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

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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?

9. 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)

10. 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

11. 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

12. Points of interest in clinical history *Onset of symptoms *Previous VTE *Family history *Risk factors (increasing number known!)

13. Chest X-ray findings suggestive for PE *Normal *Peripheral consolidation (“Hampton’s hump”) *Pleural effusion *Radiolucency (“Westermakr sign”)

14. ECG findings suggestive for PE *Right bundle branch block *Right axis shift *Tachycardia or new onset atrial fibrillation *S1Q3T3 pattern

15. 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

16. 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%)

17. 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)

18. 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

19. 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%)

20. 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%)

21. 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%)

22. 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

23. 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.

24. 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%).

25. 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

26. 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.

27. 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%)

28. 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

29. 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!

30. 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.

31. Management issues *Pregnancy *Children *Suspected recurrent PE *Chronic Thromboembolic Pulmonary Hypertension