DIAGNOSIS OF DEEP VEIN THROMBOSIS

M.M.W. Koopman, M.D., Internist E.J.R. van Beek, M.D., Resident J.W. ten Cate, M.D., Professor of Hemostasis and Thrombosis

Centre for Hemostasis, Thrombosis, Atherosclerosis and Inflammation Research, Academic Medical Centre, University of Amsterdam, the Netherlands.

Correspondence to: M.M.W. Koopman, Centre for Hemostasis, Thrombosis, Atherosclerosis and Inflammation Research, F4-133, Academic Medical Centre, University of Amsterdam, the Netherlands, Telefax 31-20-6968833.

Introduction

For several decades the diagnosis deep vein thrombosis (DVT) has been made on clinical grounds alone, because of the unawareness of the inaccuracy of the clinical diagnosis. With the introduction of contrast venography, it became apparent that the clinical diagnosis was insensitive and aspecific. Many studies have now shown that only 20-30% of the patients with the classical signs and symptoms of DVT indeed have venous thrombosis on venography.1,2,3,4 The reason for this inaccuracy of the clinical diagnosis is, that none of the signs and symptoms are unique for DVT, and many other disorders can mimic venous thrombosis. These disorders include: muscle strain, direct twisting injury to the leg, swelling in a paralyzed leg, venous stasis, postthrombotic syndrome, lymphangitis, muscle tear, ruptured Baker's cyst, cellulitis, and orthopedic lesions of the knee and ankle joint. In a consecutive series of 160 patients with signs and symptoms of DVT it was possible to make an alternative diagnosis in the majority of patients after ruling out venous thrombosis by venography.5 The clinical diagnosis is also insensitive because thrombi may occasionally be nonobstructive with minimal symptoms, such as seen in postoperative DVT. Thus, objective testing is mandatory. Moreover, treatment of all patients with clinically suspected DVT will result in unnecessary exposure of patients without the disease to anticoagulants, which is associated with the potential hazard of treatment-induced bleeding.6,7,8 Venography has been the reference method for the diagnosis of deep vein thrombosis (Figure 1).1,9,10 However, this procedure is invasive and may be associated with discomfort and side-effects, such as pain, allergic reactions, nausea and vomiting.11 Furthermore, venography has a limited feasibility, especially in severely ill patients. These disadvantages have led to the development of several non-invasive tests over the past two decades. A new diagnostic method requires extensive evaluation, before it can safely be introduced into medical practice. The test should be standardized and should be compared to venography in consecutive patients to determine the diagnostic accuracy. Only a few of the available non-invasive tests have been

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evaluated adequately and will be discussed into more detail. The accuracy of the test is depending on the nature of the patient group under consideration. Therefore it is important to distinguish three different patient categories: patients with a suspected first episode of DVT, patients with recurrent thrombosis and asymptomatic patients at high risk for DVT. Thrombi in these patient groups differ in their origin, localisation and extension and therefore influence the test outcome. Most of the thrombi in patients with a first episode of DVT have extended proximally.2,12 These patients are at high risk for pulmonary embolism. In a study of 101 patients with venography proven DVT, 51% already had scintigraphic proof of (silent) pulmonary embolism.13 Conversely, isolated calf vein thrombi appear at lower risk of embolisation, however, about 25% will extend proximally into the popliteal vein and may subsequently give rise to pulmonary emboli.14,15 Therefore, the diagnostic approach has to be sensitive and specific to detect proximal DVT as well as for calf vein thrombosis extending into the popliteal vein. After a first episode of deep vein thrombosis, approximately 10-20% of the patients will return with recurrent signs and symptoms.16,17 Only about 30-40% of these patients do have recurrent DVT. Difficulties in the diagnosis of recurrent DVT exist for all available tests. Venography has its limitations because it cannot readily be repeated and the interpretation is often difficult because of anatomical changes of the venous system, vessel damage and resultant irregularities of the vessel wall by previous thrombi. Impedance plethysmography (IPG) is a reliable method in the diagnosis of recurrent DVT as long as a normal test result was obtained following a previous thrombotic event.16 For compression ultrasonography similar rules apply as for IPG. However, a follow-up study with this technique revealed that in only 50% of the patients the ultrasound investigations normalized within one year following a first event of DVT.18 The clinical utility of a newly developed compression ultrasound method to measure residual thrombus and its application for the diagnosis of recurrent DVT seems promising and is currently under investigation.19 Patients who have undergone major surgery or were immobilised are at high risk for

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developing asymptomatic thrombosis. Thrombi in these patients are often small and nonocclusive.20 However, these small thrombi may extend proximally and give rise to pulmonary embolism. Therefore, the diagnostic approach in these patients must be able to detect these small thrombi. Furthermore, the test must be feasible in a large group of often immobilized and sometimes critically ill patients. At the moment, only venography has been extensively evaluated and proven sufficiently accurate in this patient category. This chapter will focus on the diagnosis of deep venous thrombosis with the use of various diagnostic techniques in acute and recurrent symptomatic patients as well as in asymptomatic high risk patients. The emphasis will be on those tests that have undergone adequate evaluation. However, some brief remarks with regards to other, less well investigated methods will be included.

Contrast venography

Lower extremity contrast venography is generally regarded as the reference method ("gold standard") for the diagnosis of DVT, and enables the visualization of the entire deep venous system of the lower extremity and the large pelvic veins up to the vena cava.1,9,21 Contrast venography employs radio-opaque (iodinated) contrast medium, which is usually injected into a dorsal foot vein.9 Multiple injections may be required, and views of the entire deep system in at least two projections are required to establish a definite diagnosis. For this purpose, both separate films of the calf, knee, thigh and pelvic region9 or long-leg films may be used.21 Venographic criteria for acute deep vein thrombosis have been defined previous-ly.9,21 The most reliable criterion is the presence of an intraluminal filling defect which remains constant in shape and location in at least two different projections (Figure 1). Other, less reliable

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criteria are non-filling of a segment with abrupt termination and reappearance of contrast media below and above the segment and non-filling of the deep venous system in the trajectory of the popliteal and femoral vein, respectively. As with any diagnostic technique, contrast venography may give rise to inadequate investigations or observer disagreement. Inadequate venograms may occur in as many as 21% of all examinations5,14-16,21-23, however, this may be even more frequent in the hands of less experienced radiologists. Observer disagreement on the absence or presence of thrombi occurs in circa 10% of adequate venograms.21,24 A randomized study in 249 symptomatic patients with a first episode of clinically suspected DVT compared the use of separate films (Rabinov-Paulin technique) versus long-leg films (Figure 2).21 The inadequacy rate was 20% and 2% for the separate films and the long-leg films groups, respectively. At the same time, the observer disagreement fell from 21% in the group with separate exposures to 4% in the long-leg film group.21 This latter technique may therefore be recommended. The importance of contrast venography for the clinical management of symptomatic patients was revealed by a study in 106 consecutive patients with clinical signs of DVT in whom anticoagulants were withheld following a normal venogram.5 Only two patients (1.3%) returned within five days and were shown to have developed DVT. No patients developed pulmonary embolism or died at folow up for three months, demonstrating the safety of this approach. In patients with recurrent signs and symptoms of DVT venography may be of diagnostic value. Especially if a previous venogram is available to compare new intraluminal filling defects. In view of the limited diagnostic accuracy of non-invasive tests in patients with asymptomatic thrombi (i.e. high risk (post surgery) patients), venography is the diagnostic test of choice. The disadvantages of venography are related to the fact that it is invasive, and requires the use of contrast media. The main adverse effects are discomfort and contrast media related complications11,25. The latter are more frequently encountered in the conventional hyperosmolar agents, and are much less common in the more recently developed low-osmolar contrast media.11,26-29 In a study of 463 DVT patients who underwent venography with low osmolar

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contrast media the following side effects are

recorded. Two patients (0.4%) developed severe adverse reactions (bronchospasm) and 103 patients (22.2%) suffered from minor side effects such as, local pain 12.1%, nausea 4.5%, dizziness 1.5%, skin reactions 1.1%, vomiting 0.4%, edema 1.9% and superficial thrombopflebitis 0.6%11. The frequency of post-venography DVT, as shown by

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I-fibrinogen leg scanning in

patients with initial normal venograms, may be as high as 9%.5,11,26 However, this relatively high frequency was only seen with leg scanning and could not be confirmed by repeated contrast venography. Finally, contrast venography cannot be performed in up to 10% of patients due to the inability to acquire venous access, the presence of an obvious local infection of the leg, a history of allergic reactions to contrast media or due to renal insufficiency, respectively.11,14,15,23 Although pregnancy is a relative contraindication for performing any radiological investigation, limited contrast venography with abdominal shielding reduces the radiation to the fetus to acceptable doses.30,31

Impedance Plethysmography

Impedance plethysmography (IPG), a non-invasive method, is based on the principle that blood volume changes of the leg lead to changes in electrical resistance (impedance). During the investigation, the patient is in the supine position with the lower limb elevated 25-30o and the knee flexed 10-20o. A pneumatic cuff around the thigh is inflated to a pressure of 50 cm water, thereby occluding the venous outflow of the leg. Circumferential calf electrodes detect the changes in impedance and are connected to a recorder. After a predetermined period, the cuff is

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deflated and both the total rise and fall during cuff inflation and deflation during the first 3 seconds are plotted on a two-way IPG graph. The graph includes a discriminant line separating normal and abnormal test results.23,32,33 The IPG test can be falsely normal if thrombi are non-occlusive or if proximal DVT is associated with well developed collaterals. Furthermore, the IPG approach cannot distinguish between thrombotic and nonthrombotic obstruction of venous flow. Several other disorders such as venous compression by an extravascular mass or raised central venous pressure can produce a falsely abnormal test result. Accuracy studies using contrast venography as the reference method, however, have shown an overall mean sensitivity and specificity of 92% and 95%, respectively, for patients with a first episode of proximal DVT.23,34-37 The diagnostic accuracy for calf vein thrombosis is much lower with a sensitivity of about 20%. The specificity is about 95%, this means that an abnormal test result can be used to make therapeutic decisions, but a normal test result does not rule out calf vein thrombosis and/or nonocclusive proximal thrombosis. From follow-up studies it is known that most of the calf vein thrombi resolve spontaneously and that about 20% of these thrombi may extend proximally. To detect these extending thrombi it is neccesary to repeat the non-invasive tests. over a period of one week. Therefore management studies have been designed using repeated (serial) IPG testing to detect these thrombi. Several studies have evaluated the use of serial IPG in patients with a first episode of signs and symptoms suggesting DVT and showed a high positive predictive value of 83% 95%.14-16,38 A summary of these studies is given in Table 1. The safety of withholding anticoagulant therapy in patients with repeated normal IPG findings was investigated in all these studies. Over the years, however, duration and number of IPG assesments at follow-up has steadily declined without compromising the safety. Initially IPG was performed at days 1, 2, 5, 7, 10 and 14.15 With this regimen, 6 of 311 patients (1.9%) with normal repeated IPG results returned with documented DVT within one year, while no fatalities occured.15 A subsequent study omitted the 14 day IPG test, and only one out of 289 patients (0.3%) with normal IPG findings returned with pulmonary embolism during a six-month follow-up period.14 The next two

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studies performed IPG at days 1, 2 and 7 only.16,38 In a community hospital study, one of 131 patients (0.8%) with repeated normal IPG returned with DVT16, while in a similar study in symptomatic outpatients 9 of 369 patients (2.5%) with normal serial IPG results returned with objectively documented venous thromboembolism.38 Despite these satisfactory results two recent studies reported a much lower reliability of IPG.39,40 In one study a recently developed computerized version of IPG was used.39 In 311 patients with a normal IPG test result, no anticoagulant therapy was given. During follow-up, 10 patients (3.2%) developed venous thromboembolism including 4 fatal episodes of pulmonary embolism (1.3%) at day 3, 5, 8 and at 5 months.39 The other (retrospective cohort) study reevaluated the accuracy of a newer conventional, not computerized, IPG machine for detection of DVT. In this investigation IPG showed a sensitivity of only 66% for proximal DVT.40 Possible explanations for this discrepancy with previous studies is the use of newer less sensitive equipment, and an increased awareness of DVT amongst referring physicians resulting in less extensive thrombi at onset. These results emphasize the great importance of proper evaluation of diagnostic tests and equipment before they can be used safely into medical practice.

Although less extensively evaluated, IPG seems to be a safe and effective method to detect DVT in pregnant woman.41 In a study in 139 pregnant women in whom anticoagulants were withheld on the basis of normal serial IPG findings, no thromboembolism (95% confidence interval: 0% - 2.6%) was encountered during long-term follow-up.41 In patients with suspected recurrent DVT, IPG can only be used if a normal base-line test result is available. Prospective cohort studies have shown that 12 months after the acute thrombotic episode 95% of the IPG tests return to normal.42 If the IPG test has returned to normal it can be used alone or in combination with fibrinogen leg-scanning to diagnose recurrent DVT in symptomatic patients.17,42 In one study, 270 patients were referred with clinical signs and symptoms of recurrent DVT. IPG was negative in 200 of these patients. In all IPG negative

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patients leg scanning was performed and normal test results were obtained in 181 of these 200 IPG negative patients and anticoagulant therapy was withheld. During 3 months follow up 3 of 181 patients (1.7%) were shown to have recurrent DVT despite normal IPG and legscan testresult. In another study of patients with suspected recurrent DVT, anticoagulants were withheld safely in all 18 patients with repeated normal IPG tests. IPG is not useful in the management of asymptomatic postoperative patients because of its low overall sensitivity of 22%. The additional use of

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I-fibrinogen legscanning improves

sensitivity to approximately to 50% only.43-47

Ultrasonography

Real-time B-mode Ultrasonography

Real-time B-mode ultrasonography (US) is a non-invasive method which allows direct visualization of the deep veins of the leg. During the examination the patient is in the supine position. The ultrasound probe is placed in the groin to identify the common femoral vein (medial to the common femoral artery). The whole venous traject is then visualized throughout its course until the superficial femoral vein is lost in the adductor canal. For examination of the popliteal vein the patient is in the prone or lateral position, with flexed knees. The visualization of the calf veins is more difficult due to the variable anatomical positions of the veins and the small size of the vessels. Using a 5-10 mHz high resolution transducer, it is not only possible to localize deep veins, but also to visualize the thrombus in the vessel, one of the suggested diagnostic criteria for DVT. Further diagnostic criteria comprise non-compressibility of the vein and the absence of

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vein extension upon a Valsalva manoevre. A large prospective study, however, showed that the single criterion of non-compressibility of the vein on gentle pressure with the probe is the most accurate for the detection of DVT (Figure 3a and b).48 Most of the compression ultrasound (CUS) accuracy studies have limited the examination to the common femoral vein in the groin and the vein in the popliteal fossa. The overall mean sensitivity and specificity of compression ultrasonography is high: 97% (range 83%-100%) and 97% (range 86-100%) respectively.48-55 Using this two-point CUS, isolated thrombi in the superficial femoral vein and isolated calf veins are missed. However, a recent venogram study revealed the relative low frequencies of these localizations, i.e. none of the patients (0%; 95% confidence interval 0% - 1.9%) had an isolated superficial femoral thrombus and isolated calf vein thrombosis was detected in only 12% of the patients.22 Therefore an abnormal two points CUS result can be used to make therapeutic decisions, though a normal test result does not rule out calf vein thrombosis. Although most of the calf vein thrombi resolve spontaneously, about 20% extend proximally and may give rise to pulmonary embolism. Therefore CUS should be repeated over a one week period to detect these extending thrombi, hence a similar approach as for IPG.38 Falsely normal test results can be obtained if the thrombus is located in one popliteal vein in case of duplication or when dilated collaterals are misjudged to be the popliteal or femoral vein while a totally occluding acute thrombosis is present. Compression of the vein by extravascular masses, such as a tumor or a gravid uterus may cause noncompressibility of the vein at a lower level as a result of increased venous pressure and may be the reason for a falsely abnormal test result. In patients with a previous history of DVT, residual thrombus mass in the vein can mimick acute thrombosis. In a recent study the safety of withholding anticoagulant therapy in symptomatic patients with serial normal compression US and serial normal IPG results was compared.38 From a total of 985 consecutive symptomatic outpatients, 491 were randomized to undergo serial compression US. Of this group, 89 patients with an abnormal test result underwent venography

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which confirmed DVT in 84 patients (positive predictive value: 94%). No anticoagulant therapy was given to the patients with a repeated normal CUS test result. During a six-month follow-up 6 of those patients (1.5%; 95% C.I: 0.5%-3.3%) had recurrent venous thromboembolism which was confirmed by venogram.38 Hence, the use of serial CUS appears to be a safe method in the management of patients with signs and symptoms of DVT. The usefulness of B-mode CUS in patients with recurrent thrombosis seems limited and depends on the rate of normalization of the test during follow-up.18,56 In a prospective cohortstudy the compression ultrasound results became normal in only 50% of the patients after one year.18 A newly developed quantitative method, which is based on measuring thrombus size, is now under investigation.19 In asymptomatic patients CUS seems more accurate than IPG, nevertheless the overall mean sensitivity is unfortunately as low as 59% (range 43%-100%) with an overall mean specififty of 98% (range 91%-95%) for proximal DVT.57-60 In conclusion, CUS is useful in symptomatic patients with a first episode of acute DVT, but can as yet not be recommended for the diagnosis of recurrent DVT; further studies are required to determine the diagnostic accuracy in this condition. For asymptomatic DVT, i.e. as a screening method, compression US is not sensitive enough to be used in the routine management of high-risk patients.

Doppler Ultrasonography

Doppler ultrasonography is based on the principle that an ultrasound beam is reflected by blood cells in a vessel. If the blood is stationary, no sound is recorded. In case of moving blood cells a difference in frequency between the initial and reflecting beam can be converted into a flow sound.61 During the examination the patient is in the supine position, avoiding thight clothes

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which can interfere with venous flow. The common femoral artery is first located in the groin and moving the probe to medial the common femoral vein can be identified. For examination of the popliteal vein the patient is in prone position with the knee flexed and the feet rested on a pillow. The popliteal vein is located laterally of the popliteal artery. The venous flow sound is typically low-pitched and changes with respiration and can be augmented by sqeezing the thigh and calf. Obstruction to venous outflow may result in loss of phasiticity of the venous signal and loss of the relationship with respiratory fluctuation. Furthermore, augmentation of the venous flow by sqeezing the tigh and calf may be diminished or absent.61 Several investigators have compared the accuracy of Doppler ultrasonography versus contrast venography in patients who were symptomatic of DVT.62-67 The accuracy of the Doppler ultrasonography depends on the experience of the investigator and can be disturbed by subjective interpretation of the test result. Therefore the sensitivity and specificity for proximal DVT ranges from 65-100% and 72-98% respectively.62-67 The introduction of a standardized protocol and the use of stripchart ultrasound recordings, have improved the accuracy of the test.68 Using the objective criteria indicative for proximal DVT, i.e. a continuous or absent venous doppler signal, the sensitivity and specificity can be increased to 91% and 99%, respectively.68 In a recently published study, real-time CUS and Doppler ultrasound were compared with venography in a consecutive series of 161 outpatients referred for clinically suspected DVT.69 For proximal DVT the sensitivity for CUS was 100% and for Doppler US 95% (p=0.056). However, for all thrombi (including isolated calf vein

thrombi) the sensitivity of CUS was significantly better than that of Doppler US (95% and 76%, respectively; p< 0.04). The specificity of both tests was not significantly different, 100% for compression US and 98% for Doppler US.69 In conclusion, this study showed the superiority of real-time compression ultrasonography when compared to Doppler US for detection of all venous thrombi and equal accuracy

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in detecting proximal DVT. However, prospective studies on the safety of withholding anticoagulant therapy in patients with normal Doppler-US results are lacking. The value of Doppler ultrasonography in patients with recurrent DVT and in postoperative asymptomatic patients at high risk have not been evaluated.

Color Doppler Ultrasonography

The addition of color Doppler utilities to the conventional ultrasonography equipment allows direct visualization of the flow within the vessels, which might imply a more accurate and easier performance of the test.70 However, the sensitivity and specificity (both 97%) of color Doppler ultrasonography for proximal DVT in symptomatic patients was similar to that of CUS.71-74 The potential advantage of color Doppler for the detection of thrombi in asymptomatic postoperative patients, which are often small and nonocclusive, was not confirmed in clinical studies revealing a mean sensitivity of only 43% with a specificity of 97%.75-77 In conclusion, the extra costs which are required to perform color Doppler ultrasonography are not leading to an improvement of diagnostic accuracy compared with compression ultrasonography. Additional comparative studies are currently in progress.

Scintigraphic Methods

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I-fibrinogen leg scanning

Fibrin makes up an essential part of thrombi, and radiolabelled fibrinogen, following cleavage by thrombin, becomes incorporated in thrombi. Subsequently, the radioactivity may be detected from the surface of the limb. The method was introduced over thirty years ago78-80, and

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subsequently used in the diagnosis of asymptomatic DVT in high risk patients as an investigative tool to evaluate the effectiveness of thromboprophylaxis.81-84 Although initial studies showed very high sensitivity for distal thrombi, this was later disputed by several other studies.43,44,85 In a recent review of the literature, accuracy studies and positive predictive value studies were assessed to address this apparent change in sensitivity of the

125

I-fibrinogen uptake test in later

years.86 Bias in the earlier studies was identified as the most probable cause of the apparent decrease in sensitivity.86 In addition, the sensitivity may also be related to the size of the thrombus, and may be as low as 20% for small calf vein thrombi.43 The virus safety of the product is another point of concern. Fibrinogen is derived from human plasma, and can not be pasteurized. Thus, it is possible for blood-borne virus transmission to take place. This fear was the main reason for the product removal from the market. At present, new attempts to produce a virus safe product are being made. In conclusion, 125I-fibrinogen leg scanning does not appear to be useful for the diagnosis of DVT at present. If the test were to become available again, new studies may be required to define its role.

Other scintigraphic methods

Some techniques are based on the fact that perfusion is absent in the presence of obstructing thrombi, such as

99m

Tc-labelled macroaggregated albumin or

99m

Tc-labelled

erythrocytes.87,88 Other techniques are based on incorporation of 111In-labelled platelets into the thrombus.89 However, these techniques appeared to be inaccurate and were never introduced in clinical practice.

Blood Tests

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For several decades, investigators have attempted to develop a blood test which could adequately diagnose DVT. Fibrinopeptide A, fibrin(ogen) degradation products (FDP), degradation products of cross-linked fibrin (D-dimer) prothrombin fragments 1+2 (F1+2) and thrombin-antithrombin III (TAT) complexes have been investigated.90-99 For DVT to be adequately excluded by a blood test, the sensitivity (and thus the negative predictive value) would need to approximate 100%. Using this principle, a cut-off value for Ddimer would consist of the lowest D-dimer value detected in patients with DVT. This would ensure that no patients with DVT could remain unnoticed, and this would allow safe exclusion to take place. Several investigators have shown that plasma D-dimer may be able to adequately identify those patients without DVT (Table 2). For example, an enzyme immuno assay for D-dimer reached a sensitivity of 100% in patients with suspected DVT, however, the specificity of the test was much lower in inpatients (4%) as compared to outpatients (57%).93 In another study, the value of latex and EIA D-dimer assays were determined in 62 patients with suspected DVT, using venography as a reference method.94 For latex D-dimer an inferior sensitivity of 73% was found, while EIA D-dimer reached a sensitivity of 100%. This was confirmed by other investigators in 56 consecutive out- and inpatients with suspected DVT.96 Of the tested D-dimer ELISA assay, two D-dimer latex assays, and a latex FDP test, only D-dimer ELISA showed a sensitivity of 100%. In a series of 116 consecutive outpatients with clinically suspected DVT, the diagnostic value of F1+2, TAT complexes and D-dimer were compared.98 Only D-dimer ELISA showed sufficient sensitivity and specificity to be potentially clinically useful. In a large study in outpatients with suspected DVT, the value of D-dimer was evaluated as a replacement of serial non-invasive tests for DVT (IPG or CUS).99 In this study, D-dimer was performed in addition to non-invasive tests for DVT on day 1 and the results were compared with the findings of serial IPG or CUS outcome. After determination of a cut-off value to obtain

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a sensitivity of 100% when compared to contrast venography, the assay was prospectively validated. In 309 consecutive patients, a sensitivity of 100% was obtained, but the specificity was relatively low (28%; 95% confidence interval 23-34%). A subsequently performed costeffectiveness analysis did not show decreasing costs per diagnosed deep vein thrombosis when D-dimer was used in addition to either impedance plethysmography or CUS. However, 10 of 70 patients with proven deep vein thrombosis were identified earlier using D-dimer, which could reduce the number of patients that would be required to return to hospital for serial tests to be performed.

In conclusion, D-dimer may be of potential clinical use in the exclusion of deep vein thrombosis. Unfortunately, management studies have yet to be performed. Furthermore, the reliability of fast D-dimer tests remains to be proven. Thus, at present, D-dimer can not be recommended for the routine management of patients with clinically suspected DVT.

Other noninvasive screening methods

Liquid crystal (contact) thermography is based on the fact that the temperature of a thrombotic leg will increase as compared to the unaffected limb. Several reports have demonstrated a high sensitivity, which would make this test clinically useful in the exclusion of deep vein thrombosis.100,101 However, a subsequent study in 185 patients could not demonstrate a sufficiently high negative predictive value for it to be useful as a screening test.102 Light reflection rheography uses the observation that exercise results in a decrease of blood in the venous plexus of the calf. Light which is absorbed by red cells will be increasingly reflected with the decreasing blood pool, while this returns to normal during rest. In deep venous thrombosis, the blood pool remains in the calf, which yields a different patterns in light

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reflection. This test was shown to be sensitive, but thorough evaluation has yet to take place.103

Summary

In this chapter various tests have been discussed in the diagnosis of DVT and classified according to various patient categories. To summarize, the following guidelines may be of clinical use in the management of patients with suspected DVT.

Acute, first event of suspected DVT These patients often suffer from occluding, proximal thrombi. Therefore, non-invasive tests such as CUS or IPG are most suitable for these patients. If an abnormal CUS or IPG result is found, the diagnosis is virtually proven and this may serve as a basis to treat the patient with anticoagulants. If a normal CUS or IPG result is obtained, serial testing is indicated to detect extending calf vein thrombi or non-occluding DVT, which becomes occlusive at follow up, and anticoagulants may be withheld safely if the test remains normal within one week.

Acute, recurrent suspected DVT These patients may have residual thrombi present, which makes the non-invasive tests (CUS/IPG) less usefull. However, if a normal non-invasive test was documented previous to the acute recurrent event, this test may be used. If an abnormal test result is found in the presence of a documented normal previous test outcome, this may serve as a basis for anticoagulant therapy. Although no formal studies have been performed to evaluate the safety of withholding anticoagulants if a normal CUS or IPG result is obtained, serial testing is likely to be adequate in these circumstances. Phlebography is the only truly evaluated approach, and this could be considered in all suspected recurrent DVT. Furthermore, contrast venography is the test of

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choice to discern acute from old thrombi.

Asymptomatic DVT in high risk patients The majority of these thrombi are mostly localized in the calf veins only and are often non-occlusive. This makes non-invasive tests unreliable for their detection. Therefore, only contrast venography should be used in this patient category.

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Koopman MMW, Jongbloets LMM, Lensing AWA, Büller HR, ten Cate JW. Clinical utility of a quantitative B-mode ultrasonography method in patients with suspected recurrent deep vein thrombosis (DVT).[abstract] Thromb Haemostas 1993;69:623.

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28

Table 1: Summary of various studies evaluating serial IPG.

Reference

Positive Predictive

Recurrent Venous

Value [n/n (%)]

Thromboembolism [n/n (%)] in Normal Serial IPG

Hull et al., 198515

90/95 (95%)

Huisman et al., 198614 113/123 (92%)

6/311 (1.9%) 1/289 (0.3%)

Huisman et al. 198916 38/42 (90%) Heyboer et al., 199338 89/107 (83%)

Total

*

1/131 (0.8%) 9/369 (2.5%)

330/367 (90%)*

17/1100 (1.5%)**

95% confidence interval: 86% - 94%

**

95% confidence interval: 0.9% - 2.1%

29

Table 2: Summary of studies in the evaluation of the value of plasma D-dimer in the diagnosis of DVT.

Reference

numbercut-off sensitivity

specificity

of patients

(μg/l)

Rowbotham et al, 198793

104

250

100

36

Heaton et al, 198794

62

200

100

47

Bounameaux et al, 198996

53

200

100

31

Speiser et al, 199097

97

120

100

48

Boneu et al, 199198

116

500

94

51

Heyboer et al, 199299 309

300

(%)

100

30

(%)

29

Legends

Figure 1:

Contrast venogram, showing a filling defect in the femoral vein.

Figure 2:

Normal long-leg venogram, outlining the complete deep venous system of the left leg.

Figure 3:

a. B-mode ultrasonogram showing the popliteal vein (PV) and artery (PA) withou compression by the probe. b. Normal compression B-mode ultrasonogram, leaving the popliteal artery (PA) open, but completely occluding the popliteal vein.

31