1. Reporter: CR 吳嘉芸 Supervisor: VS 邱宗傑

2. Reporter: CR 吳嘉芸 Supervisor: VS 邱宗傑

3. Outline  History  Epidemiology  Pathogenesis  Thromboprophylaxis

4. Outline  History  Epidemiology  Pathogenesis  Thromboprophylaxis

5. Cancer-associated Thrombosis The first report was published by the French physician Jean-Baptiste Bouillaud in 1823

6. Cancer-associated Thrombosis Widely quoted description by Armand Trousseau in 1865 migratory thrombophlebitis associated with an occult visceral malignancy Trousseau’s Syndrome

7. Outline  History  Epidemiology  Pathogenesis  Thromboprophylaxis

8. About 20% - 30% of venous thromboembolism (VTE) are cancer- associated Tromsø study, prospective follow-up of >26000 subjects 106 cancer in 462 VTE events (23%) 【 Am J Epidemiol 2010;171:1109–1115 】

9. Cancer patients have a 4 to 7-fold increased risk of VTE compared with the general population 【 JAMA. 2005 Feb 9;293(6):715-22 】 MEGA study, Case-control study, > 5000 subjects, 1999-2004 Odds ratio: 4.1 (3.2-5.3)

10. Epidemiology  About 20% - 30% of venous thromboembolism (VTE) are cancer- associated  Cancer patients have a 4 to 7-fold increased risk of VTE compared with the general population 【 Blood 2013 122: 1712-1723 】

11. Type of Cancer VS. Risk of VTE 【 Blood 2013 122: 1712-1723 】

12. Later stage of cancer, higher risk of VTE 【 Blood 2013 122: 1712-1723 】

13. Cancer with VTE in Taiwan  497,180 cancer patients, between 1997 to 2005, with a median follow-up of 21.3 months  Incidence: 185 events per 100,000 person-years  11.5 times higher than the general population 【 Thromb Haemost 2012; 108: 225–235 】

14. Cancer with VTE in Taiwan  497,180 cancer patients, between 1997 to 2005, with a median follow-up of 21.3 months  Incidence: 185 events per 100,000 person-years  11.5 times higher than the general population 【 Thromb Haemost 2012; 108: 225–235 】 【 Blood 2013 122: 1712-1723 】

15. Cancer with VTE in Taiwan  497,180 cancer patients, between 1997 to 2005, with a median follow-up of 21.3 months  Incidence: 185 events per 100,000 person-years  11.5 times higher than the general population  The annual incidence in Taiwan is much lower than in Western populations 【 Thromb Haemost 2012; 108: 225–235 】

16. Cancer with VTE in Taiwan 【 Thromb Haemost 2012; 108: 225–235 】

17. Cancer with VTE in Taiwan 【 Thromb Haemost 2012; 108: 225–235 】

18. Biologically aggressive cancer has higher thrombogenic potential

19. 【 J Clin Oncol 27:4839-4847 】

20. Outline  History  Epidemiology  Pathogenesis  Thromboprophylaxis

21. Pathogenesis  Mucin  Tissue Factor  Tumor Hypoxia  Cysteine Proteinase  Oncogene Activation

22. 【 Blood 2007 110: 1723-1729 】

23. 1

24. Mucin  Trousseau’s syndrome associated with mucin-producing carcinomas  Glycosylated secretory products of epithelial cells  ligands for the selectins

25. Selectin (P-selectin and L-selectin) 【 J. Clin. Invest. 112:853–862 (2003) 】

26. 【 Blood 2007 110: 1723-1729 】 2

27. Tissue Factor (TF)  TF-rich tumor surface and TF-positive, Tumor-derived microparticle  Correlation between elevated TF and VTE

28. TF-positive, Tumor-derived Microparticle (TMP) Selectin ligand Phosphatidylserine negatively-charged phospholipids 【 Blood. 2013;122(11):1873-1880 】

29. Tissue Factor  Correlation between the level of TF and VTE  Correlation between increased MP TF activity and worsened cancer stage, grade, and survival  Elevated MP-TF itself or its activity associated with development of VTE and decreased survival

30. 【 Blood 2007 110: 1723-1729 】 3

31. Cysteine Proteinase  directly activated factor X in the absence of factor VII

32. 【 Blood 2007 110: 1723-1729 】 4

33. Tumor Hypoxia  increase the expression of genes that facilitate coagulation, including tissue factor and plasminogen activator inhibitor type 1 (PAI-1)

34. 【 Blood 2007 110: 1723-1729 】 5

35. Oncogene Activation  MET oncogene involve up-regulation of PAI-1 and cyclooxygenase-2 (COX-2) genes

36. 【 Blood 2007 110: 1723-1729 】

37. Outline  History  Epidemiology  Pathogenesis  Thromboprophylaxis

38. The increasing incidence of VTE 【 Blood 2013 122: 1712-1723 】

39.  The incidence was reported to decrease over time after cancer diagnosis Treatment-related VTE (such as operation, EPO) Remission cancer reduce thrombotic risk Mortality over time

40. VTE mortality VTE increase mortality prospective follow-up of >26000 subjects Tromsø study, prospective follow-up of >26000 subjects 【 Blood 2013 122: 1712-1723 】

41. VTE related cancer mortality 【 J Thromb Haemost 2007; 5: 632–4. 】 1 2 2

42. 【 Cochrane Database Syst Rev. 2012 Feb 5;2 】 Symptomatic VTE for LMWH vs placebo NNT = 60

43. 【 Cochrane Database Syst Rev. 2012 Feb 5;2 】 Major bleeding for LMWH vs placebo

44. Risk Assessment Models RiskscoreVTE in 2.5 months Low00.3% Intermediate1-22% High>=36.7% negative predictive value of 98.5% at the cutoff point for high risk (>=3) 【 Blood 2013 122: 2011-2018 】

45. D-dimer and P-selectin soluble P-selectinD-dimer 【 Blood 2008 112: 2703-2708 】 Vienna Cancer and Thrombosis Study (CATS)

46. Risk Assessment Models ScoreVTE in 6 months 00% 310.3% >=535% 【 Blood 2013 122: 2011-2018 】

47. Risk Assessment Models in Taiwan population 【 Thromb Haemost 2012; 108: 225–235 】

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51. Conclusions  Cancer increased risk of VTE, especially advanced stage  The pathogenesis included mucin, tissue factor, and others  VTE increased mortality  Thromboprophylaxis is an issue, especially in high risk group