The Egyptian Journal of Radiology and Nuclear Medicine (2013) 44, 57–62

Egyptian Society of Radiology and Nuclear Medicine

The Egyptian Journal of Radiology andNuclearMedicine

www.elsevier.com/locate/ejrnmwww.sciencedirect.com

ORIGINAL ARTICLE

Catheter direct thrombolysis: Role of actilyse in treatment

of acute deep venous thrombosis

Mohsen Gomaa *, Hossam Fahmy, Ahmed Farouk

Radiodiagnosis Department, Faculty of Medicine, Ain Shams University, 2 Elkarim St., Ziton, Cairo, Egypt

Received 8 July 2012; accepted 7 October 2012

Available online 8 November 2012

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KEYWORDS

Thrombolysis;

Actilyse;

Deep venous thrombosis

Corresponding author. Tel.:mail address: sharkawymohs

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Abstract Purpose: To evaluate the short and long term efficiency of catheter directed thrombol-

ysis using recombinant tissue type plasminogin activator (r-TPA; Actilyse), in treating acute deep

venous thrombosis of the lower limb.

Material and methods: Twenty-eight patients with acute lower limb deep venous thrombosis under-

went treatment by direct intra clot injection of thrombolytic therapy; Actilyse.

Result: Thrombus lysis was completed in 23 (82.2%) of 28 patients, partial in 4 (14.3%) patients

and not achieved in one (3.5%) patient. There was no major complication. There was no rethrom-

bosis or post thrombotic syndrome in any of the treated 23 patients over the follow up period of one

year.

Conclusion: The treatment of acute lower limb deep venous thrombosis using recombinant tissue

type plasminogin activator (r-TPA; Actilyse), is safe, effective and achieves significantly better short

and long term clinical outcome for patients.� 2012 Egyptian Society of Radiology and Nuclear Medicine. Production and hosting by Elsevier B.V.

All rights reserved.

1. Introduction

Deep venous thrombosis of the lower extremity is recognizedas a cause of both pulmonary embolism and the post throm-botic syndrome. The therapeutic goals for treating the patients

with acute DVT include, diminishing the severity and duration

3080608; fax: +20 226359982.o.com (M. Gomaa).

tian Society of Radiology and

g by Elsevier

Radiology and Nuclear Medicine.

0.001

of lower extremity symptoms, preventing pulmonary embo-

lism, minimizing the risk of recurrent venous thrombosis andpreventing the post thrombotic syndrome [1,2]. Success inthe achievement of these clinical goals will minimize the mor-

bidity and mortality of pulmonary embolism and will diminishthe sequelae of post thrombotic syndrome [3]. Early thrombusremoval is a logical approach to improve the long term out-come of DVT [4]. Although anticoagulation (heparin followed

by oral anticoagulation) is currently considered the standardof care for protecting the patient from the manifestation ofpost thrombotic syndrome which can appear months to years

after the acute episode of DVT [5,6]. However, this regimendoes not promote lysis to reduce the thrombus load and doesnot restore the venous valve function [7]. Thrombolytic

therapy is attractive, because it can potentially help achieve

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Table 1 Symptoms and location of DVT in 28 patients.

Initial symptoms No. of

patients

Edema 25

Pain 28

Location and extension of the thrombus:

� Poplitofemoral thrombus extending to the iliac vein 22

� Poplitofemoral thrombus extending up to the IVC 6

58 M. Gomaa et al.

restoration of the lumen and removal of the thrombus liningthe venous valves. Two goals may be achieved: relief of venousoutflow obstruction and preservation of valve function [8]. The

frequently used thrombolytic agents that rapidly clear venousthrombosis include streptokinase, urokinase, and recombinanttissue type plasminogin activator (r,TPA) like alteplase and

actilyse. It can be used systemically or loco regional [9]. Trans-catheter regional infusion allows higher concentrations of thethrombolytic agent to be introduced directly into the thrombus

[10]. However, continuous infusion potentially results in pro-longed exposure of the systemic circulation to thrombolyticagents which can increase the risk of bleeding [11]. The pur-pose of this study was to determine the feasibility and safety

of catheter directed thrombolysis for treatment of lowerextremity DVT using recombinant human tissue type plasmi-nogin activator; actilyse.

2. Patients and methods

Twenty-eight consecutive patients (15 women and 13 men, age

range of 17–76 years; mean age of 38 years) with recent lowerextremity venous thrombosis of less than 15 days but withoutclinically relevant signs of pulmonary embolism, were included

in this prospective study. The onset of the thrombosis wasbased upon the date of the initial clinical symptoms. The studywas conducted in Doctor Soliman Fakeeh Hospital, Jeddah,

KSA between April 2008 and August 2011. Patients were se-lected on the basis of the following criteria: (a) symptomaticlower extremity thrombus confirmed by duplex ultrasound;(b) severe clinical symptoms; pain and swelling, which prohibit

standing on the leg; and (c) no contraindication to infusion ofthe thrombolytic agent. Contraindications to thrombolyticagents included active internal bleeding; cerebrovascular acci-

dent within previous 2 months; recent major trauma or sur-gery; recent gastrointestinal bleeding; severe hypertension;pregnancy, lactation or delivery within the last 20 days; malig-

nant disease; acute pancreatitis; hepatic failure; renal failureand coagulopathy. All patients gave written informed consentto participate after the risks and benefits of treatment were

fully explained.The left leg was involved in 18 patients, the right leg in 9

patients and the last patient had bilateral thrombosis. All pa-tients had popliteo-femoral thrombi that were seen extending

to the common iliac vein in 22 patients and to the inferior venacava in the other 6 patients. The patients were initially evalu-ated with a careful history taking to discover a possible etiol-

ogy. After a thorough examination, complete blood countand prothrombin time (PT), partial thromboplastin time(PTT) and INR were determined. The leg circumferences and

D-dimer levels were also measured and recorded before andafter thrombolytic therapy.

2.1. Technique for thrombolysis

With the patient in prone position, the ipsilateral popliteal veinof the affected limb was visualized by ultrasound. A single wallpuncture was made using a small gauge needle, to avoid inad-

vertent puncture of the adjacent popliteal artery. A hydrophilicguide wire (Guide Wire M, Terumo Corporation, Tokyo,Japan) was inserted and advanced through the whole length

of the thrombus. A 5-F vascular sheath was then inserted

through which all subsequent catheter and wire exchangeswere performed. In addition, the vascular sheath allowed theintensive care team to obtain blood samples while avoiding

the risk of phlebotomy during thrombolysis. We used thehydrophilic guide wire before insertion of the vascular sheathto be sure that we are within the thrombotic vein and to test

the accessibility of the thrombus. After that, contrast materialwas injected through the sideway of the vascular sheath to doc-ument the thrombus, to determine its distal extent, and to visu-

alize collaterals. For infusion of thrombolytic agent, aninfusion wire with multiple side holes and stiffening core (Kat-zen, Boston Scientific Corporation, Natick; USA) was used.The wire was advanced and embedded within the proximal

part of the thrombus. The stiffening core was retracted andinfusion of thrombolytic agent was started as follows: a load-ing dose of 15 mg Actilyse (rt-PA, Boehringer Mannheim,

Germany) was injected manually as three doses each of them5 mg at 10 min intervals. Actilyse was then infused into thethrombus at a rate of 1 mg/h up to 1.5 mg/h with the aid of

an infusion pump over a period of maximum 4 days. Standardunfractionated heparin (Liquemin, Hoffmann-La Roche,Grenzach-Wyhlen, Germany) was injected simultaneously in

the side arm of the vascular sheath at a fixed rate of5000 IU/h and intravenously at a rate of 5000 to 7000 IU/h,with the dosage adjusted according to the PTT value (2.0 to3.0 times normal value). Progression of lysis was controlled

by venography every 24 h. Once partial patency is achieved,the infusion wire was advanced and infusion continued fromthe proximal part of residual thrombus. The treatment was

stopped in any case if no residual thrombotic material was vis-ible or if no further lysis was observed between two consecu-tive venographies. During thrombolytic therapy, the patient

was rested in bed in intensive care unit since a close observa-tion is essential to detect any evidence of hemorrhagic compli-cation. Removal of the vascular sheath was done 12 h after

cessation of the thrombolytic infusion; care was taken with fi-nal removal for the high risk of local extravasation andhematoma.

Therapy was continued with the standard anticoagulant,

given in individual doses so that the international normalizedratio (INR) was greater than 2.5 but less than 4.0. The patientswere followed every week for the first 3 months and later every

three months for 1 year.

3. Results

Initial clinical symptoms and the distribution of thrombi aresummarized in Table 1. Treatment outcomes are summarizedin Table 2.

Table 2 Treatment outcomes in 28 patients treated for DVT.

Treatment outcome No. of patients

Lysis of thrombosis

� Complete 23

� Partial 4

� No lysis 1

Catheter direct thrombolysis: Role of actilyse in treatment of acute deep venous thrombosis 59

Successful placement of the thrombolysis catheter acrossthe occluded veins occurred in all 28 treated patients. Com-plete lysis was achieved in 23 patients (82.2%) (Fig. 1 and

2), partial lysis was achieved in 4 (14.3%) (Fig. 3). The last pa-tient (3.5%) nearly failed after 72 h of thrombolysis mostly dueto old thrombosis (misdiagnosed as muscular skeletal disorderfor more than 2 weeks) (Fig. 4). In this patient only the femo-

ral vein was recanalized after catheter insertion with no lysis ofthe thrombus in external iliac, common iliac and inferior venacava.

Minor complication of echomosis at the puncture site wasencountered in 10 of 28 (35%). None of these required surgicalintervention or blood transfusion, no major complication

encountered.Clinical follow-up and Doppler ultrasound evaluation up to

one year of the 23 treated patients who showed complete lysis

Figure 1 Complete lysis of popliteo-femoral thrombus in a 51 year old

of the left lower limb. (A&B) venogram obtained before thrombolysis, w

the left popliteal (A), and the superficial femoral vein (B), (arrows). (C)

the thrombus with still occluded distal part of SFV (arrow). (D&E) veno

of the thrombus. Arrow in (E) marks the Katzen infusion guide wire.

revealed no rethrombosis or post thrombotic sequelaesyndrome.

4. Discussion

Despite advances in the diagnosis and management of throm-boembolic disease, it remains a potentially life threatening dis-

order affecting hospitalized patients as well as healthyindividuals [12]. In addition to early risk of pulmonary embo-lism, late morbidity may develop from recurrent thrombosis

and post thrombotic syndrome [13]. The management ofDVT has evolved in recent years to encompass the outpatientuse of low-molecular weight heparin (LMWH) as well as phar-

macological thrombolysis and mechanical thrombectomy [14].During the acute phase, proximal DVT is associated with mor-bidity in the form of leg edema, pain and difficult ambulation

[15]. One of the primary goals of therapy is to relieve outflowobstruction; however this could not be accomplished entirelyby anticoagulation alone because thrombus regression occursin only 50% of patients and venous recanalization develops

in only a minority of patients [4,16].For prevention of pulmonary embolism immediate antico-

agulation with heparin is the standard of care for all patients

with significant DVT in the absence of absolute contraindica-tion. Systemic thrombolysis can be used also to prevent recur-rent PE when given with or without concomitant heparin [17].

female patient, who presented with acute onset of pain and edema

hile patient was in a prone position, shows complete thrombosis of

venogram obtained 24 h after thrombolysis showing partial lysis of

gram obtained 48 h after thrombolysis that showing complete lysis

Figure 2 Complete lysis of the left popliteo-femoral thrombus that extends up to the IVC in a 48 year old female patient. (A&B)

venogram obtained before thrombolysis, while patient was in a prone position, showing complete thrombosis of the left popliteal and

superficial femoral vein (A), and common femoral veins (B), (arrows). (C&D) venogram obtained 24 h after thrombolysis showing

complete lysis of the thrombus up to the external iliac vein, still with partial occlusion of the common iliac vein (short arrows) and the IVC

(long arrow). (E) venogram obtained 48 h after thrombolysis showing complete lysis of the thrombus at the common iliac vein (short

arrow) and the IVC (long arrow).

Figure 3 Partial lysis of the thrombus in a 36 year old male patient. (A) Venogram obtained before thrombolysis, while patient was in a

prone position, shows complete thrombosis of the left popliteal and superficial femoral veins (short arrows). Long arrow demonstrates the

Terumo guide wire advanced through the thrombus. (B) Venogram obtained 24 h after thrombolysis showing partial lysis of the

thrombus. (C&D) Venogram obtained 48 h after thrombolysis shows complete lysis of the thrombus at the popliteal and SFV, with partial

lysis at the common femoral vein (arrows). The occlusion remained after 72 h of thrombolysis with no remarkable change.

60 M. Gomaa et al.

As regards the late morbidity of post thrombotic syndromewhich develops in 20% to 50% of patients with DVT, it occursmore frequently with extensive multi level DVT and when the

oral anticoagulant regimens are inadequate [18,19]. Its symp-toms include chronic leg heaviness, leg aching and venous clau-dication, edema, varicosities, hyperpigmentation and non

healing ulcers due to the consequences of the venous valvularincompetence, venous hypertension and stasis [13]. The aboveobservations raise the need for treatment therapy that removes

the thrombus to preserve the valvular competence, reduces thevenous outflow obstruction and reduces the post thromboticsyndrome since the anticoagulant therapy prevents thrombus

propagation, PE and recurrent venous thrombosis but it donot dissolve the occluding thrombus or reduce the venous out-flow obstruction. These therapies include open surgical throm-

bectomy and pharmacological thrombolytic therapy.Pharmacological thrombolytic therapy prompts restoration

of venous patency and preservation of venous valve function.

Figure 4 Failed thrombolysis in a 42 year old male patient. (A&B) Venogram obtained before thrombolysis shows complete thrombosis

of the right superficial femoral vein, the iliac veins and the IVC (arrows), with venous return through collaterals. (C&D) Venogram

obtained 72 h after thrombolysis showing complete lysis of the thrombus at the SFV, with partial lysis at the common femoral vein and the

external iliac vein (short arrow). No lysis at the common iliac vein and the IVC (long arrows). (E) CT axial cuts and (F) coronal

reconstruction showing thrombosed both common iliac veins (arrows in E) and IVC (arrow in F).

Catheter direct thrombolysis: Role of actilyse in treatment of acute deep venous thrombosis 61

This therapy can potentially help prevent long term sequelae ofDVT. Delivery of the thrombolytic agent directly into thethrombus offers substantial advantages over systemic adminis-

tration of a thrombolytic agent, which may fail to reach andpenetrate occluded venous segment. Because thrombolyticagents activate plasminogin in the thrombus, delivery of the

drug to that site enhances its effectiveness. In addition byfocusing the delivery of higher concentration of the drug, lysisrates can be improved and the duration of treatment can be re-duced. Subsequently complication associated with exposure of

the patient to systemic thrombolytic therapy might be reduced[20].

In our study, the initial and long term results appear to be

at least as good as those of other trials involving continuousinfusion catheter directed thrombolytic therapy. In our studythe degree of lysis was found to be a significant prediction of

early and continued patency. Complete lysis was achieved in82% in concordance with the study of Verhaeghe et al. [7]who were able to restore patency in 79% of thrombosed veins

using rt-PA (alteplase); and with the study done by Chang etal. [21] who reported that 80% of his patients restored bloodflow after thrombolysis therapy by using alteplase. Our resultswere significantly better than the result of Mewissen et al. [22]

who achieved complete lysis rate in only 31% using urokinase.The discrepancy in the results here is mostly due to higher fi-brin specificity of rt-PA (like actilyse and alteplase) than those

of urokinase.In our study no patients would be classified as having

developed the post thrombotic syndrome, because all patients

are or were asymptomatic for the follow-up period of12 months. Chang et al. [21] in their study reported similar re-sult after using alteplase. They found that none of their pa-

tients experienced the post thrombotic syndrome or recurrent

thromboembolism. In contrary Prandoni et al. [23] who useanticoagulant alone (heparin) found that the incidence of postthrombotic syndrome was 18% at 1 year and almost 25% at

2 years.In addition our study showed no recurrence in a mean fol-

low-up period of 12 months and no patients were classified as

having developed rethrombosis. This was in contrast to thestudy of Mewissen et al. [22] using Urokinase who found thatalmost half of their successfully treated patients had sites ofloss of patency or re-occlusion 6–12 months after treatment.

In another study done by Prandoni et al. [23] they reported ahigh percentage of recurrence of about 17% in patients withDVT treated with anticoagulant alone. Our result was similar

to that of Chang et al. [21] study who reported no recurrentthrombosis after months of follow up of their patients usingalteplase as thrombolytic agents. In our opinion, this is mostly

due to the use of actilyse which is most specific and effectivethan other thrombolytic agents.

Although there are many effective thrombolytic agents,

actilyse (recombinant human tissue-type plasminogin activa-tor) is a serine protease that is produced by recombinantDNA technology and that is chemically identical to humanendogenous rt-PA. It acts by stimulating fibrinolysis of blood

thrombi it promotes the binding of plasminogin to the fibrinthrombus in conjunction with the increased affinity of fibrin-bound rt PA for plasminogin and it facilitates the ordered

adsorption of plasminogin and its activator to the fibrin sur-face [24], it has two characteristics that make it preferable tointra clot treatment of DVT; its binding affinity for fibrin

and its short half life (approximately 5 min) in the general cir-culation. Because it binds to the fibrin in a thrombus, actilyse,unlike streptokinase and urokinase, does not need to be

administered by continuous intra clot infusion. Although ex-

62 M. Gomaa et al.

cess actilyse diffuse from the clot into the circulation it iscleared within 2 h after intra clot installation because of itsshort half life.

Catheter directed thrombolysis has two drawbacks: it is la-bor invasive and there is the bleeding risk [7]. During our studywe encountered only echomosis at the puncture site in 10 of 28

patients. It represents 35 percent which is less than the percent-age of bleeding found by Verhaegue et al. [7] study who stated12 patients (50 percent) bleeding at the puncture site with 6

needing blood transfusion. This is mostly due to use of a lowto medium dose of actilyse (1 mg/h up to 1.5 mg/h) in compar-ison to Verhaege et al. [7] who used a high dose of 3 mg/h, solow dose and continuous needle access under the ultrasound

guidance are mandatory to avoid the inadvertent puncture ofadjacent vessels such as popliteal artery.

We only used popliteal vein as the venous access site. It al-

lows ante grade catheter traversal of the deep venous valve,which can be difficult and potentially traumatic to the leafletswhen retrograde passage is used.

We did not use IVC filter since the use of IVC filter duringthrombolysis has been questioned because of the low incidenceof complication that occurs when lysis is performed without fil-

ter protection [25].In conclusion, catheter directed thrombolysis using actilyse

appears promising and can be used to dissolve the thrombussafely and effectively from the deep veins of patients with

symptomatic lower limb DVT. Thrombolytic therapy has thepotential for protecting the patient against chronic venousinsufficiency and is related to the achievement and mainte-

nance of patency and the preservation of valve function. Thelong term benefits of this form of therapy are promising wher-ever long term follow-up to 5 year studies are necessary to

evaluate the frequency of chronic venous insufficiency.

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