1. 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 Venous Thromboembolism

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

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

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

5. 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 OCP, pregnancy, HRT Pre-test Probability - DVT [Wells PS. NEJM 2003;349:1227-35] 1 -2 score < 2: DVT unlikely score ≥ 2: DVT likely

6. D-Dimer fibrin DD DD DD fibrinolytic system

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

8. Case – Physical Examination 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 -2 score < 2: DVT unlikely score ≥ 2: DVT likely L > R by 2.5 cm

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

10. Case – Physical Examination 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 -2 score < 2: DVT unlikely score ≥ 2: DVT likely

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

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

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

14. 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 Pre-test Probability - PE 1 1.5 1 1.5 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. Clinical Suspicion for PE low moderate or high neg no test, no anticoag. imaging test pos D-dimer [Kearon, C. Ann Intern Med 2006;144:812-821] [Wells PS. Thromb Haemost. 2000;83:416-20]

16. 1.Spiral (helical; PE-protocol) CT 2.VQ scan PE Diagnosis

17. Treatment – Thrombolytics 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] Does thrombolytic Rx ↓ development of PTS? Not appropriately studied.

18. 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 Thrombolytics in DVT

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

20. Treatment – Distal DVT Proximal = popliteal vein and above 1 st 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 – 1 st Few Days [Büller HR. NEJM 2003;349:1695-702] [Büller HR. Ann Intern Med 2004;140:867-873] LMWH Fondaparinux Unfractionated heparin Overlap for at least 5 days

22. a)significant DVT b)“free-floating thrombus” c)significant PE Admission: Treatment – Outpatient? Outpatient Rx: 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] a)Effective b)Safe c)Feasable d)Cost saving

23. 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 Treatment – Outpatient? [NEJM 2006]

24. 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 Postthrombotic Syndrome = TED = TED

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-β 2 -glycoportein I antibodies

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

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

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

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

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

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

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

37. The Top 6 Questions I Get Asked 1. “What birth control options are there for women with h/o thrombosis or thrombophilia?” 3. “What can the postmenopausal woman with h/o thrombosis or thrombophilia take for vaginal dryness?” 2. “For the woman on warfarin, is it o.k. to take birth control pills?” 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