Venous Thromboembolism - Management Diagnostics

Laboratory Tests and Ancillaries

DVT

Baseline blood tests when initiating anticoagulation treatment include a complete blood count (CBC), renal and hepatic function assessment, prothrombin time (PT), and activated partial thromboplastin time (aPTT).  

D-dimer Level by Enzyme-linked Immunosorbent Assay (ELISA)  

D-dimer level by ELISA assay is a highly sensitive but non-specific screening test for the presence of VTE. Elevated D-dimer levels are non-diagnostic of DVT as they may also be elevated in patients with advanced age, MI, disseminated intravascular coagulation, cancer, inflammation, infection, necrosis, recent trauma or surgery, kidney or liver disease, pregnancy, etc. Therefore, a high concentration of D-dimer has a poor positive predictive value for DVT and cannot be used to rule in the disease. 
 
Normal D-dimer level by ELISA assay (<500 ng/mL) has a high negative predictive value and is useful to rule out VTE (including recurrent DVT); thus, reducing the need for imaging when used in conjunction with clinical probability, plethysmography, or ultrasound (US). Patients with a low clinical pretest probability of DVT and a negative D-dimer assay are considered to have no DVT or have a very low risk of subsequent DVT and can be followed up clinically without further testing unless new or progressive symptoms develop.  

This is most useful in emergency department patients, in ambulatory care settings, and in patients with recent onset of symptoms who are not currently taking anticoagulants. It can be used after a negative duplex ultrasound to determine the need for further radiologic evaluation. In elderly or inpatients, the D-dimer retains a high negative predictive value but is normal in <10% of patients and therefore is not useful in these patients.  

Recommended Diagnostic Tests Based on Clinical Pretest Probability Result  

For patients with low pretest probability (5% thrombosis), the recommended diagnostic tests include D-dimer, duplex venous ultrasonography with compression, venography, and whole-leg ultrasound.  

For patients with moderate pretest probability (25% thrombosis), the recommended diagnostic tests include D-dimer, proximal duplex venous ultrasonography with compression, venography, and whole-leg ultrasound.  

For patients with high pretest probability (60% thrombosis), the recommended diagnostic tests include proximal duplex venous ultrasonography with compression, whole-leg ultrasound, and venography.  

Pulmonary Embolism  

First-line diagnostic tests eg electrocardiography (ECG), chest X-ray, and arterial blood gases are indicated to assess the clinical probability of pulmonary embolism and general condition of the patient. Laboratory results can be normal, but some abnormal findings increase the suspicion for pulmonary embolism. Baseline blood tests when initiating anticoagulation treatment include a CBC, renal and hepatic function assessment, PT, and aPTT.  

Arterial Blood Gas  

Arterial blood gas can show hypoxemia, hypocapnia, and widened (A-a) oxygen (O₂) difference.  

Chest X-ray  

A chest X-ray may demonstrate atelectasis, pleural-based infiltrates or effusions, or rarely, an engorged central pulmonary artery associated with a paucity of peripheral vessels. It may also assess conditions that have similar presentation (eg pneumonia, pulmonary edema, pneumothorax). Near-normal radiographic results with severe respiratory compromise are highly suggestive of massive pulmonary embolism. Westermark sign (focal oligemia) may indicate massive central embolic occlusion. Hampton hump, a peripheral wedge-shaped density above the diaphragm, usually signifies pulmonary infarction. 
 
Electrocardiography (ECG)  

ECG can show right axis deviation, supraventricular arrhythmia, S1Q3T3 pattern or P-pulmonale, sinus tachycardia, or normal tracing. For massive pulmonary embolism, an ECG may show a new right bundle branch block or other evidence of RV strain (eg inverted T waves in leads V1 to V4).    

B-type Natriuretic Peptide (BNP) and Troponin  

BNP and troponin are considered in a patient with substantial clot burden, abnormal echocardiogram, or clinical findings suggestive of pulmonary embolism. Elevated BNP and troponin are associated with RV strain and increased mortality even in the absence of hemodynamic instability. An elevated troponin level without ECG findings of ischemia may suggest myocardial injury in the setting of sub-massive or massive pulmonary embolism. 

D-Dimer  

D-dimer is a highly sensitive but non-specific screening test for the presence of pulmonary embolism. Sensitivity may be decreased if the duration of VTE manifestations is >2 to 3 days prior to testing and/or if the patient is on Heparin. It is best used for the evaluation of outpatients in the emergency department.  

A negative D-dimer test via any D-dimer method (SimpliRED, Vidas, or MDA) reliably excludes pulmonary embolism in patients with low clinical probability, such patients do not require imaging for VTE. A negative result using ELISA (Vidas) or MDA methods reliably excludes pulmonary embolism in patients with intermediate probability.  

A positive D-dimer requires further radiological evaluation to exclude pulmonary embolism adequately. However, raised levels of D-dimer do not confirm the presence of VTE because such levels are found in hospitalized patients, obstetrics including postpartum period, peripheral vascular disease, cancer, infection, trauma, and many inflammatory diseases as well as increasing age.  

Consider using an age-adjusted cut-off or adapting to clinical probability as an alternative to the fixed cut-off D-dimer test level. D-dimer measurement should not be performed in those with a high clinical probability of pulmonary embolism. Inappropriate for suspected VTE with recent surgery or trauma and should proceed directly to radiologic studies (eg duplex ultrasound or CTPA). 

Imaging

DVT   

Duplex Venous Ultrasonography (DUS)  

Duplex venous ultrasonography is the primary radiologic device for the evaluation of proximal DVT. It may be in B-mode, imaging (eg 2D), and pulse-wave Doppler interrogation. It is the most often used non-invasive test to diagnose DVT in patients with moderate or high clinical pretest probability. It has a very high sensitivity and specificity for diagnosing proximal DVT in symptomatic patients, but less favorable results for calf vein and asymptomatic DVT. The primary diagnostic criteria to establish the presence of DVT by ultrasound is incomplete vein compressibility. Proximal and distal compression ultrasound (CUS) for DVT has a 90.3% sensitivity and 97.8% specificity. CUS may be used as a two-point compression technique for evaluation of the proximal veins in the groin and popliteal fossa, and as a whole-leg ultrasound scan for evaluating both the distal and proximal veins.
 
The combined use of clinical pretest probability and duplex ultrasound (with compression) is effective in confirming or excluding the diagnosis of DVT. In patients with clinical suspicion of DVT, positive D-dimer, and negative ultrasound, consider repeat ultrasound for suspected calf thrombosis or venography for suspected proximal thrombosis in 3-7 days. Recurrent DVT may be diagnosed by non-compressibility of a previously unaffected ipsilateral femoral or popliteal vein segment or an increase of the thrombus diameter in a previously affected vein segment of at least 4 mm on serial CUS with D-dimer measurement.
 
In patients with negative computed tomographic pulmonary angiography (CTPA) results and positive D-dimer and a pulmonary embolism likely clinical probability, further evaluation with duplex venous ultrasound should be used to improve the clinical likelihood of diagnosing disease and avoid more invasive testing. A positive result confirms the diagnosis of DVT and requires treatment regardless of the presence or absence of pulmonary embolism. For a negative result, the incorporation of clinical pretest probability can improve diagnostic accuracy and potentially avoid unnecessary pulmonary angiography.   

CT Venography (CTV)  

CTV is an effective method for the diagnosis of proximal DVT in patients with suspected DVT and pulmonary embolism. It has the advantage over ultrasound in the evaluation of pelvic veins or inferior vena cava and in the detection of concurrent medical conditions causing pain and swelling. It facilitates vessel measurement and case planning when intervention is needed due to its high-quality spatial resolution. It may be considered in patients with suspected proximal DVT with inconclusive ultrasound assessment or when ultrasound is not feasible. Its disadvantages include cost, use of iodine contrast, and radiation exposure.  

Contrast Venography  

Contrast venography is historically considered the gold standard for establishing the diagnosis of DVT. It offers precise details of the venous anatomy in multiple recurrent DVT and the ability to reliably exclude thrombosis in the calf. It can also help distinguish between old and new clots. 
 
It is excellent for calf veins, but it is an invasive procedure, not always technically possible, and carries a small risk of an allergic reaction or venous thrombosis. Other disadvantages include cost, patient discomfort, significant resource use, availability, the requirement for foot vein cannulation, intravenous contrast use, radiation exposure, and the possibility of secondary thrombi.  

In some countries, its use has been supplanted by venous ultrasound. It is generally reserved for difficult diagnostic cases. It may be considered in patients with suspected proximal DVT with inconclusive ultrasound assessment or when ultrasound is not feasible.  

Magnetic Resonance Imaging (MRI)  

MRI provides morphological and functional information about lung perfusion and right heart function but compared to CT scan MRI needs improvement in the image quality. It is useful in patients with suspected thrombosis of the superior and inferior vena cava or pelvic veins; but should be deferred in patients with suspected first lower extremity DVT.  

MRI helps distinguish an acute recurrent thrombus from a persisting thrombus in the same location and is useful in follow-up after DVT. It may be considered in patients with suspected proximal DVT with inconclusive ultrasound assessment or when ultrasound is not feasible. It has a similar diagnostic accuracy to that of ultrasound for assessing proximal DVT.
 
Plethysmography  

Computerized strain gauge plethysmography is rapid and easy to perform. It has shown a sensitivity of 90% for proximal DVT (popliteal, femoral, or iliac vein) and 66% for distal (calf vein) DVT.  

Impedance plethysmography (IPG) is another type of plethysmography. A normal finding with serial IPG is associated with a low risk of clinically important pulmonary embolism (<1%) or recurrent venous thrombosis (2%). Serial testing with IPG for 10 to 14 days appears to be effective for identifying patients with extending calf DVT.    

Spiral CT (sCT)

sCT has shown promise for the diagnosis of DVT and other soft tissue diseases in patients with leg swelling. It visualizes proximal obstructions and common, and superficial and deep femoral veins.  

Pulmonary Embolism  

Computed Tomographic Pulmonary Angiography (CTPA)  

CTPA is recommended as the initial lung imaging modality for patients with suspected pulmonary embolism, as it is the gold standard for the diagnosis of pulmonary embolism. It is increasingly used as an adjunct or alternative to other imaging modalities and is superior in specificity to ventilation-perfusion isotope scanning. 

Multidetector CT angiography (CTA) has 83% sensitivity and 96% specificity. A positive CTPA, with intermediate or high clinical pretest probability, is confirmed positive for pulmonary embolism and no further diagnostic testing is needed. A normal CTPA, with low or intermediate clinical pretest probability, is confirmed negative for pulmonary embolism and no further diagnostic testing is needed.  

It enables direct visualization of the pulmonary emboli and may provide information about parenchymal abnormalities that might help to establish an alternative diagnosis. It is more useful for patients with underlying cardiac disease, chronic obstructive pulmonary disease (COPD), or asthma. It has a high specificity and sensitivity for central clots and for the diagnosis of lobar and segmental pulmonary embolism. The main disadvantage of CTPA to that of conventional pulmonary angiography is that subsegmental clot is less likely to be seen. Patients with a good quality negative CTPA do not require further investigation or treatment for pulmonary embolism.  

Echocardiography  

Echocardiography is the most useful initial test which typically shows indirect signs of acute pulmonary hypertension and RV overload if acute pulmonary embolism is the cause of the hemodynamic changes. If the patient is unstable, thrombolytic treatment or surgery can be done based only on compatible echocardiography findings. If the patient has been stabilized, a definitive diagnosis should be pursued. Lung scan, sCT, and bedside transesophageal echocardiography (TEE) are usually able to confirm diagnosis. Normal lung scan or sCT angiogram suggests that another cause of shock should be found.  

It is useful for rapid triage in acutely ill patients with suspected massive pulmonary embolism. It is usually reliable to differentiate between illnesses that have radically different treatments compared to pulmonary embolism (eg acute MI, pericardial tamponade, infective endocarditis, aortic dissection, etc). It may suggest or reinforce clinical suspicion of pulmonary embolism with the findings of RV overload and dysfunction in the presence of Doppler signs of increased pulmonary arterial pressure. It may also definitively confirm the diagnosis of pulmonary embolism by visualization of proximal pulmonary arterial thrombi.  

It has not been confirmed that echocardiography can identify patients who will benefit from thrombolytic therapy if they present without shock or hypotension.  

sCT   

Higher-resolution multidetector-row CT imaging may be used as an initial imaging procedure for the diagnosis of pulmonary embolism. It has excellent sensitivity and specificity and can identify subsegmental embolus.  

Conventional Pulmonary Angiography  

Conventional pulmonary angiography is historically considered the gold standard for the diagnosis of pulmonary embolism. It is now rarely performed and has been replaced by CTPA. Limitations include the requirement of expertise in performance and interpretation, it is invasive and there are associated risks; if with subsegmental clot, there can be inter-observer disagreement in up to ⅓ of cases.  

Angiography should be reserved for patients in whom non-invasive tests remain inconclusive or are not available. The use of pulmonary angiography may also depend on the patient’s clinical status and the necessity to obtain an absolute diagnosis.  

Ventilation-Perfusion Lung Scanning (V/Q scan)  

Normal or near-normal lung scan with normal chest X-ray are sufficient to exclude pulmonary embolism, regardless of pretest probability. Low probability scans in combination with a low pretest probability make the probability of pulmonary embolism low. High-probability scans provide the predictive power to establish diagnosis in the context of reasonable suspicion of pulmonary embolism. A V/Q single-photon emission CT (SPECT) may also be considered for the diagnosis of pulmonary embolism. The rate of non-diagnostic tests is low at <3% compared with planar V/Q scan.
 
Venous Ultrasonography (US)  

Most pulmonary emboli arise from the deep veins of the legs thus it is rational to search for a residual DVT in suspected pulmonary embolism patients. It is used to improve the estimation of the clinical probability of pulmonary embolism and avoid more invasive testing in patients with a negative lung imaging study (eg CTPA). A CUS demonstrating a proximal DVT in a patient suspicious of pulmonary embolism confirms the diagnosis of VTE (and pulmonary embolism). If pulmonary embolism was confirmed using a positive proximal compression ultrasound, consider risk assessment to guide the patient’s management. 

A normal ultrasound examination of the leg veins does not rule out pulmonary embolism, hence, close monitoring is advised. Ultrasound studies may have false-positive results or may detect residual abnormalities from past VTE. Only definite positive studies under certain clinical circumstances (eg patient without a history of VTE but has a high clinical probability of pulmonary embolism) should serve as a basis for the start of therapy. 

Magnetic Resonance Angiography (MRA)  

MRA may be used as an alternative to CTPA in patients with iodinated contrast allergy or when other modalities are contraindicated. MRA appears to be promising in human and animal models. It avoids ionizing radiation but has poor sensitivity for subsegmental clots and limited access is likely to continue for several years.