- 1 Prince Charles Hospital, Merthyr Tydfil, Mid Glamorgan CF47 9DT
- 2 Princess of Wales Hospital, Bridgend, Mid Glamorgan CF31 1RQ
- Correspondence to: C Tovey
Venous thromboembolic disease has an estimated annual incidence in developed countries of one in 1000 people.1 The disorder commonly manifests as deep vein thrombosis of the leg, but deep venous thrombosis may also occur in other veins (cerebral sinus, arms, retina, and mesentery).
The sequelae of deep vein thrombosis vary from complete resolution of the clot without any ill effects through to death due to pulmonary embolism. Morbidity due to deep vein thrombosis includes post-thrombotic syndrome, encompassing chronic venous hypertension causing limb pain, swelling, hyperpigmentation, dermatitis, ulcers, venous gangrene, and lipodermatosclerosis.
Pain or swelling of a lower limb is a common presenting complaint, and a wide differential diagnosis exists (box 1). No single investigation for the diagnosis of deep vein thrombosis has ideal properties (100% sensitivity and specificity, low cost, no risk), and often several tests are performed, either sequentially or in combination.
Box 1: Possible causes of pain or swelling of the lower limb
Deep vein thrombosis
Chronic venous insufficiency
Torn gastrocnemius muscle
Acute arterial ischaemia
Hypoproteinaemia (for example, cirrhosis, nephrotic syndrome)
Deep vein thrombosis is an important cause of morbidity and mortality
Clinical diagnosis is unreliable
Screening investigations include D-dimer tests and plethysmographic techniques
Definitive diagnosis is usually by venography or ultrasonography
Initial treatment is with heparin—unfractionated or low molecular weight—followed by oral anticoagulation
Outpatient treatment of deep vein thrombosis is safe
With the introduction of low molecular weight heparins it is now possible to treat deep vein thrombosis as an outpatient condition. This review describes the investigations used in the diagnosis of deep vein thrombosis of the lower limb and the further management of the condition.
We reviewed the literature by searching the Medline database for the period 1990–2002 for the following key words in various combinations: “diagnosis,” “management,” “DVT,” “deep vein thrombosis,” “venous thromboembolism,” “D-dimer,” “plethysmography.” We also searched the Cochrane database of abstracts for reviews of the treatment of venous thromboembolism.
A clinical model has been devised (table), and prospectively validated in a large series, whereby patients are classified as having a high, intermediate, or low probability of developing deep vein thrombosis, based on history and clinical signs.4 This clinical model has been used in diagnostic algorithms to reduce the number of diagnostic tests required on patients with suspected deep vein thrombosis.4–6
Screening tests for deep vein thrombosis
The search has been continuing for a screening test with a high negative predictive value, which can be used as a rule-out test to reduce the need for imaging. A fast, reliable, non-invasive, and inexpensive screening test is needed that can be performed immediately on attendance at hospital. In recent years interest has focused on the use of D-dimer tests and plethysmography (box 2).
Box 2: Screening investigations for deep vein thombosis
Laboratory tests: Enzyme linked immunosorbent assay (ELISA) Latex agglutination
Near patient tests: SimpliRED (agglutination test) Simplify (immunochromatography test)
Strain gauge plethysmography
Plasma D-dimers are specific cross linked derivatives of fibrin, produced when fibrin is degraded by plasmin, so concentrations are raised in patients with venous thromboembolism. Although sensitive for venous thromboembolism, high concentrations of D-dimers are insufficiently specific for making a positive diagnosis because they occur in other disorders such as malignancy and pregnancy and after operations. Nevertheless, D-dimer tests generally have a high negative predictive value and are useful rule-out tests that reduce the need for imaging when used in conjunction with clinical probability, plethysmography, or ultrasonography.5–8
Several D-dimer assays are in clinical use. Two of the most extensively studied are the laboratory based VIDAS enzyme linked immunosorbent assay (ELISA) and the SimpliRED whole blood agglutination test.9 10 The SimpliRED test provides a qualitative result (positive or negative) within 10 minutes and is suitable for near patient testing. An immunochromatography D-dimer test (Simplify), which is suitable for near patient testing, has also been introduced recently, but no published studies have evaluated the usefulness of the test. Some evidence exists that D-dimer concentrations should be measured after the end of the anticoagulation period, to determine the risk of re-thrombosis.11
Plethysmography is the term given to the recording of changes in the size of the limb due to tissue fluid or pooled blood in the veins. This measurement can be undertaken in various ways: photoplethysmography, strain gauge, and electrical impedance.
Digital photoplethysmography—Photoplethysmography depends on the absorption of light by haemoglobin in the red cells. Digital photoplethysmography is assisted by a microprocessor, and the test is easy to perform.12 A digital measurement probe is placed on the skin, 10 cm above the medial malleolus of the affected leg (fig 1). The patient then dorsiflexes the foot 10 times according to a standard protocol and then rests for 45 seconds. Based on the characteristics of the reflected light the venous refilling time is calculated and presented as a printed graph (fig 2). In one study of 100 hospital inpatients a venous refilling time of longer than 20 seconds excluded a deep vein thrombosis and had a sensitivity of 100% and a specificity of 47%.12 Digital photoplethysmography is a simple screening test to perform, but bigger studies are needed to evaluate its usefulness fully.
Computerised strain gauge plethysmography—The principle behind computerised strain gauge plethysmography is to measure changes in calf dimensions while venous outflow is occluded by inflation of a thigh cuff.13 The rate of decrease in calf size when this occlusion is removed gives a measure of venous outflow. Rapid emptying is the rule in a healthy venous system. Obstruction to outflow is seen with thrombotic occlusion of proximal vessels. Computer software is used to calibrate the strain gauge and calculate blood flow measurements in the leg. The test can be performed in 15 minutes, and the procedure can be performed with minimal training. One study of 307 consecutive patients showed a sensitivity of 90% for proximal (popliteal, femoral, or iliac vein) deep vein thrombosis and 66% for distal (calf vein) deep vein thrombosis.13
Impedance plethysmography—Impedance plethysmography relies on the principle that the volume of blood in the leg affects the blood's ability to conduct an electrical current, which is inversely proportional to the impedance between two electrodes placed along the calf. A cuff is inflated around the thigh to obstruct venous outflow but not arterial inflow. As blood accumulates in the leg below the cuff, impedance between the calf electrodes falls. The sudden release of the cuff results in the blood volume of the leg decreasing, resulting in a rapid increase in impedance. Obstruction to venous flow such as with a deep vein thrombosis causes a reduction in the rate of venous emptying (and slower increase in impedance) than normal. The technique is operator dependent, and the sensitivity in some studies has been low.14 Some centres therefore now combine impedance plethysmography with D-dimer tests.7
Definitive investigations for deep vein thrombosis
Investigations used for the definitive diagnosis of deep vein thrombosis visualise the thrombus (box 3). These investigations include contrast venography, ultrasonography, computed tomography, and magnetic resonance imaging.1 2 5 I fibrinogen leg scanning is now seldom used.
The gold standard for establishing the diagnosis of deep vein thrombosis has been contrast venography.15 However, this procedure is invasive, not always technically possible, and it carries a small risk of an allergic reaction or venous thrombosis. Figure 3 is a venogram showing a popliteal deep vein thrombosis.
Ultrasonography is considered to be the best non-invasive diagnostic method and has been evaluated against venography in many studies, showing an average sensitivity and specificity of 97% for proximal deep vein thrombosis.14 However, ultrasonography cannot be relied on to diagnose calf vein thrombosis, and the sensitivity for symptomatic calf vein thrombosis has been reported to be as low as 75%.14
Three ultrasonography techniques are in use.
Compression ultrasound—The most simple ultrasonic criterion for diagnosing venous thrombosis is non-compressibility of the vascular lumen under gentle probe pressure (compression ultrasound). If no residual lumen is observed the vein is considered to be fully compressible, which indicates the absence of venous thrombosis.
Duplex ultrasonography—Patients are examined in an identical way to that with conventional compression ultrasound. In addition, blood flow characteristics are evaluated by using the pulsed Doppler signal. Blood flow in normal veins is spontaneous and phasic with respiration and can be augmented by manual compression distal to the ultrasound transducer. When the phasic pattern is absent, flow is defined as continuous, indicating the presence of venous outflow obstruction.
Colour flow duplex imaging—The technique of colour coded Doppler ultrasonography (colour Doppler) is identical to duplex ultrasonography. In colour flow sonography, pulsed Doppler signals are used to produce the images. When a Doppler shift is recognised, it is assigned a colour (red or blue) according to its direction towards or away from the probe. Therefore colour Doppler results in a display of flowing blood as a colour overlay to the grey scale ultrasound image, which makes it easier to identify the veins.
Calf vein deep vein thrombosis is not identified reliably by ultrasound techniques. As the thrombosis can extend into the proximal veins several strategies have been used to identify patients with this condition. One diagnostic strategy has been to repeat ultrasonography after five days in patients whose result is negative.16 The disadvantage of this strategy is that all patients with a negative ultrasound scan must return for further evaluation.
Ultrasonography combined with pre-test probability of deep vein thrombosis or D-dimer test
In some centres compression ultrasound imaging of the proximal veins of the leg is combined with a clinical model (table). It has been suggested that patients with a low clinical probability and a normal ultrasound scan can be safely discharged without serial ultrasonography.4
Box 3: Definitive investigations for deep vein thrombosis
Ultrasonography: Compression ultrasound Duplex ultrasonography Colour coded Doppler ultrasonography
Magnetic resonance imaging
Another strategy is to combine ultrasonography with a D-dimer test. It has been suggested that patients with a normal initial ultrasound test and normal D-dimer concentration do not need a repeat ultrasound examination.17
Spiral computed tomography venography and magnetic resonance imaging
Spiral computed tomography venography of the leg has shown promise for the diagnosis of deep vein thrombosis and other soft tissue diseases in patients with leg swelling.18 A small study of 53 patients, in which magnetic resonance imaging was used to detect deep vein thrombosis, showed that this technique may be better than current non-invasive methods for diagnosing deep vein thrombosis in the calf. This technique is not likely to be used widely until costs decrease.19
Treatment of deep vein thrombosis
The standard initial management of deep vein thrombosis has traditionally meant admission to hospital for continuous treatment with intravenous unfractionated heparin. Treatment then continued with a transition to long term use of oral anticoagulants (vitamin K antagonists). Recently a change has taken place, and low molecular weight heparins are being used.
Guidelines prepared by the haemostasis and thrombosis task force recommend that patients receive heparin for at least four days and treatment should not be discontinued until the international normalised ratio has been in the therapeutic range for two consecutive days.20 According to these guidelines, a patient with a first episode of a proximal vein thrombosis should receive anticoagulants for six months, with a target international normalised ratio of 2.5. The issue of length of anticoagulation is still under debate.
Unfractionated heparin is a heterogenous mixture of polysaccharide chains. Low molecular weight heparins are fragments of unfractionated heparin created by depolymerisation.21 Advantages of low molecular weight heparin over unfractionated heparin are that it offers a more consistent and predicable anticoagulant response, has a longer half life, and so permits once daily subcutaneous administration without the need to monitor activated partial thromboplastin time.
Low molecular weight heparin is at least as effective as unfractionated heparin in preventing recurrent venous thromboembolism, and statistically significantly reduces the occurrence of major haemorrhage during initial treatment and overall mortality at the end of follow up.22 Long term treatment with low molecular weight heparin is sometimes indicated rather than treatment with oral anticoagulants, for patients with contraindications to anticoagulants (for example, pregnant women).
Common practice in the United Kingdom is to use low molecular weight heparin during pregnancy, with either low molecular weight heparin or warfarin for six to 12 weeks after the birth. Practice, however, still varies widely, with some centres using unfractionated heparin.
There is weak evidence that thrombolytics such as streptokinase may produce more rapid resolution of symptoms and preserve venous valve integrity and hence decrease the incidence of the post-phlebitic syndrome.23 However, the risk of bleeding complications is three times greater, and for this reason thrombolytics are now seldom used.
Inferior vena cava filter
Inferior vena cava filters are inserted to reduce the rate of pulmonary embolism. The indications for their use include:
Pulmonary embolism with contraindication to anticoagulation, and
Recurrent pulmonary embolism despite adequate anticoagulation.
In the United Kingdom most vena cava filters are temporary and removed three weeks after the period during which the risk of embolisation is greatest. No consensus has been reached on whether patients with long term filters should receive long term treatment with anticoagulants or not.
Elastic compression stockings
Patients with a deep vein thrombosis should wear compression stockings as the rate of post-thombotic syndrome may be reduced. In one study of 194 patients (with a first episode of proximal deep vein thrombosis) the rate of post thrombotic syndrome was reduced by 50% if graded compression stockings were used.24
Outpatient treatment of deep vein thrombosis
With the advent of low molecular weight heparins, outpatient treatment of deep vein thrombosis without monitoring activated partial thromboplastin time is now possible. Many trials have compared a home treatment regimen with hospital treatment for the initial phase of treatment for deep vein thrombosis. Most of the trials have been uncontrolled, and their limited evidence shows that home treatment is cost effective, preferred by patients, and no more liable to lead to complications than hospital treatment.25
The precise pattern of screening and diagnostic tests performed to evaluate the patient with suspected deep vein thombosis of the lower limb remains dependent on local practice. These patients will also generally undergo further investigations to identify an underlying cause or predisposition. Cancer and immobility are the leading causes of deep vein thrombosis in people over 45, and in people under that age thrombophilia becomes important.
Fondaparinux sodium is a synthetic pentasaccharide that inhibits activated factor X. This drug has recently been licensed in the United Kingdom for prophylaxis of venous thromboembolism in patients having major orthopaedic surgery of the legs. The potential use of this drug for treating deep vein thrombosis has not yet been fully evaluated
Length of anticoagulation
The British Thoracic Society is currently organising a large multicentre trial comparing the long term
Additional educational resources
Information for patients
Victims of air related DVT association (VARDA)—The aim of VARDA is to campaign for prevention of deep vein thrombosis among air passengers (www.aviation-health.org/varda.html) outcome of patients having three months or six months anticoagulation after a first episode of deep vein thrombosis.
Contributors CT drafted the original manuscript. The final paper was written jointly by both authors. CT is the guarantor.
Competing interests CT has been reimbursed by Pharmacia, the manufacturers of Fragmin, for attending a conference.