Epidemiology and diagnostic tests for venous thromboembolism Edwin JR van Beek, MD PhD FRCR Section of Academic Radiology University of Sheffield, UK

Personal background Medical School, Rotterdam, NL 1987 MD Rotterdam, NL Surgical jobs, UK and NL 1994 PhD Amsterdam, NL (Pulmonary embolism) 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 findings suggestive for PE *Normal *Peripheral consolidation (“Hampton’s hump”) *Pleural effusion *Radiolucency (“Westermakr sign”)

ECG findings suggestive 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 %)

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 %) *Fatal PE: 1 (0.5%; 95% CI %)

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