Diagnosis of deepvein thrombosis Introduction

Many patients develop DVT in the presence of well-known risk factors, such as, immobility and malignancy. DVT can, however, occur unprovoked (idiopathic DVT). An underlying thrombophilia (inherited or acquired) may be present in some patients with idiopathic DVT, while the remainder have no demonstrable thrombophilia. The management of DVT is often straightforward. Problems leading to morbidity and mortality can result from misdiagnosis, treatment failure, and anti-coagulant-related haemorrhage.

Diagnosis of first episode of DVT

Symptoms of DVT vary and may be minimal or atypical. In addition, its diagnostic clinical features can be found in other disorders. DVT confirmed objectively is found in only about 25% of patients who present with such symptoms. As the clinical diagnosis is poor and non-specific, confirmation with objective testing is paramount. In addition, although anti-coagulant therapy is highly effective, its unnecessary use should be avoided because it can cause serious morbidity and mortality. Despite the limitations of clinical diagnosis, the first step in evaluating a patient with suspected DVT remains history and full clinical examination.126

Clinical assessment

A proper clinical evaluation involves a careful assessment of the patient's symptoms, signs, and risk factors for venous thrombosis. Patients with symptomatic DVT can present with painful swelling, tenderness along the distribution of the deep leg veins, and localised erythema consequent to venous obstruction or perivascular inflammation. These signs can also be found in patients with cellulitis, ruptured Baker's cyst, superficial thrombophlebitis, and other muscu-loskeletal conditions. Therefore, the most important objective of the clinical evaluation is to determine whether the presenting features are more or less likely to be caused by one of these alternative diagnoses. If the patient has no known risk factors for venous thrombosis an alternative diagnosis is considered more likely and, therefore, the likelihood of DVT is significantly reduced. In contrast, if the patient has one or more known risk factors for thrombosis, the likelihood of DVT is increased. Well-established risk factors for venous thrombosis include recent major surgery or trauma, recent hospitalisation, malignancy, prolonged immobilisation, pregnancy and the puerperium, use of combined oral contraceptives or hormonal replacement therapy, and presence of anti-phospholipid syndrome and known heritable thrombophilia. Obesity, smoking, and long distance flights are considered weaker risk factors. Standardisation of the clinical assessment can be achieved by using one the clinical models available. The first model designed to assess the pretest probability (clinical likelihood) of DVT was developed and validated by Wells and colleagues (Table 5) in outpatients who presented with suspectedDVT.127,128 Following their clinical presentation, patients are stratified and assigned into low, medium, or high probability category for having DVT. Outpatients with classical findings of DVT and at least one risk factor have 85% probability of having DVT, while those with atypical features and

Table 5. Wells et al. Prior Clinical Probability (PCP) for Deep Vein Thrombosis

Clinical Features

Yes

No

Active cancer (on-going treatment or within previous

1

0

6 months or palliative)

Paralysis, paresis, or recent plaster immobilisation of the

1

0

lower limbs

Recently bed-ridden for more than 3 days or major

1

0

surgery, within 4 weeks

Localised tenderness along the distribution of the deep

1

0

venous system

Entire leg swollen

1

0

Calf swelling by more than 3 cm when compared with

1

0

the asymptotic leg (10 cm below the tibial tuberosity)

Pitting oedema (greater in the symptomatic leg)

1

0

Collateral superficial veins (non-varicose)

1

0

Intravenous drug abuse

1

0

Alternative diagnosis as likely or greater than that of DVT

-2

0

High score > 3; moderate score 1-2; low score < 0.

High score > 3; moderate score 1-2; low score < 0.

no identifiable risk factors have only about 5% probability of having thrombosis.127 Shows a simplified version of the original model.128 Although the identification of an alternative diagnosis may prove difficult, the model has been applied successfully to different patient settings, including patients in hospital and patients who present to the Accident and Emergency Department and acute admission and assessment wards.129,130

Wells has further streamlined the diagnostic process more recently by stratifying patients into two broad risk categories: ''DVT unlikely'' if the clinical score is 1 or less, and ''DVT likely'' if the score is more than 1.6.131 Other investigators have adapted the modified model after removing the alternative diagnosis point. Junior medical staff were able to use this modified model without difficulty to triage patients with suspected DVT presenting to the emergency department.132

Initial objective testing

The most useful objective tests for diagnosing DVT are venous compression ultrasonography (CUS) and D-dimer testing. The need for contrast venography (the reference standard for diagnosing DVT) has been markedly reduced by combining clinical assessment with compression ultrasonography and D-dimer testing. Validation studies have shown that diagnostic strategies incorporating clinical pretest probability, ultrasonography, and D-dimer testing are safe, reliable, and cost-effective in managing patients with suspected DVT.

Compression venous ultrasonograph

Compression venous ultrasonography (CUS) is the first objective test of choice in patients with high or moderate pretest probabilities. Lack of compressibility of the common femoral vein or popliteal vein or both is diagnostic for proximal DVT. Compression B-mode ultrasonography with or without colour duplex has sensitivity of 95% and specificity of up to 98% for diagnosing symptomatic, proximal DVT. It has sensitivity and specificity of 60 to 70% for isolated calf vein thrombosis.133 Therefore, with concordant pretest probability and CUS of the proximal venous system, the accuracy and the predictive values of the positive and the negative combinations approach 100%.134 Accordingly, DVT is confirmed when the pretest probability is intermediate or high and the CUS result is positive, while it is safe to exclude a diagnosis of DVT and withhold anti-coagulant therapy when the clinical suspicion is low and the CUS result is negative. In contrast, further objective testing will be required when other combinations occur because DVT is present in a range between 14 and 63%.127,128 The major limitation of CUS is its reduced specificity and, therefore, accuracy in diagnosing distal calf thrombosis. Its limited availability outside routine working hours, including weekends and holidays, is also a problem.

D-dimer testing

D-dimer testing is used as the first objective test in patients with suspected DVT and low pretest probability. D-dimer assays were developed about 20 years ago to measure cross-linked fibrin degradation products. Since then many different assays have been evaluated for their accuracy and utility in diagnosing DVT (Table 6). In

Table 6. Performances of D-Dimer Testing in Suspected Venous Thromboembolism

Series

Patients n

Negative Predictive Value (NPV) % (95% CI)

Suspected DVT

Classical ELISA

1337

96 (93-98)

Vidas-DD

785

98 (95-99)

Classical latex

733

92 (84-91)

Simplified

1108

92 (90-94)

general, a negative result using a sensitive D-dimer test is useful for excluding acute DVT. Conversely, a positive D-dimer result is not useful because the test lacks specificity. Furthermore, D-dimer levels are raised not only in acute thrombosis, but also in other conditions, such as, trauma, postoperative, immobility, pregnancy, infection, and malignancy. In addition, D-dimer levels are raised in elderly patients. Unfortunately, commercially available D-dimer assays vary in their sensitivity and specificity and, therefore, the performance of one assay cannot be extrapolated to another.135 The most reliable and extensively evaluated tests are two rapid enzyme-linked immunosor-bent assays (ELISAs; Instant-IA D-dimer, Stago, Asnie'res, France and VIDAS DD, bioMe'rieux, Marcy-l'Etoile, France) and a rapid whole blood assay (SimpliRED D-dimer, Agen Biomedical, Brisbane, Australia). The sensitivity of the rapid ELISAs is over 95% and that of the SimpliRED D-dimer assay is approximately 85%.

Earlier studies suggested that DVT can be safely excluded in outpatients who have a low pretest probability on standardised clinical assessment and a negative D-dimer result.136,137 This proposed approach has now been validated by management studies that indicate an initial CUS is unnecessary in patients with a low pretest probability and a negative D-dimer result, because less than 2% of these patients will develop symptomatic DVT over the next 3 months.132,138 Using this approach, an initial CUS can be avoided in 23 to 40% of patients who present with a suspected first episode of DVT.132,138 Furthermore, management studies have also concluded that CUS can be combined with D-dimer testing to reduce serial CUS by about 60%.139,140 Even independent of the pretest probability, if the initial

CUS result is negative and normal D-dimer result, further testing with serial CUS is unnecessary and anti-coagulant therapy can be withheld safely.139--141 Therefore, D-dimer testing can greatly reduce the number of CUS required to investigate first episode of suspected DVT.

Follow-up testing

Serial CUS or venography is indicated in the presence of disagreement between the clinical assessment and CUS or D-dimer result. If the clinical probability is moderate or high, but the ultrasound is negative, further testing is indicated to detect a calf vein thrombus. Isolated calf vein thrombosis occurs in 15 to 20% of patients with symptomatic, confirmed thrombi and only about 20% of calf thrombi undetectable at initial presentation will extend proximally within 1 to 2 weeks of initial presentation.142 Therefore, serial CUS (repeat CUS in 5 to 7 days or sooner, if clinically relevant) is a safe approach because it detects thrombus extension into the popliteal vein and because isolated calf vein thrombus that does not extend during the period of testing does not produce serious complications. Systematic review of management studies using serial CUS found a rate of conversion (from a negative to a positive) of only 1 to 2% during the period of testing, and the risk of a patient dying from pulmonary embolism while awaiting serial testing is 0.06% (95% CI, 0.00--0.32%).134 Venography is indicated in patients unsuitable for serial CUS or those with severe symptoms and high clinical probability; those with poor cardiorespiratory reserve; and if the CUS result is inconclusive. It is also indicated in patients with unexplained swelling of the entire leg, but a negative CUS, as it is important to exclude an isolated iliac vein thrombus because the iliac veins are not routinely visualised with lower limb CUS. Isolated iliac vein thrombosis is infrequent, but it can occur in pregnancy and in patients who have extensive pelvic malignancy or have undergone recent pelvic surgery. An intraluminal filling defect on venography is considered as evidence of new or recent thrombosis. If the diagnosis is still inconclusive, it is reasonable to treat patients with anti-coagulant therapy and follow patients with abnormalities in distal veins with serial CUS.

Pregnant women with suspected DVT

The diagnosis of venous thrombosis in pregnancy can be challenging because: (1) unilateral left leg swelling can be caused by compression of the left iliac vein by the gravid uterus; (2) leg swelling can be caused by isolated common iliac vein thrombosis that may not be detectable by CUS, and (3) venographic examination of pelvic veins is problematic because ofirradiation risk to the foetus. CUS is the initial test of choice in all patients, and the use of venography is limited to patients with suspected isolated iliac vein thrombosis, when the vein cannot be identified by CUS. Although venography exposes the foetus to irradiation, the risk of a fatal pulmonary embolism from a missed iliac thrombus probably outweighs the risk of radiation exposure to the foetus. Examination of the external and common iliac veins is technically feasible in the first two trimesters and can sometimes be done even in the third trimester with appropriate positioning. As in non-pregnant women, patients who have a negative initial ultrasound should be followed up with serial testing.

DVT diagnosis algorithm

This algorithm is based on the balance of evidence, a diagnostic strategy that combines clinical assessment using a standardised model, rapid ELISA D-dimer testing, and CUS. In patients with a low pretest probability, D-dimer testing should be the first investigation. If the D-dimer result is negative, further testing with CUS is unnecessary and DVT can be safely excluded; if the D-dimer result is positive, CUS should be performed. For all patients who have an intermediate or high pretest probability, the first investigation should be a CUS. If the ultrasound result is negative, D-dimer testing is helpful in selecting patients for further evaluation. Follow-up testing is not required if the D-dimer test is negative, while serial CUS or venography is indicated if the D-dimer result is positive (Fig. 14).

This strategy simplifies the diagnostic process and reduces the cost by reducing the number of patients who require both D-dimer testing and CUS examinations. As for all algorithms, there is room for the clinician to exercise their clinical judgment. For example, serial

CUS should be performed earlier than 5 to 7 days if the patient has severe or worsening symptoms, and venography should be considered in a patient with high clinical probability, normal CUS, and severe calf symptoms. Furthermore, if confirmatory tests cannot be performed in a timely manner and the clinical suspicion is high, empiric anticoagulant therapy should be started before objective testing in the absence ofcontraindications.

Diagnosis of recurrent DVT

Although establishing a diagnosis of recurrent DVT is difficult because of the lack of a validated clinical model, and residual organised thrombus can complicate the interpretation of CUS, a similar strategy to that used in patients with suspected first episode of DVT is employed. This includes clinical assessment, CUS, and D-dimer testing in all patients who present with suspected recurrent DVT. Two important determinants influence pretest probability of recurrent DVT. These are a history of post-phlebitic syndrome (PPS) and the current use of anti-coagulant therapy. In patients with established PPS, it may be difficult to distinguish between an acute exacerbation of chronic symptoms and an episode of recurrent DVT. In patients already receiving anti-coagulant therapy, the likelihood of recurrence is reduced if the international normalised ratio (INR) is in the therapeutic range. Patients with advanced malignancy or anti-phospholipid syndrome are, however, at increased risk for recurrence despite a therapeutic INR value.143,144 Although a new non-compressible segment on CUS is diagnostic ofrecurrent thrombosis, an earlier test result is needed to make this determination. CUS remains abnormal in up to 50% ofpatients one year after the initial diagnosis. Therefore, a single abnormal CUS, especially when there is no previous result available for comparison, does not necessarily confirm recurrent DVT.144 In contrast, an intraluminal filling defect on venography is diagnostic for DVT, and a previous examination is not required for comparison. Venography is, however, technically demanding and invasive. It involves the risk of contrast related complications, is not readily available, and is impractical for repeated use. Although D-dimer testing has not been formally evaluated in this setting, there is no reason why a negative D-dimer result should not be as reliable for excluding a diagnosis of recurrent DVT as it is for first episode of venous thrombosis. Based on the above considerations, a diagnosis of recurrent DVT is confirmed if there is a new non-compressible segment on CUS. Alternatively, recurrence is ruled out if the patient has a normal CUS and a negative D-dimer result. In patients who have a high clinical suspicion or other combinations of CUS and D-dimer results, venography or serial CUS is indicated.

Cost-effectiveness

The safety and cost-effectiveness of several strategies were compared in a recent decision analysis. For a mortality of untreated deep vein thrombosis of 2.5%, the difference in mortality was only 1 to 2 per 10,000 patients managed by the single ultrasound strategy compared to serial ultrasound.

Performing a single initial diagnostic ultrasound in association with an initial D-dimer reduced the requirement for ultrasound to 70 scans per 100 patients managed compared with 130 to 170 for the serial testing strategy (Table 7).145 This enabled a cost reduction of 9 to 15% in the single scan compared with the serial ultrasound schemes. Therefore, in a patient with a suspected DVT, clinical probability with an initial ELISA D-dimer test followed by a single

Table 7. Cost-Effectiveness of Various Diagnostic Strategies for Deep Vein Thrombosis145

Strategy

* Lives **Costper Venography or

Saved/1000 QALY Saved ($) Angiogram/100

Patients

Patients

Suspected DVT

Serial CUS 4.3

PTP + serial CUS 4.4

15,475 14,934 14,339 13,115

na na 19 14

*Difference in mortality per 1000 patients compared with ''no treatment'' strategy in which no investigation or therapy is undertaken.

** Compared with no treatment strategy for a 60-year-old patient considered to have a life expectancy of 20.5 years.

diagnostic ultrasound with venography only in patients with a high clinical probability and a normal ultrasound appears to be safe and is a cost-effective strategy (Table 7).

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