Venous%20thromboembolism%20-%20management Diagnosis

Recommended Diagnostic Tests for DVT based on Clinical Pretest Probability Result 

• Low pretest probability: D-dimer, duplex venous ultrasonography (DUS) with compression, venography, whole-leg ultrasonography (US)
• Moderate pretest probability: D-dimer, proximal DUS with compression, venography, whole-leg US
• High pretest probability: Proximal DUS with compression, whole-leg US, venography

Diagnostic Tests for PE

• 1st-line diagnostic tests (eg electrocardiogram [ECG], chest X-ray and arterial blood gases) are indicated to assess clinical probability of PE and general condition of patient

According to Anatomical Level

• Accurate anatomical classification is important for diagnostic, therapeutic, and prognostic purposes as risk of PE, post-thrombotic syndrome development and overall prognosis are different depending on the affected veins
• Classified into:
  • Proximal DVT: Thrombosis of iliac, femoral, and/or popliteal veins with or without calf DVT
    • Femoropopliteal DVT
    • Iliofemoral DVT which commonly occurs on the left
  • Distal DVT: Thrombosis is confined to the calf deep veins (eg peroneal, posterior tibial, gastrocnemius or soleal veins)
    • Often associated with transient risk factors (eg recent surgery, plaster placement for limb fracture, travel)

According to Etiology

• Classified as provoked or unprovoked based on the presence of risk factors
  • Unprovoked or idiopathic DVT: Venous thrombosis without identifiable environmental or acquired risk factors
  • Provoked DVT: Occurs in the presence of risk factors which may be transient minor or major risk factors, or persistent risk factors
• Risk of recurrence and anticoagulation therapy will differ based on etiology and chronicity of the risk factors
  • Risk of recurrence is higher when DVT is provoked by a persistent and progressive risk factor (eg cancer)
  • Risk of recurrence after stopping anticoagulation is very low when DVT is provoked by a major transient risk factor (eg trauma, surgery, estrogen therapy, pregnancy, puerperium) provided the risk factor is no longer present
  • Patients with unprovoked DVT have an intermediate risk of recurrence

Deep Vein Thrombosis

Clinical findings are important to the diagnosis of DVT but are poor predictors of the presence or severity of thrombosis

• Pretest probability is needed to guide the diagnostic process



WELLS SCALE OF CLINICAL PRETEST PROBABILITY FOR DEEP VEIN THROMBOSIS
Clinical Features	Points	Pretest              Total  Probability          Points
Entire leg swollen	1.0	High risk≥3 Moderate risk1-2 Low risk≤0 If both legs are symptomatic, score the more severe side Simplified version*: Likely≥2 Unlikely<2
Calf swollen by >3 cm compared to the asymptomatic side (measured 10 cm below tibial tuberosity)	1.0
Localized tenderness along the deep venous system distribution	1.0
Pitting edema (greater in the symptomatic leg)	1.0
Collateral superficial veins (non-varicose)	1.0
Immobilization for >3 days or major surgery within 12 weeks	1.0
Paralysis, paresis, recent plaster immobilization of lower extremity	1.0
Previously documented DVT	1.0
Active cancer (ongoing treatment within the last 6 months or current palliative therapy)	1.0
Alternative diagnosis as likely or greater than that of DVT	-2.0
Reference: Institute for Clinical Systems Improvement. Health care guideline: venous thromboembolism diagnosis and treatment. 13th ed. Jan 2013. *National Institute for Health and Care Excellence (NICE). Venous thromboembolic diseases: diagnosis, management and thrombophilia testing. https://www.nice.org.uk. 26 Mar 2020.

Pulmonary Embolism

Clinical Evaluation

• A reasonable clinical suspicion is required to avoid missing the diagnosis of PE
• Evaluating the likelihood of PE in an individual patient according to the clinical presentation is of utmost importance in the interpretation of diagnostic test results and the selection of an appropriate diagnostic strategy
  • A bedside transthoracic echocardiogram may be done in patients who are hemodynamically unstable to differentiate suspected high-risk PE from other acute life-threatening conditions
  • Patients should also be evaluated for risk factors for VTE
• It is recommended to perform initial risk stratification in hemodynamically unstable patients with suspected or confirmed PE to identify those with a high risk of early mortality 
• Acute PE severity may be stratified using validated scores from combined clinical, laboratory and imaging prognostic factors in patients who are hemodynamically stable   
  • The Pulmonary Embolism Severity Index (PESI) identifies the patient's overall mortality risk using PE severity and comorbidity 
    • A score of ≥1 indicates a 30-day mortality risk of 10.9% in the simplified version of PESI

Massive Pulmonary Embolism

• Accounts for 5-10% of cases 
• In patients with suspected massive pulmonary embolism who are too unstable for lung imaging, right ventricular (RV) dysfunction can usually be found at the bedside
  • Left parasternal heave, distended jugular veins and systolic murmur of tricuspid regurgitations that increases with inspiration

Sub-massive Pulmonary Embolism 

• Occurs in approximately 20-25% of patients 
• Subgroup of non-massive PE patients who present with the following:
  • Normal BP, normal tissue perfusion and clinical or echocardiographic evidence of RV dysfunction or myocardial necrosis
  • Elevation troponin, N-terminal pro B-type natriuretic peptide (NT-proBNP) or BNP

Low-Risk Pulmonary Embolism 

• Affects approximately 70% of patients with PE 
• PE that presents with normal systemic arterial pressure and RV function, and no elevated cardiac biomarkers 
• Patients with suspected or confirmed low-risk PE may be considered for outpatient treatment after clinical assessment and after being determined suitable using a validated risk stratification tool 

Pretest Probability of Pulmonary Embolism 

• All patients with possible PE should have clinical probability assessed and documented
  • Clinical probability may be estimated empirically or explicitly by a prediction rule
• There are 2 frequently used pretest probabilities of PE: Geneva score (Europe) and Wells scale (Canadian rule)

Geneva Score 

• Requires arterial blood gas measurement and a chest radiograph

GENEVA CLINICAL PREDICTION RULE FOR PULMONARY EMBOLISM
Clinical Features	Points	Simplified Version	Pretest               Total  Probability           Points	Simplified Version
Age >65 years	1	1	Based on likelihood of PE PE likely≥6 PE less likely0-5 According to risk groups High≥11 Intermediate4-10 Low0-3	≥3 0-2 ≥5 2-4 0-1
Active cancer	2	1
Fracture or surgery within the past month	2	1
Heart rate      75-94 bpm      ≥95 bpm	3 5	1 2
Hemoptysis	2	1
Previous DVT or PE	3	1
Unilateral edema and pain on lower-limb deep venous palpation	4	1
Unilateral pain in lower limb	3	1
Reference: 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). Eur Respir J. 2019 Aug 31.

Wells Scale

• Requires that the patient has clinical features suggestive of PE (eg breathlessness, and/or tachypnea with or without pleuritic chest pain and/or hemoptysis)
• Along with 2 other features:
  • Absence of another reasonable clinical explanation
  • Presence of a major risk factor

  WELLS SCALE OF CLINICAL PRETEST PROBABILITY FOR PULMONARY EMBOLISM
  Clinical Features	Points	Simplified Version*	Pretest               Total  Probability           Points
  Clinical signs and symptoms of DVT	3.0	1	Based on likelihood of PE PE likely>4 PE less likely≤4 According to risk groups High>6 Intermediate2-6 Low<2   Simplified version*: Likely≥2 Unlikely<2
  Alternative diagnosis is less likely than PE	3.0	1
  Heart rate ≥100 bpm	1.5	1
  Immobilization for ≥3 days or surgery within the past 4 weeks	1.5	1
  Previous DVT/PE	1.5	1
  Hemoptysis	1.0	1
  Malignancy (with treatment within the last 6 months)	1.0	1
  Reference: Institute for Clinical Systems Improvement. Health care guideline: venous thromboembolism diagnosis and treatment. 13th ed. Jan 2013. *2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). Eur Respir J. 2019 Aug 31.

Pulmonary Embolism Rule-Out Criteria (PERC)

• Use to identify group at very low risk of PE and to determine if additional investigations for PE are warranted 
  • May be used to determine the need for testing for D-dimer in patients with a low probability of PE presenting in the emergency department (ED)
• If the patient has answered yes in any of the following questions, the patient is Pulmonary Embolism Rule-Out Criteria (PERC) positive:
  • Is the patient >49 years?
  • Is the patient’s heart rate >99 bpm?
  • Is the patient’s pulse oximetry reading <95% while breathing room air?
  • Does the patient have hemoptysis?
  • Is the patient on exogenous estrogen? Does the patient have prior diagnosis of VTE?
  • Has the patient had surgery or trauma in the previous 4 weeks?
  • Does the patient have unilateral leg swelling at the calves?
• In selected patients, PE can be ruled out without imaging tests or D-dimer if PERC is negative  

• Lab results can be normal but some abnormal findings increase the suspicion for PE
• Baseline blood tests when initiating anticoagulation treatment includes a complete blood count (CBC), renal and hepatic function assessment, prothrombin time (PT) and activated partial thromboplastin time (aPTT) 

Arterial Blood Gas (ABG)

• Can show hypoxemia, hypocapnia and widened (A-a) O₂ difference

Electrocardiogram (ECG)

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

B-type Natriuretic Peptide (BNP) and Troponin

• Consider in a patient with substantial clot burden, abnormal echocardiogram or clinical findings suggestive of PE
• Elevated BNP and troponin are associated with RV strain and increased mortality even in the absence of hemodynamic instability

Plethysmography

• Computerized strain gauge plethysmography
  • Rapid and easy to perform
  • Has shown a sensitivity of 90% for proximal DVT (popliteal, femoral, or iliac vein) and 66% for distal (calf vein) DVT 

• Impedance Plethysmography (IPG)
  • Normal finding with serial IPG is associated with a low risk of clinically important PE (<1%) or recurrent venous thrombosis (2%)
  • Serial testing with IPG for 10-14 days appears to be effective for identifying patients with extending calf DVT

Deep Vein Thrombosis

Duplex Venous Ultrasonography (DUS) 

• B-mode, imaging (eg 2D) and pulse-wave Doppler interrogation
• Primary radiologic device for the evaluation of proximal DVT
  • Most often used non-invasive test to diagnose DVT in patients with moderate or high clinical pretest probability
  • 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 ultrasonography is incomplete vein compressibility
    • Proximal and distal compression US (CUS) for DVT has 90.3% sensitivity and 97.8% specificity
• Combined use of clinical pretest probability and duplex ultrasonography (with compression) is effective in confirming or excluding the diagnosis of DVT
  • In patients with clinical suspicion of DVT , positive D-dimer and negative ultrasonography, consider repeat ultrasonography for suspected calf thrombosis or venography for suspected proximal thrombosis in 3-7 days
• In patients with negative computed tomographic pulmonary angiography (CTPA) results and positive D-dimer and a PE likely clinical probability, further evaluation with DUS should be used to improve 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 PE 
  • For a negative result, incorporation of clinical pretest probability can improve diagnostic accuracy and potentially avoid unnecessary pulmonary angiography

Computed Tomography Venography (CTV)

• Effective method for diagnosis of proximal DVT in patients with suspected DVT and PE
• Has advantage over US in the evaluation of pelvic veins or inferior vena cava and in the detection of concurrent medical conditions causing pain and swelling
• Facilitates vessel measurement and case planning when intervention is needed due to its high-quality spatial resolution
• May be considered in patients with suspected proximal DVT with inconclusive US assessment or when US is not feasible
• Disadvantages include cost, use of iodine contrast and radiation exposure

Contrast Venography

• The gold standard for establishing the diagnosis of DVT
  • Offers precise detail of the venous anatomy and the ability to reliably exclude thrombosis in the calf
  • Can help distinguish between old and new clots
• Excellent for calf veins, but it is an invasive procedure, not always technically possible and carries a small risk of an allergic reaction/venous thrombosis
  • Other disadvantages include cost, patient discomfort, significant resource use, availability, requirement for foot vein cannulation, intravenous contrast use and possibility of secondary thrombi
  • In some countries, its use has been supplanted by venous ultrasonography
  • Generally reserved for difficult diagnostic cases
• May be considered in patients with suspected proximal DVT with inconclusive US assessment or when US is not feasible

Magnetic Resonance Imaging (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
• Useful in patients with suspected thrombosis of the superior and inferior vena cava or pelvic veins; should be deferred in patients with suspected first lower extremity DVT
• Helps distinguish acute recurrent thrombus from a persisting thrombus in the same location and is useful in follow-up after DVT
• Has a similar diagnostic accuracy to that of ultrasonography for assessing proximal DVT
• May be considered in patients with suspected proximal DVT with inconclusive US assessment or when US is not feasible

Spiral Computed Tomography (sCT) Scan

• Has shown promise for the diagnosis of DVT and other soft tissue diseases in patients with leg swelling
• Visualizes proximal obstructions and common, superficial and deep femoral veins

Pulmonary Embolism

Chest X-ray

• May demonstrate atelectasis, pleural-based infiltrates or effusions or rarely engorged central pulmonary artery associated with a paucity of peripheral vessels
• Near-normal radiographic results with severe respiratory compromise is highly suggestive of massive PE
• Westermark sign (focal oligemia) may indicate massive central embolic occlusion
• Hampton lump, a peripheral wedge-shaped density above the diaphragm, usually signifies pulmonary infarction

Computed Tomographic Pulmonary Angiography (CTPA)

• Recommended as the initial lung imaging modality for non-massive PE 
• Increasingly used as an adjunct or alternative to other imaging modalities and is superior in specificity to ventilation-perfusion isotope scanning
• Multidetector computed tomographic angiography (CTA) has 83% sensitivity and 96% specificity  
• A positive CTPA, with intermediate or high clinical pretest probability, is confirmed positive for PE and no further diagnostic testing is needed
• A normal CTPA, with low or intermediate clinical pretest probability, is confirmed negative for PE and no further diagnostic testing is needed 
• Enables direct visualization of the pulmonary emboli and may provide information about parenchymal abnormalities that might help to establish an alternative diagnosis
• More useful for patients with underlying cardiac disease, chronic obstructive pulmonary disease (COPD) or asthma
• Has a high specificity and sensitivity for central clots
• 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 PE 

Echocardiography 

• Most useful initial test which typically shows indirect signs of acute pulmonary hypertension and RV overload if acute PE is the cause of the hemodynamic changes
• If patient is unstable, thrombolytic treatment or surgery can be done based only on compatible echocardiography findings
• If 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
• Useful for rapid triage in acutely ill patients with suspected massive PE
  • Usually reliable to differentiate between illnesses that have radically different treatments compared to PE (eg AMI, pericardial tamponade, infective endocarditis, aortic dissection, etc)
  • May suggest/reinforce clinical suspicion of PE with the findings of RV overload and dysfunction in the presence of Doppler signs of increased pulmonary arterial pressure
  • May also definitively confirm diagnosis of PE by visualization of proximal pulmonary arterial thrombi
• It has not been confirmed that echocardiography can identify patients who would benefit from thrombolytic therapy if they present without shock or hypotension

Other Diagnostic Tests for PE

Conventional Pulmonary Angiography 

• Historically considered the gold standard for the diagnosis of PE 
• Limitations include requirement of expertise in performance and interpretation, it is invasive and there are associated risks
  • With subsegmental clot, there can be inter-observer disagreement in up to ¹/₃ of cases
• Angiography should be reserved for patients in whom non-invasive tests remain inconclusive or are not available
• Use of pulmonary angiography may also depend on patient’s clinical status and necessity to obtain an absolute diagnosis

Ventilation-Perfusion Lung Scanning (V/Q Scan)

• Normal or near-normal lung scans are sufficient to exclude PE, regardless of pretest probability
• Low probability scans in combination with a low pretest probability make probability of PE low
• High probability scans provide the predictive power to establish diagnosis in context of reasonable suspicion of PE 
• A VQ single-photon emission computed tomography (SPECT) may also be considered for the diagnosis of PE 
  • Rate of non-diagnostic tests is low at <3%

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 PE patients
• Normal US exam of the leg veins does not rule out PE
• US studies may have false positive or may detect residual abnormalities from past VTE
  • Only definite positive studies under certain clinical circumstances (eg patient without history of VTE but has a high clinical probability of PE) should serve as a basis for the start of therapy
• Used to improve estimation of the clinical probability of PE and avoid more invasive testing in patients with a negative lung imaging study
• A compression ultrasonography (CUS) demonstrating a proximal DVT in patient suspicious for PE confirms the diagnosis of VTE (and PE)   
  • If PE was confirmed using a positive proximal compression ultrasonography, consider risk assessment to guide patient’s management 

Magnetic Resonance Angiography (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 a poor sensitivity for subsegmental clots and limited access is likely to continue for several years

D-dimer Level by Enzyme-Linked Immunosorbent Assay (ELISA) for DVT

• A highly sensitive but nonspecific screening test for the presence of VTE 
  • D-dimer levels may also be elevated in patients with myocardial infarction, sepsis, cancer, inflammation, infection, necrosis, trauma, pregnancy, etc
  • Therefore, 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 thus reducing the need for imaging when used in conjunction with clinical probability, plethysmography, or ultrasonography (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 ED patients, in ambulatory care settings and in patients with recent onset of symptoms who are not currently taking anticoagulants
  • Can be used after a negative duplex US 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

D-dimer Level for PE

• A highly sensitive but a nonspecific screening test for the presence of PE
  • Sensitivity may be decreased if the duration of VTE manifestations is >2-3 days prior to testing and/or if the patient is on Heparin
  • Best used for evaluation of outpatients in the ED
• A negative D-dimer test via any D-dimer method (SimpliRED, Vidas or MDA) reliably excludes PE in patients with low clinical probability, such patients do not require imaging for VTE 
• A negative D-dimer test using ELISA (Vidas) or MDA methods reliably excludes PE in patients with intermediate probability
• A positive D-dimer requires further radiological evaluation to exclude PE 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 high clinical probability of PE 
• Inappropriate for suspected VTE with recent surgery or trauma and should proceed directly to radiologic studies eg DUS or CTPA

Absolute Contraindications to Thrombolysis

• Hemorrhagic stroke or stroke of unknown origin at any time
• Major trauma, surgery, or head injury in the past 3 weeks
• Ischemic stroke within the past 6 months
• CNS damage or tumors
• Severe coagulation disorders
• Active bleeding
• Known increased risk for bleeding (bleeding diathesis)

Relative Contraindications

• Transient ischemic attack within the past 6 months
• Puncture of a non-compressible vessel
• Uncontrolled severe hypertension (SBP >180 mmHg, diastolic BP [DBP] >100 mmHg)
• Neurosurgery or ophthalmologic surgery within the last 1 month
• Ischemic stroke within the last 2 months
• GI bleeding within the last 10 days
• Active peptic ulcer disease
• Recent traumatic cardiopulmonary resuscitation
• Pregnancy or within 1 week postpartum
• Infective endocarditis
• Oral anticoagulant therapy
• Advanced liver disease