Stephan Moll, MD University of North Carolina Chapel Hill, N.C. Dept. of Medicine, Heme-Onc smoll@med.unc Tel: 919-966-3

1. Venous Thromboembolism Stephan Moll, MD University of North Carolina Chapel Hill, N.C. Dept. of Medicine, Heme-Onc smoll@med.unc.edu Tel: 919-966-3311 Richmond 9/29/2006

2. A. Diagnosis Clinical assessment D-dimer B. Treatment LMWH, Fondaparinux, unfract. Heparin Outpatient versus inpatient Length of warfarin postthrombotic syndrome C. Other Education resources Overview

3. Case - History • HPI • 28 yr old woman with • left calf pain x 1 week • noticeable left ankle + thigh swelling • started without trigger • PMH • appendectomy age 16 • obesity (BMI 32.0) • Family Hx • Large family • Maternal grandmother: “clot in her leg at 63” • Meds • Yasmin®

4. L > R by 4 cm L > R by 2.5 cm Case – Physical Examination

5. Pre-test Probability - DVT • Clinical characteristics (Well’s criteria): • Active cancer • Paralysis or plaster immobilization • Bedridden ≥ 3 d; major surgery in 3 mo • Entire leg swollen • Calf swelling > 3cm • Pitting edema in affected leg • Collateral non-varicose superficial veins • Localized tenderness along deep veins • Previous DVT • Alternative dx more likely 1 1 1 1 1 1 1 1 1 -2 • score < 2: DVT unlikely • score ≥ 2: DVT likely • OCP, pregnancy, HRT [Wells PS. NEJM 2003;349:1227-35]

6. fibrin D D D D D D D-Dimer fibrinolytic system

7. D-dimer pos neg no test, no anticoag. imaging test Clinical Suspicion for DVT unlikely likely [Wells PS. NEJM 2003;349:1227-35]

8. Clinical characteristics (Well’s criteria): • Active cancer • Paralysis or plaster immobilization • Bedridden ≥ 3 d; major surgery in 3 mo • Entire leg swollen • Calf swelling > 3cm • Pitting edema in affected leg • Collateral non-varicose superficial veins • Localized tenderness along deep veins • Previous DVT • Alternative dx more likely 1 1 1 1 1 1 1 1 1 -2 Case – Physical Examination L > R by 2.5 cm • score < 2: DVT unlikely • score ≥ 2: DVT likely

9. D-dimer pos neg no test, no anticoag. imaging test Clinical Suspicion for DVT unlikely likely [Wells PS. NEJM 2003;349:1227-35]

10. Clinical characteristics (Well’s criteria): • Active cancer • Paralysis or plaster immobilization • Bedridden ≥ 3 d; major surgery in 3 mo • Entire leg swollen • Calf swelling > 3cm • Pitting edema in affected leg • Collateral non-varicose superficial veins • Localized tenderness along deep veins • Previous DVT • Alternative dx more likely 1 1 1 1 1 1 1 1 1 -2 Case – Physical Examination • score < 2: DVT unlikely • score ≥ 2: DVT likely

11. D-dimer pos neg no test, no anticoag. imaging test Clinical Suspicion for DVT unlikely likely [Wells PS. NEJM 2003;349:1227-35]

12. DVT Diagnosis • Doppler ultrasound • CT venogram • MR venogram • Contrast venography

13. D-Dimer Caveats • Know which test your lab uses • Neg. D-Dimer does not r/o distal DVT

14. Pre-test Probability - PE • Pre-test probability for PE: • Active cancer • Bedridden ≥ 3d or major surgery past 4 wks • Previous DVT/PE • Hemoptysis • Heart rate > 100/min • PE is most likely dx • Clinical signs + symptoms c/w DVT 1 1.5 1.5 1 1.5 3 3 • score ≤ 4: PE unlikely • score 4-6: moderate probability • > 6 high probability [Kearon, C. Ann Intern Med 2006;144:812-821] [Wells PS. Thromb Haemost. 2000;83:416-20]

15. D-dimer pos neg no test, no anticoag. imaging test Clinical Suspicion for PE low moderate or high [Kearon, C. Ann Intern Med 2006;144:812-821] [Wells PS. Thromb Haemost. 2000;83:416-20]

16. PE Diagnosis • Spiral (helical; PE-protocol) CT • VQ scan

17. Treatment – Thrombolytics • Does thrombolytic Rx ↓ development of PTS? • Not appropriately studied. ACCP guidelines for DVT: • Recommend against routine use [1A] • Confined to selected patients (limb salvage) [2C] [ACCP guidelines. Büller H et al. Chest 2004;126:401S-428S]

18. Thrombolytics in DVT My approach/indications: • Massive DVT (phlegmasia coerulea dolens) • Young patient with extensive DVT • Cancer patient – quality of life, short-term • Individual discussion • Catheter-directed, tPA 0.5 mg/h (1-2 ports) for 24 hr or longer

19. Thrombolytics in PE • Give in life-threatening PE • Consider in “submassive” PE (pulm. HTN or right ventricular dysfunction [NEJM 2002;347:1143-50] [NEJM 2002;347:1131-32]

20. Treatment – Distal DVT • Proximal = popliteal vein and above • 1st DVT with transient risk factor: Symptomatic calf vein DVT: Rx same as prox DVT • Spontaneous distal DVT: no comments [ACCP guidelines. Büller H et al. Chest 2004;126:401S-428S; page 410S]

21. Treatment – 1st Few Days • LMWH • Fondaparinux • Unfractionated heparin [Büller HR. NEJM 2003;349:1695-702] [Büller HR. Ann Intern Med 2004;140:867-873] • Overlap for at least 5 days

22. Treatment – Outpatient? Outpatient Rx: • Effective • Safe • Feasable • Cost saving ACCP on Acute DVT and PE: • LMWH qd or q 12 hr preferred over UFH (DVT/PE) • Outpatient if possible (DVT) [Büller H et al. Chest 2004;126:401S-428S] Admission: • significant DVT • “free-floating thrombus” • significant PE

23. Treatment – Outpatient? • Think twice! • Can patient afford cost of LMWH? • S.c. injection teaching • Access to INR-determination (anticoagulation clinic) • Warfarin dosing (nomogram) • Warfarin teaching • Elastic bandages/stockings – prescription Outpatient Rx • LMWH q 12 hr or q d • Fondaparinux q d • S.c. heparin, fixed-dose [NEJM 2006]

24. = TED Postthrombotic Syndrome Compression stockings • Grade 2, graduated (35 mm Hg at ankle, 25 at mid-calf, 18 at thigh) • individually fitted • below knee / above knee • as long as there is leg swelling

25. Postthrombotic Syndrome

26. Case – Thrombophilia w/u • Thrombophilia w/u: • FVLeiden • II 20210 mutation • ATIII activity • Protein C activity • Protein S test • Homocysteine • Anticardiolipin antibodies • Lupus anticoagulant • Anti-β2-glycoportein I antibodies

27. DVT Recurrence Rate • Low • Transient risk factor • Moderate • No abnormality detected • hetero factor V Leiden • hetero II 20210 Spontaneous VTE • Higher • APLA • AT III • hetero FVLeiden plus II 20210 • homo factor V Leiden?

28. DVT Recurrence Rate [NEJM 2004;350:2558-63]

29. DVT Recurrence Rate • D-dimer pos • Residual clot • Elevated factor VIII • Elevated factor IX • Elevated factor XI • Men > women D-dimer (on anticoagulants) VIII [Thromb Haemost 2002;88:162-3] [NEJM 2000;343:457-62] [Blood 2003;102:abstract 1133] [NEJM 2004;350:2558-63] [Br J Haematol 2004;124:504-10] D-dimer (off anticoagulants) [Thromb Haemost 2002;87:7-12] [Blood 2004;103:3773-6] [JTH 2006;4:1208-14] Residual clot IX [Blood 2004;103:3773-6] XI [Blood 2004;103:3773-6]

30. Obtain: D-dimer Doppler legs Lowest risk: woman; DVT; neg. D-dimer; no residual clot; was on OCP Stop warfarin INR 2.0- 3.0 • Stable INRs? • Bleeding • Lifestyle changes? • Patient preference Highest risk: man, PE; pos. D-dimer; + residual clot Length of warfarin Rx My own approach Acute DVT/PE 6 mo

31. Low-dose warfarin? • Full-intensity warfarin (INR 2-3) is more effective than low-intensity (INR 1.5-2.0) • Low-intensity is also effective • Bleeding with full-intensity warfarin is similar to low-intensity • When choosing long-term warfarin, choose full-intensity. [PREVENT trial: NEJM 2003;348:1425-34] [ELATE trial: NEJM 2003;349:631-639]

32. Case – @ 6 months • Significant chronic left leg swelling + pain • D-dimer negative • Doppler Ultrasound: - “Leg: no residual clot”- “Suggestion of obstruction prox. to inguinal ligament”. • You think she may have……? May Thurner syndrome • You order…..? Pelvic CT or MR venogram

33. May Thurner Syndrome Stenting

34. Postthrombotic Syndrome • www.biocompression.com • www.lympha-press.com

35. Thrombosis risk Birth Control Options • Estrogen combination pill • 3rd generation • 2nd generation ??? Yasmin® Ortho Evra® • Progestin-only • Depot Provera® • Minipill • Mirena IUD ® Non-hormonal methods www.fvleiden.org

36. For Health Care Providers www.nattinfo.org NATT

37. The Top 6 Questions I Get Asked 1. “What birth control options are there for women with h/o thrombosis or thrombophilia?” 2. “For the woman on warfarin, is it o.k. to take birth control pills?” 3. “What can the postmenopausal woman with h/o thrombosis or thrombophilia take for vaginal dryness?” 4. “What can be done about warfarin-associated fatigue?” 5. “What can be done about warfarin-associated hairloss?” 6. “What can be done about widely fluctuating INRs?”

38. Summary • High / low likelihood of DVT/PE (Well’s criteria) • D-dimer if low likelihood of DVT/PE • Thrombolytics: occasionally • Outpatient Rx: yes, but assess feasability • Thrombophilia w/u • Length of warfarin (thrombophilias, ♂ > ♀; D-dimer; lifestyle) • Compression stockings (grade 2); stents; pumps • www.nattinfo.org • DVT Prophylaxis