to quantify normal venous pressure, they reported that the combination of luminal occlusion and popliteal valve incompetence resulted in the highest ambulatory venous pressures (85 ± 14 mmHg). Studies have consistently demonstrated that patients with chronic venous obstruction have the most severe postthrombotic morbidity.5,6 Although this is generally true for all segments of the venous system, patients who have multisegment venous involvement17,8 and iliofemoral obstruction suffer the most profound morbidity.

Akesson et al2 showed that 95% of patients with iliofemoral DVT treated with anticoagulation alone had ambulatory venous hypertension at 5 years, and 90% suffered symptoms of CVD. During this relatively short follow up, 15% of patients had already developed venous ulceration and another 15% had debilitating symptoms of venous claudication. In 39 exercised patients with iliofemoral DVT who were treated with anticoagulation, Delis et al3 found that 40% complained of venous claudication. All but one patient complained of chronic symptoms of heaviness, swelling, pruritus, pain, and itching.

Benefits of Thrombus Removal

It has become increasingly evident that early thrombus resolution (by whatever means) after the onset of acute DVT is associated with improved outcomes. Experimental observations, natural history studies of acute DVT treated with anticoagulation, venous thrombectomy data, and observations following both systemic and catheter-directed thrombolysis confirm that a strategy of thrombus removal reduces postthrombotic morbidity.

Experimental observations of acute DVT in canine models demonstrated that thrombolysis preserves endothelial function by preserving ADP-mediated relaxation and valve competence immediately, and at 4 weeks after therapy, compared with placebo. There was less residual thrombus in veins treated with a plasminogen activator, increasing the likelihood that the vein’s structural integrity would be maintained.9,10 Valve function was frequently preserved in humans with acute DVT who were treated with anticoagulation alone and had spontaneous lysis occur early (< 90 days).11–13

Early trials of thrombolytic therapy for acute DVT infused plasminogen activators systemically. Cumulative results of these trials demonstrated that although 45% of patients had substantial or complete lysis, most patients did not.14 However, those patients who had their thrombus successfully lysed had a significant reduction in postthrombotic morbidity and enjoyed preservation of venous valve function. Goldhaber et al15 reviewed outcomes from 8 randomized trials of systemic streptokinase infusion for patients with acute DVT; they found that moderate or significant lysis was achieved almost three times more frequently in patients treated with thrombolysis than in those receiving anticoagulation alone. Unfortunately, systemic lytic therapy was associated with more bleeding complications.

The long-term benefit of thrombus removal in patients with acute iliofemoral DVT was objectively recorded by Plate et al in their randomized trial of iliofemoral venous thrombectomy with an arteriovenous fistula (AVF) and anticoagulation versus anticoagulation alone.16–18 They reported follow-up results at 6 months, 5 years, and 10 years, which demonstrated a clear benefit in patients randomized to venous thrombectomy. (Although the focus of this paper is on catheter-directed thrombolytic techniques, a recent paper described the technical details of contemporary venous thrombectomy,19 which should further improve outcomes of venous thrombectomy.)

The previous observations, which range from the research laboratory to systemic thrombolysis to operative venous thrombectomy, provide evidence that thrombus removal in patients with acute iliofemoral DVT results in significantly less postthrombotic morbidity. Technology has advanced to the point that both mechanical thrombus removal and pharmacologic thrombolysis are combined via percutaneous techniques. Thus, it is expected that bleeding complications will be reduced while still providing the benefits of thrombus removal or reduction.

Rationale for Intrathrombus Catheter-directed Thrombolysis

The mechanism that leads to clot dissolution (via thrombolysis) is the activation of fibrin-bound plasminogen to form the active enzyme plasmin, which dissolves clot.20 During thrombosis, circulating GLU-plasminogen is converted to LYS-plasminogen (in thrombus) as a result of binding to fibrin. LYS-plasminogen has more binding sites for plasminogen activators and is more efficiently activated to plasmin than GLU-plasminogen. Therefore, intrathrombus infusion of plasminogen activators should be the most effective method of thrombolysis. Furthermore, intrathrombus delivery naturally protects plasminogen activators from neutralization by circulating plasminogen activator inhibitors (PAI-1) and also protects the resultant active enzyme plasmin from neutralization by circulating antiplasmins. Catheter-directed delivery of plasminogen activators into the thrombus facilitates thrombolysis, which, in turn, increases the likelihood of a successful outcome. Moreover, accelerated lysis reduces the overall dose and duration of plasminogen activator infusion; consequently, it is reasonable to expect that complications also will be reduced.

Results of Intrathrombus Catheter-Directed Thrombolysis

Numerous reports have emerged demonstrating favorable outcomes of catheter-directed thrombolysis for acute DVT; these have been discussed in detail previously.21 Three of the larger reports, combined for a total of 422 patients, document approximately an 80% success rate, as measured by greater than 50% lysis of clot (Table 1).22–24 Most of these patients had acute DVT as defined in Bjarnason’s paper as < 4 weeks since onset of symptoms. Mewissen’s paper defined acuity as < 10 days from onset, with 81% of people having acute DVT.

Had treatment been restricted to patients with acute iliofemoral DVT, it is likely that initial success rates would have been higher. Catheter-directed urokinase was used in each of these studies. Importantly, patients with underlying iliac vein stenoses were treated with balloon angioplasty, stenting, or both to ensure unobstructed venous drainage into the vena cava, thereby reducing the risk of recurrent thrombosis. Of interest, in Bjarnason’s paper, patients who underwent stent placement had a lower patency rate at 1 year than patient swho did not undergo stent placement. This was accounted for by the fact that 47% of the stented patients had had previous DVT versus 27% of non-stented patients.

Major bleeding complications occurred in 5% to 10% of cases (primarily at puncture sites), and intracranial bleeding was rare, occurring in three patients reported from the National Venous Registry.23 Symptomatic pulmonary embolism (PE) occurred in only 1% of patients in the National Venous Registry and in the report by Bjarnason et al,22 and fatal PE occurred in only one out of the combined total of 422 patients. Therefore, death as a result of catheter-directed thrombolysis was rare.

The large database of the National Venous Registry offered an opportunity to objectively evaluate the long-term impact of catheter-directed thrombolysis on patients with iliofemoral DVT. Since the National Venous Registry collected data only on patients treated with thrombolytic therapy, a contemporary cohort of iliofemoral DVT patients treated with anticoagulation in the same institutions was identified.25 All of the anticoagulated patients were candidates for lytic therapy, but were treated with anticoagulation alone, due to physician preference. A validated quality-of-life (QOL) questionnaire26 was used to query patients at 16 and 22 months post treatment. Of 98 patients studied, 68 were treated with catheter-directed thrombolysis and 30 were treated with anticoagulation alone. Patients treated with catheter-directed thrombolysis reported significantly better QOL than those treated with anticoagulation alone.25

Quality-of-life results were directly related to the initial success of thrombolysis. Patients with successful thrombus resolution reported a significantly better health utilities index, improved physical functioning, less stigma of CVD, reduced health distress, and fewer overall postthrombotic symptoms. Patients in whom catheter-directed thrombolysis failed had similar outcomes to patients treated with anticoagulation alone. These efficacy data combined with the observed reduction in complications with intrathrombus infusion of plasminogen activators offer a sound argument for the management of patients with iliofemoral DVT with catheter-directed thrombolysis. Subsequently, a randomized trial was performed by Elshawary et al,27 comparing catheter-directed thrombolysis to anticoagulation alone. These authors demonstrated that catheter-directed thrombolysis resulted in significantly better outcomes at 6 months. This was measured by restoration of patency of 72% in lytic group versus 12% in the anticoagulation-only group and by evidence of venous reflux in 11% of patients lysed versus 41% of patients receiving anticoagulation alone.

Assuming patients are properly managed with anticoagulation, thereby avoiding recurrent DVT, this 6-month observation should reflect their long-term outcome.

Now that it has been established that catheter-directed thrombolysis can be performed safely with minimal systemic complications, the next question becomes whether the risk of bleeding complications may be further decreased. An interesting therapeutic approach was reported by Chang et al28 when they used repeated intrathrombus bolus dosing of rt-PA in 12 lower extremities of 10 patients with acute DVT. They infused rt-PA intrathrombus using the pulse-spray technique and no more than 50 mg per treatment. Following the pulse-spray bolus, patients were returned to their rooms and brought back the following day for repeat phlebographic evaluation and repeat infusion, if necessary. Treatment was repeated up to four times. Eleven of the 12 extremities had significant or complete lysis and one had 50–75% lysis. Although the average total dose of rt-PA was 106 mg, bleeding complications were minor, and no patient dropped their hematocrit more than 2%. This intriguing technique deserves further study to evaluate its applicability to the general population of DVT patients.

Pharmacomechanical Thrombolysis

Preserving venous valve function and luminal patency is the goal of all strategies of thrombus removal for acute DVT. Generally, the preferred method has been catheter-directed thrombolysis, but adding mechanical methods as an adjunct to catheter-directed lytic therapy is quickly setting a new standard for catheter-based treatment of acute DVT.29–31 However, using percutaneous mechanical thrombectomy alone is less successful than catheter-directed thrombolysis, and there appears to be a higher incidence of embolic complications with mechanical thrombectomy. In a prospective evaluation of pulse-spray pharmacomechanical thrombolysis of clotted hemodialysis grafts,32 it was found that PE (documented by ventilation perfusion scan) occurred in 18% of patients treated with a plasminogen activator pulse-spray solution versus 64% of patients treated with a heparinized saline pulse-spray solution (P = .04). Since clotted hemodialysis grafts are in direct communication with the venous circulation, they can be considered similar to proximal veins with acute DVT treated with mechanical thrombus disruption alone (in terms of embolic potential). Observations would likely be magnified when treating larger venous thromboses. This is an important concept, suggesting that mechanical intervention without protection and without adding plasminogen activators will increase the risk of embolization.

This concept was reinforced by Greenberg et al,33 who, in an experimental model, evaluated mechanical, pharmacomechanical, and pharmacologic thrombolysis. Their findings, consistent with anecdotal clinical observations, as well as the results reported by Kinney et al,32 demonstrated that pulse-spray mechanical thrombectomy alone was associated with the largest number and greatest size of distal emboli. When urokinase was added to the pulse-spray solution, the embolic particles diminished in number and size and the speed of lysis increased while time-to-reperfusion shortened. Catheter-directed thrombolysis alone was associated with the slowest time-to-reperfusion but the fewest distal emboli. In general, mechanical thrombectomy alone is generally inadequate. Hemolytic complications of rheolytic mechanical thrombectomy are common and occasionally can result in anemia and renal dysfunction.

One of the more promising pharmacomechanical treatment options for patients with acute iliofemoral DVT is isolated segmental pharmacomechanical thrombolysis (ISPMT), which uses the Trellis Peripheral Infusion System (Bacchus Vascular, Santa Clara, California). The Trellis is a hybrid catheter that isolates the segment of thrombosed vein between two occluding balloons and infuses a small dose of a lytic agent into the target segment. The intervening catheter assumes a spiral configuration which, when activated, spins at approximately 1500 revolutions per minute for 15 to 20 minutes. Following aspiration of the liquefied and fragmented thrombus, the treated vein segment is re-evaluated and re-treated, if necessary. Once the vein is cleared of thrombus, the catheter is repositioned to treat the next thrombosed segments. Phlebographic evaluation of the result is performed before treating additional segments of the thrombosed vein.

Martinez et al34 found that ISPMT offered more effective thrombus removal in less time and with a reduced dose of thrombolytic agent when compared with catheter-directed thrombolysis alone. They treated 43 patients: 16 patients were treated with ISPMT + CDT, 6 with ISPMT alone, and 21 with CDT alone. Patients were treated with ISPMT+ CDT if thrombus persisted after ISPMT. Quantitative assessment of thrombus removal was performed after repeat phlebographic imaging. Overall, patients treated with ISPMT had a larger percentage of their thrombus removed. Moreover, treatment time was shorter (23.4 vs 55.4 hours, P < 0.001) and the dose of rt-PA reduced (59.3 vs 33.4 mg; P = .0009). Complications appear to be reduced when using ISPMT. One patient in the CDT group developed acute renal failure secondary to hemoglobinuria and dye load; this patient was treated with aggressive rheolytic pharmacomechanical thrombolysis but, due to incomplete thrombus clearance, re-thrombosed. One patient in the ISPMT group developed a symptomatic puncture site hematoma requiring blood transfusion.

The advantages of ISPMT include its ability to combine mechanical and pharmacologic therapies and increase the rapidity with which lysis can be achieved. Furthermore, because the infusate is aspirated, this treatment can be offered to patients who have conventional contraindications to thrombolytic therapy. Martinez et al34 reported only one patient with ISPMT having a major bleeding complication, which was at the puncture site in the popliteal fossa.

The rationales behind the design of this catheter include: 1) rapidly resolving thrombus during a short course of treatment; 2) limiting or avoiding systemic thrombolysis by reducing exposure to plasminogen activators as a result of aspirating liquefied thrombus and infused plasminogen activator; and 3) preventing PE by proximal balloon occlusion. A clinical trial designed to evaluate the success and complication rate of this technique is currently underway.

The emission of ultrasound waves from an infusion catheter delivering the plasminogen activator is an interesting new adjunct to catheter-directed thrombolysis. Ultrasound enhancement of the fibrinolytic activity of tissue plasminogen activator has been observed in vitro.39–41 Clinical reports have emerged, indicating that an infusion catheter with ultrasound transducers built into the infusion portion of the catheter accelerates thrombolysis.35–38 This effect is the result of clot fibrin fragmentation, increasing exposed fibrin surface and allowing greater plasminogen activator binding to fibrin, due to its larger available surface area.42–44 In vivo models45 and clinical trials46 are now underway to objectively assess the potential value of ultrasound enhancement of thrombolysis for the management of acute DVT.

The application of all of the patient management principles discussed in this manuscript is illustrated by the following case of a patient who presented with phlegmasia cerulea dolens one day after laparotomy (Figure 1). Venous duplex showed clot from his posterior tibial veins to his external iliac veins. The spectrum of percutaneous techniques was used to rapidly clear his proximal and distal venous system of clot followed by venoplasty and stenting of his iliac veins to relieve persistent obstruction. Routine computed tomographic (CT) scans of the chest and abdomen revealed mediastinal and retroperitoneal lymphadenopathy, leading to the diagnosis and treatment of his previously undiagnosed non-Hodgkins lymphoma. Head, chest, abdominal, and pelvic CT scans are now part of our routine evaluation for all patients with iliofemoral DVT, resulting in a high yield of asymptomatic PE and other benign and malignant pathology important for proper patient care.47

Conclusions

Evidence for a strategy of thrombus removal as the preferred treatment approach for patients with acute iliofemoral DVT comes from randomized trials, observational studies, large and small clinical reports, and basic laboratory research. Catheter-directed thrombolysis is effective and has become safer with the use of direct intrathrombus infusion and adjunctive mechanical techniques. As technology continues to advance and as physicians become more comfortable with catheter-based techniques, lytic infusion times will shorten and more patients will become eligible for catheter-based treatment of their acute DVT. Most importantly, patients treated with a strategy of thrombus removal will be spared the otherwise certain morbidity of the postthrombotic syndrome. The ATTRACT trial, which will be a multicenter, randomized, controlled trial comparing pharmacomechanical thrombolysis versus anticoagulation, will be starting shortly. The pharmacomechanical techniques evaluated will be rheolytic and ISPMT. Outcomes include technical success, QOL, Villalta Scale, and Venous Clinical Severity Score. We expect that this trial will likely confirm what has been stated above.

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From Jobst Vascular Center, The Toledo Hospital, Ann Arbor, Michigan.

Address for correspondence: Anthony J. Comerota, MD, Director, Jobst Vascular Center, The Toledo Hospital, 2109 Hughes Dr., Suite 400, Toledo, OH 43606. Email: marilyn.gravett@promedica.org.