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You are in: eMedicine Specialties > Radiology > VASCULAR/INTERVENTIONAL

Deep Venous Thrombosis, Lower Extremity

Article Last Updated: Apr 5, 2007

Background

Deep venous thrombosis (DVT) is the presence of coagulated blood, a thrombus, in one of the deep venous conduits that return blood to the heart. The clinical conundrum is that symptoms (pain and swelling) are often nonspecific or absent. However, if CT is untreated, the thrombus may become fragmented or dislodged and migrate to obstruct the arterial supply to the lung, causing a potentially life-threatening pulmonary embolus (PE).

DVT and PE are the manifestations of a single disease entity, namely, venous thromboembolism (VTE). In terms of incidence, lower-extremity DVT is the most common venous thrombosis, with a prevalence of 1 case per 1000 population. In addition, it is the underlying source of 90% of acute PEs, which cause 25,000 deaths per year in the United States (Havig, 1977; National Center for Health Statistics [NCHS], 2006). Other than the immediate threat of PE, the risk of long-term major disability from postthrombotic syndrome (PTS) is high.

Pathophysiology

In 1856, Virchow described the classic triad of predisposing factors for DVT, namely, venous stasis, injury of the vascular wall, and a hypercoagulable state.¹ Events or conditions that alter the equilibrium of one or more of these factors may produce DVT.

Thrombosis is the homeostatic mechanism whereby blood coagulates or clots, a process crucial to the establishment of hemostasis after a wound. Several pathways initiate thrombosis and usually consisting of cascading activation of enzymes that magnify the effect of an initial trigger event. A similar complex of events results in fibrinolysis, or the dissolution of thrombi. The balance of trigger factors and enzymes is complex. Microscopic thrombus formation and thrombolysis (dissolution) are continuous events, but with increased stasis, procoagulant factors, or endothelial injury, the coagulation-fibrinolysis balance may favor the pathologic formation of an obstructive thrombus. Clinically relevant DVT is the persistent formation of macroscopic thrombus in the deep proximal veins.

In the absence of rhythmic contraction of the leg muscles, as in walking or moving, blood flow in the veins slows and even stops in some areas, predisposing patients to thrombosis.²

Thrombus usually forms behind valve cusps or at venous branch points, the majority of which begin in the calf. Venodilation may disrupt the endothelial cell barrier and expose the subendothelium. Platelets adhere to the subendothelial surface by means of von Willebrand factor or fibrinogen in the vessel wall. Neutrophils and platelets are activated, releasing procoagulant and inflammatory mediators. Neutrophils also adhere to the basement membrane and migrate into the subendothelium. Complexes form of the surface of platelets and increase the rate of thrombin generation and fibrin formation. Stimulated leukocytes irreversibly bind to endothelial receptors and extravasate into the vein wall by means of mural chemotaxis. Because mature thrombus composed of platelets, leukocytes and fibrin develops, and an active thrombotic and inflammatory process occurs at the inner surface of the vein, and an active inflammatory response occurs in the wall of the vein.^{3, 4}

In the postoperative patient, up to one half of all isolated calf vein thrombi resolve spontaneously within a few hours, whereas approximately 15% extend to involve the femoral vein. A many as one third of untreated symptomatic calf vein DVTs extend to the proximal veins.⁵ At 1-month follow-up of untreated proximal DVT, 20% regress and 25% propagate (Nielsen 1994). Although calf vein thrombi are rare sources of clinically significant PE, the incidence of PE with untreated proximal thrombi is 29-50%.^{6, 5} Most PEs are first diagnosed at autopsy.^{7, 8}

Over a few months, most acute DVTs evolve to complete or partial recanalization, and collaterals develop (see Images 2-3).^{9, 10, 11, 12, 13, 14} Although blood flow may be restored, residual evidence of thrombus or stenosis is observed in one half of patients after 1 year. Furthermore, the damage to the underlying valves and those compromised by peripheral dilation and insufficiency usually persists and may progress. Venous stasis, venous reflux, and chronic edema are common in patients who have had a large DVT.¹⁵

The acute effect of an occluded outflow vein may be minimal if adequate collateral pathways exist. As an alternative, it may produce marked pain and swelling if flow is forced retrograde. In the presence of deep vein outflow obstruction, contraction of the calf muscle produces dilation of the feeding perforating veins, it renders the valves nonfunctional (because the leaflets no longer coapt), and it forces the blood retrograde through the perforator branches and into the superficial system. This high-pressure flow may cause dilation of the superficial (usually low-pressure) system and produce superficial venous incompetence. In clinical terms, the increased incidence of reflux in the ipsilateral greater saphenous vein increases 8.7-fold on follow-up of DVT.⁹ This chain of events, ie, obstruction to antegrade flow producing dilation, stasis, further valve dysfunction, with upstream increased pressure, dilation, and other processes, may produce hemodynamic findings of venous insufficiency.

Another mechanism that contributes to venous incompetence is the natural healing process of the thrombotic vein. The thrombotic mass is broken down over weeks to months by inflammatory reaction and fibrinolysis, and the valves and venous wall are altered by organization and ingrowth of smooth muscle cells and production of neointima. This process leaves damaged, incompetent, underlying valves, predisposing them to venous reflux. The mural inflammatory reaction breaks down collagen and elastin, leaving a noncompliant venous wall.^{9, 10, 11, 12, 13, 14, 4}

Persistent obstructive thrombus, coupled with valvular damage, ensures continuation of this cycle. Over time, the venous damage may become irreversible. Hemodynamic venous insufficiency is the underlying pathology of PTS. If numerous valves are affected, flow does not occur centrally unless the leg is elevated. Inadequate expulsion of venous blood results in stasis and a persistently elevated venous pressure or venous hypertension. As fibrin extravasates and inflammation occurs, the superficial tissues become edematous and hyperpigmented. With progression, fibrosis compromises tissue oxygenation, and ulceration may result. After venous insufficiency occurs, no treatment is ideal; elevation and use of compression stockings may compensate, or surgical thrombectomy or venous bypass may be attempted Saarinen, 2000).^{16, 17, 18, 19}

With anticoagulation alone, as many as 75% of patients with symptomatic DVT present with PTS at 5-10 years.^{20, 19} However, the incidence of venous ulceration is far less, at 5%. Of the half million patients with venous ulcers in the United States, 17-45% report having a history of DVT.²¹

Mortality/Morbidity

The sequelae and treatment complications tend to be more problematic in chronic disease than the acute disease.

Anatomy

DVT is often divided into proximal and distal thromboses. The proximal veins are the popliteal, femoral (also known as superficial femoral), deep femoral, common femoral, and iliac veins and the inferior vena cava (IVC). Calf-vein DVT involves at least 1 of the paired deep calf veins: anterior tibial, posterior tibial, peroneal, or deep muscular veins. Calf-vein DVT is rarely a cause of symptomatic PE (Buller, 2004). Proximal DVT is reported to produce relatively severe symptoms and consequences related both to the congestion of collateral veins and to the risk of PE (Meignan, 2000; Stein, 2000; Kearon, 2003).

Clinical Details

Numerous factors, often in combination, contribute to DVT. These may be categorized as acquired (eg, medication, illness) or congenital (eg, anatomic variant, enzyme deficiency, mutation). A useful categorization may be an acute provoking condition versus a chronic condition, as this distinction affects the length of anticoagulant therapy.

The most common risk factors are obesity, previous VTE, malignancy, surgery, and immobility. Each is found in 20-30% of patients (Caprini 2005). Hospitalized and nursing home patients often have several risk factors and account for one half of all DVTs (with an incidence of 1 case per 100 population) (Heit, 2002).

The frequent causes of DVT are due to augmentation of venous stasis due to immobilization or central venous obstruction. Immobility can be as transient as that occurring during a transcontinental airplane flight or that during an operation under general anesthesia. It can also be extended, as during hospitalization for pelvic, hip, or spinal surgery, or due to stroke or paraplegia. Individuals in these circumstances warrant surveillance, prophylaxis, and treatment if they develop DVT (Arfvidsson, 2000; Geroulakos, 2000; Kelsey, 2000; Kesteven, 2000; Kovacevich, 2000; Slipman, 2000).

Increased blood viscosity may decrease venous blood flow. This change may be due to an increase in the cellular component of the blood in polycythemia rubra vera or thrombocytosis or a decrease in the fluid component due to dehydration.

Increased central venous pressure, either mechanical or functional, may reduce the flow in the veins of the leg. Mass effect on the iliac veins or IVC from neoplasm, pregnancy, stenosis, or congenital anomaly increases outflow resistance.

Anatomic variants that result in diminution or absence of the IVC or iliac veins may contribute to venous stasis. In iliocaval thromboses, an underlying anatomic contributor is identified in 60-80% of patients (Chung, 2004). The best-known anomaly is compression of left common iliac vein at the anatomic crossing of the right common iliac artery. The vein normally passes under the right common iliac artery during its normal course (see Image 1). In some individuals, this anatomy results in compression of the left iliac vein and can lead to band or web formation, subsequent stasis, and left leg DVT. The reasons are poorly understood. Compression of the iliac vein is also called May-Thurner syndrome or Cockett syndrome.

IVC variants are uncommon. Anomalous development is most commonly detected and diagnosed on cross-sectional imaging or venography. The embryologic evolution of the IVC is from an enlargement or atrophy of paired supracardinal and subcardinal veins. Anomalous embryologic development may result in absence of the normal cava. These variations may increase the risk of symptoms because small-caliber vessels may be most subject to obstruction (Kraimps, 1993; Pless, 1993; Ruggeri, 2001). In patients younger than 50 years who have DVT, the incidence of a caval anomaly is as high as 5% (Garcia-Fuster, 2006).

A double or duplicated IVC results from lack of atrophy in part of the left supracardinal vein, resulting in a duplicate structure to the left of the aorta. The common form is a partial paired IVC that connects the left common iliac and left renal veins. When caval interruption, such as placement of a filter, is planned, these alternate pathways must be considered. As an alternative, the IVC may not develop. The most common alternate route for blood flow is through the azygous vein, which enlarges to compensate. If a venous stenosis is present at the communication of iliac veins and azygous vein, back pressure can result in insufficiency, stasis, or thrombosis (Hamoud, 2000).

In rare cases, neither the IVC nor the azygous vein develops, and the iliac veins drain through internal iliac collaterals to the hemorrhoidal veins and superior mesenteric vein to the portal system of the liver. Hepatic venous drainage to the atrium is patent. Because this pathway involves small hemorrhoidal vessels, thrombosis of these veins can cause severe acute swelling of the legs.

Thrombosis of the IVC is a rare occurrence and is an unusual result of leg DVT unless an IVC filter is present and stops a large embolus in the cava, resulting in obstruction and extension of thrombosis (Greenfield, 2000). Common causes of caval thrombosis include tumors involving the kidney or liver, tumors invading the IVC, compression of the IVC by extrinsic mass, and retroperitoneal fibrosis (Rhee, 1994; Vorwerk, 1996; Pittman, 1999; Tsuji, 2001).

Researchers have identified inherited hypercoagulable states as contributing risk factors in many cases of DVT, particularly recurrent DVT (Piemontino, 1999; Motykie, 2000). Genetic thrombophilia is identified in 30% of patients with idiopathic venous thrombosis (Santamaria, 2005). Altered procoagulant enzyme proteins include factor V, factor VIII, factor IX, factor XI, and prothrombin. Altered or diminished anticoagulants include protein C and protein S (Johnson, 2005).

Factor V Leiden is a mutation that results in a form of factor Va resists degradation by activated protein C, leading to a hypercoagulable state. Its importance lies in the 5% prevalence in the American population and its association with a 3- to 6-fold increased risk for VTE (Lensen, 2000). Antiphospholipid syndrome is considered a disorder of the immune system, where antiphospholipid antibodies (cardiolipin or lupus anticoagulant antibodies) are associated with a syndrome of hypercoagulability. Although not a normal blood component, the antiphospholipid antibody may be asymptomatic. It is present in 2% of the population, and it may be detected in association with infections or the administration of certain drugs, including antibiotics, cocaine, hydralazine, procainamide, and quinine.

Tests for these genetic defects are often not performed in patients with recurrent venous thrombosis because therapy remains symptomatic. In most patients with these genetic defects, lifetime anticoagulation therapy with warfarin (Coumadin) or low molecular weight heparin (LMWH) is recommended after recurrent DVT without an alternative identifiable etiology is documented. The risk of recurrent DVT is multiplied 1.4-2 times, with the most common genetic polymorphisms predisposing individuals to DVT. However, the low incidence of factor V Leiden and prothrombin G20210A may not warrant aggressive prophylaxis. Therefore, genetic testing might not be warranted until a second event occurs (Santamaria, 2005; Ho, 2006; Wu, 2006).

Other diseases and states can induce hypercoagulability in patients without other underlying risks for DVT. They can predispose patients to DVT, though their ability to cause DVT without intrinsic hypercoagulability is in question. The conditions include malignancy, dehydration, and use of medications (eg, estrogens) (Bloemenkamp, 1999; D'Souza, 1999; Hoibraaten, 1999; Lewis, 1999; Douketis, 2000; Grady, 2000; Kontopoulou, 2000; Lowe, 2000; Stewart, 2000; Vandenbrouke, 2000). Acute hypercoagulable states also occur, as in disseminated intravascular coagulopathy (DIC) resulting from infection or heparin-induced thrombocytopenia.

Injury may be obvious, such as those due to trauma, surgical intervention, or iatrogenic injury, but they may also be obscure, such as those due to remote DVT (perhaps asymptomatic) or minor (forgotten) trauma. Previous DVT is a major risk factor for further DVT (Vaitkus, 2005). The increased incidence of DVT in the setting of acute urinary tract or respiratory infection may be due to an inflammation-induced alteration in endothelial function (Smeeth, 2006).

The presence of risk factors plays a prominent role in the assessing the pretest probability of DVT (Wells, 1997). Furthermore, transient risk factors permit successful short-term anticoagulation, whereas idiopathic DVT or chronic or persistent risk factors warrant long-term therapy.

DVT and thromboembolism remain a common cause of morbidity and mortality in bedridden or hospitalized patients, as well as generally healthy individuals. The annual incidence of DVT in the United States is estimated to be 250,000, or 48 cases per 100,000 population (Anderson, 1991; Silverstein 1998; Russell, 2002; White, 2003). In the elderly, the incidence is increased 4-fold (Kniffin, 1994). The reported incidence of PE with or without DVT is 23-69 cases per 100,000 population, and 25,000 per year die from PE (Silverstein, 1998; Horlander, 2003). The in-hospital case-fatality rate for VTE is 12%, rising to 21% in the elderly (Anderson, 1991; Kniffin, 1994).

VTE remains an underdiagnosed disease, and most PEs are diagnosed at autopsy. Diagnosis depends on a high level of clinical suspicion and the presence of risk factors that prompt diagnostic study. Because the presentation is nonspecific and because the consequence of missing the diagnosis is serious, it must be excluded whenever it is a feasible differential diagnosis. Because the prevalence of the disease is 15-30% in the population at clinical risk, a widely applicable (inexpensive and simple) screening test is required.

Conclusive diagnosis historically required invasive and expensive venography, which is still considered the criterion standard. Since 1990, the diagnosis has been obtained noninvasively by means of (still expensive) sonographic exam (Lensing, 1989) (see Ultrasound). The recent validation of the simpler and cheaper D-dimer test as an initial screening test permits a rapid, widely applicable screening that may reduce the rate of missed diagnoses. Algorithms are based on pretest probabilities and D-dimer results. As many of 40% of patients with a low clinical suspicion and a negative D-dimer result require no further evaluation (Wells, 2003).

Traditional therapy entails anticoagulation with intravenous (IV) unfractionated heparin (UFH) and conversion to oral warfarin to prevent further clot formation. Treatment guidelines from the American College of Chest Physicians (ACCP) recommend LMWH or UFH for 5 days in conjunction with a vitamin K antagonist (eg, warfarin) until an international normalized ratio (INR) of greater than 2 is stable. At that time, heparin can be discontinued.

Acute DVT may be treated in an outpatient setting with LMWH. Anticoagulant therapy is recommended for 3-12 months depending on site of thrombosis and on the ongoing presence of risk factors (Buller, 2004). If DVT recurs, if a chronic hypercoagulability is identified, or if a PE is life threatening, lifetime anticoagulation therapy may be recommended. This treatment protocol has a cumulative risk of bleeding complications of less than 12% (Landefeld, 1989).

Anticoagulant therapy remains the mainstay of medical therapy for DVT because it is noninvasive, it treats most patients (¡Ý90%) with no immediate demonstrable physical sequelae of DVT, it has a low risk of complications, and its outcome data demonstrate an improvement in morbidity and mortality (Burke, 2000; Merli, 2000; Hirsh, 2001). Meta-analyses of randomized trials of UFH and LMWH showed that they were similar, with risk of recurrent DVT of 4%, a risk of PE of 2%, and a risk of major bleeding of 3% (Dolovich, 2000; Mismetti, 2005).

Anticoagulation does have problems. Although it inhibits propagation, it does not remove the thrombus, and a variable risk of clinically significant bleeding is observed. In 2-4% of patients, DVT progresses to symptomatic PE despite anticoagulation. In the setting of a PE, 8% of patients have recurrences despite anticoagulation, 30-45% of which are fatal (Carson, 1992; Decousus, 1998). Although anticoagulation markedly reducing the risk of PE and extension of the DVT, it does not reduce the incidence of PTS, which requires expedited removal of the existing thrombus without damaging the underlying venous valves.

Systemic IV thrombolysis once improved the rate of thrombosed vein recanalization; however, it is no longer recommended because of an elevated incidence of bleeding complications, slightly increased risk of death, and insignificant improvement in PTS (Goldhaber, 1984; Schulman, 1986; O'Meara, 1994). The lack of a significantly reduced incidence of PTS after systemic thrombolysis (40-60%) likely reflects the inadequacy of the relatively low threshold volume of thrombus removal that was considered successful.

Percutaneous transcatheter therapy of DVT is aimed at removing the thrombus and/or preventing PE. PE prevention is achieved by mean of caval interruption with an IVC filter. Pharmacologic thrombolysis entails the administration of enzymes to reduce the hypercoagulable component of the triad and to shift the balance to thrombus removal. Direct administration of a thrombolytic into the thrombus during percutaneous catheter-directed thrombolysis (CDT) is most effective approach. Significant lysis is achieved in 12% of patients with anticoagulation, in 30% receiving a systemic administration of a thrombolytic, and in 80% with CDT (Wells, 2001). Furthermore, the transvenous approach allows for treatment of an underlying venous stenosis by means angioplasty (balloon dilation) or stent placement. The cost of rapid, more complete lysis is reflected in the major risk of bleeding, which is increased to 8-11% with CDT.

As discussed, the immediate symptoms of DVT often resolve with anticoagulation alone, and the rationale for intervention is often reduction of the 75% long-term risk of PTS. Patients' negative assessments of the trade-off between an increased risk of major bleeding in exchange for a potentially decreased risk of PTS has reduced the use of systemic thrombolysis (O'Meara, 1994). The bleeding risk is similar to that of CDT, and the risk of PTS may further decrease risk. However, whether CDT is preferred to anticoagulation has not been examined. The addition of percutaneous mechanical thrombectomy to the interventional options may facilitate decision-making, because recanalization may be achieved faster than before and with a decreased dose of lytic; therefore, the bleeding risk may be decreased.

Of patients evaluated for DVT of the lower extremity, only a quarter of them have the disease (Huisman, 1986; Birdwell, 1998; Cogo, 1998). DVT is characterized by pain and swelling of the limb, which are not specific. Numerous patients with DVT are asymptomatic.

Other Problems to Be Considered

Achilles tendonitis
Arthritis
Cellulitis
Muscle strain or tear
Hematoma
Soft-tissue injury
Stress fracture
Pain
Swelling in a paralyzed limb
Arterial insufficiency
Peripheral occlusive disease
Thromboembolism
Superficial thrombophlebitis
Postphlebitic syndrome
Varicose veins
Dependent edema
Hepatic disease
Renal failure
Nephritic syndrome
Lymphedema

Findings

The CT finding of intraluminal thrombus is documented as a filling defect on a delayed contrast-enhanced scan.

Spiral multidetector-row CT venography (CTV) from the popliteal fossa to the pelvis offers good diagnostic accuracy and correlation with sonographic findings (Shah, 1999; Cham, 2000; Loud, 2000; Coche, 2001). The radiation dose, cost, and scanning time, as well as the recent explosion in the number of requests for CT scanning at most hospitals, have made it prohibitive to use CT to evaluate extremity DVT alone.

Studies of multidetector-row CTV showed that that venous-phase scanning after arterial-phase scanning is feasible and possibly cost effective (Shah, 1999; Fishman, 2000; Garg, 2000; Goodman, 2000; Loud, 2000; Loud, 2001). In practice, adding indirect CTV to the now relatively standard CT pulmonary arteriography for suspected PE lead to additional diagnoses of thrombotic disease in only a few patients. However, this is an incremental increase of 15-38% of VTE diagnoses (Coche, 2001; Loud, 2001; Cham, 2005). Among patients in emergency departments, the yield is relatively low, and management is unlikely to be changed because DVT is rarely identified in the absence of PE (Johnson, 2006). In the converse, in an oncology population, the addition of CTV to CT pulmonary angiography (CTPA) resulted in a 20% increase in detection of thrombotic disease. CTV showed DVT isolated to iliac or pelvic veins in 4.5% (Loud, 2001).

CTV is useful for evaluating for DVT versus other causes of leg swelling in patients with equivocal or negative Doppler sonographic results and for obtaining additional information in patients with known DVT before endovascular treatment. CTV reliably depicts the extent of the thrombi and underlying anatomic abnormalities (Chung, 2004), and it may help in defining the chronicity of the lesion (Roh, 2002). Increased attenuation of the thrombus (>60 HU) and an increased diameter of the vessel (>150% the diameter of the contralateral normal vein) are correlated with acuity, and they are predictors of successful CDT (Roh, 2002).

CT requires the use of iodinated contrast agent, and some patients are allergic to this. In addition, renal insufficiency is a contraindication because of the large dose of contrast agent needed.

The radiation dose for bilateral lower-extremity CTV is 3-8 mSv (less than that of abdominal CT) (Begemann, 2004).

Claustrophobia, extreme patient girth, certain metallic implants, or inability to remain immobile can produce nondiagnostic studies, though these factors generally less important with CT than with MRI.

Degree of Confidence

In preliminary studies, CTV findings that were used to exclude iliofemoral thrombi had a sensitivity equivalent to that of ultrasonography. Studies in which indirect CTV was compared with venography showed 100% sensitivity and 96-97% specificity (Baldt, 1996; Garg, 2000; Begemann, 2004). Contrast enhancement of vessels to greater than 60 HU is desired. In the studies, CTV required 80% less contrast agent than venography.

In an ICU setting, combined CTPA and CTV yielded a 25% incidence of nondiagnostic DVT studies because of inadequate contrast opacification or because of artifacts due to metallic hardware (Kelly, 2006). CT scans do not help in differentiating chronic from acute DVT.

False Positives/Negatives

False-positive findings include tumor thrombus and/or invasion (pelvis and cava), compression by extrinsic mass (usually detected), inflow defects from unopacified blood (usually seen at the iliac confluence to the IVC, brachiocephalic confluence, or inflow at the renal vein), and poorly timed CT scanning with indeterminate findings.

False-negative findings include small thrombi ( <1 cm) when CT is performed at large gaps or intervals (ie, 5 mm of every 20 mm scanned) to reduce the radiation dose. This technique reduces sensitivity as well.

Findings

Findings on magnetic resonance venography (MRV) depend on the sequence used. If nonenhanced (flow, bright blood) or contrast-enhanced (gadolinium-enhanced) images are obtained, they demonstrate a bright rim around a dark intraluminal filling defect.

Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have recently been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). For more information, see the eMedicine topic Nephrogenic Fibrosing Dermopathy. The disease has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or MRA scans. As of late December 2006, the FDA had received reports of 90 such cases. Worldwide, over 200 cases have been reported, according to the FDA. NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble

movingor straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness. For more information, see the FDA Public Health Advisory or Medscape.

Although MRI is highly sensitive and relatively specific, the cost of the examination, the technical complexity, and the lack of general availability limit the use of MRV as a screening tool (Michiels, 1999; Nawaz, 1999). Specific indications for MRV are primarily as an alternative to CT (particularly in patients with an allergy to contrast material, in those with renal failure, and those in whom an evaluation of the iliocaval veins are required for questionable sonographic findings) or for a preinterventional evaluation of the extent of a thrombus.

MRI cannot be used in patients with ferromagnetic implants or in those who depend on metallic devices that cannot be placed in the imaging unit.

Claustrophobia, extreme patient girth, certain metallic implants, or an inability to remain immobile can produce nondiagnostic studies.

False Positives/Negatives

MRV is effective and accurate, with sensitivity and specificity for iliac and femoral DVT approaching 100% compared with venography and a 92% sensitivity in detecting isolated calf-vein thrombus (Carpenter, 1993; Laissy, 1996; Fraser, 2002 and 2003). In addition, pelvic veins that are nearly impossible to visualize on sonography and difficult to view by other means are consistently imaged well with MRV (Spritzer, 2001).

In general, MRI findings are subject to many artifacts that simulate vascular disease. Adjacent metallic objects, inadequate contrast enhancement, turbulent or sluggish venous blood flow, inflow from another vein into a vessel filled with contrast agent, and reflux (reversal) of venous blood flow may affect the signal received, depending on the machine and protocol chosen. False-positive findings may result from slow or turbulent flow, an adjacent pulsatile structure, or hypointense inflow defects.

Findings

Compression ultrasonography entails imaging the calf to the groin in the axial plane with a 5- to 10-MHz transducer. Compression is intermittently applied to induce complete coaptation of the walls of the patent vein. If the vein does not compress, it is occluded. Attempts to visualize iliac and pelvic veins are made.

Regarding clinical outcomes, the negative predictive value at 3 months after compression ultrasonography yields normal results is 97-98%, and greater than 99% with serial sonography (Michiels, 2005). A more comprehensive study than this includes color Doppler imaging. In addition to compressibility, the evaluation includes an assessment for incomplete color filling, flow augmentation (vein patency peripheral to the transducer), and respiratory variation (patency central to the transducer). A negative single, complete duplex color sonogram of the entire lower extremity obtained to assess suspected DVT has a negative predictive value of 99.5% (Subramaniam, 2005).

Ultrasonography is the current first-line imaging examination for DVT because of its relative ease of use, absence of irradiation or contrast material, and high sensitivity and specificity in institutions with experienced sonographers (Zierler, 2004).

Patient size limits the use of sonography because large patients are difficult to scan with accuracy. Good-quality sonograms depend on the experience of the technologist performing the examination. The iliac and pelvic veins are not imaged consistently with sonography.

Degree of Confidence

In patients with clinically suspected disease, compression ultrasonography is 95-99% sensitive for proximal venous thrombus compared with contrast venography (Lensing, 1989; Heijboer, 1993). For isolated calf-vein thrombus, the sensitivity decreases below 50% (Lensing, 1989). The high accuracy of ultrasonography versus venography for the diagnosis of proximal DVT has been demonstrated in asymptomatic patients (Kassai, 2004). In clinical evaluations in which anticoagulation was withheld on the basis of negative serial compression sonograms, the incidence of thromboembolic complications was 0.07-1.5% at 6-month follow-up (Cogo, 1998; Heijboer, 1993).

Because of the limitation of diagnostic study in the proximal veins, serial scans are required to ensure that calf-vein DVT is not progressing. A few become positive over 7-day follow-up (Prandoni, 2002). However, because of the cost and patient-compliance issues with follow-up testing, investigators evaluated the usefulness of single, complete lower-extremity compression sonography. The technical-failure rate was 1.5%; these cases required additional study. The outcome evaluated was thromboembolic complication at 3 months, which occurred in 0.2-0.8% of studies (Elias, 2003; Schellong, 2003; Stevens, 2004; Subramaniam, 2005).

Visualization of iliac or proximal thrombus is often difficult. In the presence of thigh swelling or an abnormal common femoral vein, the central iliocaval veins warrant evaluation. Interposed bowel gas may compromise duplex ultrasonography, and CTV or MRV have been useful adjuncts (Chung, 2004). Visualization at the adductor canal is similarly difficult, and a focal thrombus may not be identified; however, this has not compromised the clinical relevance of a negative study. If indeterminate findings occur, extremity venography remains the diagnostic criterion standard.

False Positives/Negatives

False-positive findings may result from a technical error in scanning or from interpreting chronic DVT as acute DVT. However, the use of compression ultrasonography with a consideration of venous diameter is highly sensitive in identifying recurrence (Prandoni, 1993).

False-negative findings may result from inadequate scanning due to the size of the patient's leg; edema; or inexperience of the technologist, who must carefully scan each segment. In addition, iliac or pelvic DVT may be missed because of overlying bowel gas, which is the major limitation of duplex scanning in patients with DVT. In most patients, an iliac or pelvic DVT cannot be completely excluded.

Femoral vein duplication is a congenital variant that poses a pitfall in diagnosis. If a patent femoral vein is identified, an occluded duplicated vein may be missed if the anomaly is not recognized (Quinlan, 2003).

Findings

Radiolabeled peptides that bind to various components of a thrombus have been investigated. Apcitide, a technetium Tc 99m–labeled platelet glycoprotein IIb/IIIa receptor antagonist, is approved for diagnostic studies of DVT. Other peptides in development include fragments of fibronectin with a distinct fibrin-binding domain and analogs of laminin and thrombospondin, which bind to platelet receptors (Knight, 2003).

The cost of the tests and the inability to visualize the anatomy of the area of involvement (which many clinicians prefer) has lead to the underuse of scintigraphy. The radiation dose is 6.8 mSv, equivalent to lower-extremity CTV.

Degree of Confidence

Foci of increased activity indicate an acute thrombus in that location. This scanning technique is used in institutions where practitioners have experience and confidence in the technique.

A multicenter evaluation of apcitide study compared with the standard of venography in 243 symptomatic or high-risk patients revealed 75.5% sensitivity. However, after patients with a history of DVT or PE were excluded, the sensitivity and specificity were 90.6% and 83.9%, respectively, with respect to venography (Taillefer, 2000).

The suggestion of improved sensitivity for acute thrombus was supported in a subsequent study that showed a sensitivity of 92% and a specificity of 85% for differentiating between acute and chronic DVT (Bates, 2003).

Findings

The classic finding of acute thrombus is an intraluminal filling defect in the contrast opacified vein. Lack of opacification of a vein or venous segment indicates occlusion. Occlusion is consistent with an acute or chronic thrombus. Findings of intraluminal septation, webs, or stenoses are consistent with a healed or remote DVT. In chronic DVT, recanalization can result in a linear filling defect in the vein, sometimes termed the tram-track pattern. The vein appears as if it were 2 small, paired veins.

Until the 1980s, venography was the criterion standard examination for DVT (Rolfe, 1977; Hull, 1981). This procedure is now uncommonly performed because of the patient's discomfort from needle puncture, the potential for infiltration of contrast agent at the injection site or allergy to the agent, and the cost in time and infrastructure necessary to perform the examination. The development of highly sensitive, noninvasive ultrasonography and impedance plethysmography protocols for DVT has relegated the use of venography to specific indications.

Venography remains the examination of choice when absolute determination of the presence and extent of thrombus is needed. This study is often required in obese patients, in patients with severe leg edema, or in patients in whom results of noninvasive tests are equivocal or negative in the setting of high clinical suspicion.

An IV line is placed in a dorsolateral foot vein, and several tourniquets (placed at the ankle and below and above the knee), or reverse Trendelenburg positioning are used to shunt contrast material into the deep venous system. The pelvis is imaged by compressing the femoral vein while the leg is elevated or while the table is moved from the reverse Trendelenburg to the Trendelenburg (head-down) position. Compression is then released while the external iliac vein is rapidly imaged.

Images are obtained from the foot to the pelvis, and detailed images of the entire deep venous system, including the paired tibial veins, iliacs, and IVC can be obtained. The internal iliac vein in the pelvis is not imaged, and a clot in this area cannot be excluded. The mean radiation dose for a single extremity is 6 mSv.

Degree of Confidence

Venography is considered the criterion standard. If technically adequate, the study offers a high degree of confidence. Technical limitations include poor IV access in the foot, poor contrast opacification of the deep veins (contrast material shunted to superficial veins, injection too slow, poor tourniquet compression), motion artifact, and excessive muscular contractions or spasms.

False Positives/Negatives

False-positive findings may result from poor filling of the deep venous system with contrast material or inadvertent injection of air bubbles. A tumor thrombus may appear as a filling defect that is not be recognized as tumor without a cross-sectional study. Extrinsic compression or compartment syndrome may cause occlusion of the vein, which may be falsely positive for thrombus.

Image-guided therapy

Percutaneous transcatheter treatment of patients with DVT consists of thrombus removal with CDT, mechanical thrombectomy, angioplasty, and/or stenting of venous obstructions. Patients may or may not be given PE prophylaxis by means of filter placement in the IVC. The lack of data from multicenter prospective randomized trial data regarding the safety and efficacy of these therapies complicated the decision to intervene and the choice of intervention. Problems in the existing literature are variability in patient selection and the lack of standard definitions of short- or long-term efficacy and complications. A consensus regarding indications exists, though it is based on mid-level evidence from nonrandomized controlled trials (Vedantham, 2006).

Goals of endovascular therapy include reducing the severity and duration of lower-extremity symptoms, preventing PE, diminishing the risk of recurrent venous thrombosis, and preventing PTS. When an invasive procedure is considered, the benefit must be weighed against the added risk compared with standard anticoagulant therapy. If it is to be performed, the intervention must improve the results of current medical therapy. The risk of PE is 2%, the risk of recurrent DVT is 4%, and the risk of major bleeding is 5%. Most difficult to discern, the risk of PTS is 45% at 2 years.

Asymptomatic DVT is not considered an indication for endovascular intervention at this time. The incidence of PTS at 5 years after asymptomatic calf or proximal DVT is low at 5% (Ginsberg, 2000). The absence of symptoms may reflect the lack of the obstructive effect that is proposed to initiate the insufficiency. Although the incidence of PTS may not warrant treatment, some reports suggest that treatment of asymptomatic DVT may be necessary to prevent most cases of PE that are diagnosed at autopsy (Linblad, 1991). Asymptomatic proximal DVT had a mortality risk of 13.7% versus 2% in patients without DVT (Vaitkus, 2005).

Catheter-directed thrombolysis

Indications for intervention include the relatively rare phlegmasia or symptomatic IVC thrombosis that responds poorly to anticoagulation alone, or symptomatic iliofemoral or femoropopliteal DVT in patients with a low risk of bleeding. In the last groups, the goal is to reduce the high risk of PTS or to achieve symptomatic relief in conjunction with angioplasty or stent placement.

Phlegmasia cerulea dolens is an indication for emergency CDT in patients with moderate or low bleeding risks (Vedantham, 2006). This recommendation is based on reports of limb salvage without the high rates of limb amputation and death when alternative therapies are used (Patel, 1988; Robinson, 1993; Eklof, 2000). In patients with a high risk for hemorrhagic complications, surgical thrombectomy remains an effective option, though it often results in incomplete thrombus removal, recurrent DVT, and an increased incidence of systemic complications.

Acute or subacute IVC thrombosis that causes at least moderate pelvic congestion, limb symptoms, or compromised visceral venous drainage warrants CDT (Janssen, 2005; Vedantham, 2006). Involvement of the suprarenal cava, renal veins, and/or hepatic veins may precipitate acute renal or hepatic failure. Thrombus that involves the upper IVC may make it impossible to place an IVC filter for PE prophylaxis.

Subacute and chronic iliofemoral DVT is accompanied by moderate-to-severe pelvic or limb symptoms with a low bleeding risk. Because of recanalization of the iliac vein is unlikely, iliofemoral DVT often produces valvular reflux. This combination of outflow obstruction and reflux is associated with the most symptomatic forms of PTS (Markel, 1992; Meissner, 1993). In this situation, patients have venous damage, and the alternative is venous bypass. In these instances, CDT is seldom expected to completely clear the vein, but it is often used to remove any acute component of thrombus and to uncover chronic stenoses or underlying anatomic abnormality as an adjunct to angioplasty or stent placement. Compared with systemic thrombolysis, CDT improves the preservation of valve competence (44% vs 13%).

The indication for CDT in the relatively common event of acute iliofemoral or femoropopliteal DVT is somewhat controversial. CDT may be superior to anticoagulation with regard to decreasing the incidence of recurrent DVT and PTS (Vedantham, 2006). However, the evidence is not conclusive (Watson, 2004). CDT improves thrombus clearance compared with systemic thrombolysis (Wells, 2001). Few DVT resolve after heparin therapy, but systemic thrombolysis improves the rate to 30%, and CDT removes e80% of thrombi (Grossman, 1999). Reports of CDT for the management of acute DVT between 1994 and 2004 described anatomic and clinical success rates of 76-100%. The incidence of major hemorrhagic complications was 0-24% (Vendantham, 2006).

A prospective registry of 287 patients treated with a mean 53-hour urokinase (uPA) infusion showed anatomic success in 83%. About 34% of patients received adjunctive stent placement for underlying lesions. Complications of major bleeding and rethrombosis were observed in 11% and 25% of patients, respectively, at 30-day follow-up (Mewissen, 1999).

A randomized trial in which surgical thrombectomy with anticoagulation was compared with anticoagulation alone demonstrated the early clearance of thrombus to reduce PTS. At 10-year follow-up of the surgical versus anticoagulation cohorts, the rate of lower-extremity swelling was 18% and 71%, respectively, whereas the incidence of ulceration was 8% and 18%, respectively (Plate, 1997). Any clinical advantage for rapid clearance with CDT (similar to surgical thrombectomy) relies on a demonstration that outcomes reflect a similar reduction in the incidence of PTS, and furthermore, on a determination of whether that reduction justifies the increased incidence of major bleeding (11% vs 3% with anticoagulation) (Goldhaver, 1990; Schweizer, 2000; Breddin, 2001; Janssen, 2005).

Three studies demonstrated improved long-term venous function after CDT versus anticoagulation alone. Two showed a decrease in reflux or symptoms from 41-70% to 11-22% (AbuRahma, 2001; Elsharawy, 2002). In a retrospective case-control study, quality-of-life scores (including stigmata, health distress, physical function, and symptoms) were improved at 22-month follow-up after CDT with anticoagulation versus anticoagulation alone (Comerota, 2000).

The transcatheter approach facilitates the diagnosis of predisposing anatomic lesions or anomalies. In patients with iliofemoral DVT, CDT was successful for recanalization in 92-100% of patients, and it revealed an underlying lesion in 50-66%. Treatment of these stenoses with angioplasty and stent placement reestablished unobstructed flow and achieved a prompt clinical response (AbuRahma, 2001; Chung, 2004; Vedantham, 2004; Sillesen, 2005; Lee, 2006). Studies with 2-year follow-up documented a 5-11% incidence of valvular incompetence (Elsharawy, 2002; Sillesen, 2005).

Access to the popliteal vein is usually obtained with ultrasonographic guidance, though the common femoral, tibial, or internal jugular veins are also used. When thrombolysis is planned, use of ultrasonography and a micropuncture 21-gauge needle are recommended to minimize bleeding risk. Diagnostic venography is used to identify the extent of DVT, and fluoroscopic guidance is the most accurate and straightforward means of placing infusion catheters or devices. A sheath is placed, and a multiple–side-hole catheter or wire is used to deliver the drug and maximize exposure of the lytic to the surface area of the thrombus.

Plasminogen activators include streptokinase, u-PA, tissue-type plasminogen activator (tPA), tenecteplase (TNK), and recombinant tPA (r-tPA). The US Food and Drug Administration (FDA) has approved only streptokinase for systemic thrombolytic therapy of DVT. However, this agent is not currently recommended because of high rates of allergic reaction and bleeding complications and because of the availability of lower-risk agents. uPA was used extensively in the 1980s and 1990s, but it was temporarily taken off the market, and tPA and r-tPA subsequently became the agents of choice. In a retrospective analysis of CDT for DVT, no significant differences were observed between uPA, tPA, and r-tPA with regard to success rate (>97%) or major complications (3-8%) (Grunwald, 2004).

Recommended continuous dosages for CDT of unilateral leg DVT are tPA 0.5-1.0 mg/h, r-tPA 0.25-0.75 U/h, or TNK 0.25-0.5 mg/h. Other administration options include an initial lacing dose, which entails an initial bolus given throughout the target thrombus, and a front-loaded dose, which is a high concentration given for the first few hours. No advantage has been demonstrated for either approach.

Most practitioners use concomitant heparinization. Full heparinization was commonly used in conjunction with uPA, whereas the current trend has been to administer subtherapeutic heparin with tPA. LMWH has not been studied in this setting. In the coronary literature, enoxaparin improved outcomes (death and myocardial infarction reduced from 12 to 9.9%), but it significantly increased bleeding complications (from 1.4% to 2.1%) (Antman, 2006).

During thrombolysis, patients remain on bed rest with frequent monitoring of vital signs, and puncture sites. Pericatheter oozing, enlarging hematoma, or evidence of GI-GU bleeding warrant immediate attention. Additional punctures, particularly arterial or intramuscular punctures, should be avoided. A separate IV access facilitates blood sampling to be performed at 6-hour intervals to monitor the patient's hematocrit, platelet count, activated partial thromboplastin time (aPTT, if concomitant heparinization is used), and possibly fibrinogen values. Monitoring fibrinogen levels is controversial, though levels 4.4 µmol/L ( <150 mg/dL) might indicate a clinically significant systemic effect.

Contraindications are the same as those for thrombolysis in general. Absolute contraindications include active internal bleeding or DIC, a cerebrovascular event, trauma, or neurosurgery within 3 months. Relative contraindications include major surgery within 10 days, obstetric delivery, major trauma, organ biopsy, intracranial or spinal cord tumor, uncontrolled hypertension, major GI hemorrhage (within 3 mo), serious allergic reaction to a thrombolytic agent, known right-to-left cardiac or pulmonary shunt or left-heart thrombus, and an infected venous thrombus.

Percutaneous mechanical thrombectomy devices

Percutaneous mechanical thrombectomy devices are a popular adjunct to CDT. Although these devices may not completely remove thrombus, they are effective for debulking and for minimizing the dose and time required for infusing a thrombolytic. In patients at high risk for hemorrhagic complications of thrombolysis, mechanical thrombectomy may obviate infusion. Such devices are most commonly used to initially restore antegrade flow (in cases of limb threat) or to manage a resistant thrombus identified during thrombolysis (Sharafuddin, 2003).

The most basic mechanical method for thrombectomy is thromboaspiration, or the aspiration of thrombus through a sheath. Balloon maceration of the thrombus may be done to facilitate the procedure. The most technically advanced devices, approved primarily for interventions requiring hemodialysis access, may be divided by mechanism into categories of recirculation and fragmentation. Recirculation devices engage thrombus and destroy it by continuously mixing it by creating a hydrodynamic vortex.

Fragmentation devices leave macroscopic particulate effluent and include devices that chop, brush, or cut the clot. With these devices, concomitant lytic infusion and possible IVC filter placement are necessary to ensure PE prophylaxis. With recirculation devices, only the Trellis-8 Peripheral Infusion System (Bacchus Vascular, Inc., Santa Clara, CA) is FDA approved for the treatment of DVT. The AngioJet system (Possis Medical Inc., Minneapolis, MN), has the broadest FDA-approved uses, including uses in the coronary and peripheral arteries and in obtaining arteriovenous access; this is one of the most effective devices (Kasirajan, 2001; Bush, 2004).

Reports have described use of the Arrow-Trerotola, AngioJet (Possis Medical), and Helix percutaneous thrombectomy devices for iliofemoral DVT, combined therapy (often with adjunctive thrombolysis, angioplasty and stenting, and placement of an IVC filter with the Arrow-Trerotola). These devices had 74-100% initial technical and 24-hour clinical success rates. Complete thrombus removal was variable (23-100%). The remainder improved with lytic infusion, with a mean infusion time of 6 hours. Only 1 study had a 6% incidence of major bleeding complications. The primary patency rate at 1 year was 85%, and clinical success was obtained in 92%. At 9- to 12-month follow-up, 2 studies demonstrated an 8% rate of venous insufficiency, whereas 2 others showed repeat DVT in 15-23% (Kasirajan, 2001; Vedantham, 2004; Lee, 2006).

Although the literature lacks conclusive evidence, some data support the argument that DVT treated with anticoagulation results in a high risk of PTS 5-10 years later. Active removal of the thrombus with surgery or catheter-directed lysis clears the thrombus relatively quickly and improves preservation of valvular function while reducing the incidence and severity of PTS. However, systemic or catheter-directed pharmacologic lysis entails a high risk of bleeding complications. Initial data suggest that combination therapy that includes percutaneous mechanical thrombectomy to reduce the dose and duration of lysis may achieve a level of thrombus clearance that reduces the incidence of PTS without elevating the bleeding risk.

IVC filters

In most patients with DVT, prophylaxis against the potentially fatal passage of thrombus from the lower extremity or pelvic vein to the pulmonary circulation is adequately accomplished with anticoagulation. An IVC filter is a mechanical barrier to the flow of emboli larger than 4 mm. Indications for filter placement include DVT with a contraindication to anticoagulation, major bleeding due to anticoagulation therapy, or failed anticoagulation (manifest by progressive DVT or new PE during adequate anticoagulation).

In the past, IVC filters were placed in 4.4% of patients. Recent use was documented in 14% of patients with DVT (Jaff, 2005); this rate was perhaps due to broadened indications with the introduction of removable filters. Temporary or removable filters, all of which may also be left as permanent, permit transient mechanical PE prophylaxis. This option may be useful in the setting of polytrauma, head injury, hemorrhagic stroke, known VTE, or major surgery when PE prophylaxis must be maintained during a short-term contraindication to anticoagulation.

In a randomized trial, the addition of an IVC filter to anticoagulation for DVT increased the risk of recurrent DVT (11.6% to 20.8%), and it did not improve the 2-year survival rate (Decousus, 1998). However, the filter group had significantly fewer PEs (1.1% vs 4.8%). Of note was the risk of major bleeding at 3 months (10.5%). This result agrees with other reports (Levine, 2004) and highlights the usual trade-off of prophylaxis with a filter versus anticoagulation and the respective complication risks of new DVT (peripheral to the filter) versus major hemorrhage. In the elderly patient with an increased risk of bleeding, and particularly if the patient is at risk for trauma, the risk and benefits may favor use of a filter (Beyth, 1998; Karni, 2001).

CDT does not add to the risk of PE to warrant routine filter placement (Mewissen, 1999). However, for patients with contraindications to pharmacologic lysis in whom a PMT device is to be used, a filter may be a useful adjunct.

Valve replacement

Percutaneously placed bioprosthetic venous valves are under development and may provide a minimally invasive therapy to the long-term complication of PTS due to valve destruction (Pavcnik, 2003). If successful, this approach may provide a percutaneous therapeutic alternative for patients with primarily palliative options to manage their venous reflux symptoms. An effective therapy should diminish one of the primary indications for aggressive thrombolytic therapy for acute DVT.