Acute Lower Extremity Deep Vein Thrombosis

David L. Dawson

Holly M. Gray

The first reports of the use of Doppler ultrasound for the evaluation of lower extremity venous disease appeared in the late 1960s.¹,² In 1972, Gene Strandness and his colleague David Sumner published their observations on the use of Doppler ultrasound for the diagnosis of venous thrombosis.³ A 1982 case report by Steven Talbot, a vascular technologist, is generally regarded as the first publication to describe the use of B-mode imaging for the diagnosis of deep vein thrombosis (DVT).⁴,⁵ Within a few years, ultrasound pioneers recognized the potential for venous duplex scanning.

An area that has been relatively unexplored is the detection of acute venous thrombosis. The veins of the lower extremity from the level of the iliac to the popliteal vessels can be imaged and their blood flow detected. Thus there is little doubt in my mind that duplex scanning can be used for both diagnostic and follow-up purposes for this important aspect of peripheral vascular disease.⁶

—D. Eugene Strandness, Jr. (1985)

The expense, invasive nature, discomfort, and lack of repeatability of ascending venography, coupled with its potential for initiating thrombosis, tarnished the luster of the venography “gold standard.”⁷,⁸ Duplex scanning rapidly became the primary imaging modality for the screening, diagnosis, and follow-up of DVT of the lower extremities (Table 19.1).⁹,¹⁰ Testing for lower extremity DVT is now the most commonly performed study in many vascular laboratories, with applications in numerous clinical settings (Table 19.2).¹¹ The capability for duplex ultrasound scanning with color flow Doppler is a requisite for any vascular laboratory to be accredited in peripheral venous testing by the Intersocietal Accreditation Commission—Vascular Testing.¹² Clearly, Dr. Strandness’ early vision has been realized.

EPIDEMIOLOGY OF VENOUS THROMBOEMBOLISM

DVT and pulmonary embolism (PE), jointly termed “venous thromboembolism” (VTE), represent a major clinical problem. Prevalence estimates suggest that there are over 900,000 VTE cases annually in the United States, with as many as 300,000 PE deaths each year.¹³ After heart disease and stroke, VTE is the third most common vascular disease. To put the magnitude of the problem in perspective, it has been pointed out that deaths from PE are five times more common than deaths from breast cancer, motor vehicle accidents, and AIDS combined.¹⁴ Data used by the American College of Chest Physicians (ACCP) for VTE risk estimation have suggested that 31% of hospitalized patients are at risk for VTE, which represents approximately 12 million patients per year.¹⁵

In addition to the acute risks associated with DVT, many patients subsequently develop symptoms of postthrombotic syndrome (PTS), with pain and limb swelling that can be debilitating (see Chapter 21). These symptoms can develop months or years after the acute episode of thrombosis.¹⁶,¹⁷ PTS can substantially impact quality of life. The overall incidence of PTS is estimated to be as high as 30%, although the incidence of symptoms may be higher for some subgroups of DVT patients, in particular those with iliofemoral venous thrombosis.¹⁸

The significance of VTE as a public health problem prompted the US Surgeon General to issue a “Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism” in 2008.¹⁹ This initiative urged greater understanding of the risk factors and triggering events for developing DVT and PE, better recognition of the symptoms, and implementation of steps to prevent and treat these serious conditions. VTE patient
safety measures were developed as a result of the National Consensus Standards for the Prevention and Care of Deep Vein Thrombosis project between the Joint Commission and the National Quality Forum (NQF). Six VTE measures were endorsed by the NQF in May 2008, and these aligned with priorities of the Centers for Medicare and Medicaid Services.²⁰ Joint Commission Hospital National Patient Safety Goals emphasize the need for appropriate prophylactic measures.²¹

TABLE 19.1 IMAGING OPTIONS FOR PATIENTS WITH SUSPECTED LOWER EXTREMITY DEEP VEIN THROMBOSIS

▪ IMAGING PROCEDURE	▪ RATING (Scale: 1 = least appropriate, 9 = most appropriate^a)	▪ COMMENTS	▪ RELATIVE RADIATION EXPOSURE LEVEL
US lower extremity with Doppler	9		None
MRV lower extremity and pelvis without and with contrast	7	This is the primary modality for pelvic or thigh DVT if US is nondiagnostic.	None
MRV lower extremity and pelvis without contrast	7	This procedure can be performed when contrast is contraindicated.	None
CTV lower extremity and pelvis with contrast	7	This procedure can be performed when MRV is not available or contraindicated.	High
X-ray venography, pelvis	6	This procedure is reserved for inconclusive noninvasive studies or when thrombolysis is planned.	Medium
X-ray venography, lower extremity	4	This procedure is reserved for inconclusive noninvasive studies or when thrombolysis is planned.	Medium
^aRating scale: 1, 2, 3 usually not appropriate; 4, 5, 6 may be appropriate; 7, 8, 9 usually appropriate.
Adapted from American College of Radiology ACR Appropriateness Criteria®, 2013.⁹
US, ultrasound; MRV, magnetic resonance venography; CTV, computed tomographic venography; DVT, deep vein thrombosis.

RISK FACTORS

A number of VTE risk factors have been identified, and new factors are currently being investigated. Individuals with an inherited blood clotting disorder or who experience a triggering event such as hospitalization, surgery, or long periods of immobility are more likely to develop DVT or PE. The risk for DVT and PE increases with age, especially after age 50. Women who are pregnant or take hormones (for birth control or menopausal therapy) are at increased risk. Predisposing conditions are summarized in Table 19.3.⁴¹,⁴²,⁴³,⁴⁴,⁴⁵,⁴⁶,⁴⁷,⁴⁸,⁴⁹,⁵⁰,⁵¹,⁵²,⁵³,⁵⁴,⁵⁵,⁵⁶,⁵⁷,⁵⁸,⁵⁹ Screening for a hypercoagulable state should be considered for atypical presentations of venous thrombosis,⁶⁰ including thrombosis in unusual locations (i.e., mesenteric veins or portal vein), idiopathic venous thrombosis, recurrent venous thrombosis, and superficial venous thrombosis (SVT) in a nonvaricose great saphenous vein.

CLINICAL DIAGNOSIS OF DVT

Anticoagulation for proximal DVT prevents thromboembolic complications in most patients, and it effectively prevents propagation of distal limb thrombi,⁶¹ but anticoagulation is inconvenient and costly and can be associated with serious bleeding complications, so indiscriminant use of anticoagulant therapy is to be avoided. Thus, it is necessary to accurately make the diagnosis of DVT. The clinical diagnosis of DVT is notoriously inaccurate, lacking both sensitivity and specificity.⁶² The optimal strategies for clinically assessing DVT risk (pretest probability) consider a combination of demographic and clinical factors. Several risk-scoring algorithms have been developed, including that from Wells et al (Table 19.4).⁶³ DVT risk estimates based on data from ambulatory and hospitalized populations may differ. Some have suggested that DVT prevalence may be higher in primary care settings than might be expected using the Wells calculations.⁶⁴

D-Dimer

The D-dimer antigen is a marker of fibrin degradation from the action of thrombin, factor XIIIa, and plasmin on thrombus. Fibrin degradation products are created, exposing the D-dimer antigen. D-dimer antigen can exist on fibrin degradation products derived either from soluble fibrin or from fibrin clot that has been degraded by plasmin. D-dimers are unique fibrin degradation products, as they are produced only from the lysis of cross-linked fibrin (factor XIII cross-links the E-element to two D-elements).

The D-dimer concentration will be elevated in the presence of DVT, though an elevated D-dimer is nonspecific. In other words, a positive D-dimer result can indicate thrombosis, but it has other potential causes. This means a normal D-dimer measurement can be helpful for the exclusion of acute VTE, but a positive result does not confirm a DVT diagnosis, as D-dimer is a marker of activation of the coagulation system in other settings.⁶⁵ The D-dimer level can be high due to liver disease, inflammation, malignancy, trauma, pregnancy, and recent surgery, as well as advanced age. False negatives with D-dimer

testing can be encountered if a blood sample is obtained early in the process of thrombus formation, with limited thrombosis (e.g., limited to calf veins), or if testing is delayed for several days. Additionally, use of anticoagulant therapy can interfere with the test. Thus, the principal effectiveness of D-dimer testing is to exclude the diagnosis VTE when its probability is low, based on clinical criteria.⁶⁶

TABLE 19.2 AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION (ACCF) APPROPRIATE USE CRITERIA FOR LOWER EXTREMITY VENOUS DUPLEX ULTRASOUND

	▪ APPROPRIATE USE SCORE	▪ LIMB SWELLING	▪ LIMB PAIN (WITHOUT SWELLING)	▪ SHORTNESS OF BREATH	▪ FEVER	▪ KNOWN LOWER EXTREMITY VENOUS THROMBOSIS	▪ SCREENING EXAMINATION FOR LOWER EXTREMITY DVT	▪ POSTENDOVENOUS (GREAT OR SMALL) SAPHENOUS ABLATION	▪ OTHER SYMPTOMS OR SIGNS OF VASCULAR DISEASE
Appropriate	9	Unilateral, acute
	8	Bilateral, acute	Tender, palpable cord in the lower extremity	Suspected pulmonary embolus		New lower extremity pain or swelling, not on anticoagulation (i.e., contraindication to anticoagulation)		Lower extremity swelling or pain
	7	Chronic persistent	Nonarticular pain in the lower extremity (e.g., calf or thigh)	Diagnosed pulmonary embolus		Surveillance of calf vein thrombosis for proximal propagation in patient with contraindication to anticoagulation (within 2 wk of diagnosis) New lower extremity pain or swelling while on anticoagulation Surveillance after diagnosis of lower extremity superficial phlebitis—not on anticoagulation, phlebitis location ≤5 cm from deep vein junction		Routine postprocedural follow-up, no lower extremity pain or swelling—within 10 d postprocedure	Physiologic testing positive for venous obstruction Patent foramen ovale with suspected paradoxical embolism for patient without lower extremity pain or swelling obstruction
May Be Appropriate	6	Bilateral, chronic, persistent; no alternative diagnosis identified (e.g., no congestive heart failure or anasarca from hypoalbuminemia)
	5				Fever of unknown origin (no indwelling lower extremity venous catheter) Fever with indwelling lower extremity venous catheter	Shortness of breath in a patient with known lower extremity DVT before anticipated discontinuation of anticoagulation treatment Surveillance after diagnosis of lower extremity superficial phlebitis—not on anticoagulation, phlebitis location ≥5 cm from deep vein junction
	4		Knee pain
Rarely Appropriate	3						After orthopedic surgery, prolonged ICU stay (e.g., >4 d) In those with high risk: acquired, inherited, or hypercoagulable state
	2						Positive D-dimer test in a hospital in patient
*Appropriate Care: Median Scores 7 to 9*
An appropriate option for management of this patient population due to benefits generally outweighing risks; effective option for individual care plans, although not always necessary.
*May Be Appropriate Care: Median Scores 4 to 6*
At times an appropriate option for management of this patient population due to variable evidence or agreement regarding the benefits/risks ratio, potential benefit based on practice experience in the absence of evidence, and/or variability in the population; effectiveness for individual care must be determined.
*Rarely Appropriate Care: Median Scores 1 to 3*
Rarely an appropriate option due to the lack of a clear benefit/risk advantage; rarely an effective option for individual care plans; exceptions should have appropriate documentation.
Adapted from: American College of Cardiology Foundation Appropriate Use Criteria Task Force; American College of Radiology; American Institute of Ultrasound in Medicine. ACCF/ACR/AIUM/ASE/IAC/SCAI/SCVS/SIR/SVM/SVS/SVU 2013 appropriate use criteria for peripheral vascular ultrasound and physiological testing. Part II: Testing for venous disease and evaluation of hemodialysis access. Vasc Med 2013;18(4): 215-231. doi: 10.1177/1358863X13497637. PMID: 23897935.

Use of Combined Prediction Rules for DVT Diagnosis

Bayes’ theorem is the statistical principle which states that the likelihood of a test yielding a true positive is highest if the test is applied to a population with a high prevalence of the condition that is the subject of the test. The diagnostic accuracy of testing for DVT improves when clinical probability is estimated before diagnostic tests are performd.⁶⁷ Due to the poor specificity of D-dimer testing for DVT, this laboratory test should be used as one element of an integrated diagnostic strategy that includes clinical probability assessment and imaging.⁶⁸

In a systematic review of 14 studies involving more than 8,000 outpatients, the value of clinical prediction rules for the diagnosis of DVT, either with or without D-dimer, was evaluated.⁶⁹ The studies included all had sufficient information to allow the calculation of the prevalence of DVT for at least one of the three clinical probability estimates (low, moderate, or high) and had patient follow-up for a minimum of 3 months. The prevalence of DVT in the low, moderate, and high clinical probability groups was 5.0%, 17%, and 53%, respectively. The overall prevalence of DVT was 19%. Pooling the studies, the sensitivity and specificity of D-dimer testing in the low-probability group were 88% and 72%; in the moderate-probability group, 90% and 58%; and in the high-probability group, 92% and 45%. The likelihood ratio for a normal result on a highly sensitive D-dimer assay among patients with (1) low clinical suspicion was 0.10, (2) moderate clinical suspicion was 0.05, and (3) high clinical suspicion was 0.07. Thus, it was very uncommon to have a normal D-dimer result in settings where DVT was likely. Patients with low clinical probability on the predictive rules have a prevalence of DVT of less than 5%.

Another review by Fancher et al analyzed 12 studies with more than 5000 outpatients tested with a rapid D-dimer assay after categorization into low, intermediate, or high clinical probability of DVT on the basis of clinical criteria. Using a less sensitive D-dimer assay, the 3-month incidence of VTE was 0.5% among patients with a low clinical probability of DVT and a normal D-dimer concentration. When a highly sensitive D-dimer assay was used, the 3-month incidence of VTE was 0.4% among outpatients with low or moderate clinical probability of DVT and a normal D-dimer concentration.⁷⁰

To summarize, in low-probability patients with negative D-dimer results, a diagnosis of DVT can be excluded without additional diagnostic testing (e.g., venous duplex scan), but in patients for whom there is a high clinical suspicion for DVT, D-dimer results should not affect clinical decisions.

VASCULAR LABORATORY TESTS FOR DVT

Plethysmography

Plethysmographic techniques are indirect tests that evaluate venous hemodynamics by assessing the changes in limb volume that occur as the venous capacitance vessels fill or empty. These techniques include impedance plethysmography (IPG), air plethysmography (AP),⁷¹ mercury strain gauge plethysmography (SGP),⁷²,⁷³ photoplethysmography (PPG),⁷⁴,⁷⁵,⁷⁶ and foot volumetry. The limb increases in volume when a thigh cuff is inflated to a pressure below arterial but above the venous pressure. Normally, limb volume rapidly returns toward baseline with release of the thigh cuff. In most cases, half of the venous emptying occurs in the first 2 seconds after cuff release.

IPG was an early vascular laboratory standard for diagnosis of DVT associated with hemodynamically significant venous outflow obstruction.⁷⁷,⁷⁸,⁷⁹,⁸⁰ The impedance plethysmograph measured changes in electrical impedance in an extremity after inflation and release of a proximal venous tourniquet to diagnose the presence of compromised venous outflow.⁸¹,⁸²,⁸³,⁸⁴ A normal IPG test was helpful to rule out the presence of the highest-risk DVT condition, a large proximal DVT.⁸¹

Plethysmographic techniques do not provide anatomically specific information; they only suggest the diagnosis of DVT. Delayed venous outflow after cuff release indicates a more central obstruction, but the finding is not specific for the location or cause of the outflow obstruction. Plethysmography cannot reliably detect distal (calf vein) or nonocclusive thrombi. Other physiologic or physical abnormalities can produce false-positive tests—including obesity, pregnancy, congestive heart failure, external venous compression, and chronic DVT—but these conditions may also be risk factors for acute DVT. Lack of patient cooperation, arterial occlusive disease, and low-ambient temperatures may also contribute to inadequate venous plethysmography results. Based on these limitations, venous plethysmography is no longer appropriate for the evaluation of suspected acute DVT, although it may have an ancillary role for physiologic evaluations in the vascular laboratory.

Doppler Flow Detection

The use of continuous-wave or pulsed Doppler ultrasound for flow detection was another early technique to assess for venous thrombosis.⁸⁵,⁸⁶,⁸⁷,⁸⁸,⁸⁹,⁹⁰,⁹¹,⁹² The absence of Doppler-detectable flow in an insonated segment was used as a criterion for the diagnosis of DVT, but the early Doppler ultrasound systems lacked the imaging capability needed to allow the technologist to be certain about which vein was being evaluated, and they did not provide information about anatomic abnormalities.

The early techniques of Doppler flow detection were insensitive to calf vein thrombi and to limited or nonocclusive thrombus. Performance and interpretation of these examinations required highly experienced personnel, as Doppler findings alone were subjective. False-positive examinations resulted from chronic disease interpreted as acute thrombosis or from the interpretation of low-amplitude signals as indicative of thrombosis, though this might have been a nonpathologic finding in calf veins, in obese patients, or with excessive Doppler probe pressure impairing venous flow.⁹³,⁹⁴ A negative Doppler flow study in a patient with low suspicion for acute DVT was considered sufficient to rule out the diagnosis, but venography was needed when the noninvasive study was equivocal or when the clinical circumstances strongly suggested the diagnosis.⁹⁵,⁹⁶,⁹⁷

Ultrasound Imaging Techniques

First described by Talbot in 1982,⁴ B-mode ultrasound imaging for diagnosis of lower extremity venous thrombosis has proved to be practical and widely adopted. DVT is diagnosed by direct visualization of thrombus in the veins. Unlike normal veins that easily collapse with extrinsic compression, thrombosed segments appear dilated and do not collapse with the application of manual (transducer) pressure over the imaged segment.

TABLE 19.3 RISK FACTORS ASSOCIATED WITH VENOUS THROMBOEMBOLISM (VTE)

▪ ACQUIRED²²

▪ GENETIC²³,²⁴,²⁵,²⁶,²⁷,²⁸,²⁹,³⁰,³¹,³²,³³,³⁴,³⁵,³⁶

▪ HEMATOLOGIC DISEASES²⁴,³⁷,³⁸,³⁹,⁴⁰

Age

Malignancy

Surgery (especially orthopedic)

Trauma

Presence of central venous catheter

Immobilization

Oral contraceptive use

Hormone replacement therapy

Tamoxifen, thalidomide, lenalidomide

Pregnancy and the puerperium

Obesity

Neurologic and cardiac diseases

Antiphospholipid antibody syndrome

Inflammatory bowel disease

Nephrotic syndrome

Congestive heart failure

Activated protein C (APC) resistance/factor V Leiden mutation

Deficiencies of antithrombin, proteins C and S

Prothrombin 20210A gene variants

Antithrombin deficiency/reduced heparin cofactor II activity

Hyperhomocysteinemia

Dysfibrinogenemia

Dysplasminogenemia

Elevated levels of clotting factors XI, IX, VII, VIII, X, and II

Elevation in plasminogen activator inhibitor 1

Heparin-induced thrombocytopenia (HIT)

Polycythemia rubra vera

Essential thrombocytosis

Myelodysplasia

Early validation studies comparing venous ultrasonography to the reference standard of contrast venography identified shortcomings in the use of B-mode imaging as a stand-alone modality, as imaging of deeper structures was limited and some normal venous segments might not collapse with moderate probe pressure (e.g., femoral vein at the level of the adductor hiatus). Venous compressibility can also be limited by obesity, edema, or tenderness. It was soon recognized that duplex scanning, the combination of B-mode imaging and Doppler-derived information about the presence and nature of venous flow in the interrogated segments, improved the accuracy of the examination.⁹⁸

Duplex scanning was rapidly adopted for diagnosis of DVT due to its clear advantages over the more cumbersome indirect plethysmographic methods. A review by White et al⁹⁹ found the sensitivity of duplex ultrasound for detecting proximal limb thrombi in four well-designed studies (1980-1988) was 92% to 95%, with reported specificity of 97% to 100%. Similar findings were noted in nine other studies that had minor methodologic flaws. It was also recognized that ultrasound imaging could identify a nonthrombotic cause of leg symptoms in 5% to 15% of cases.

TABLE 19.4 WELLS SCORE FOR ESTIMATING PROBABILITY OF DEEP VEIN THROMBOSIS

1 POINT EACH FOR: Active malignancy Paralysis, paresis, recent plaster immobilization of lower limb Recently bedridden for more than 3 d or major surgery in past 4 wk Localized tenderness along distribution of deep venous system Entire limb swollen Calf swelling more than 3 cm compared to asymptomatic leg Pitting edema Collateral superficial veins
2 POINTS FOR: Alternative diagnosis as likely or more likely than that of DVT
PROBABILITY:
High	≥3 points
Intermediate	1-2 points
Low	≤0 points

Advances in imaging technologies have further improved the accuracy and ease of venous studies for DVT. The addition of color flow Doppler imaging facilitates vessel identification in large limbs and helps with calf vein evaluation. All examination protocols, however, utilize compression as a basic element of the study.

In a clinical practice guideline from the American Thoracic Society, the sensitivity and specificity of various ultrasound techniques for DVT diagnosis were reviewed.¹⁰⁰ In those papers reporting results from appropriately designed prospective studies with venographic correlation, the sensitivity of real-time B-mode (compression) ultrasound for suspected proximal DVT in symptomatic patients was 89% to 100%, with reported specificity ranging from 86% to 100%. Studies of venous duplex scanning reported sensitivities of 88% to 97% and specificities of 80% to 100%. Reports of the accuracy of color flow Doppler ultrasound indicated a sensitivity of 95% to 96% and specificity of 99% to 100%.

Because of its accuracy, low cost, and noninvasive nature, venous duplex scanning is now the diagnostic method of choice for DVT.¹⁰¹ However, a potentially unwanted effect of the test
being so safe, inexpensive, and widely available is its overuse. Providers may tend to request the examination unnecessarily for irrelevant clinical signs and in the absence of any evident DVT risk factors.¹⁰²,¹⁰³

Point of Care Ultrasound Imaging for DVT

The availability of point of care ultrasound (POCUS) systems in emergency rooms, intensive care units, and other clinical settings can facilitate testing for DVT, but with potential for diagnostic errors.¹⁰⁴ With appropriate training, however, it appears that nonvascular specialist physicians can diagnose femoropopliteal DVT with accuracies approaching those of vascular laboratory professionals.¹⁰⁵ The two-point compression ultrasound examination of the common femoral and popliteal veins as a screening test for acute proximal lower extremity DVT is discussed in Chapter 27. It is anticipated that venous POCUS applications will become increasingly important in clinical practice.

ADVANCED IMAGING MODALITIES

Although venous duplex ultrasonography has become the standard for detection of acute DVT, adjuvant modalities have roles in selected cases.¹⁰⁶

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Sep 23, 2016 | Posted by drzezo in CARDIOLOGY | Comments Off

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