Epidemiology and diagnostic Epidemiology and diagnostic tests fortests for

venous thromboembolism venous thromboembolismEdwin JR van Beek, MD PhD FRCR

Section of Academic Radiology

University of Sheffield, UK

Personal background

1980-87 Medical School, Rotterdam, NL

1987 MD Rotterdam, NL

1987-90 Surgical jobs, UK and NL

1994 PhD Amsterdam, NL (Pulmonary embolism)

1994-99 Radiology training, NL

1999 FRCR, London, UK

Venous thromboembolism (VTE)

* Consists of two clinical pictures:

1. Deep vein thrombosis (DVT)

2. Pulmonary embolism (PE)

* Intimately related in etiology, treatment and outcome.

* 50% of proven DVT also have PE

* 70% of proven PE also have DVT

Incidence of Venous thromboembolism

* Clinical suspicion PE: 2-3 per 1000/ year* Proven PE: 0.5 per 1000/year* Clinical suspicion DVT: 2-3 per 1000/year* Proven DVT: 1 per 1000/year* Japan: 50 to 100-fold less common

Risk factors: congenital

* Deficiencies: antithrombin, protein C, protein S, plasminogen, factor XII

* Mutations: factor V Leiden (APC-R), prothrombin 20210A

* Congenital dysfibrinogenemia* Hyperhomocysteinemia* Thrombomodulin disorders* Dysplasminogenemia* Anticardiolipin antibodies* Excessive plasminogen activator inhibitor

Risk factors: acquired

* Surgery (incl. Orthopaedics, trauma, neurosurgery)* Immobilisation: fractures, stroke* Malignancy, chemotherapy, central venous catheters* Heart failure, chronic venous insufficiency* Pregnancy, puerperium, oral contraceptives* Albumin loss: Crohn’s disease, nephrotic syndrome* Hyperviscosity (Polycythemia, Waldenstrom’s

macroglobulinemia)* Platelet abnormalities

Importance of Diagnosis

* 70% of patients with clinical suspicion will not have diagnosis confirmed

* Anticoagulants may have serious adverse (haemorrhagic) effects:

- 1 per 100 treatment years: fatal bleeding

- 4%-16% serious hemorrhagic events

Risk of Missed Diagnosis

* 30% of patients with untreated PE will suffer fatal second event

* 30% of patients with untreated PE will suffer non-fatal second event:

- pulmonary hypertension risk increase?

- post-thrombotic syndrome risk increase?

Role of diagnostic strategy

* Balance between missed/over-diagnosis

* Initial risk of recurrent PE: physicians will be likely to treat patients

* Diagnostic tests are there to:

1. Offer alternative diagnosis

2. Exclude VTE

3. Prove VTE (this affects management least)

Main diagnostic aids in suspected PE

* Clinical diagnosis (history, examination)

* ECG, chest X-ray

* Traditional tests: lung scintigraphy, angiography

* Newer tests: US, CT, D-dimer, cardiac US, MRA

Clinical signs VTE

* Dyspnea (often sudden onset)

* Haemoptysis

* Collapse

* “Fear of dying”

* Redness of leg

* Pleural chest pain

* Tachycardia

* Cyanosis (subclinical)

* Coughing

* Leg swelling

* Tenderness of calf

Points of interest in clinical history

* Onset of symptoms* Previous VTE* Family history* Risk factors (increasing number known!)

Chest X-ray findingssuggestive for PE

* Normal

* Peripheral consolidation (“Hampton’s hump”)

* Pleural effusion

* Radiolucency (“Westermakr sign”)

ECG findingssuggestive for PE

* Right bundle branch block* Right axis shift* Tachycardia or new onset atrial fibrillation* S1Q3T3 pattern

Pulmonary angiography

* Gold standard

* Normal angiogram effectively rules out PE

* Physicians are reluctant to use it:

- fear, “invasive”, availability

* Major changes:

contrast agents, catheters, guide wires, DSA

Pulmonary angiography:Safety

* Studies before 1990:

* 2203 patients

* 5 deaths (0.2%)

* 42 compl (1.9%)

* Studies after 1990* 3613 patients* 1 death (0.03%)* 17 compl (0.47%)

Lung scintigraphy:PIOPED Classification

* Normal (<1% PE)* Very low probability (<10% PE)* Low probability (<19% PE)* Intermediate probability (20-79% PE)* High probability results (>80% PE)

Lung scintigraphy:Classification discussions

* How low is low probability?

* PIOPED: very low: 10% PE; low: 16% PE

* Clinicians do not realize this!!

* Suggested: normal, high probability and non-diagnostic

Lung scintigraphy:Normal perfusion scan

* Obtained in 20-30% of ?PE patients* 3 studies with 693 patients: anticoagulants

withheld and follow-up 3-6 months* Risk of recurrence: 0.3% (95%CI 0.2-0.4%)

Lung scintigraphy:High probability VQ scan

* Obtained in 20-30% of ?PE patients* 9 studies with 350 patients compared with

pulmonary angiography* Pos. Pred.Value: 88% (95%CI 84-91%)

Lung scintigraphy:Non-diagnostic (V)Q scan

* Obtained in 40-60% of ?PE patients* 12 studies with 1529 patients compared

with pulmonary angiography* PE present: 25% (95%CI 24-28%)

Ultrasonography of the deep venous system

* Direct visualization of thrombus in PE and DVT

* Based on 70-90% prevalence of DVT in proven PE.

* Repeated ultrasonography over 7-10 day period:

- replaces venography in suspected DVT

- may be able to replace angiography in suspected PE

Ultrasonography of the deep venous system in suspected PE

* Single investigation: sens 30%, spec 97%

* Only to prove PE!

* Problem: false positive leads to treatment.

* Cost-effectiveness in doubt.

Plasma D-dimer

* Break-down product of cross-linked fibrin.

* Only ELISA and recent rapid unitary ELISA reach sensitivity approaching 100%.

* Able to safely exclude >35% of suspected patients in A&E department.

* Comorbid conditions increase D-dimer levels (specificity approximately 50%).

Helical CT pulmonary angiography: studies

* 12 studies CT vs scintigraphy/angiography

* 1171 patients, prevalence PE 39%

* Sensitivity 88%, Specificity 92%

* Problem 1: high prevalence

* Problem 2: poor results in subsegmental PE

Anatomical distribution of PE

* 3 studies using pulmonary angiography.* 1 retrospective and 2 prospective.* 15-30% isolated subsegmental PE* In all with suspected PE: 5-8% isolated

subsegmental PE.

Helical CT: two management studies

* Study 1: 164 patients: N-D lung scan, normal US.* Prevalence PE 24%, follow-up only in 109 patients* Recurrent VTE: 6 (5.5%; 95% CI 2-12%)* Fatal PE: 1 (1%; 95% CI 0.02% - 4.3%)* Study 2: 398 hCT, 285 normal (72%)* Follow-up only in 198 (70%)* Recurrent PE: 2 (1%; 95% CI 0.12-3.57 %)* Fatal PE: 1 (0.5%; 95% CI 0.01-2.75%)

Echocardiography for suspected PE

* Direct visualization of (central) thrombus* Assessment of right ventricular function* Measurement of pulmonary arterial pressure* Useful in suspected massive PE* Potentially useful for therapy monitoring

Magnetic Resonance Angiography

* No ionizing radiation, non-invasive.

* Promising new technology, fast developments.

* Pulmonary perfusion studies possible.

* Early results show similar problems to helical CT: subsegmental PE difficult!

Management strategies for suspected PE: clinical factors

* Massive PE: hemodynamic instability.

* Sub-massive PE: echocardiographic signs of RV dysfunction only.

* Non-massive PE: no hemodynamic effects detectable.

Management issues

* Pregnancy

* Children

* Suspected recurrent PE

* Chronic Thromboembolic Pulmonary Hypertension