PE / DVT

1. PE / DVT Andrea Wilson May 20/ 2004

2. Virchow’s triad • Hypercoagulability • Stasis • Venous injury

3. Hypercoagulability Previous DVT/PE Malignancy Inflammatory conditions (SLE, IBD, PVD) Nephrotic syndrome Sepsis HIT Coagulation disorders Factor V Leiden mutation Resistance to activated Protein C  Protein S deficiency  Protein C deficiency  Antithrombin deficiency  Disorders of fibrinogen or plasminogen  Antiphospholipid antibodies (lupus anticoagulant and anti-cardiolipin) Increased estrogen (causes urinary loss of protein S and AT III) Pregnancy & Post-partum < 3 months Elective abortion or miscarriage OCP or other estrogens Intimal damage Intravenous drug abuse Trauma /Recent surgery Central lines Multifactorial Trauma Recent surgery Immobilization >3 days Long trips > 4hr in past 4 wks Age > 60 Cardiac disease: MI, CHF Obesity CVA, neurotrauma Lower limb arteriopathy Risk factors (EMR)

4. DVT

5. PATHOPHYSIOLOGY INCITING EVENT INTIMAL DEFECT IN VEIN COAGULATION CASCADE ACTIVATED AND PROMOTES PROXIMAL GROWTH OF THROMBUS VENOUS HYPERTENSION DEVELOPS PAIN AND SWELLING EMBOLIZATION (NOT UNIVERSAL)

6. PATHOPHYSIOLOGY FIBRINOLYTIC SYSTEM OPPOSES COAGULATION CASCADE CLOT ORGANIZES/DISSOLVES (PARTIALLY) RECANALIZATION OVER SEVERAL WEEKS FIBROBLASTS AND CAPILLARY DEVELOPMENT LEAD TO INTIMAL THCKENING VENOUS HYPERTENSION AND RESIDUAL CLOT DESTROY VALVES POSTPHLEBITIC SYNDROME (EDEMA, SCLEROSIS, ULCERATION, ACUTE EPISODES OF PAIN/SWELLING)

7. Pathophysiology: • most start in calf, extend proximally (~90%) • 70% PE have DVT evidence at autopsy • Symptomatic DVT in popliteal or prox veins in >80% cases • Most pts with symptomatic prox DVT but no chest sx have PE (40% high probability scans)- Kearon • Anand 1999 says 50% Clive Kearon, CMAJ 2003 Tintinalli

8. History • Many No Sx • Leg pain in 50% -> nonspecific • Amount pain / tenderness do not correlate to severity • What questions would you ask?

9. History • 1. Have you or anyone in your family ever had a blood clot in their leg or lung? • 2. Have you been on a long trip (e.g., car, plane, etc.)? • 3. Have you recently been bedridden for more than three days? • 4. Have you had surgery or trauma in the last 2-3 months? 5. Have you been pregnant in the last three months (Therapeutic abortion, miscarriage, current pregnancy)? • 6. Are you on birth control pills and do you smoke? • 7. Do you have any medical problems (e.g., malignancy, SLE, CHF)? • 8.Have you had chest pain or shortness of breath? Colucciello SA. Protocols for Deep Venous Thrombosis (DVT): A State-of-the-Art Review Part I: Risk Factor Assessment, Physical Examination, and Current Diagnostic Modalities. www.EMR online

10. Physical • No ONE reliable history / physical finding • Sensitivity 60-96%, Specificity 20-72% • Need to look @ combination of factors • Anand SS, Wells PS, Hunt D, Brill-Edwards P, Cook D, Ginsberg JS. Does this patient have deep vein thrombosis? JAMA. 1998 Dec 2;280(21):1828-9.

11. ?

12. Physical • Edema (unilateral) (> 3cm) • Homan’s (50% sens) = USELESS • Superficial thrombophlebitis (up to 40% can have) • Fever (>39.5, something else) • Phlegmasia cerulea dolens • Swollen purple leg re venous engorgement • Cyanosis re massive venous obstruction • Phlegmasia alba dolens • Whitish inflammation associated with arterial spasm 2nd to massive venous obstruction • Worry about arterial occlusion

13. Anand SS, Wells PS, Hunt D et al. Does This Patient Have Deep Vein Thrombosis? JAMA 1998; 279: 1094-1099.

14. DIFFERENTIAL DIAGNOSIS • cellulitis • abscess • Baker’s cyst • CHF • MSK injury • lymphedema • postphlebitic syndrome • malignancy • superficial phlebitis • factitious • fracture • AV fistula • compartment syndrome • acute arthritis • nerve root irritation • myositis Colucciello SA. Protocols for Deep Venous Thrombosis (DVT): A State-of-the-Art Review Part I: Risk Factor Assessment, Physical Examination, and Current Diagnostic Modalities. www.EMR online

15. Clinical Presentation:DVT • Calf-popliteal • 80-90%, many asymptomatic • pain & swelling • spreads proximally • Ileofemoral • pain in buttock, groin • thigh swelling • 10-20% cases

16. Case • 55-year-old woman • pain, swelling, warmth, and redness R calf. • She denies injury to the leg, or previous DVT. • On IV chemotx for ovarian carcinoma dx 6 mos ago. Extensive pelvic LN involvement, R>L, was present at diagnosis, • ?due to extrinsic compression of the right iliac vein • Now… no LNs palpable & recent pelvic U/S showed a reduction in the adenopathy. • Pitting edema, erythema, increased warmth of R calf (> 3.5 cm greater than L), & tenderness of the popliteal vein. Anand SS, Wells PS, Hunt D et al. Does This Patient Have Deep Vein Thrombosis? JAMA 1998; 279: 1094-1099.

17. Wells Criteria for Probability of DVT LOW PROB < 0 points MOD PROB 1 or 2 points HIGH PROB >3 points

18. What if • 60 yo man with calf swelling and active cancer • ? • D-dimer + • ? • Duplex U/S negative • ?

19. Algorithm for Suspected first DVT:Perrier. Lancet, 1999

20. LOW PROBABILITY DVT D-Dimer Neg Positive STOP CUS legs DVT Normal STOP TREAT

21. MODERATE PROBABILITY DVT D-Dimer Neg Positive STOP CUS legs Normal DVT CUS leg in 1 week TREAT Normal Positive STOP TREAT

22. HIGH PROBABILITY DVT CUS legs Normal DVT Venography TREAT Normal Positive STOP TREAT

23. Incidence of DVT by Clinical Probability

24. D-Dimer • Enzyme-linked immunosorbent assays, latex agglutination assays, and a whole blood agglutination test • PPV poor; NPV excellent • NOT to r/o PE in high PTP

25. DIAGNOSIS: BLOOD TESTS • D-dimer • degradation product of cross-linked fibrin • measured by whole blood agglutination (SimpliRED), latex agglutination, and ELISA • advantages: rapid, 93% sensitive for proximal DVT • disadvantages: low specificity, false positives in patients with recent surgery/trauma, hemorrhage,recent MI/CVA, acute infection, DIC, pregnancy/recent delivery, active collagen vascular disease, liver disease, metastatic Ca, 90% +ve >80 yrs old • highest NPV in low risk patients

26. D-dimer AssaysVan der Graaf. Thromb Haemost, 2000.

27. Alveolar dead space? • Alveolardeadspace should increase after PE as a result of arterial vascular occlusion because some pulmonary segments are ventilated but not perfused. • Kline et al (JAMA) evaluated the diagnostic accuracy of alveolar dead space determination + d-dimer assay for dx of PE. • combination of tests performs slightly better than either test alone (negative likelihood ratio). Niemann JT. Diagnostic Accuracy of a Bedside D-Dimer Assay and Alveolar Dead-Space Measurement for Rapid Exclusion of Pulmonary Embolism: A Multicenter Study. Annals of Emergency Medicine. 2001; 38 (6)

28. Ultrasound • Duplex doppler ultrasound • combines Doppler flow with 2D scanning • Doppler component evaluates blood flow for proximal obstruction, color flow provides most accurate images, and 2D scan provides 2D image of vein and surrounding structures • non-invasive, portable • loss of compression = DVT • We don’t look below popliteal

29. Diagnostic Imaging for DVT • Duplex / compression U/S +ve in 30-50% PE; 5% non-dx V/Q scans • 97% sensitive for acute thrombi above the knee, 94%specific (Tintinalli) • Only 58% sensitive in asymptomatic DVT (Anand) • also good for other causes of leg swelling • limitations: expensive, operator dependent, less sensitive for: clots below knee (73%), pregnancy, and nonoccluding thrombi, acute vs chronic

30. Serial Venous U/S • may avoid angiography in ?PE • In low-risk: an initial N U/S or 2 done 1 wk apart carries a <1% risk of symptomatic proximal DVT or PE at 3 mos. • You can hold the anticoagulant if initial U/S negative (safe) • 1-2% +ve in 2 weeks (?PE)

31. Anand et al 1999 • Making the point that if results are discordant then further testing needed. • A lot of venography / different than ours.

32. Impedance Plethysmography • measures change in lower extremity volume as a function of venous outflow in response to certain stimuli • changes in calf circumference, cutaneous blood flow, or electrical resistance occur when there is obstruction of venous return • Does not allow direct visualization of veins • suggests that DVT is present when significant outflow obstruction present, (if no extrinsic venous compression or conditions associated with elevated central venous pressure). • operator dependent

33. Impedance plethysmography • IPG • false positives occur in the setting of post phlebitic syndrome, abdominal tumors, pregnancy, and CHF • sensitivity 73-96% , specificity 83-95%, 97%NPV (Tintinalli) • sensitivity over a 10d-2 week follow-up period approaches that of ultrasound, thus used for outpt F/U (Calgary protocol is day 1, 4, 7, and 10 after negative U/S at day 0) • Not good for calf clots either

34. IPG vs. Doppler • N=985 • PPV U/S=94% (CI 87-98%) • PPV IPG =83% (CI 75-90%) • P=0.02 • Harriet Heijboer, Harry R. Buller, Anthonie Lensing, Alexander Turpie, Louisa P. Colly, and Jan Wouter ten Cate. A Comparison of Real-Time Compression Ultrasonography with Impedance Plethysmography for the Diagnosis of Deep-Vein Thrombosis in Symptomatic Outpatients NEJM Volume 329:1365-1369November 4, 1993Number 19.

35. U/S • What if the U/S or IPG is inconclusive or there was a potential for false + or false - results? • With tx of proximal DVT, residual thrombosis is evident on U/S scans in ~50% of pts after 1 yr • Contrast venography or MRI

36. Venography • “?Gold Standard?” • Invasive • Contrast • Need experienced readers • Non-diagnostic up to 25% • May induce DVT in 3% (Anand)

37. DIAGNOSIS:IMAGING • Venography • gold standard, but: • radiologists’ interpretations differ 10% of the time • 5-15% are inadequately done • 2-5% of patients develop phlebitis (sup. or deep) • risk of anaphylactoid reactions exists +able to distinguish between acute and chronic events as well as collateral channels +test of choice for the post-surgical patient as U/S not sensitive enough +useful if U/S inconclusive

38. Anand SS, Wells PS, Hunt D et al. Does This Patient Have Deep Vein Thrombosis? JAMA 1998; 279: 1094-1099.

39. Diagnostic Imaging (Tintinalli)

40. Treatment • Goal: prevent PE

41. TREATMENT • Unfractionated heparin • works on intrinsic pathway • activates antithrombin III to prevent conversion of fibrinogen to fibrin • prevents extension of thrombus but does not remove existing thrombus • narrow therapeutic window • significant bleeding in 7-30% of patients • thrombocytopenia in 3% • use weight based nomogram instead of fixed dosing (more patients therapeutically anticoagulated within 12 hours) • largely replaced by LMWH for treatment of DVT

42. TREATMENT • Low molecular weight heparin • primarily inhibits factor Xa more so than IIa, therefore, doesn’t affect PTT and no need for therapeutic monitoring • greater bioavailability and more predictable therapeutic anticoagulant effect • tinzaparin (Innohep) approved for use in Canada for DVT, enoxaparin (Lovenox) in the U.S. • Can still test for hypercoagulable states • reversible with protamine 1 mg/100 U LMWH • continue until INR therapeutic for 2 consecutive days, then stop • safety of home administration well-established

43. Treatment of VTE:Anticoagulation • LMWH superior to UFH? (Gould 1999) • More predictable anticoag effect, easier, lower incidence of major bleeding and HIT, lower mortality, reduction in clot extension, fewer recurrent thromboembolic events • out-pt Rx safe in PE (Kovacs, 2000) • Cost-effective (Gould 1999) • Only measure anti-Xa levels in renal failure pts. • Avoid if CR > 180 umol/L

44. Anticoagulation • Enoxaparin 1mg/kg bid or 1.5mg/kg od (max 180 mg) • Tinzaparin 175 anti-Xa u/kg od (max 18,000 U) • Weight-based dosing (actual not ideal weight) • start warfarin 5mg on day 1 • d/c LMWH when INR >2.0 x 2 days • Rx 3 mos if 1st and reversible cause • 6 mos if non-reversible • indefinite if recurrent, CA, genetic • Anticoagulation Clinic

45. TREATMENT • Warfarin • acts on extrinsic pathway (factor VII) to inhibit vitamin K dependent factor synthesis (II, VII, IX, X) • started same day as heparin • theoretical risk of worsening thrombosis if started before heparin in patients with protein C or S deficiency (procoagulant effect) but studies have demonstrated safety of starting in ED • INR between 2-3 provides adequate anticoagulation without serious increase in bleeding risk

46. TREATMENT • IVC – controversial: no survival benefit • If anticoag C/I, major bleed, HIT, persisting DVT or embolization after 1-2 wks therapeutic anticoag. • Thrombolytics • may have decreased risk of post-phlebitic syndrome over patients treated with heparin? • increased risk of hemorrhagic complications over heparin has prevented its widespread use • should be used for phlegmasia dolens if heparin fails (also consider thrombectomy) • Consideration for extensive iliofemoral thrombosis and UEDVT: SK or tPA + heparin

47. Indications for Admission • Unable to ambulate • Poor social support • Unreliable follow up • Unable to educate re: drug administration • Need for lytic or invasive tx • Query arterial ischemia, cellulitis or pelvic mass • (Tintinalli)

48. SPECIAL CONSIDERATIONS • Superficial phlebitis • while isolated cases are benign and can be treated with NSAIDs and compression bandages, • Incidence of DVT from extension of a superficial thrombus ~3% but incidence of embolization very low • recommended that all patients be followed serially with U/S or IPG to ensure no propagation to deep venous system • Do F/U U/S in 1 week • (Tintinalli)

49. SPECIAL CONSIDERATIONS • Upper extremity DVT • 2-4% of all DVT in axillary or subclavian V • can cause PE (originally thought to be benign) • etiology: “effort thrombosis” in physically active people, thoracic outlet syndrome, cervical rib, central line, malignancy • 25% Paget-von Schroetter syndrome • Exertional DVT • Caused by underlying MSK deformities

50. Upper Extremity DVT • N=58 Sx UEDVT • IPG, Doppler, venography • Test Sens & Spec: • compression ultrasonography (96% and 93.5%) • color flow Doppler imaging (100% and 93%) • 27 (47%) + UEDVTPE “Objectively” found in 36% • 2 yr F/U: 2 recurrent VTE • RF: • CVC • Thrombophilia • Previous VTE • Prandoni P, Polistena P, Bernardi E, et al Upper-extremity deep vein thrombosis. Risk factors, diagnosis, and complications. Arch Intern Med. 1998 Sep 28;158(17):1950-2.