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The American Journal of Medicine (2005) Vol 118 (8A), 31S–36S

ndovascular management of acute deep vein thrombosisndrew Blum, MD,a Erin Roche, MSb

Division of Vascular Interventional Radiology, Midwest Heart Specialists, Elmhurst, Illinois, USA; and

Riverside, California, USA.

The goals of successful management of deep vein thrombosis (DVT) include relief of acute symptomswith restoration of venous patency, prevention of clot propagation and subsequent pulmonary embo-lism, and maintenance of venous valvular function. Valvular incompetence is the leading cause ofpostthrombotic syndrome (PTS), which is characterized by chronic leg heaviness and aching, lowerextremity edema, and impaired viability of subcutaneous tissues, which may lead to chronic trophic skinchanges and venous ulceration.

Anticoagulation with unfractionated or low-molecular-weight heparin followed by warfarin is rec-ognized as the standard therapy for acute DVT. Although this approach may effectively preventrecurrent thrombosis, it often fails to meet the other treatment goals. Recent studies have demonstratedthat early clot lysis through the use of catheter-directed thrombolytic therapy and other adjunctive endo-vascular techniques rapidly restores venous patency, more effectively preserves valvular function, andimproves quality of life. When used in conjunction with anticoagulation, these minimally invasive endo-vascular techniques have the potential to lead to improved long-term outcomes in patients with DVT.© 2005 Elsevier Inc. All rights reserved.

KEYWORDS:Deep vein thrombosis;Low-molecular-weightheparin;Postthromboticsyndrome;Unfractionated heparin

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Deep vein thrombosis (DVT) is a common condition,ith �250,000 new cases reported annually in the Unitedtates.1 When inadequately treated, DVT may be compli-ated acutely by the development of pulmonary embolismPE) and in the long-term by chronic venous insufficiency,lso known as postthrombotic syndrome (PTS). As many as

million individuals experience complications of severehronic venous disease,2 many cases of which are the directesult of previous DVT. The economic impact of compli-ations related to PTS have been estimated to account for asuch as 75% of the total care cost of DVT.3

urrent treatment of deep vein thrombosis

istorically, the standard treatment for DVT has been thedministration of anticoagulant drugs to prevent thrombus

Requests for reprints should be addressed to Andrew Blum, MD,ivision of Vascular Interventional Radiology, Midwest Heart Specialists,29 North York Road, Elmhurst, Illinois 60126.

tE-mail address: ablum@midwestheart.com.

002-9343/$ -see front matter © 2005 Elsevier Inc. All rights reserved.oi:10.1016/j.amjmed.2005.06.007

ropagation and embolization. Anticoagulation typicallyonsists of a short course of treatment with intravenous (IV)nfractionated heparin (UFH) followed by a period of 3 tomonths of oral warfarin.4 Results from several recent

andomized clinical trials demonstrate that outpatient anti-oagulant treatment with subcutaneous low-molecular-eight heparin (LMWH) is feasible, and may confer several

dvantages over inpatient treatment with IV UFH.5 Theotential advantages of LMWH include once- or twice-dailyosing due to its longer half-life and fixed dosages due to aore predictable antithrombotic effect. The use of LMWH

herefore eliminates the need for laboratory monitoring,educing the costs associated with hospital stays in theseatients and promoting earlier discharge.6

Although anticoagulation is useful in the reduction ofecurrent thrombotic events and the prevention of PE,7 usedlone it is rarely able to facilitate clot lysis adequately.8

reservation of valve function and prevention of PTS hasot been established with UFH use.8,9 Anticoagulation reg-mens, along with their strengths and weaknesses, are fur-

her explored by Merli elsewhere in this supplement.10 The

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32S The American Journal of Medicine, Vol 118 (8A), August 2005

bjective of this article is to review the utility of thrombo-ytic therapy and other adjunctive endovascular techniquesn the setting of more extensive iliofemoral DVT.

oals of deep vein thrombosis treatment

ithout adequate treatment, many patients with DVT ex-erience persistent venous outflow obstruction and valvularncompetence, both of which are known to contribute to theevelopment of PTS. It is estimated that 6 million to 7illion patients in the United States have chronic venous

nsufficiency as a result of PTS, including about 500,000ho may eventually progress to ulceration.2 Patients withore extensive DVT involving the proximal segments, in-

luding the iliac veins and inferior vena cava (IVC), areore likely to develop PTS.Successful treatment of DVT and prevention of post-

hrombotic complications require realization of the follow-ng 5 goals: (1) prevention of clot propagation; (2) preven-ion of PE and recurrent thrombosis; (3) restoration ofenous patency and flow; (4) preservation of valvular func-ion; and (5) elimination of clinical symptoms associatedith PTS.Although studies of new anticoagulation regimens focus

n short-term goals, such as prevention of PE, few considerhe long-term aim of preservation of valvular function as aignificant therapeutic end point. It has been demonstratedhat early recanalization of thrombi correlates with preven-ion of valvular reflux and preservation of valve function.11

hese factors are considered to be highly important in therevention of PTS12 and its associated complications, andhrombolytic agents are better able than standard anticoag-lation alone to achieve this end point (Table 1).2,8,13

atheter-directed thrombolysis anddjunctive endovascular treatment options

ractitioners who manage patients with DVT should beamiliar with the various interventional and surgical treat-ent strategies, which include pharmacologic thrombolysis,

ercutaneous mechanical thrombectomy, adjunctive stent-ng, and surgical thrombectomy. The endovascular strate-ies are often used in combination, allowing for betteresolution of venous clot burden than when a single modal-ty is used alone. Results with surgical thrombectomy havemproved with the advent of the Fogarty balloon and otherefined techniques, yet the procedure has generally fallenut of favor because of the associated operative morbidity.urgery remains a valid option, however, in the event of

mpending venous gangrene or failure of endovascular tech-iques.

Streptokinase, urokinase, and tissue plasminogen activa-or (t-PA) are the primary thrombolytic agents used in the

reatment of DVT. These agents dissolve thrombi by cata- t

yzing the conversion of plasminogen into its active form,lasmin, which in turn breaks down fibrin into solubleyproducts. In a randomized trial that compared thrombol-sis and anticoagulation with anticoagulation alone in pa-ients with iliofemoral DVT, thrombolysis was associatedith improved patency (72% vs. 12%; P �0.001) andenous valvular competence (89% vs. 59%; P � 0.04) at 6onths.14 Although most studies of venous thrombolysis

ave used urokinase, more recent data suggest that treat-ent with tissue t-PA also may be effective.13

Although systemic thrombolysis (via a peripheral IVnfusion) is more effective than treatment with anticoagu-ation alone, this method results in significantly less throm-us dissolution in obstructed segments than in partiallyhrombosed segments (10% vs. 52%).15 This is likely due toeduced diffusion of these agents into larger venous thrombinder conditions of little or no flow.13 There is also a greaterisk of bleeding associated with systemic thrombolysis thanith standard anticoagulation alone. The limitations of sys-

emic thrombolytic therapy have prompted studies of cath-ter-directed, “local” infusions of thrombolytic agents inrder to enhance clot dissolution and minimize bleed-ng.16–18 These interventional techniques offer the advan-ages of more concentrated delivery of the thrombolyticgent into the clot, with less risk of systemic bleeding.hese methods also allow for imaging of the affected veinsith the option of adjunctive endovascular techniques such

s stent placement to ensure optimal patency and flow.In 1994, Semba and colleagues17 reported their initial

xperience with catheter-directed thrombolysis in 21 pa-ients with iliofemoral DVT. These authors reported a tech-ical and clinical success rate of 85%. Based on theseesults, the National Venous Thrombosis Registry was ini-iated, through which 287 patients with large obstructedenous segments (71% with iliofemoral DVT) were re-ruited from 63 participating centers and observed over aeriod of 1 year after treatment with catheter-directed uroki-ase. Complete resolution of thrombus was achieved in1% of cases, and partial (50%–99%) thrombus resolutionas reported in 52%.18 At 1 year, primary patency was0%. The study enrolled patients with both acute andhronic forms of DVT, and success rates were considerablyigher in the population with acute DVT. Only 6 patients in

Table 1 Outcome of anticoagulation versus systemicthrombolytic infusion for acute deep vein thrombosis: resultsof 13 studies

Treatment (N)

Lysis

None/Worse(%)

Partial(%)

Significant/Complete (%)

Heparin (254) 82 14 4Thrombolysis (337) 37 18 45

Adapted with permission from Semin Vasc Surg.13

he study developed PE, and, of those cases, 2 resulted in

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33SBlum and Roche Endovascular Management of Acute Deep Vein Thrombosis

eath. Major bleeding complications were primarily relatedo catheter-insertion site bleeding, and were noted in 11% ofatients.18

In a subsequent study involving a subset of this registry’satients, Comerota and coworkers19 demonstrated betterhysical functioning and health-related quality of lifeHRQOL) in patients with iliofemoral DVT treated by cath-ter-directed thrombolysis than in those patients treatedith anticoagulation alone. Patients successfully treatedith urokinase reported better overall physical functioning

P � 0.046), less health distress (P � 0.022), and fewerncidents of PTS (P � 0.006), compared with patientsreated with heparin alone. Patients in the urokinase groupho failed to achieve adequate lysis had HRQOL scores

imilar to those of patients treated with heparin.Data from the National Venous Thrombosis Registry

ave established the optimal catheter-directed treatment ap-roach and patient population.18 An antegrade catheter-irected approach using urokinase in patients with acuteliofemoral DVT duration of �10 days and no prior historyf DVT leads to the best result, with complete lysis in 65%f those patients.

Analysis of long-term clinical outcome is pending, butarly results suggest improved valve function and fewerymptoms at 1 year in patients with complete thrombolysis.hese promising data should serve as the basis for future

andomized trials of catheter-directed thrombolysis for thereatment of acute DVT.

Recently, the development of percutaneous mechanicalhrombectomy devices has added to the interventional ar-amentarium in the management of DVT. These devices

re a natural extension of traditional open surgical tech-iques. A variety of low-profile mechanical devices areurrently in investigational use in this setting. Early resultsith these devices are promising, with dramatically reduced

nfusion times and bleeding complications, and may obviate

Table 2 Contraindications for thrombolytic therapy

Absolute Contraindications Relative Contraindications

● Active or recent internalbleeding

● Recent major surgery/organ biopsy

● Recent cerebrovascularaccident

● Known intracranialneoplasm

● Recent craniotomy orspinal surgery

● CPR● Trauma● Pregnancy● Diabetic hemorrhagic

retinopathy● Uncontrolled

hypertension● Bacterial endocarditis● Hepatic failure● Renal failure

CPR � cardiopulmonary resuscitation.

he need for thrombolysis in some circumstances. t

ontraindications for thrombolytic therapynd risk of pulmonary embolism

rimary contraindications for thrombolytic therapy includeoncomitant medical conditions that increase the risk ofleeding complications, such as recent surgery, stroke, orastrointestinal bleeding (Table 2). In addition to hemor-hage, potential complications of catheter-directed throm-olysis include migration of the thrombus and subsequentE. In published thrombolytic series, these complicationsre rare, and routine prophylactic IVC filter placement hasot been necessary during these infusions. The recent intro-uction of temporary retrievable filters, however, may lowerhe threshold for placement, as they may be removed fol-owing clot dissolution.

In general, patients who might benefit from IVC filtersnclude those for whom anticoagulation therapy is contra-ndicated, has resulted in complications, or has failed torevent embolic events. This includes patients at high riskor bleeding, e.g., those with extensive trauma or malig-ancy and those undergoing certain surgical procedures.4

nder certain circumstances, IVC filter placement and an-icoagulation may be used in conjunction. This approach isften used for patients with severe cardiopulmonary diseasen whom a recurrent embolic event may otherwise prove toe fatal.

ay-Thurner syndrome

ome patients develop DVT for anatomic rather than phys-ologic reasons. May-Thurner syndrome, most commonlyound in young women with DVT, is a condition in whichhe left common iliac vein is narrowed by extrinsic com-ression by the overlying right common iliac artery. Intralu-inal venous webs may develop as a result. Before the moreidespread use of imaging studies, this anomaly often wentndetected. Venography following thrombolytic infusionay identify such a culprit lesion, allowing for subsequent

ndovascular stenting or surgical repair (Figure 1).20

hlegmasia cerulea dolens

hlegmasia cerulea dolens (PCD) refers to an ischemicondition caused by massive venous thrombosis that oftennvolves the IVC and extends to the collateral veins andmall postcapillary venules. The condition is characterizedy massive edema with cyanosis due to arterial stasis andompromise, and it may lead rapidly to acute compartmentyndrome and venous gangrene (Figure 2). There are mul-iple triggering factors, including May-Thurner syndrome,alignancy, and surgery.The initial treatment for mild PCD should be conserva-

ive measures, including steep limb elevation, anticoagula-

ion with IV heparin, and fluid resuscitation.21 Strong con-

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34S The American Journal of Medicine, Vol 118 (8A), August 2005

ideration should be given to thrombolytic therapy in moredvanced cases, with surgical thrombectomy an option ifhere is no immediate response. Thrombectomy alone can-ot open the small venules affected in venous gangrene, andome investigators have used thrombolysis via an intra-rterial infusion as an alternative that delivers the thrombo-ytic agent to the arterial capillaries and subsequently to theenules.13,21 Data from the National Venous Thrombosisegistry has shown that this procedure restored venousutflow and arrested tissue ischemia in a number of pa-ients.22

ase study

istory and presentation

75-year-old woman with a confirmed history of DVT andeveral previous recurrences presented with severe bilateralower extremity edema and impending PCD or venous gan-rene 6 months after IVC filter placement. Venographyevealed extensive thrombus within bilateral femoral veinsFigure 3). There was a filling defect and no flow within theVC filter, which is consistent with caval thrombosis andcclusion at that level (Figure 4).

ntervention

nfusion catheters were advanced from both popliteal veins

igure 1 May-Thurner syndrome (iliac vein compression syn-rome).

cross the thrombosed femoral segments and extended into

he occluded IVC filter (Figure 5). A thrombolytic infusionf urokinase was administered via these catheters for aeriod of 18 hours.

Figure 2 Phlegmasia cerulea dolens.

Figure 3 Thrombosed femoral vein (right side shown).

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35SBlum and Roche Endovascular Management of Acute Deep Vein Thrombosis

linical response

ollow-up venography after thrombolysis demonstratedlearance of the thrombus and restoration of patency andow within the filter, IVC, and femoral veins (Figure 6).here was rapid resolution of clinical symptoms.

ummary

nticoagulation remains the standard treatment regimen inatients with acute DVT. With the advent of LMWH, out-atient treatment is initially more cost-effective. However,n more severe cases with extensive clot, or in the younger,

igure 4 Thrombotic occlusion of inferior vena cava at level ofnferior vena cava filter.

Figure 6 (A) Patency of inferior vena cava postthrombolysis

ore active patient, the risk of PTS and its complicationsemains high with anticoagulation alone. In these situations,nticoagulation and thrombolysis are complementary. Cath-ter-directed thrombolysis, aided by adjunctive endovascu-

Figure 5 Placement of infusion catheters for thrombolysis.

. (B and C) Patency of femoral vein postthrombolysis.

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36S The American Journal of Medicine, Vol 118 (8A), August 2005

ar techniques, followed by outpatient management withnticoagulation is highly recommended in such instances.lacement of temporary or permanent IVC filters beforeatheter-directed thrombolysis may benefit patients at highisk for PE and is a stand-alone option for those withomplications from or contraindications for anticoagulationherapy and thrombolysis. Surgical thrombectomy is re-erved for patients who have failed therapy with theseess-invasive techniques. With continuing development andgrowing body of experience with these new and/or refinedethods to treat DVT, the goals of successful management

re closer to being met.

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