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DOI: 10.1148/radiol.2461062076
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(Radiology 2008;246:619-629.)
© RSNA, 2008

Vascular and Interventional Radiology

Deep Vein Thrombosis of Lower Extremity: Direct Intraclot Injection of Alteplase Once Daily with Systemic Anticoagulation—Results of Pilot Study1

Richard Chang, MD, Clara C. Chen, MD, Anthony Kam, MD, PhD, Edie Mao, MB, Thomas H. Shawker, MD, and McDonald K. Horne, III, MD

1 From the Departments of Diagnostic Radiology (R.C., A.K., E.M., T.H.S.) and Nuclear Medicine (C.C.C.), Imaging Sciences Program, and Hematology Service, Department of Laboratory Medicine, Clinical Pathology Department (M.K.H.), Warren G. Magnuson Clinical Center, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892. Received December 6, 2006; revision requested February 7, 2007; revision received April 3; accepted May 18; final version accepted July 2. This clinical research project was completed at and supported by intramural research funds of the Warren G. Magnuson Clinical Center of the National Institutes of Health. Address correspondence to R.C. (e-mail: rchang{at}cc.nih.gov).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
ADVANCES IN KNOWLEDGE
IMPLICATION FOR PATIENT CARE...
 References
 
Purpose: To prospectively evaluate the outcome of patients with acute deep vein thrombosis (DVT) of the lower extremity treated with "lacing" of the thrombus with alteplase (recombinant tissue plasminogen activator, or rTPA).

Materials and Methods: This HIPAA-compliant study was approved by the Institutional Review Board of the National Heart, Lung, and Blood Institute and was funded by the National Institutes of Health. After giving written consent, 20 patients with first-onset acute DVT were treated with direct intraclot lacing of the thrombus with alteplase (maximum daily dose, 50 mg per leg per day; maximum of four treatments) and full systemic anticoagulation. Alteplase was chosen because its high fibrin affinity obviates continuous infusion of this thrombolytic agent. Ventilation-perfusion (V/Q) scans were performed for evaluation of embolic risks, and clinical and imaging examinations were supplemented with pharmacokinetic studies to enable further assessment of treatment outcomes.

Results: The 20 patients included 13 men and seven women aged 18–79 years. Antegrade blood flow was restored throughout the deep venous system in 16 patients (80%) during thrombolytic therapy, with complete resolution of symptoms in 18 patients (90%) after 6 months of anticoagulation. Pharmacokinetic studies showed rapid clearance of circulating alteplase and recovery of plasminogen activator inhibitor-1 levels within 2 hours after termination of alteplase treatment. V/Q scans revealed a 40% incidence of pulmonary embolism before treatment and a 15% incidence of asymptomatic pulmonary embolism during thrombolytic therapy. There were no cases of clinically important pulmonary embolism or serious bleeding during thrombolytic therapy. During a mean follow-up period of 3.4 years, no patient developed a postthrombotic syndrome or recurrent thromboembolism.

Conclusion: Intraclot injection or lacing of the thrombus with a fibrin-binding thrombolytic agent such as alteplase is an alternative to continuous-infusion thrombolytic regimens and minimizes the duration of systemic exposure to thrombolytic agents.

© RSNA, 2008


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
DISCUSSION
ADVANCES IN KNOWLEDGE
IMPLICATION FOR PATIENT CARE...
 References
 
While greatly reducing the risk of pulmonary embolism, treatment of deep vein thrombosis (DVT) with anticoagulation does not reliably preserve venous function of the lower extremity and results in a high rate (approximately 25%–30%) of recurrent venous thromboembolism and postthrombotic syndromes (1–6). Results of many small studies (7–17) suggest that thrombolytic therapy can reduce the frequency of postthrombotic syndromes. However, because of the increased risk of bleeding, thrombolytic therapy is currently recommended for only the most severe cases of DVT (18–22).

The prevailing method for administering thrombolytic therapy is continuous infusion of a lytic agent directly into thrombi through catheters embedded in the clots (23–26). However, continuous infusion potentially results in prolonged exposure of the systemic circulation to thrombolytic agents, which can increase the risk of bleeding. Thus, we "lace" the entire thrombus in the time needed to catheterize the involved venous segments and we disperse alteplase (recombinant tissue plasminogen activator [tPA], or rtPA) throughout the clot, as previously described (27,28). By choosing a thrombolytic agent that binds to fibrin in the clot and is rapidly cleared from the general circulation, we can eliminate continuous infusion of the drug and minimize the duration of systemic exposure to the thrombolytic agent. The purpose of our pilot study, therefore, was to prospectively evaluate the outcome of patients with acute DVT of the lower extremity treated with lacing of the thrombus with alteplase.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
ADVANCES IN KNOWLEDGE
IMPLICATION FOR PATIENT CARE...
 References
 
Protocol, Support, and Funding
This prospective study complied with Health Insurance Portability and Accountability Act requirements; was approved by the Institutional Review Board of the National Heart, Lung, and Blood Institute; and was solely supported by research funds of the National Institutes of Health for 20 patients. No funding, medication, or material support in any form was provided by any other institution or corporation.

Patient Selection
All patients gave written informed consent to participate. Patients who were at least 18 years old and who had first-time DVT confirmed with ultrasonography (US) or venography that involved the popliteal or more proximal deep veins of the leg and/or pelvis were eligible, provided that the duration of symptoms was no longer than 14 days.

Patients were excluded for any of the following conditions: current pregnancy; renal insufficiency (creatinine level, >2.0 mg/dL [176.8 µmol/L]); allergy to iodinated contrast material or heparin; atrial fibrillation; known right-to-left shunt; thrombocytopenia (<50 000 platelets per microliter); bleeding diathesis not attributable to heparin; fibrinogen level of less than 0.15 g/dL (4.4 µmol/L); and severe hypertension (systolic pressure > 200 mm Hg and diastolic pressure > 100 mm Hg). Other exclusion criteria included a history of cerebrovascular accident or hemorrhage in the preceding 4 weeks and any of the following within the preceding 2 weeks: gastrointestinal, urinary tract, or internal bleeding; major trauma; major surgical procedure; and biopsy of a noncompressible site. The first 20 patients who met these criteria were included.

Diagnostic Evaluation
Each patient underwent a duplex US examination to verify the diagnosis of DVT and a ventilation-perfusion (V/Q) scan to identify pulmonary emboli present before the start of thrombolytic therapy. A second V/Q scan was performed in all patients, independent of symptoms, the day after completion of thrombolytic therapy to identify emboli that might have arisen as a consequence of treatment. Inferior vena cava filters were not placed prior to or during any of the treatments in these patients. In most patients, a dorsal foot vein was cannulated for venography, which was performed primarily to supplement the US studies in the evaluation of the calf and iliac veins prior to the start of thrombolytic therapy.

Measurements of prothrombin time, activated partial thromboplastin time, D-dimer, plasma fibrinogen, platelet count, and hemoglobin were obtained at least daily during the phase of thrombolytic therapy and early anticoagulation.

Administration of Alteplase and Catheterization Methods
Alteplase (Activase; Genentech, South San Francisco, Calif), reconstituted with sterile water as directed by its manufacturer to a concentration of 1 mg/mL, was administered directly into the thrombus with brisk, forceful hand injection of 0.5–1.0-mL aliquots through 4-F pulse-spray catheters with 2-cm pulse-spray segments (Angiodynamics, Queensbury, NY) in large veins (popliteal and larger) and with more gentle hand injections through standard end-hole 4- and 3-F coaxial catheters into smaller thrombosed calf veins (29). Each day, the entire thrombus was laced with approximately 0.5–1.0 mg alteplase per centimeter of thrombus, not exceeding 50 mg alteplase per leg per day. Doses of alteplase were reduced as the clot burden decreased on ensuing days of treatment. The protocol was limited to a maximum of four doses (or 4 days).

Both the number of catheters and the catheterization approaches (antegrade and/or retrograde) employed depended on the sites of thrombosis, and we followed the general principles described by Chang et al (28), with some modifications. In all patients, the right internal jugular vein was first catheterized with 100-cm-long 4-F catheters for evaluation (and treatment, when needed) of any internal iliac, greater saphenous, and profunda femoral vein thrombosis often associated with iliofemoral DVT or as an aid for identifying the femoral vein (also known as the superficial femoral vein) during retrograde catheterization of this vessel in treatment of femoropopliteal DVT. After alteplase administration, the jugular catheters were exchanged for short 4- or 5-F central venous catheters (Arrow International, Reading, Pa) to allow blood drawing for coagulation and pharmacokinetic studies when the patients returned to their rooms.

With extensive calf vein thrombosis, retrograde catheterization from ipsilateral femoral access was preferred to allow treatment of multiple calf vein branches and duplications of the popliteal and superficial femoral veins. In one patient (patient 20), additional antegrade catheterization of the posterior tibial vein at the ankle was performed to ensure adequate delivery of alteplase to this thrombosed segment. If the calf veins and lower popliteal veins were free of thrombosis, as in many cases of iliofemoral DVT, antegrade catheterization of the ipsilateral popliteal vein was the preferred approach for pulse-spray thrombolysis, but additional ipsilateral femoral vein catheterization was performed when balloon dilation or stent placement was required for treatment of the May-Thurner syndrome. After the alteplase was administered, 4-F catheters (dilators for the antegrade femoral and popliteal approaches and 65-cm-long hydrophilic catheters or peripherally inserted central catheters for the retrograde femoral approach) were left in place in the affected veins to enable intravenous heparin administration, subsequent reaccess, and/or venography. After each alteplase treatment, patients returned to a standard patient care floor, where they were kept at strict bed rest for 2 hours and then were allowed bathroom privileges and were encouraged to ambulate. When tolerated, sequential pneumatic compression devices (Kendall Division of Tyco International, Mansfield, Mass) were applied whenever the patient was recumbent.

The administration of alteplase with these techniques requires a substantial commitment of time in the radiology department. As described previously, alteplase is administered with a brisk injection of 0.5–1.0-mL aliquots, followed by moving the pulse-spray catheter to a different segment of thrombus and typically waiting 30 seconds before injecting alteplase into this next segment (28). A 30-second interval between injections is used to allow the previous aliquot of alteplase to bind to the clot (or thrombus) and to prevent its immediate displacement by the next injection. Just the administration of a 50-mg (50-mL volume) dose of alteplase requires between 25 and 50 minutes, in addition to the time required for preparation of potential catheterization sites and the actual catheterization and negotiation of catheters into the thrombosed vein segments. The typical procedure time for first treatment of an uncomplicated iliofemoral DVT was 1.5 hours. When extensive calf vein thrombosis was present, as is common in femoropopliteal DVT, procedure time could be doubled or almost tripled because the access method we used—retrograde catheterization of the femoral vein—is challenging, often requiring negotiation of catheters past numerous valves in three sets of thrombosed calf veins. In each case, the procedure times for second or subsequent alteplase treatments were much shorter because reaccess for treatment was quickly established by exchanging the catheters left in place after the first treatment for new treatment catheters by using standard guidewire techniques.

The end point of thrombolytic therapy was antegrade flow in the thrombosed deep veins demonstrated at venography, after which we relied on therapeutic anticoagulation to allow residual thrombus to clear. Once this end point was reached or if the maximum of four doses had been given, no additional doses of alteplase were administered.

Ancillary Treatments
The only ancillary treatment allowed in this study was balloon dilation with or without stent placement (10–12-mm-diameter SMARTTM; Cordis, Miami Lakes, Fla) for treatment of May-Thurner syndrome. No mechanical thrombectomy devices were employed in this study.

Anticoagulant Regimens
All patients had begun receiving unfractionated or low-molecular-weight heparin before their entry into the study. During thrombolytic therapy, therapeutic anticoagulation was maintained with intravenous unfractionated heparin, with the goal of prolonging the activated partial thromboplastin time to 50–70 seconds.

Oral anticoagulation with warfarin was usually begun on the 2nd day of thrombolytic therapy, while heparin was continued until a target international normalized ratio of 2–3 was achieved on 2 consecutive days. Warfarin was continued until the patient's final evaluation at the end of 6 months. Each patient was fitted with elastic compression stockings once edema had regressed.

Pharmacokinetic Studies
Plasma concentrations of alteplase or tPA activity, plasminogen activator inhibitor-1 (PAI-1) activity, D-dimer, plasminogen, and antiplasmin were measured before, immediately after, and at 30 minutes, 1 hour, and 2 hours after the first treatment with alteplase, as well as at the times (about every 6 hours) when blood was drawn for monitoring anticoagulation. The methods for these assays have been described previously (30).

Evaluation and Follow-up Studies
Venography was performed prior to, during, and for follow-up (4–6 weeks) of thrombolytic treatment. Venography was performed the day after each thrombolytic treatment to assess the result of the previous treatment and the need for additional treatment. There is no scoring system that is universally accepted for grading acute venous thrombosis of the lower extremity, and a recent review article (31) cited three scoring systems that have been used in previous publications. Although none of these systems is comprehensive enough to enable scoring of all the venous segments that can be involved in extensive DVT, we favor the Marder scoring system because it seems well suited to scoring those venous segments that can be evaluated at foot vein venography and because it assigns maximum point values to occluded segments in proportion to their length or volume (32). Total occlusion of a venous segment scored in the Marder system receives a maximum multiplier of 1, and, for lesser degrees of occlusion, we have used the following multipliers: 0 for restoration of flow with no evidence of residual thrombus; 0.25 for restoration of flow with some residual nonocclusive thrombus; 0.5 for continued obstruction—even focal obstruction—despite substantial thrombolysis; and 1 for continued complete occlusion. Because our goal for thrombolysis is to restore flow, achieving this end point in this scheme would require a reduction in Marder score of 75%–100%.

The long-term outcomes are more important than the immediate outcomes because the principal goal of thrombolytic therapy is to reduce the incidence of postthrombotic syndromes after DVT. The timing of additional follow-up examinations was guided by published results of previous thrombolytic trials (26), which showed progressive loss of patency beginning at 1 month and progressing until 6 months to 1 year after treatment. Our patients returned for clinical follow-up, contrast material–enhanced venography, and duplex US examination at 4–6 weeks after thrombolytic treatment and returned again at 6 months for clinical follow-up and duplex US examination (supplemented with femoral catheterization for iliac venography in patients with May-Thurner syndrome). Thereafter, we followed their long-term outcomes by using the same approach employed in the anticoagulation study of Prandoni et al (2,3).

Duplex US examinations were performed at 6 weeks and 6 months to evaluate all vein segments (except iliac segments) for patency and to evaluate deep vein segments from the common femoral vein to the popliteal vein for valvular incompetence by using Valsalva and thigh and calf compression and rapid release maneuvers. Venous reflux was graded as follows: grade I indicated retrograde flow lasting 1 second to 2 seconds; grade II, reflux lasting 2–3 seconds; grade III, reflux persisting for 4–6 seconds; and grade IV, reverse flow lasting as long as a Valsalva effort was maintained or for more than 6 seconds (33).

Nomenclature for Venous Segments
Two systems of nomenclature for the veins of the leg are firmly embedded in the literature and differ in the designation of the femoral vein in the thigh. Radiology and vascular surgery journals often designate this artery and/or vein as the superficial femoral artery and/or vein as a way to distinguish it from the deeper, profunda artery and/or vein that supplies the musculature of the thigh. In this article, to avoid confusing this vein for a superficial vein, we choose to use the anatomist's designation for this long segment in the thigh as the femoral vein, keeping the profunda femoral vein designation for the muscular vein of the thigh and designating the confluence of these veins in the inguinal region as the common femoral vein.

Authors, Areas of Specialization, and Contributions to Study
This study was the collaborative effort of a hematologist (M.K.H., with 25 years of experience), two interventional radiologists (R.C., with 20 years of experience, and A.K., with 3 years of experience), a nuclear medicine physician (C.C.C., with 12 years of experience), a US technologist (E.M., with 5 years of experience), and a US physician (T.H.S., with 25 years of experience). The protocol was jointly proposed and designed by R.C. and M.K.H. For thrombolytic therapy, R.C. treated all patients, with the assistance of A.K. in about 30% of cases. Evaluation of all posttreatment venograms was performed and decisions regarding alteplase dosing were made jointly by R.C. and M.K.H. Short- and long-term anticoagulation were supervised by M.K.H., who was in regular contact with each patient's primary care physician after the patient was discharged. C.C.C. supervised and interpreted all V/Q studies without prior knowledge of treatment doses or venographic outcomes. Similarly, E.M. and T.H.S. performed the US evaluations, and T.H.S. interpreted the US findings without prior knowledge of treatment doses or venographic outcomes. Pharmacokinetic assays were completed in the hematology research laboratories of M.K.H. Follow-up of patient outcomes beyond 6 months was performed by R.C. and M.K.H.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
ADVANCES IN KNOWLEDGE
IMPLICATION FOR PATIENT CARE...
 References
 
Patients and Marder Scores
The study patients included 13 men and seven women, who ranged in age from 18 to 79 years (Table 1). The majority of patients had identifiable clinical or genetic factors predisposing them to thrombosis. The patients had been symptomatic for 3–14 days. Besides edema, the principal reason for these patients seeking more aggressive treatment was pain that was unrelieved by anticoagulant therapy and was sometimes so severe as to cause the patient to be bedridden (patient 2) or to use crutches for ambulation (patient 14). Marder scores of the extent of DVT at presentation ranged from a low of 18 (patient 1) to the maximum possible score of 40 (patient 2) and are shown in Table 2, along with posttreatment (1 day after last alteplase dose) scores.


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  		Table 1. Demographic Data

 

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  		Table 2. Doses of Alteplase and Outcomes

 
Clinical Outcomes
Seven patients had iliofemoral DVT, and two of these patients had thrombosis extending into the calf veins (Table 2). The remaining 13 patients had femoropopliteal DVT, and 12 of these patients had extensive thrombus in the calf veins (Fig 1). Fifteen patients required only one or two doses (days) of thrombolytic therapy. The average total dose of alteplase was 83 mg.


Figure 1
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  		Figure 1: Patient 4. Femoropopliteal DVT. Serial venograms (anteroposterior views) obtained with foot vein injection in 79-year-old man with left leg DVT. A, Before treatment, most of the injected contrast material diverts into superficial veins, despite use of tourniquets at ankle. Only a segment of a peroneal vein is visualized and shows filling defects (arrows) due to thrombosis. Above this level, deep popliteal and femoral veins in the thigh were also occluded (not shown). B, Venogram obtained 1 day after pulse-spray intraclot injection of alteplase shows preferential filling of calf veins. Although there is evidence of residual thrombus in calf veins, flow was reestablished in calf, popliteal, and femoral veins. The patient's calf discomfort had resolved, and no additional thrombolytic therapy was given. Anticoagulation was continued for 6 months. C, Foot venogram obtained 6 weeks after initial therapy shows restoration of flow in calf and popliteal veins. Mild incompetence of perforating veins allows visualization of small varicose vein segment (arrow) in superficial venous system.

 
Antegrade flow was restored in all seven patients (patients 2, 3, 11, 12, 14, 17, and 18) with iliofemoral DVT. Although patient 3 had residual compression of the common iliac vein because of adenopathy related to metastatic prostate cancer, after thrombolytic therapy, his pain and edema completely resolved, and he had full recovery of function of his lower extremity until his death 3 months later. Because of residual swelling in three of the five patients with May-Thurner syndrome, either angioplasty alone (patient 14) or angioplasty followed by stent placement (patients 17 and 18) was performed, with complete relief of symptoms and normalization of venographic findings. All seven patients with iliofemoral DVT remained fully functional and asymptomatic until death or for follow-up periods of up to 2.5 years.

Antegrade blood flow was also restored in nine of the 13 patients with femoropopliteal DVT. These patients had rapid return to full function and complete resolution of edema and discomfort. US examination at 6 months confirmed continued patency, and these patients were asymptomatic at the time of last contact, 7 months to 8.5 years (mean, 3.4 years) after thrombolytic treatment.

Venograms in three patients (patients 7, 8, and 15) of the remaining four with femoropopliteal DVT showed chronic phlebitic changes (Fig 2) that probably represented previous episodes of unrecognized calf vein phlebitis. Although reversal of the calf vein abnormalities was not possible, all three patients gradually recovered patency of the more proximal venous segments during thrombolytic therapy and the ensuing 6 months of anticoagulation. Consequently, all three patients experienced symptomatic improvement: Two patients were asymptomatic with the use of compression stockings and one patient (patient 8) was left with only painless mild postural or dependent edema. The remaining patient (patient 10), although free of pain, continues to have mild residual dependent ankle edema at the end of the day. US and venographic studies showed that this patient had the most severe reflux (grade II–III [Table 2]) identified in our patients, and that, despite treatment, we had failed to recover the posterior tibial division of the calf veins.


Figure 2
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  		Figure 2: Venograms (anteroposterior views) show chronic phlebitic changes in calf veins characterized by absence of valves, linear synechiae, and focal strictures or occlusions. Normally, numerous valves are found in calf veins (see Fig 1, B), but they are absent here. A, Venogram in patient 7 obtained with left foot vein injection shows atretic posterior tibial vein (white arrows) and focal strictures in peroneal vein (black arrows). A long atretic segment of the lesser saphenous vein (unmarked) can also be visualized. B,C, Retrograde popliteal injection venograms of, B, right leg in patient 8 and, C, left leg in patient 15 show absence of valves, linear synechiae (white arrows), and focal strictures (black arrows). Absence of valves allows retrograde-injected contrast material to reflux down almost to ankle.

 
Duplex US studies, available for 19 of the patients, showed no evidence of reflux in 11 (58%), segmental grade I reflux in six (32%), and grade II or higher reflux in two (11%) patients (Table 2)—a frequency of reflux that is higher than in the general population (2% at the common femoral vein to 5% at the popliteal region) (34,35).

The pretherapy V/Q scans (Table 1) showed that eight patients (patients 1, 5, 6, 9, 13, 15, 16, and 19) (40%) already had evidence of pulmonary emboli prior to the start of treatment. Evidence of pulmonary emboli had either greatly or completely resolved on the postthrombolytic therapy V/Q scans in seven patients. In the eighth patient (patient 16), the original V/Q scan abnormalities persisted, and two new small defects appeared after thrombolytic therapy. Two patients had normal V/Q scans before alteplase therapy and abnormal scans afterward. Therefore, although all were asymptomatic, three patients (15%) had new V/Q scan abnormalities after treatment with alteplase.

Two minor bleeding complications occurred during the thrombolytic phase of the treatment: a biceps hematoma approximately 20 cm3 in volume and transient macroscopic hematuria, which lasted for a few days into the anticoagulation period and then spontaneously resolved. A third patient (patient 19) incurred a hip hematoma after a fall during the 4th month of oral anticoagulation.

Pharmacokinetic Studies
Systemic tPA activity was greatly elevated during and immediately after administration of alteplase but cleared within 2 hours afterward. PAI-1 activity was undetectable during the period of tPA excess (Fig 3). Two hours after alteplase administration, however, PAI-1 levels had recovered and rose higher than baseline levels for the remainder of the day. D-Dimer levels peaked about 6 hours after alteplase administration and then gradually decreased. There was no decrease in plasminogen and antiplasmin levels until daily doses of alteplase exceeded 30 mg, and decreases in plasma fibrinogen levels were not seen until the daily dose of alteplase exceeded 40 mg. A more detailed account of the pharmacokinetic changes has been published (30).


Figure 3
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  		Figure 3: Graph of data in patient 14 shows typical pharmacokinetic changes of once-daily intraclot injection of alteplase: tPA activity (dashed line) is markedly elevated (maximum, 307 U/mL on day 1 and 167 U/mL on day 2) during alteplase injection but decreases rapidly within 2 hours. Conversely, PAI-1 activity ({circ}, solid line) becomes undetectable during the period of tPA excess, although it not only recovers as tPA clears but also remains higher than baseline levels. D-Dimer levels ({square}, dotted line) do not peak in the systemic circulation until 4–6 hours after alteplase injection, well after tPA activity has cleared and PAI-1 activity has recovered.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
ADVANCES IN KNOWLEDGE
IMPLICATION FOR PATIENT CARE...
 References
 
Follow-up examinations in our study were performed according to the same principles used by Prandoni et al (3), who summarized the outcomes of 528 patients with DVT who were treated with anticoagulation and compression stockings. Using a scoring system that generally required both pain and edema, chronic skin changes, or venous ulceration for the diagnosis of a postthrombotic syndrome, Prandoni et al found an incidence of postthrombotic syndromes of 18% at 1 year, almost 25% at 2 years, and nearly 30% at 5 years after anticoagulation treatment of DVT. According to these same criteria, none of our patients would be classified as having developed postthrombotic syndromes, because 18 patients are or were (until death) asymptomatic and two patients have only mild dependent edema, without any pain or skin changes. Prandoni et al also reported a high incidence of recurrent episodes of thromboembolism in patients with DVT treated with anticoagulation: 17% at 2 years, 24% at 5 years, and 30% at 8 years. In our series, there have been no recurrences, and, although our series is small, this low incidence of recurrent DVT with the addition of thrombolytic treatment of DVT is encouraging.

Our initial and long-term results (Table 2) appear to be at least as good as those of other trials involving continuous-infusion catheter-directed thrombolytic therapy. Critical for evaluation of thrombolytic therapy for DVT are long-term outcomes, and our results appear to be durable in that our patients showed no deterioration in patency and no recurrence of DVT in a mean follow-up period of 3.4 years. This is in contrast to reports from a multicenter urokinase registry (26) that indicated that almost half of successfully treated patients (35% of patients with iliofemoral DVT and 52% of patients with femoropopliteal DVT) had sites of loss of patency or reocclusion 6–12 months after treatment.

During thrombolytic therapy, we encountered only two incidences of problematic bleeding (a biceps hematoma that we believe was a result of overaggressive automatic blood pressure monitoring during a session of alteplase injection, and gross hematuria of unknown etiology), and neither required transfusion. The risk of bleeding from anticoagulant therapy is sometimes overlooked, and, in our series, the most serious hemorrhage was sustained by patient 19 in a mountain-biking accident during the 4th month of anticoagulation with warfarin. This is not unlike the 5.3% incidence of major hemorrhages reported by Prandoni et al (3) in follow-up of patients with DVT treated with anticoagulation alone.

V/Q studies used to assess embolic risks associated with our treatment revealed that more patients (40%) experienced pulmonary embolism before the start of thrombolytic therapy than during our treatment regimen (three [15%] of 20 patients, each of whom was asymptomatic). These data are consistent with the experience reported with urokinase (24–26).

The success of this treatment paradigm, we believe, is largely due to our choice of alteplase as the thrombolytic agent. Although there are many effective thrombolytic agents (7–10,36–39), alteplase has two characteristics that make it preferable for intraclot treatment of DVT—its binding affinity for fibrin and its short half-life (approximately 5 minutes) in the general circulation. Because it binds to the fibrin in a thrombus, alteplase, unlike streptokinase and urokinase, does not need to be administered by continuous intraclot infusion. The whole thrombus can be treated at once by distributing the drug in small boluses throughout its entirety. Although excess alteplase diffuses from the clot into the circulation, it is cleared within 2 hours after intraclot instillation because of its short half-life. Furthermore, the plasma concentration of the natural inhibitor of alteplase, PAI-1, recovers to higher levels after the excess tPA activity has cleared from the circulation as further protection against development of a systemic fibrinolytic state (30). Yet alteplase continues to be locally active in the thrombus, as indicated by the increase in the plasma concentration of the fibrin breakdown product D-dimer that continues for many hours. Our results are in agreement with findings reported as early as 20 years ago by Agnelli et al (40–42), who first pointed out that short infusions of tPA had prolonged fibrinolytic action but caused less bleeding than longer infusions.

The fibrin-binding property of alteplase allows us to take an expectant approach in which, once we have laced one thrombosed vein segment with a sufficient dose of alteplase, we immediately move on to catheterize and treat the next segment. We do not wait for one segment to clear before we treat the next segment. Many more venous segments can be treated this way than by using the traditional approach of continuously infusing a lytic agent (eg, urokinase) for hours until flow is reestablished one vein at a time.

The ability to treat many different segments efficiently is especially important in DVT, where all components of the venous system (deep veins, superficial veins, muscular veins, and perforators) can be involved when the DVT is extensive. Duplications of the calf veins are the rule, and variations or duplications in the popliteal and femoral veins are frequent, further increasing the number of venous segments that need to be treated to optimize therapy for each patient (43–45). The treatment of calf vein DVT is technically challenging and difficult, often requiring triple the time required to treat an uncomplicated iliofemoral DVT. However, the calf veins are the most common site of DVT in the lower extremity, and we make every effort to treat calf vein thrombosis (which is frequently part of femoropopliteal DVT), as well as internal iliac vein thrombosis, greater saphenous vein thrombosis, and profunda femoral vein thrombosis when these segments are secondarily involved in iliofemoral thrombosis (46–48). Poor calf muscle function has been correlated with postthrombotic venous ulceration, and we believe that the durability of our long-term outcomes may be due to our efforts to preserve the calf muscle pump mechanism through restoration of calf vein patency whenever possible (49).

Although the outcomes are encouraging, the results of this pilot study do not yet indicate that this treatment is ready for general clinical use. To accurately evaluate the adequacy of once-daily intraclot alteplase injection, we had to eliminate the possibility that unsuccessful outcomes were due to incomplete treatment of the thrombus. Often, we used multiple sites of catheterization to identify and treat a thrombus wherever it extended in the deep venous system. Treatment of the calf vein component of DVT is particularly challenging and time consuming, and simpler and more efficient treatment strategies are needed before thrombolytic therapy can be a practical treatment for the entire spectrum of DVT. Safety remains the critical issue for thrombolytic therapy for DVT. Because standard anticoagulant therapy has largely eliminated the life-threatening risks of pulmonary embolism, the potential benefit of preventing postthrombotic syndromes by adding thrombolytic therapy is only a quality of life benefit. Hence, thrombolytic therapy will not be accepted for DVT treatment until it has been proved to have a high degree of safety in large clinical trials. Our study results indicate that the doses we tested can be effective, without causing major bleeding complications, but our funding allowed us to study only 20 patients. There is no evidence that the doses used in our study are optimal doses, and other dose regimens should be investigated before much-needed larger clinical trials to demonstrate safety are begun.

The safety of thrombolytic therapy is maximized by choosing the minimum dose of thrombolytic agent that is still effective, and our pharmacokinetic data suggest that the doses in our pilot study were excessive. The decrease in plasminogen and antiplasmin at alteplase doses exceeding 30 mg per day indicate that at these doses, the concentration of circulating tPA is high enough to initiate non–fibrin-specific fibrinolytic activity in the systemic circulation, increasing the risk of bleeding, which fortunately is mitigated temporally by the short half-life of tPA in the circulation. In addition, there are theoretical reasons that lower doses would continue to be effective in lysing thrombi (50–52). We are currently studying the once-daily intraclot alteplase treatment method by using substantially lower doses of alteplase. We believe that with proper dose selection, and with administration of alteplase in a manner that takes advantage of its unique properties, a thrombolytic regimen can be developed that is effective yet sufficiently safe to be acceptable for wider application in treatment of DVT.


   ADVANCES IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
ADVANCES IN KNOWLEDGE
IMPLICATION FOR PATIENT CARE...
 References
 


   IMPLICATION FOR PATIENT CARE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
ADVANCES IN KNOWLEDGE
IMPLICATION FOR PATIENT CARE...
References
 


   ACKNOWLEDGMENTS
 
We thank Richard O. Cannon III, MD, for his support for this protocol during initial and annual reviews by the institutional review board and for assistance in arranging admissions for patients in this study. Also, we acknowledge Donna Jo McCloskey, PhD, RN, for assistance in maintaining patient records and files and for scheduling and assisting in follow-up evaluations of our study patients.


   FOOTNOTES
 

Abbreviations: DVT = deep vein thrombosis • PAI-1 = plasminogen activator inhibitor-1 • tPA = tissue plasminogen activator • V/Q = ventilation-perfusion

See Materials and Methods for pertinent disclosures.

Author contributions: Guarantors of integrity of entire study, R.C., M.K.H.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, R.C., M.K.H.; clinical studies, all authors; statistical analysis, R.C., M.K.H.; and manuscript editing, all authors


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
ADVANCES IN KNOWLEDGE
IMPLICATION FOR PATIENT CARE...
 References
 

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