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2268 Part XII: Hemostasis and Thrombosis Chapter 133: Venous Thrombosis 2269

The clinical diagnosis of DVT is highly nonspecific because each of the changes are nonspecific and may occur as a result of surgery, trauma,
symptoms or signs can be caused by nonthrombotic disorders. The rare infection, inflammation, or infarction. None of the above reported lab-
exception is the patient with phlegmasia cerulea dolens (occlusion of the oratory changes can be used to establish the diagnosis of VTE or predict
whole venous circulation, extreme swelling of the leg, and compromised its development with high probability. The fibrin breakdown frag-
arterial flow), in whom the diagnosis of massive iliofemoral thrombosis ment D-dimer can be measured by an enzyme-linked immunosorbent
is obvious. This syndrome occurs in less than 1 percent of patients with assay (ELISA) or by a latex agglutination assay. Some of these assays
symptomatic venous thrombosis. In most patients, the symptoms and have a rapid turnaround time and some are quantitative. A negative
signs are nonspecific. In 50 to 85 percent of patients, the clinical sus- D-dimer result is useful for excluding the diagnosis in many patients
picion of DVT is not confirmed by objective testing. 17–19 Patients with with suspected DVT or suspected PE (see “Objective Testing for Deep
minor symptoms and signs may have extensive deep venous thrombi. Vein Thrombosis” and “Objective Testing for Pulmonary Embolism”
Conversely, patients with florid leg pain and swelling, suggesting exten- below). 16,27,28,31 A positive result is highly nonspecific.
sive DVT, may have negative results by objective testing.
Although the clinical diagnosis is nonspecific, prospective stud-
ies have established that patients can be categorized as low, moder- DIFFERENTIAL DIAGNOSIS OF
ate, or high probability for DVT using a clinical prediction rule that DEEP VEIN THROMBOSIS
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incorporates signs, symptoms, and risk factors. A systematic review
of the studies found that the prevalence of DVT in the low, moderate, The differential diagnosis in patients with clinically suspected
and high probability categories, respectively, was 5 percent (95 percent DVT includes muscle strain or tear, direct twisting injury to the leg,
confidence interval [95% CI]: 4 to 8 percent), 17 percent (95% CI: 13 to lymphangitis or lymphatic obstruction, venous reflux, popliteal cyst,
23 percent), and 53 percent (95% CI: 44 to 61 percent). The prevalence cellulitis, leg swelling in a paralyzed limb, and abnormality of the knee
in the pretest category of “low probability” is not sufficiently low to joint. An alternate diagnosis frequently is not evident at presentation,
withhold further diagnostic testing and treatment, and the prevalence so excluding DVT is not possible without objective testing. The cause
in the “high probability” category is not sufficiently high to give antico- of symptoms often can be determined by careful followup once DVT
agulant therapy without performing further diagnostic testing. Conse- has been excluded by objective testing. In approximately 25 percent of
quently, the key role for clinical pretest categorization is for use within patients, however, the cause of pain, tenderness, and swelling remains
integrated diagnostic strategies employing measurement of D-dimer uncertain even after careful followup. 19
and venous imaging.

PULMONARY EMBOLISM OBJECTIVE TESTING FOR DEEP VEIN
The clinical features of acute PE include the following symptoms THROMBOSIS
and signs that may overlap: (1) transient dyspnea and tachypnea in
the absence of other clinical features; (2) pleuritic chest pain, cough, D-DIMER ASSAY
hemoptysis, pleural effusion, and pulmonary infiltrates noted on chest Measurement of plasma D-dimer has been extensively evaluated as
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radiogram caused by pulmonary infarction or congestive atelectasis an exclusion test in patients with clinically suspected DVT. The dif-
(also known as ischemic pneumonitis or incomplete infarction); (3) severe ferent D-dimer assays (ELISA, quantitative rapid ELISA, latex agglu-
dyspnea and tachypnea and right-side heart failure; (4) cardiovascular tination, and whole-blood agglutination) have different sensitivities,
collapse with hypotension, syncope, and coma (usually associated with specificities, and likelihood ratios for DVT. ELISA and quantitative
massive PE); and (5) several less common and nonspecific clinical pre- rapid ELISA have high sensitivity (96 percent) and negative likelihood
sentations, including unexplained tachycardia or arrhythmia, resistant ratios of approximately 0.10 for DVT in symptomatic patients. Thus,
cardiac failure, wheezing, cough, fever, anxiety/apprehension, and con- for excluding DVT in symptomatic patients with a low or intermediate
fusion. All of these clinical features are nonspecific and can be caused by clinical pretest probability, a negative D-dimer result by a quantitative
a variety of cardiorespiratory disorders. Patients can be assigned to cate- rapid ELISA technique is as diagnostically useful as a negative result
gories of pretest probability using implicit clinical judgement, or clinical by duplex ultrasonography. Measurement of D-dimer using an appro-
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decision rules such as the Geneva score or approach of Wells. 27–30 How- priate assay method can also be combined with ultrasonography imag-
ever, the prevalences of PE in these categories are not sufficiently low or ing. If the two tests are negative at presentation, repeat ultrasonography
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high to withhold further investigation altogether, and the measurement imaging is unecessary. Use of the D-dimer test for patient care deci-
of D-dimer and/or diagnostic imaging is mandatory to exclude or con- sions depends on the local availability of an appropriate assay that has
firm the presence of PE. The assessment of clinical pretest probability is high sensitivity and has been validated by clinical outcome studies. The
an important first step in integrated diagnostic strategies that employ, use of age-adjusted D-dimer cut-off levels for a negative result enhance
for example, D-dimer, computed tomographic angiography (CTA), and the clinical utility of the test. Figure 133–1 shows a practical approach
objective testing for DVT. 27–30 for the diagnosis of suspected DVT.

LABORATORY FEATURES IMAGING TESTS
VTE is associated with nonspecific laboratory changes that constitute The objective diagnostic imaging tests that have a role in patients with
the acute-phase response to tissue injury. This response includes ele- clinically suspected DVT are ultrasonography and venography. Both
vated levels of fibrinogen and factor VIII, increases in leukocyte and of these tests have been validated by properly designed clinical trials,
platelet counts, and systemic activation of blood coagulation, fibrin including prospective studies with long-term followup that have estab-
formation, and fibrin breakdown, with increases in plasma concen- lished the safety of withholding anticoagulant treatment in patients with
trations of prothrombin fragment 1.2, fibrinopeptide A, complexes of negative test results. 17–19,33 Ultrasonography is the preferred imaging
thrombin–antithrombin, and fibrin degradation products. All of these test for most patients. The role of venography is for selected patients,

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