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Year : 2019  |  Volume : 22  |  Issue : 3  |  Page : 399-405

Ultrasound-accelerated catheter-assisted thrombolytic therapy applicatıons in deep vein thrombosis

1 Department of Cardiovascular Surgery, Faculty of Medicine, Gazi University, Ankara, Turkey
2 Department of Anesthesiology and Reanimation, Faculty of Medicine, Gazi University, Ankara, Turkey
3 Department of Radiology, Faculty of Medicine, Gazi University, Ankara, Turkey

Date of Acceptance25-Nov-2018
Date of Web Publication6-Mar-2019

Correspondence Address:
Dr. M Arslan
Department of Anesthesiology and Reanimation, Gazi University Medical Faculty, Ankara- 06510
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/njcp.njcp_27_18

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Background: Ultrasound-accelerated catheter-directed thrombolysis (UCT) increases the invasion of thrombolytic agent into the thrombus using ultrasonic energy, provides less infusion of thrombolytic agent, reduces complication, and post-thrombotic syndrome (PTS) development rates. For these reasons, this procedure is a promising method for the treatment of deep vein thrombosis (DVT). Materials and Methods: Patients diagnosed with DVT by ultrasonography (USG) who underwent UCT between May 2013 and August 2014 at Gazi University Hospital Cardiovascular Surgery Clinic were included in the study. The demographic characteristics and postoperative acute and long-term patency rates and deep venous insufficiency rates were evaluated retrospectively to determine the efficacy of the UCT procedure. Patients were classified as acute, subacute, and chronical DVT according to the onset of complaints. The efficacy of the UCT procedure was assessed by Doppler USG performed 6 months and 2 years after the procedure, and patients were re-evaluated for deep venous insufficiency and thrombus findings to determine the relationship between UCT procedure and deep venous insufficiency. Results: In acute phase, 57.1% (n = 8) complete and 35.7% (n = 5) partial openings were obtained. No complete patency was obtained in any of the subacute patients. However, partial openness rate was 60%. In patients admitted during the chronic period, complete patency was obtained in 20% (n = 8) and partial openings in 60% (n = 3). Although thrombolysis success was not considered as statistically significant, the success rate was numerically higher in the acute phase. Conclusion: As a result, UCT applications provide thrombolysis especially in acute deep vein thrombosis, preventing deep venous insufficiency and especially post-thrombotic syndrome formation. UCT prevents bleeding complications by keeping thrombolytic amount low and can be used as an endovascular method of high safety in patient population with high bleeding complications such as patients with malignancies.

Keywords: Deep vein thrombosis, post-trombotic syndrome, recanalization, ultrasound-accelerated catheter directed thrombolysis

How to cite this article:
Kartal H, Erer D, Oktar G L, Zor M H, Arslan M, Akkan K. Ultrasound-accelerated catheter-assisted thrombolytic therapy applicatıons in deep vein thrombosis. Niger J Clin Pract 2019;22:399-405

How to cite this URL:
Kartal H, Erer D, Oktar G L, Zor M H, Arslan M, Akkan K. Ultrasound-accelerated catheter-assisted thrombolytic therapy applicatıons in deep vein thrombosis. Niger J Clin Pract [serial online] 2019 [cited 2019 May 21];22:399-405. Available from:

   Introduction Top

Deep vein thrombosis (DVT) of the lower extremity, a common cardiovascular condition with substantial morbidity and mortality, is estimated to 1–5% of the population in the world. Patiens with acute DVT are treated with anticoagulation, compression therapy, and mobilization.[1] This standard therapy decreases mortality by preventing life-threatening pulmonary embolism (PE) and propagation of thrombosis but has no direct thrombolytic effect.[2],[3] Recanalization and the preservation of normal venous valve function depend on the effectiveness of the patient's own fibrinolytic system resulted in high morbidity due to post-thrombotic syndrome (PTS).[4] Thus, there is a great need for improving the functional outcomes of the patients.

Systemic thrombolytics clean the thrombus but does not adequately reduce PTS risk because it is not sufficiently invasive to deep venous valves. Thrombolytic therapy with ultrasound-accelerated catheter-assisted thrombolytic therapy (UCT) is a promising method, reducing complications and PTS development through increasing the invasion of thrombolytic agents into the thrombus with ultrasonic energy.[5],[6],[7]

   Materials and Methods Top

The study included patients diagnosed as DVT with Doppler ultrasonography (USG) between May 2013 and August 2014 at Gazi University Hospital Cardiovascular Surgery Clinic with UCT treatment. The patients had acute, subacute, or chronic DVT. Demographic characteristics, postoperative acute period, prolonged period patency rates, and deep venous insufficiency rates of patients undergoing UCT procedure were evaluated retrospectively to determine the factors affecting these rates. The procedures were performed under sterile conditions, using USG and scopy in the angiography laboratory. Catheter placement was performed under local anesthesia with Seldinger method with ultrasound guidance from popliteal vein. Proper placement was confirmed by giving some radiopaque contrast agent under fluoroscopy, and the sheath was placed [Figure 1]. The hydrophilic wire was advanced from the inside of the sheath to the inferior vena cava level. The catheter in which the tissue plasminogen activator-heparin-containing coolant liquid was delivered andadvanced in the wire guide. With the help of the guiding points on the catheter, it was left to cover the most proximal and distal most of the thrombus. After removing the hydrophilic wire, another wire emitting the ultrasonic wave was advanced through the catheter. Ultrasonic wave emitting wire and TPA catheter are the same length, so ultrasonic wire did not come out from the catheter. All of these procedures were done under fluoroscopy [Figure 2]a, [Figure 2]b, [Figure 2]c. Recombinant human tissue plasminogen activator 5 mg (5 cc) (alteplase (Actilyse ®, Boehringer Ingelheim GmbH & Co, Ingelheim, Germany)) was diluted with 5 cc physiological saline to 10 cc. The diluted liquid was rapidly given 5 cc from the portion of the TPA to be delivered. During patient transport, the remaining 5 cc fluid was given intermittently to ensure that the holes on the liquid catheter were not blocked. To cool the catheter, 2 cc (5000 units) of heparin was added to 1000 cc of physiological saline, and heparinized solution was prepared. In addition, this solution was given intermittently to prevent the catheter clogging during the patient transport phase (amount 10 cc). After the patient is stabilized recombinant human tissue plasminogen activator from the drug-given portion of catheter was infused at 0.02 mg/kg/h dose for 24 or 48 h. The heparinized liquid catheter prepared by adding 5000 units of heparin into 1000 cc of saline was administered at a dose of 50 ml/h from the central lumen. The catheter's ultrasonic wave function was active during the entire procedure. Patients were followed clinically for PE and bleeding after the procedure. The patients were followed at intervals of 12 h with hematocrit and activated clotting time test. At the end of 24 h, after the procedure, patients were evaluated by physical examination and doppler USG. According to this evaluation, it was decided to terminate the treatment of UCT or to extend it from 36 to 48 h. Following the procedure, the catheter was removed. Venous structure was checked by USG or venography. The patients were discharged on warfarin or low molecular weight heparin (LMWH) treatment. International normalized ratio (INR) values in patients using warfarin was maintained between 2 and 3. In addition, all patients were advised to wear venous compression stocking for at least 6 months. All patients were also started diosmin hesperidin to reduce the incidence of venous insufficiency secondary to DVT. Patients were controlled after 1 month of discharge and evaluated with Doppler USG. They were called for 6 months intervals for general and Doppler USG controls to determine if there was reflux in the deep venous structures and whether thrombosis or PTS findings were present. Acetylsalicylic acid treatment was also added to all the patients. Frequent mobilization and venous compression stockings were suggested for all patients.
Figure 1: Insertion of popliteal catheter: (a): Entry of seldinger needle through USG. (b-d): Entering of sheat to popliteal vein. (e): Control of the place of the sheat through USG. (f): Fixation of sheat

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Figure 2: (a-c): Some radiopaque agent was given into the popliteal vein after penetration. Using scopy it is seen that the popliteal sheat is in the vein. In order not to create a risk of pulmonary thromboembolism, it is not given more opaque liquid through the catheter. After the catheter is advanced to the vena cava, a small amount of opaque is administered through the catheter to check whether the catheter tip is in the vena cava

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Statistical analysis

The Statistical Package for the Social Sciences (SPSS, Chicago, IL, USA) 20.0 software was used for the statistical analysis. Variations in oxidative state parameters and histopathological examination between study groups were assessed using the Kruskal-Wallis test. The Bonferroni-adjusted Mann-Whitney U-test was used after significant Kruskal-Wallis test to determine which groups differed from the others. Results were expressed as mean ± standard deviation (Mean ± SD). Statistical significance was set at a P value of <0.05 for all analyses.

   Results Top

The mean age of the patients was 44.83 ± 15.49. Approximately, 50% of the patients (n = 12) were male, and 50% (n = 12) were female. The mean time from the onset of symptoms was 15.08 days. Of these, 58.4% (n = 14) were acute, 20.8% (n = 5) were subacute, and 20.8% (n = 5) were chronic. Thrombosis was in the left leg in 75% (n = 18), in the right leg in 20.8% (n = 5), and in the left calf in 4.2% (n = 1). Thrombosed veins were common femoral veins in 33.3% (n = 8), common iliac veins in 25 % (n = 8), external iliac veins in 33.3 % (EIV), subclavian vein in 4.2% (n = 1), and vena cava inferior in 4.2% (n = 1) [Table 1]. Six patients (25%) had a history of immobilization. The other risk factors were oral contraceptive (OC) use in 20.8% (n = 5), malignant neoplasm in 20.8% (n = 5), hereditary thrombophilia in 16.7% (n = 4), and postpartum status with cesarean section in 8.3% (n = 2). Hereditary thrombophilia was observed in 3 of 5 patients using OC [Table 2].
Table 1: Characteristics of the patients in the group [Mean±SD (Minimum-Maximum), n (%)]

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Table 2: Comorbidity data in patients [n, (%)]

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Patients were divided into four groups according to the evaluation of early postoperative venous recanalization. First group was the completely recanalized group in which the thrombus was completely absent. In the second group (partial recanalization), there were venous wall thrombus residues. The third was minimal recanalization group that allows a small amount of blood flow to pass through the vein and a large part of the thrombus persisting after the procedure. The fourth group is the no recanalization group in which there is no thrombolysis or the thrombus develops again within hours after the procedure. Minimal recanalization and lack of recanalization were accepted as failure of the procedure. Complete and partial recanalization was accepted as a successful result [Figure 3]a, [Figure 3]b, [Figure 3]c. Thrombolysis was successful in 83.3% of the patients (n = 20). Complete recanalization was achieved in 37.5% of the patients (n = 9). Partial recanalization was obtained in 45.8% of the patients (n = 11). The rate of minimal recanalization and no recanalization was 16.7% (n = 4). Minimal recanalization was observed in 12.5% (n = 3) of the patients with failed procedure, and in 4.2% (n = 1) no recanalization was observed.
Figure 3: (a-c):Complete, partial, and minimal recanalization seen in early period postoperative venography

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Venous opening status during long-term follow-up was classified as complete open, minimal thrombosis, and partial clearance. In 37.5% of patients (n = 9), venous structure was found to be completely open, in 33.3% (n = 8), partial thrombosis was found, and in 16.6% (n = 4), partial recanalization was found. In the evaluation of long-term valve function, after completion of the first year of treatment, Doppler USGs were considered. In the Doppler USG examination, venous reflux was checked because it was technically impossible to examine all of the venous valves individually. Pathologic venous reflux was not observed in 45.86% (n = 11) of the patients, whereas 41.7% (n = 10) of the patients had significant reflux. In the PTS evaluation, control examinations, the complaints, and examination findings were considered. In 77.5% of patients (n = 21), PTS symptoms and signs were not observed. However, when the patients who could not get long-term follow-up because exitus was removed, post-trombotic syndrome was not observed in 100% of the patients evaluated. Approximately, 75% (n = 18) of the patients were using warfarin + acetylsalicylic acid (ASA) and 25% (n = 6) were using LMWH [Table 3]. Complete openness was obtained in 57.1% (n = 8) of the patients admitted in the acute phase, whereas partial openness was obtained in 35.7% (n = 5). Complete openness was not obtained in any of the subacute patients, and partial openness was obtained in 60% (n = 3). Complete openness was obtained in 20% (n = 1) of the patients treated in the chronic period, and partial openness was obtained in 60% (n = 3). However, numerically more rate of successful thrombolysis was found to be statistically insignificant in the acute phase [Table 4].
Table 3: Post-treatment data [n, (%)]

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Table 4: Detailed data on thrombolysis in patients [n, (%)]

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Reflux was observed in 28.6% (n = 4), 60% (n = 3), and 60% (n = 3) of the patients admitted in acute, subacute, and chronic periods, respectively, in Doppler USG examination. Although the number of reflux in acute thrombolysis patients was little, it was not statistically significant because it cannot be compared with those patients who received standard deep vein thrombosis therapy or parenteral thrombolytic therapy [Table 5].
Table 5: Reflux data after thrombolysis in patients [n, (%)]

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   Discussion Top

The proportion of male and female patients in the study population was evenly distributed. In general, deep venous thrombosis is more common in females. The risk of DVT increases with age from birth. Eighty-year-old male populations have DVT prevelance of 7.65/1000, whereas females have 8.22/1000. The risk ratio increases 30-fold at age 80 years compared to age 30 years. For children up to the age of fourteen, the DVT rate is 0.006/1000, and the 40–54 age population has rate of 0.7/1000.[8] Active cancer is an independent risk factor for venous thromboembolism. The rate of recurrent venous thromboembolism in cancer patients is higher than in non-cancer patients. The risk of recurrent venous thromboembolic event rate is 17.5% at 2 years, 24.6% at 5 years, and 30.3% at 8 years. The risk of post-trombotic syndrome is 22.8% after 2 years, 28% after 5 years, and 29.1% after 8 years.[9] Of the 24 patients included in the study, 20.8% (n = 5) were in the group receiving treatment for cancer and 3 of these patients could not be evaluated for long-term because of exitus. PTS is not observed in the remaining 2 patients. In cancer patients of higher risk of bleeding, uncomplicated UCT treatment evidences the safety of UCT treatment in this patient population. In addition, in the patient group who had cancer diagnosis, one patient was diagnosed intra-abdominal mass by screening in USG. Results of acute term openness after UCT procedure applied to cancer diagnosed patients were as follows: minimal re-canalization in 1 patient, partial re-canalization in 3, and complete re-canalization in 1 patient. In this study, UCT procedure was used safely in cancer patients.

Twenty-five percent of venous thromboembolic events seen in women of reproductive age have a relationship with OCs. Approximately, 2% of deaths in young women are due to thromboembolic events. OC related mortality is 1.3/100000 between the ages of 20–34 and 3.4/100000 between the ages of 34–45. The use of OCs creates a synergistic effect with events that cause thrombus formation (trauma, travel, etc.), or with hereditary thrombophilic diseases. In situations such as protein C-S deficiency or Factor V Leiden mutation, the risk of DVT increases by 30–50 fold.[10] There were OC use in 5 of the 12 women in this the study. In addition, 3 of these 5 patients using OCs had thrombophilia. In this group of patients with OCs and hereditary thrombophilia, no other cause was found in the etiology of DVT, and these patients consisted of young women during the reproductive period. By looking at these data, it can be said that our study confirms previous work.

Six of the 24 patients in the study had immobilization history because of various causes. In studies with I-125 fibrinogen, in 50% of patients of acute hemiplegia developed DVT within 2 weeks, if heparin therapy was not performed. Most thromboses are hemiplegic extremities and asymptomatic. It is usually seen under the knee in 2/3 ratio. Symptomatic DVT can also be seen in nonparalytic limbs. They are usually proximal thromboses and are frequently seen in 2–7 days.[11] The risk of DVT is proportional to the severity of the paralysis. It is more frequent in elderly and atrial fibrillation patients. The risk of venous thromboembolism in the last 20 weeks of pregnancy is higher than in the first weeks. The uterus grows and impairs venous return and the most pressure occurs on the left iliac vein. Thus, in 81%–97% of the radiologically proven DVT cases, thrombus were observed in this region.[8] In a study of 50,000 postpartum patients, the incidence of venous thromboembolism was 3.6% at week 1 and 1.5% at week 2.[12] Immobilization was found in 2 of 12 female patients in our study. One of the two patients was in the acute phase, and long-term outcomes after UCT procedure revealed minimal thrombus residuals and normal venous valve function. In the other patient who came in the chronic period, partial recanalization was obtained and pathological reflux was found. During the UCT procedure, there were no complications in these patients. The patients were discharged with LMWH.

DVT is a serious public health problem because mortality is high, it is long and expensive, and it impairs quality of life. With early diagnosis and treatment, these complications can be reduced considerably.[13] Standard DVT therapy is anticoagulant therapy to prevent PE. However, anticoagulant therapy is not effective on the lesion directly. In addition, standard treatment does not prevent permanent valve damage. Rapid and effective destruction of the venous thrombus from the luminal side protects the venous valves and reduces reflux and venous obstruction. As a result, the development of PTS, a late complication of DVT, and the recurrence of thrombosis are avoided.[14] Long-term outcomes of 21 of the 24 patients in our study revealed no evidence of PTS in any of the patients. Reflux was detected in 10 of 21 patients (41.7%), and no reflux was detected in 11 patients (45.8%). Venous reflux is absent in 57.1% of patients in acute phase, 40% of patients in subacute phase, and 20% of patients in chronic phase. These findings indicate that the function of venous valve protection in UCT treatment is higher in patients treated in the acute phase [Figure 4].
Figure 4: Approximately, 1.5 years after procedure doppler USG results of a patient and common femoral and superficial femoral vein image

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The rate of major bleeding in catheter-mediated ultrasound accelerated catheter thrombolytic therapy is very low; in which the thrombolytic drug is delivered directly into the thrombus in a much lesser amount than in systemic thrombolytic therapy. The ultrasonic waves used both to facilitate the spread of the thrombolytic agent into the clot and increase the come up of the plasminogen receptors. Classical thrombolytic therapy only provides systemic thrombolysis, and there is no effect on the thrombi remaining behind the venous valves; these malfunctioning valves cause PTS. This explains why the results of ultrasonically accelerated catheter-mediated thrombolysis therapy are more favorable than classical thrombolytic therapy.[5] In the study group, low-dose thrombolytic (0.02 mg/kg/h) was administered to the patients, and there was no serious complication due to bleeding. Complications such as minimal leakage from the side of the sheat, ecchymosis in the places where the blood was taken were observed. In a study performed by Uğurlu on 69 patients, anticoagulation with systemic heparin was applied to 20 patients, systemic thrombolytic therapy was applied to 49 patients, and they evaluated the recanalization scores. In only one (5%) of the patient's anticoagulated with heparin, re-flow was observed, whereas 28 of the patients treated with thrombolytic therapy had recanalization (57%). Two patients had bleeding and were treated conservatively. Success rate was 87% in patients treated within the first four days, and 31% in patients treated in five days and thereafter.

UCT has some advantages over other percutaneous mechanical thrombectomies. Recent studies have demonstrated the efficacy and usefulness of mechanical percutaneous thrombectomy devices. However, the risk of venous injury, venous valve injury, and PE are still serious problems for these techniques.[15] Compared with other mechanical thrombectomy methods, UCT provides rapid and complete thrombolysis and cause less bleeding and thromboembolic complications.[16] In addition, UCT reduces the duration of thrombolytic therapy and infusion.[17]

   Conclusion Top

UCT provides thrombolysis by protecting venous valves, especially in acute deep vein thrombosis, and prevents PTS formation because fewer thrombolytic agents are given. Bleeding complications are less, and it is a safe endovascular method for patients who have a high risk of bleeding such as cancer.

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   References Top

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


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