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Diagnostic and Therapeutic Keys to
Deep Vein Thrombosis
The significance of Virchow's triad, the use of risk factors as an aid in differential diagnosis, the comparative merits of various imaging techniques, the implications of pregnancy, and the management of acute disease on an outpatient basis are among the topics in this discussion of deep vein thrombosis.
By J. Christian Fox, MD, RDMS, Karimdad Otarodifard, BS, and Mark Deavers, BS
Each year, two million cases of deep vein thrombosis (DVT) are diagnosed in the United States and another 600,000 patients are diagnosed with pulmonary embolus (PE). Deep vein thrombosis results in significant morbidity due to chronic swelling, ulceration, pain, and future risk of PE. Furthermore, 50% of patients with DVT show perfusion defects on ventilation/perfusion scans, and another 21% of patients diagnosed with acute DVT have high-probability lung scans for PE. In addition, 82% of patients diagnosed with PE have venogram-proven DVT.
In this article, we will review the clinical presentation of DVT, appropriate diagnostic studies, and special considerations for pregnant patients. We will also discuss various therapeutic approaches to DVT.
VIRCHOW’S TRIAD
Three primary influences predispose to thrombus formation in DVT. Collectively termed Virchow’s triad, they include the combination of blood stasis, vessel wall damage, and hypercoagulability. Initially, compression, immobility, and increased blood viscosity lead to stasis, typically within the pockets of vein valves. Clot formation, or thrombosis, develops at these sites as stasis induces the activation of platelets and blood coagulation.
Endothelial damage contributes to platelet activation and also amplifies blood coagulation via the release of tissue factor and subsequent rapid generation of thrombin. As a result, red blood cells and fibrin accumulate and advance as the leading edge of the clot. In addition, eddy currents aid in thrombus deposition, increasing the size of the thrombus and occluding blood flow. Attached to the vessel wall only at its point of origin, the thrombus floats freely in the bloodstream at high risk of dislodgement and embolism at other sites in the vasculature.
Hypercoagulability contributes less frequently in the predisposition for DVT. Nevertheless, it can play an important role in thrombus formation. In normal blood vessels, hemostasis maintains a balance between the actions of natural anticoagulants and procoagulant factors. However, conditions such as antithrombin, protein C, and protein S deficiencies create abnormal levels of procoagulant and fibrinolytic molecules.
Inheritable factor V Leiden and prothrombin gene mutations are also major contributors to hypercoagulability, resulting in cleavage-resistant coagulation factors and elevated prothrombin levels, respectively. This ultimately disrupts the hemostatic balance and potentiates thrombus formation.
PATIENT PRESENTATION
Typically, patients with suspected lower extremity DVT present with pain, erythema, tenderness, and swelling of the lower leg, which will be larger in circumference than the unaffected leg. However, DVT is far from an easy diagnosis because these same symptoms and findings may also manifest other conditions, including ruptured Baker’s cysts (more commonly associated with osteoarthritis and rheumatoid arthritis than DVT), cellulitis (associated with breaks in the skin, especially between the toes, and coexistent fungal infection), and compartment syndrome.
Assessment of the risk factors associated with DVT proves useful in differentiating DVT from these alternative diagnoses. Risk factors for DVT include: a history of venous thromboembolism, prolonged immobility, limb paralysis, orthopedic surgery, obesity, acute myocardial infarction, cerebrovascular accident, congestive heart failure, estrogen use, cancer, age over 40, lupus, trauma, hip fractures, spinal cord injury, activated protein C resistance, protein C or S deficiency, and antithrombin III deficiency.
A D-dimer level, which will be elevated due to increased plasmin-activated fibrinolysis during thrombosis, is an effective adjuvant for detecting DVT. A positive test (above 2000 ng/ml) is indicative of abnormal thrombotic activity. Many radiology departments now require a positive D-dimer test prior to performing imaging analysis in suspected cases of DVT. Thus, the use of rapid D-dimer testing in combination with risk factor assessment can be helpful in determining which patients require more intensive investigation.
Wells’ criteria (see table) are also useful for differentiating low-probability
patients (less than 10% probability of DVT) from high-probability patients
(more than 65% probability of DVT).
CONTRAST VENOGRAPHY AND ULTRASOUND
Imaging studies that can aid in the diagnosis of DVT include contrast venography, compression ultrasound with Doppler, computed tomography (CT), and magnetic resonance imaging (MRI). Of these modalities, contrast venography is the gold standard, especially with calf and upper extremity DVT. An invasive procedure, it is used when noninvasive tests are not diagnostic or impossible to perform. Moreover, it allows differentiation between acute and chronic DVT. However, this test is not always practical; it is invasive, painful, expensive, not portable, and may result in phlebitis, hypersensitivity reactions, and in DVT itself.
On the other hand, compression ultrasound with real-time B-mode imaging is noninvasive and widely available and has been proved accurate for diagnosing acute, symptomatic, and proximal DVT. Duplex is the combination of D-mode and B-mode ultrasound utilizing both the Doppler (for flow) and brightness (for gray-scale compression), which increases the accuracy of diagnosing proximal DVT in symptomatic patients. Compression ultrasound utilizes a linear probe in the higher frequency range of 5 to 8 mHz, and the optimal plane for venous compression is the transverse. With this technique, the probe is placed over the femoral or popliteal vein and enough pressure is applied to collapse the vein. (Too much pressure will collapse the artery.) Under this pressure, a normal vein should completely collapse. A DVT will prevent vein wall coaptation.
Other techniques can be used with compression ultrasound in the detection of DVT. For example, with the patient’s cooperation, the Valsalva maneuver can be utilized to rule out DVT during ultrasound. Normally, a 50% to 200% increase in venous return is associated with the Valsalva maneuver. However, clot formation will preclude this response and no increase will be observed. Thus, a normal Valsalva response excludes DVT. However, an abnormal response does not necessarily confirm the diagnosis of DVT because other conditions, such as CHF, can cause such a result.
Clot echogenicity and gray-scale visualization of the clot would seem to be the most direct way to diagnose DVT. However, factors such as probe frequency, age of the clot, and extent of the thrombolytic process affect how accurate clot visualization actually is. For example, slow-flowing blood within a vessel often appears sufficiently echogenic to mimic the appearance of a clot and thus falsely indicates a positive result for DVT. Gray-scale visualization is therefore unreliable and should not be used to diagnose the age of a clot.
DOPPLER TECHNIQUES
On the other hand, Doppler techniques such as augmentation, spontaneity, and phasic variation are useful in diagnosing DVT. With the augmentation technique, increased flow through a suspected thrombotic vein is produced by compressing a more distal region of the leg. The patency of the vein is determined between the point of compression and the sampling site. A normal vein will fill with color following compression, while a thrombotic vein will exhibit a filling defect.
Detection of blood flow in larger vessels should occur spontaneously without squeezing the calf, a phenomenon known as spontaneity. If this does not happen, it may indicate a clot. Variations in venous flow normally occur during the respiratory cycle—namely, an increase and decrease in Doppler signals during expiration and inspiration, respectively. The absence of this cycle may be indicative of thrombosis.
Can lower extremity Doppler ultrasound performed by emergency physicians to detect DVT be both accurate and fast? In a study of 112 patients examined with limited ultrasound in an emergency department, followed by complete examination in radiology, 34 cases of DVT were accurately diagnosed by emergency physicians. This exhibited a 98% concordance with radiology results; there was disagreement in only two cases.
CT AND MRI STUDIES
Computed tomography with contrast is another clinically useful tool for the detection of DVT. It allows for near-immediate treatment of DVT, without waiting for other test results and with only an additional one to four minutes of scanning time. Also, CT is not limited by casts, pain, open wounds, severe burns, or obesity and allows visualization of the contralateral limb, inferior vena cava, superior vena cava, and heart.
Magnetic resonance imaging can also be used for the diagnosis of DVT. An MRI scan directly images thrombi and nonocclusive clots and is very useful for visualization of both acute and chronic clots in the pelvis, inferior vena cava, and arms. Another advantage is that neither contrast nor radiation is required. Also, MRI can potentially diagnose PE. However, no level I evidence for this is yet available, and MRI does require the involvement of an experienced radiologist. As a result, CT is still the gold standard for detection of calf vein thrombosis.
The challenges in examining the veins of the calf, which include their variable anatomy, smaller diameter, and slower blood flow, have ultimately resulted in technically inadequate studies. Ultrasound, for example, cannot be used to exclude calf vein thrombosis. The sensitivity of duplex ultrasound is 81% for calf vein thrombosis in symptomatic patients. In asymptomatic high-risk patients, on the other hand, its sensitivity is as low as 33%. However, when calf veins are adequately visualized, sensitivity and specificity approach 100%.
Serial ultrasounds are recommended for symptomatic patients with negative initial studies. If follow-up with serial studies cannot be guaranteed, then contrast venography is warranted. Symptomatic patients with negative ultrasounds require further investigation.
Treatment of isolated calf DVT with low-molecular-weight heparin (LMWH) has been studied prospectively by following the progression of muscle vein thrombosis (MVT) to calf DVT. Using compression ultrasound to diagnose MVTs and calf vein thrombosis, progression from MVT to calf DVT occurred in 8 of 32 patients who were not receiving LMWH. Of the 52 patients studied who did receive LMWH, none progressed to calf DVT. Neither group had progression of MVT to proximal DVT, although all patients who developed calf DVT were treated with LMWH. This remains a controversial topic.
SPECIAL CASES
Special considerations apply to patients who are pregnant and to certain individuals who may be at risk for upper extremity DVT.
Pregnancy. Risk for DVT is increased two- to fourfold by pregnancy, and even more if a cesarean section is performed. Deep vein thrombosis can develop during any trimester. Increased estrogen concentrations during pregnancy produce increased venous distensibility, which ultimately results in venous stasis.
Moreover, a hypercoagulable state occurs during pregnancy and persists after childbirth, increasing the likelihood of DVT. This is further complicated by the fact that D-dimer levels increase with gestational age and also with complicated pregnancies.
Contrast venography cannot be used to diagnose DVT in pregnant patients because it is toxic to the fetus. Magnetic resonance venography, on the other hand, is considered a safe alternative because of its accuracy and lack of ionizing radiation, but more research is needed in this area.
If DVT is diagnosed in a pregnant patient, warfarin cannot be used because it is harmful to the developing fetus. Unfractionated heparin (UFH) and LMWH, on the other hand, are not harmful to the fetus, but they can cause maternal osteoporosis and thrombocytopenia and are difficult to administer over long periods of time. Yet, although these risks are present, withholding anticoagulant therapy after a negative ultrasound is not an option. It has not been shown to be safe in pregnant patients because one cannot rule out iliac thrombosis.
With chronic DVT, the thrombi become adherent to the vessel wall after several weeks and are not likely to embolize. Instead, patients who present with chronic DVT may suffer from either recurrent DVT or post-phlebitic syndrome. Unless a follow-up ultrasound shows normalization, this study cannot be relied on to diagnose recurrent DVT. The rate of normalization following acute DVT is only 55% after 12 months in post-phlebitic syndrome.
Upper extremity DVT. Risk factors for the development of an upper extremity DVT include a previous history of leg DVT and placement of a central venous catheter. In a prospective study of 58 patients with upper extremity DVT, PE was detected in 36%. The sensitivity of ultrasound in the diagnosis of DVT varies from 78% to 100% in symptomatic patients and is approximately 31% in asymptomatic patients.
Patients with upper extremity DVT have traditionally been admitted for UFH therapy for at least five days while an INR of 2.5 was reached with warfarin. Other therapeutic approaches include the use of LMWH, which can be safely discontinued after five days once the patient’s INR is greater than 1.9 for 24 hours.
OUTPATIENT TREATMENT
How can outpatient treatment of acute venous thromboembolic disease be safely implemented in practice? Analysis of five clinical trials investigating outpatient treatment of DVT with LMWH not only revealed that it was safe, but also that it results in greater cost savings, improved health-related quality of life, and patient satisfaction. However, it is necessary to first educate the patient on the signs of bleeding (black stools, pink urine) and recurrence (limb pain, swelling, shortness of breath, hemoptysis, syncope) before initiating this treatment, so that the patient will understand when to return for immediate medical treatment.
Also, it is important to inform the patient that physical activity must be reduced. This should include bed rest with leg elevation for at least the first 24 hours.
The details of self-administering LMWH must be reviewed with the patient. He or she should be informed that the drug should be administered subcutaneously, not intramuscularly, and that a local hematoma is a normal sign. Alternate injection sites in the lateral wall of the abdomen should be reviewed.
Low-molecular-weight heparin therapy may include any of the following drugs: dalteparin 100 U/kg every 12 hours (up to a maximum of 18,000 U/day), enoxaparin 1 mg/kg every 12 hours (up to a maximum of 180 mg), tinzaparin 175 U/kg/day (up to a maximum of 18,000 U/day), or nadroparin 86 U/kg every 12 hours (up to a maximum of 17,100 U/day).
The goal of concomitant warfarin therapy should be to reach an optimal INR
of between 2.0 and 3.0. The dose required to achieve this INR will vary from
patient to patient, and therefore no standard dosage is recommended. Rather,
a dosage nomogram is suggested (see table).
On days 1 and 2 of LMWH therapy, 10 mg of oral warfarin should be
taken. On days 3 through 5, the patient’s INR should be checked and the dose
adjusted based on the warfarin nomogram. However, the initial 10-mg dose may
need to be reduced in certain patients, especially in the elderly or those
at risk for developing bleeding disorders.
ACEP POLICY
The American College of Emergency Physicians (ACEP) formed a clinical policy subcommittee on suspected lower extremity DVT that reviewed policies from the American Heart Association, American College of Chest Physicians, and American Thoracic Society. They focused on three main issues: the utility of D-dimer testing in the diagnostic evaluation of lower extremity DVT, the utility of venous Doppler ultrasonography in the diagnostic evaluation of lower extremity DVT, and indications for fibrinolytic therapy in DVT.
The clinical policy was supported with three levels of recommendations: a high degree of clinical certainty based on the strength of evidence from class I studies or overwhelming evidence from class II studies (level A), moderate clinical certainty based on the strength of evidence from class II studies or a strong consensus of strength of evidence from class III studies (level B), or preliminary, inconclusive, or conflicting evidence or, in the absence of any published literature, panel consensus (level C).
As for the question of whether lower extremity DVT can be excluded by D-dimer testing, the ACEP committee found level B evidence for excluding proximal or distal DVT on the basis of a negative D-dimer test in patients with a low-risk clinical probability of DVT. However, the most recent evidence indicates that a negative D-dimer and low-risk categorization as determined by the Wells criteria may not safely rule out the presence of DVT in all low-probability patients. In a cross-sectional study of 1295 patients with suspected DVT, 2.9% of low-risk patients with negative D-dimer results were found to have DVT on subsequent ultrasound examination. This again indicates the benefits of incorporating imaging into the diagnostic workup.
On the issue of whether a lower extremity DVT can be excluded by normal findings on a venous ultrasound, the ACEP policy stated the following level B recommendations: DVT can be excluded only in patients with a low clinical pretest probability of DVT. Negative findings on a single venous ultrasonographic scan, even in symptomatic patients, excludes proximal DVT and clinically significant distal DVT. In patients with a moderate to high pretest probability of DVT, serial ultrasonographic exams are needed. Lastly, ACEP recommended that patients with a high probability of pelvic or inferior vena cava thrombosis may require additional imaging.
In determining the indications for fibrinolytic therapy in lower extremity DVT, ACEP issued level C recommendations that such therapy must be considered in patients with limb-threatening thrombosis where the benefits of treatment outweigh the risks for serious bleeding complications.
Finally, physicians dealing with DVT should keep the Wells criteria easily
accessible and use them in their clinical decision-making. For patients with
a negative ultrasound but a Wells criteria score that is not low, additional
imaging studies must be obtained within three to five days. Also, contrast
venography or MRI may be warranted. Outpatient treatment should be considered
in reliable patients without comorbidities.
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