Clot Controversies: Thrombolysis and VTE Prophylaxis

1. Clot Controversies: Thrombolysis and VTE Prophylaxis Timothy A. Morris, M.D. Professor of Medicine Division of Pulmonary and Critical Care Medicine University of California, San Diego

2. “A.S.” • 68 y.o. man • obese, smoker, inactive, inguinal hernia • Lost weight • Quit smoking • Exercise program • Elective inguinal hernia repair • “I want to do everything!”

3. Elective Inguinal Hernia Repair • Uneventful operative course • No prophylaxis

4. Disaster • 5 days post-op • Sudden cardiac arrest • No neurological recovery • Dx: massive PE

5. PE Epidemiology • 600,000 annual incidence of clinically recognized thromboembolism • True incidence may be three to ten times this amount.

6. Unsuccessful Pre-Hospital Resuscitation Silfvast. J Int Med. 1991;229:331-5

7. Mortality From “Massive” PE Kasper, et al. J Am Coll Cardiol, 1997

8. Ante-Mortem Dx of PE

9. Ages: freq distrib

10. Screening isn’t effective • Asymptomatic DVT are less detectable • Outcome studies show no effect of pre-discharge screening

11. Why doesn’t everybody prophylax?

12. Illusion of individual observation I’ve always done just fine without… • seatbelts • giving up smoking • fire escapes • DVT prophylaxis

13. Who gets DVTs and PEs Risk Stratification

14. Pathophysiology: Etiologies • Venous stasis • Endothelial damage • Hypercoagulability

15. Venous Stasis • bed rest, immobility • surgery (esp. for age >40 and time >30 min) • congestive heart failure • venous obstruction (especially previous DVTs) • obesity (most prevalent factor in Framingham study)

16. Endothelial Damage • previous DVTs • trauma • hip or knee replacement • Local inflammation • Torsion on vessel

17. Hypercoagulability • estrogen in pharmacologic doses • Factor V Leiden • Protein C or S deficiency • Lupus “anticoagulant” • Cancer • Ortho surg: mediators from marrow. • Contralateral leg DVT in 15-20% of cases

18. FVL and Hip/Knee Replacement Ryan, Ann Intern Med 1998

19. Risk Categories.

20. Low Risk • Minor surgery • No risk factors for DVT • Age under 40

21. Moderate Risk • Minor surgery • Risk factors for DVT • Surgery • Age 40-60

22. High Risk • Surgery • Age > 60 • Age 40-60 + risk factors for DVT

23. Highest Risk • Major surgery • Multiple risk factors for DVT • Hip or knee arthroplasty • Hip fracture surgery • Major trauma • Spinal cord injury

24. Risk of DVT and PE

25. Incidence of VTE* • General medical patients 10-26%1,2 • Stroke 11- 75%3 • Myocardial infarction (MI) 17-34%3 • Spinal cord injury 6 -100%3 • Congestive heart failure 20- 40%4 • Medical intensive care 25- 42%1,5,6 • 1. Cade 1982. 2. Belch et al., 1981. 3. Nicolaides et al., 1997. 4. Anderson et al., 1950. 5. Dekker et al., 1991. 6. Hirsh et al., 1995.

26. Prevention of DVT and PE:Medicine Patients

27. DVT in the ICU • 100 ICU patients followed for DVT1 • Screened with DUS (upper and lower) • On ICU admission • Twice weekly • One week after discharge 1. Hirsch, et al JAMA 1995

28. DVT in 100 ICU pts

29. DVT in MICU patients • 2/3 were off prophylaxis • 70% were positive on the first test • 43% of them had been in house > 5 days • All 5 UE clots were associated with IV catheters

30. Fatal PE in Medical Patients • 400 consecutive autopsies reviewed • Incidence of PE? • 200 consecutive admissions reviewed • Mortality? • Fatal PE (autopsy proven)? Baglin et al. J Clin Path 1997

31. Fatal PE in Med Pts Baglin et al. J Clin Path 1997

32. What type of prophylaxis?

33. Prophylaxis • Mechanical: venous compression • Pharmaceutical: anticoagulants

34. Venous compression • “TEDS” stockings: custom-made • Intermittent pneumatic compression stockings (IPC) • Safe: leg ischemia is a relative contraindication • Convenient • Effective: 48% RR for prox DVT

35. Mechanical Prophylaxis • OR of 0.28 for DVT in ICU1 • Five pooled trails • No comparative trials b/w IPC and TEDS • Very few adverse effects 1. Attia J et al Arch Int Med 2001

36. Anticoagulants • consider risk factors for thrombosis • consider bleeding risk

37. Clinical Decisions Thrombosis Bleeding

38. Antithrombotic Drugs • AT3 mediated • UH • LMWH • pentasaccharide • Direct Thrombin Inhibitors • Hirudin-like drugs • Synthetic drugs • Factor depleting Drugs • Ancrod • Warfarin

39. Thrombin Thrombin + Fibrinogen ogen Fibrin

40. Thrombin or Factor Xa Antithrombin 3 Antithrombin

41. Thrombin or Factor Xa Antithrombin 3 Heparin Antithrombin + Heparin

42. Heparin • Polysaccharide • Specific pentasaccharide necessary to interact with Antithrombin-3 • Function changes with size

43. Heparin Heparin Domains Mol. Wt. “Inhibits”: Domain 3 IIa > Xa 7500 Xa > IIa Domain 2 5400 Xa Domain 1 Pentasaccharide, found in only 1/3 of molecules

44. Low Molecular Weight Heparins • Depolymerize heparin • Produce smaller chains

45. Thrombin or Factor Xa Antithrombin 3 Heparin Antithrombin + Heparin

46. Thrombin or Factor Xa Antithrombin 3 LMWH Antithrombin + LMWH

47. Factor Xa Antithrombin 3 Antithrombin + Pentasaccharide Pentasaccharide

48. Heparin Heparin Domains Mol. Wt. “Inhibits”: Domain 3 IIa > Xa 7500 Xa > IIa Domain 2 5400 Xa Domain 1 Pentasaccharide, found in only 1/3 of molecules

49. dalteparin tinzaparin Heparin 4.5K (3K-6K) 5K (2K-9K) Sizes of Heparin Preparations heparin enoxaparin Fonadaparinux 4.5K (3K-8K) 12K-15K (5K-30K)

50. ACCP Consensus • Acute MI: Low-dose UFH 2 • Stroke: Low-dose UFH or LMWH 1,2 • Medical ICU: Low-dose UFH3 • Med pts Low-dose UFH or LMWH 1,2 • with risk factors: 1. Nicolaides et al., 1998; 2. Clagett et al., 1997; Cade et al, 1982