Applied Radiology

Dr. Eclavea is a clinical research fellow in the Section of Vascular & Interventional Radiology at the Indiana University School of Medicine, Indianapolis, IN.

Dr. Patel is an associate professor in the Section of Vascular & Interventional Radiology at the Indiana University School of Medicine, Indianapolis, IN.

Hospital- and population-based studies, using objective confirmation, report annual incidence ranging from 48 to 182 new cases of acute deep vein thrombosis per 100,000 Western industrialized inhabitants. ^1,2 Clinical features of acute iliofemoral deep venous thrombosis (IFDVT) include massive unilateral leg edema, pain, and cyanosis. As initially described by Virchow, ³ three factors are of primary importance in the development of deep venous thrombosis (DVT): (a) abnormalities of blood flow, (b) abnormalities of blood, and (c) vessel wall injury. Several of the risk factors associated with DVT can be related to one or more of these elements (Table 1). However, it is now recognized that most thromboses arise from the interaction of multiple inherited and acquired risk factors, giving rise to the concept of "thrombotic potential" as proposed by Rosendaal et al. ⁴ When the cumulative thrombotic potential of all risk factors exceeds a certain threshold, clinical thrombosis is likely.

Sequelae and natural history of acute deep venous thrombosis

The short-term sequela of DVT is propagation of the thrombus to a more clinically significant portion of the venous system and embolization (figure 1) of thrombus to the pulmonary tree. ^5,6 With anticoagulant therapy, clot propagation is deterred and the intrinsic fibrinolytic system begins to clear the clot. This recanalization process results in a series of pathological events. Thrombi that are not dissolved by intrinsic fibrinolysis become organized--connective tissue cells invade the thrombus, incorporate it into the vein wall, and form scar tissue that may damage or destroy vein valves. Alternatively, a new channel may develop through the thrombus, recanalizing the vein. But the new channel is irregular and does not permit free blood flow. This impedance often results in recurrent deep venous thrombosis.

The major long-term sequela of DVT is post-thrombotic syndrome (PTS). ⁷ This is manifested as chronic edema, pain, and muscle fatigue (venous claudication), varicosities, hyperpigmentation of the skin, subcutaneous fibrosis, and venous stasis skin ulcers (figure 2). PTS becomes apparent only months to years after an episode of DVT. Patients with IFDVT are at a high risk; 66% develop PTS, and 10% to 15% develop venous stasis skin ulcers. ^7-11 PTS is the result of chronic elevation of venous pressures (venous hypertension) in the lower limb due to venous outflow obstruction and/or valvular incompetence. The single most important implicated cause of PTS is valvular insufficiency in the popliteal and superficial femoral veins. ^9,12,13

Anticoagulant therapy and its shortcomings

The standard treatment of DVT is anticoagulation therapy with supportive care (bed rest, leg elevation, and venous compression stockings). Traditionally, the patient with DVT is admitted to the hospital for intravenous unfractionated heparin while converting to long-term oral anticoagulation using warfarin. With the introduction of low-molecular weight heparin (LMWH) compounds (i.e., enoxaparin, 1 mg/kg, bid sq; Lovenox, Rhone-Poulenc, Collegeville, PA), outpatient anticoagulation therapy can be administered subcutaneously. This method offers substantial cost-savings since no hospitalization or laboratory monitoring of the partial thromboplastin time (PTT) is required. ¹⁴

A common misconception among physicians is the notion that systemic anticoagulation dissolves thrombus. By forming a complex with antithrombin III, heparin inhibits the formation of thrombin and thus suppresses thrombus formation and propagation. Heparin does not act on the formed thrombus. With anticoagulation therapy, recanalization of the occluded vessel depends solely on the effectiveness of the patient's own fibrinolytic system. Unfortunately, the body's natural fibrinolytic system cannot completely remove the large clot burden of extensive IFDVT. Subsequently, the thrombus organizes leading to permanent obstruction and occlusion of the vein with development of valvular incompetence. ¹⁵ The clinical consequence is the onset of PTS. ⁷

Krupski et al ⁵ found that only 6% of patients with acute extensive lower-extremity DVT showed complete lysis of the thrombus within 10 days when treated with heparin alone. Propagation of the thrombus occurs in 38% of these patients despite having therapeutic levels of heparin. Johnson et al ¹⁵ found 59% of patients to be asymptomatic at a mean follow-up of 3 years after an episode of deep vein thrombosis. Valve function and venous patency was shown by Doppler ultrasonography to have normalized in only 18% of the symptomatic limbs and 3% of the asymptomatic limbs. The frequency of reflux and obstruction in the asymptomatic limbs was similar to that in symptomatic limbs. However, when residual obstruction accompanied reflux, PTS was more likely to develop. In a 5-year follow-up study, 95% of symptomatic patients with IFDVT treated with anticoagulation alone had muscle pump function and severe compromise of valvular competency. ¹⁶ Furthermore, 50% developed venous claudication and job disability, and 86% developed venous stasis skin ulcers. The recurrence rate of deep vein thrombosis is 7% to 30% in patients successfully treated with anticoagulant therapy. ¹⁷ Although heparin is of benefit in reducing the incidence of pulmonary embolism (PE), it appears to be of little value in reducing the incidence of PTS.

Surgical thrombectomy and systemic thrombolytic therapy

In contrast to anticoagulant therapy, surgical thrombectomy (figure 3) and thrombolytic therapy directly remove the clot burden. Unfortunately, surgical thrombectomy is hindered by early rethrombosis rates (up to 72%) and plagued by recurrent DVT. ¹⁸ This, in part, is related to incomplete removal of the thrombus burden and venous endothelial damage incurred by the Fogarty balloon.

The primary goal for thrombolytic therapy includes eliminating the thrombus in order to restore venous blood return while preserving valvular function. ¹⁹ Sherry ²⁰ reviewed the results of a multi-institutional study comparing the acute benefits of systemic heparin therapy with systemic thrombolytic therapy using streptokinase (SK). He found that 81% of the patients in the heparin group had persistent venographic occlusion at 1 week compared with 33% in the SK group (33%); partial lysis was 13% in the heparin group compared with 20% in the SK group; and complete lysis was 6% in the heparin group compared with 47% in the lysis group. Overall, 67% of the patients treated with systemic thrombolysis had partial or complete restoration of patency, compared with only 19% in the heparin group. Two prospective studies comparing heparin and SK have assessed the long-term benefit following thrombolysis. Arneson et al ^21,22 found the incidence of PTS (at 6.5 years) was 67% in the heparin-treated patient group compared with 23% in the SK-treated patient group. Furthermore, the symptoms were severe (with ulceration) in 17% of the heparin-treated patient group and 0% of the SK-treated patient group. Elliot et al ²³ showed that 90% of the patients were symptomatic in the heparin-treated group with 24% having severe symptoms, whereas 45% of the patients in the SK-treated group were symptomatic but only 9% had severe symptoms. Comerota and Aldridge ²⁴ performed a meta-analysis of 13 major studies comparing systemic anticoagulant therapy with systemic thrombolytic therapy; 254 patients treated with heparin therapy showed complete clot lysis in 4% and partial clot lysis in 14%, whereas, 337 patients treated with systemic thrombolytic therapy showed complete clot lysis in 45% and partial clot lysis in 18%.

Despite these encouraging results, the threefold increased risk in major bleeding complication rates, ²⁵ recently reported at 5% (12 of 250) compared with none using heparin alone, ²⁶ has limited the widespread acceptance of systemic thrombolytic therapy for DVT. Also, systemic thrombolytic therapy met with only limited success in patients with extensive IFDVT because only the exposed surfaces of the clot burden interacted with the lytic drug. Acute thrombus is more responsive to lysis with systemic infusion of a lytic drug than is chronic thrombus. Theiss et al ²⁷ found acute occlusions <3 days old responded to lysis 94% of the time, while occlusions 1 to 2 weeks old responded 80% of the time. Occlusions 5 to 8 weeks old had only a 14% response rate to lysis.

Catheter-directed thrombolytic therapy

In 1994, Semba and Dake ²⁸ provided the initial insight on the potential role of catheter-directed thrombolysis (CDT) using urokinase (UK) in the treatment of IFDVT. They successfully treated 25 of 27 limbs in 21 consecutive patients with CDT. Complete lysis was achieved in 18 patients (72%), partial lysis was achieved in 5 patients (20%), and lysis was unsuccessful in 2 (8%) patients. There were no major complications or clinically detectable PE. The technical and clinical success rates were 85%. At 3 months, 12 limbs were studied with Doppler ultrasonography, and veins were patent in 92%. One patient with a chronic occlusion experienced a recurrent occlusion.

Comerota et al ²⁹ also advocated that the initial treatment of a patient with acute IFDVT should be CDT. This minimally invasive endovascular technique entails embedding a multi-sidehole infusion catheter directly into the thrombus burden for local, intrathrombotic delivery of the lytic drug. The benefits of CDT over systemic thrombolytic therapy are: (a) rapid clearance of the thrombus burden; (b) higher doses of the lytic drug introduced directly into the clot burden, thereby increasing the lytic efficiency; (c) reduction in overall dose and duration of lytic infusion; and (d) decrease in the risk of producing a systemic fibrinolytic state, thereby reducing the major bleeding complication rate.

These encouraging reports resulted in the establishment of the North American Venous Registry to determine the impact of CDT using UK in the treatment of symptomatic lower-extremity DVTs. ³⁰ Between January 1995 and December 1996, 473 patients with symptomatic lower-limb DVT were entered into the registry prospectively. CDT was used for 306 infusions, most commonly via an ipsilateral popliteal venous approach. From conventional venography, clot lysis was graded as follows: Grade I (<50% lysis), Grade II (>50% lysis) or Grade III (complete lysis). Based on follow-up duplex ultrasound examinations, 1-year cumulative primary patencies were calculated for different subgroups and compared using life-table methods. With CDT, significant lysis (>50%) was found in 83%; Grade III lysis in 31%; Grade II in 52%; and Grade I in 17%. In acute DVT limbs, Grade II lysis occurred in 34% and Grade III lysis in 60%, which was significantly greater compared with that achieved in the chronic DVT limbs. The lysis grade obtained after lysis and stenting was a major predictor of continued patency. For Grade III, Grade II, and Grade I lytic outcomes, the 1-year patencies were 79%, 58%, and 32%, respectively ( P <0.001). At 6 months, approximately 70% of limbs with significant lysis (>50%) remained patent; moreover, 90% of limbs with complete lysis remained patent. Reflux at follow-up at 6 months was found in <30% of those with complete lysis, 45% of those with >50% lysis, and >60% with <50% lysis.

Based on health-related quality of life (HRQOL) evaluation, Comerota et al ³¹ recently reported on the benefits of CDT in patients entered in the venous registry with IFDVT. After thrombolytic therapy, patients reported better overall physical functioning, less stigma, less health distress, and fewer post-thrombotic symptoms compared with similar patients treated with anticoagulation alone. Successful lysis was directly correlated with improved HRQOL, with patients who were classified as thrombolytic failures having similar outcomes to patients treated with heparin alone.

Thrombolytic agents

Thrombolytic therapy utilizes a group of medications (classified as plasminogen activators) that enzymatically cleaves circulating serum protein plasminogen into the active protease plasmin. Plasmin functions to disrupt the proteinacious fibrin cross-linked strands that provide the framework for platelet and red blood cell aggregation in a thrombus.

Urokinase (UK) (Abbokinase, Abbott Laboratories, Abbott Park, IL) acts directly on plasminogen and is derived from neonatal renal cell tissue culture. UK has a relatively lower fibrin affinity/specificity and a longer half-life (14 min) with the reputation of being consistent, predictable, efficacious, and safe. UK has been the lytic drug of choice over streptokinase and tissue plasminogen activator for CDT for IFDVT when fibrin specificity, immunogenicity, major bleeding complication rate, and cost are all considered. ³² A common criticism of CDT using UK for IFDVT has been cost, since it often costs hospitals several thousand dollars for the lytic drug alone and generates large charges to the third party payers. UK was the most widely used lytic drug until the U.S. Food and Drug Administration (FDA) banned the distribution in late 1998 due to the theoretical risk of transmitting viral disease. ^33,34

Streptokinase (Streptase, AstraZeneca Laboratories, Westboro, MA) is a purified derivative from Group C beta-hemolytic streptococci and indirectly activates plasminogen conversion. Anistreplase (Eminase, Roberts Pharmaceuticals, Eatontown, NJ) is the anisoylated stabilized intermediate complex of streptokinase and plasminogen. These complexes are inactivated by circulating antibodies and can be typically used only once in the same patient due to the risk of drug-related fever and antibody reaction (serum sickness) when administered repeatedly. Both are considered first-generation lytic drugs and are not regarded as the optimal replacement for UK due to their antigenicity and inferior efficacy. ³²

Alteplase (Activase, Genentech, Inc., South San Francisco, CA) is a recombinant engineered human tissue plasminogen activator (t-PA) analog, which has high fibrin affinity/specificity and a short circulating half-life (5 min). Tissue plasminogen activator is a naturally occurring serine protease, which is secreted by vascular endothelial cells and plays a major role in maintaining the normal homeostasis of the blood vessel. The gene sequence that expresses t-PA is isolated and removed from the human melanoma cell line and introduced into the ovarian cell of the Chinese hamster, where sufficient quantities of the protein are produced for commercial use. Only a few trials exist using rt-PA as a systemic lytic drug for the treatment of DVT; however, experience with CDT using rt-PA is emerging. ^35,19 While clinical studies have shown efficacy of rt-PA, there remains generalized concern about the risk of adverse bleeding using rt-PA compared with UK, especially in lieu of early trials in which extraordinarily high doses of rt-PA (>2 mg/hr with full heparinization) were utilized for prolonged overnight infusions. ^36-39 Because of these concerns, the Advisory Panel on Catheter-Directed Thrombolytic Therapy of the Society of Cardiovascular and Interventional Radiology recently published initial practice guidelines regarding the dosing of rt-PA and recommends doses far below the initial published experiences of the late 1980s. ³⁹

Reteplase (Retavase, Centocor/ Johnson & Johnson, Malvern, PA) is a new recombinant derivative of tissue plasminogen activator. It is a single-chain protein consisting of 355 of the 527 amino acid sequence in rt-PA. However, by genetically removing the finger, growth factor, and 1 kringle domain, reteplase (R-PA) has less fibrin affinity and increased half-life (15 min) compared with alteplase (rt-PA). The decreased fibrin affinity of R-PA has been perceived as allowing the lytic drug to seep through the clot more easily than rt-PA, but large-scale trials in acute myocardial infarction have shown rt-PA and R-PA to be equivalent in terms of safety, efficacy, and long-term outcomes. ^40,41 Early clinical experience using R-PA as an alternative to UK is also emerging, and it is likely that its performance will be safe and efficacious for CDT. ⁴²

Tenecteplase (TNKase, Genentech, Inc.), the newest recombinant lytic drug, represents a triple-mutated version of the parent molecule rt-PA. Compared to rt-PA, TNK-tPA possesses enhanced fibrin specificity, a longer half-life, and increased resistance to plasminogen activator inhibitor-1. This lytic drug may have potential impact on thrombolytic therapy in the near future.

Protocol for CDT for acute (extensive) IFDVT

IFDVT should be documented by conventional venography and/or duplex Doppler ultrasonography (figure 4), although magnetic resonance imaging and computed tomography are also useful modalities. An inferior vena cava filter should be reserved for those patients with recurrent PE despite anticoagulation or with "free-floating" thrombus in the iliac veins or inferior vena cava.

Baseline coagulation parameters (platelet count, prothrombin time, partial thromboplastin time, serum fibrinogen, hemoglobin, and hematocrit) are obtained, a peripheral arm intravenous line is started, and a Foley urinary bladder catheter is inserted. The ipsilateral popliteal vein is accessed antegrade with a 4F micropuncture set (Cook, Inc., Bloomington, IN) under ultrasound guidance, so the risk of valvular damage is minimized. If there is extensive calf vein and popliteal thrombus, then the posterior tibial or lesser saphenous vein can be used for access. ^43,44 A complete ascending venogram is performed (figure 5). A vascular sheath (5F or 6F, depending on the infusion system to be used) is placed. A hydrophilic catheter and hydrophilic guidewire are advanced under fluoroscopy into the inferior vena cava (IVC) and a venocavagram is performed. A multi-sidehole (i.e., Cragg-McNamara infusion catheter, Micro Therapeutics, Inc., Irvine, CA) or multi-slit (i.e., Unistep infusion catheter, Angiodynamics, Inc., Queensbury, NY) infusion catheter with an infusion length that spans the entire thombus burden is placed. Either 0.5 to 1.5 mg/hr of alteplase (rt-PA) or 0.5 to 1.0 mg/hr of reteplase (R-PA) is infused with the dose split between the vascular sheath and the infusion catheter. Heparin should not be mixed with these lytic drugs because of the possibility of precipitation. Subtherapeutic heparin (2500 U bolus, 500 U/hr maintenance) may be administered through the peripheral arm intravenous line. Serum fibrinogen level and partial thromboplastin time are obtained every 6 to 8 hours and are maintained >100 mg/dL and <60 sec, respectively. However, it is important to note that serum fibrinogen values may not be predictive of adverse bleeding. ³⁹

Several scenarios may be seen at the initial follow-up venography (Table 2), usually performed 6 to 12 hours after initiating thrombolysis. After complete or near-complete lysis of the deep vein thrombosis, a residual obstructive lesion is found in the common iliac vein in the majority of the cases, and synechiae may be found in the superficial femoral vein. The synechiae may be disrupted with an angioplasty balloon or mechanical device (figure 6). However, the iliac vein lesion rarely responds to angioplasty alone, and placement of a self-expanding endovascular stent is generally required (figure 7).

Ideally, a stent diameter oversized by 20% deployed flush with the iliocaval junction is an easily attainable goal. The stent is then expanded using the appropriately sized angioplasty balloon. Stenting below the inguinal ligament should typically be avoided, although Semba and Dake ^19,28 have not found any untoward sequelae as long as the stent does not extend below the lesser trochanter of the femur.

The overall role of adjunctive mechanical thrombectomy devices is not well defined. Most interventionalists use a maximum duration of therapy with rt-PA of 48 hours but hope to stop earlier since bleeding complications increase over time. ⁴⁵ The patients should be anticoagulated (INR between 2 and 3) for 6 months following successful lysis. Many authors advocate giving antiplatelet therapy (75 mg Plavix, Bristol-Myers Squibb/Sanofi Pharmaceuticals, New York, NY) for 6 weeks in patients in whom a stent was placed.

The patient should be followed clinically with serial duplex Doppler sonographic imaging performed on the morning after completion of thrombolytic therapy, and then at 6 and 12 months, and annually thereafter.

Conclusion

Although the factors leading to venous thrombosis have been known for over a century, Virchow's initial model of thrombosis has been refined extensively. Activated coagulation is now recognized to be of primary importance in venous thrombogenesis; the concept of venous injury has been expanded to include molecular changes in the endothelium; and stasis has been redefined as a largely permissive factor. Furthermore, it is now clear that venous thrombi undergo a dynamic evolution beginning soon after their formation. The natural history of acute DVT is a balance between recurrent thrombotic events and processes that restore the venous lumen, both of which have important implications for the development of complications.

Although pulmonary embolism is clearly the most life-threatening complication of acute DVT, the long-term socioeconomic consequences of PTS have perhaps been underemphasized in clinical trials. The development of post-thrombotic manifestations is related to both residual venous obstruction and valvular incompetence. Recognition of the factors that contribute to a poor outcome, including recurrent thrombotic events, the rate of recanalization, the global extent of venous reflux, and the anatomic distribution of reflux and obstruction, is important, as there may be therapeutic alternatives to alter the natural history of acute DVT. CDT for acute deep vein thrombosis could provide rapid thrombus clearance with improved lytic efficiency while preserving valvular function and decreasing bleeding complications. The treatment alternatives will continue to expand with the introduction of new therapeutic drugs and mechanical thrombectomy devices. *