1. FRR Testing for thrombophilia: is it ever useful? F.R. Rosendaal, Leiden ISTH Educational Course on Thrombosis, Thrombophilia, Thrombolysis and DIC Moscow, 17-19 September 2014

2. FRR Thou art always figuring diseases in me, but thou art full of error: I am sound (Shakespeare W. Measure for measure 1604; Act I, Scene II)

3. FRR Tests through history the very first test....

4. Georgio Giulio Clovio Book of Hours (1546) Eve tests Adam (test of faith/love)

5. Titian (1550)

6. Judgement of Paris (test of beauty)

7. Roman augur (test for going to war)

8. Rice water diarrhoea (test for cholera)

9. FRR Modern tests Test for clinical disease (e.g. ECG) Test for early disease (e.g. Pap smear) Test for risk of disease (e.g. blood pressure) Test for fetal disease (e.g., amniocentesis) Test for risk of fetal disease (e.g. carrier testing) Test for past infection (e.g. Mantoux) Test for state (e.g. pregnancy test) etc

10. FRR Not always happy end Sistine Chapel Michelangelo (1512)

11. FRR Not always a happy end.. a thousand ships (film: Troy, 2004)

13. FRR Costs and benefits medical benefits (NNT, NNS) medical costs (side effects) psychosocial benefits (+ Qol) psychosocial costs (-QoL) economical benefits (+ €) economical costs (- €)

14. FRR Testing for thrombophilia Factor V Leiden worldwide most performed genetic test Often in combination with protein C, protein S, antithrombin, factor VIII, MTHFR 677T and homocysteine

15. FRR How many tests are done? survey over 4 months via large diagnostic center 2000 questionnaires to ordering physicians response 63% (n=1132) extrapolation: 15 000 per year –EU: 500 000 per year –USA: 300 000 per year Population 16 million (Coppens, J Throm Haemost 2007)

16. FRR Indications for testing Internal Medicine, Vascular Medicine, Hematology, Pulmonology, Cardiology, Surgery, Obstetrics, General Practitioners VT 42% arterial 23% obstetric 17% family 16% (Coppens J Throm Haemost 2007) no changes in management in 24%

17. FRR Indications for testing obstetric arterial disease venous thrombosis weak relation with pregnancy loss no effective treatment weak relation with arterial disease no specific treatment

18. FRR If testing: for what?

19. FRR Confirmed genetic risk factors patients (%)pop. (%)RRPAR (%) AT/PC/PS deficiency 3 10 1 Factor V Leidenrs602519 37.917 PT 20210Ars1799963 6 22.8 3 FGG C10034Trs2066865 12 62.4 8 non-00 bloodgroup71571.831 FGB his95argrs600319141.5 7 FXIII leu34val (rec.)rs598596941.427 PROC A2418Grs179980922191.3 5 FGA Thr312Alars605029261.2 5 FGB 455 G/Ars180078826211.3 6 F11rs228925248411.313 F5rs452479731.319 GP6rs161366284821.211 SERPINC1rs222758917101.3 3

20. FRR Testing for genetic variants To be discussed –deficiencies of protein C, S or antithrombin –factor V Leiden –prothrombin 20210A all others too weak effect

21. FRR Testing for genetic variants Aim –prevent thrombosis (death) Method –screening –intensified treatment or removal risk factors Target –asymptomatic patients (prevent 1st event) –symptomatic patients (prevent recurrence)

22. FRR Major distinction unselected individuals –patients, relatives, non-related selected patients (familial thrombophilia) –patients, relatives

23. FRR Unselected individuals screening of asymptomatics –everybody –prior to risk situations (surgery, OCs) all relatives of patients testing of symptomatics –prevention of recurrencies prolonged anticoagulant treatment liberal short-term prophylaxis

24. FRR Testing for genetic variants Aim –prevent thrombosis (death) Method –screening –intensified treatment or removal risk factors Target –asymptomatic patients (prevent 1st event) –symptomatic patients (prevent recurrence)

25. FRR Gene-environment interaction (Vandenbroucke, Lancet 1994) Absolute risks: Neither0.5 / 10 000 OC2.0 / 10 000 FVL4.0 / 10 000 Both14 / 10 000 What can be gained -10 / 10000 (VT) - 1 / 10000 (death)

26. FRR How many to test to prevent one Risk: 10/10 000 - 1000 with FVL should not take OCs to prevent one VT - 10000 with FVL should not take OCs to prevent one death How to find 1000 women with factor V Leiden - Population (5%) : test 20 000 - Patients’ relatives - Patients (20%): test 5 to find one with FVL - Relatives (25-50%): test 2-4 to find one - to find 1000 women with FVL: - test 10 000 patients and >2000 relatives

27. FRR Costs whether patients or asymptomatic women we need to test > 10 000 individuals to prevent one VT we need to test > 100 000 individuals to prevent one death cost per consultation and test: € 150,- cost to prevent one VT: 1.5 million euros cost to prevent one death: 15 million euros

28. FRR Screening asymptomatics risk reduction too low to render it cost- effective not rational this includes screening looking for relatives of patients

29. FRR Testing for genetic variants Aim –prevent thrombosis Method –screening –intensified treatment or removal risk factors Target –asymptomatic patients (prevent 1st event) –symptomatic patients (prevent recurrence)

30. FRR Testing thrombosis patients testing of unselected patients can only be useful if –patients with positive test have higher recurrence risk than those without –there are ways to reduce this risk with a positive risk-benefit ratio (side-effects)

31. FRR Testing thrombosis patients testing of unselected patients can only be useful if –patients with positive test have higher recurrence risk than those without –there are ways to reduce this risk with a positive risk-benefit ratio (side-effects)

32. FRR Leiden Thrombophilia Study 474 consecutive patients with DVT –exclusion: malignancy prospective follow-up mean follow-up 7.3 yr (max 12 yr) 90 recurrent thrombotic event event rate 2.6 percent per year (Christiansen, JAMA 2005)

33. FRR No long-term effect thrombophilia (Christiansen, JAMA 2005) abnormalities PC, PS, AT FVL, PT20210A FVIII, FIX, FXI homocysteine HR: 1.4 (CI95: 0.9-2.2)

34. FRR Cambridge study ( Baglin, Lancet 2003) N=489 2 yr follow-up anticoagulant defects PC, PS, AT FVL, PT20210A HR 1.50 (CI95 0.8-2.8)

35. FRR Recurrence risk by defect RRCI95 factor V Leiden1.20.7 - 1.9 prothrombin 20210A 0.70.3 - 2.0 PC/PS/AT deficiency 1.80.9 - 3.7 high FVIII1.10.7 - 1.8 high FIX0.90.5 - 1.7 high FXI0.60.3 - 1.1 hyperhomocysteinemia0.90.5 - 1.6 (Christiansen, JAMA 2005)

36. FRR Conclusion Effect of laboratory abnormalities on recurrence small or absent Test result does not predict who is at increased risk

37. FRR Testing thrombosis patients testing of unselected patients can only be useful if –patients with positive test have higher recurrence risk than those without –there are ways to reduce this risk with a positive risk-benefit ratio (side-effects)

38. FRR (Agnelli, N Engl J Med 2001) Prolonged anticoagulation idiopathic VT N=267 3 vs 12 months catch-up no benefit

39. FRR Conclusion Effect of laboratory abnormalities on recurrence probably small No clear strategy to reduce risk except life- long anticoagulation –risk of severe hemorrhage 1-2 percent per year

40. FRR Real predictors Relative risk sex men vs women 3- to 4-fold type of first event idiopathic vs secondary2- to 3-fold (Baglin, Lancet 2003; Baglin, JTH 2004; Kyrle, NEJM 2004; Christiansen, JAMA 2005)

41. FRR Unselected individuals screening asymptomatic individuals –risk reduction too low to render it cost-effective –not rational screening symptomatic patients –does not identify those at high risk of recurrence –does not open treatment options –not rational

42. FRR Selected individuals

43. FRR Familial thrombosis It is probably more than coincidence when six or more members of the same family each develop from one to five thromboembolic conditions and when most of them eventually die of such conditions (Wright, 1952) TE † † † † † TE: thromboembolism †: fatal thromboembolism

44. FRR Selected individuals Age at first thrombosis: consecutive patients with 1st VT (N=378) –protein C deficiency47 yr –no defect found43 yr familial thrombophilia (24 families, N=229) –protein C deficiency35 yr –no defect found33 yr (Lensen, Blood 1997)

45. FRR EPCOT study 9 centres in Europe all their patients with clear familial thrombophilia prospective follow-up (1995-2001) 1626 patients (probands and relatives) AT/PC/PS deficiency or FVL (Leiden, Barcelona, Glasgow, Sheffield, Frankfurt, Vienna, Malmö, Bologna, Paris)

46. FRR EPCOT: asymptomatic people incidence of venous thrombosis (no AC) –0.8 % per year (CI95 0.5-1.2%) majority of events spontaneous risk not greater than that of anticoagulation testing will not affect management (Vossen, J Thromb Haemost 2005)

47. FRR EPCOT: symptomatic patients patients with one prior event divided in those +/- long-term anticoagulation incidence of venous thrombosis –long term AC: 1.1 % per year –no AC: 5.3 % per year gradient of risk over type of thrombophilia –AT-def: 10.5%/yr (2.7 on AC), FVL: 3.8%/yr (0.0 on AC) incidence of major hemorrhage: 0.6%/yr (Vossen, Arterioscler Thromb Vasc Biol 2005)

48. FRR Familial thrombophilia asymptomatic people (relatives) –no obvious advantage of screening –no obvious management choices symptomatic patients –suggestive of benefit of long-term anticoagulation (esp. AT-deficiency) –no randomised studies

49. FRR Testing for genetic variants screening in unselected individuals or patients with thrombosis not indicated Screening symptomatic individuals in highly penetrant familial thrombophilia may be indicated –only antithrombin deficiency –no studies that prove positive benefit-risk-ratio

50. FRR Testing in selected patients Symptomatic patients with familial thrombophilia: very small group

51. FRR Experimental evidence case-cohort study of patients with recurrent VT idea: compare patients with recurrence to those without if testing prevents recurrence, more tests in the latter 197 patients with recurrent VT during follow-up 324 patients without recurrence (Coppens, J Throm Haemost 2008)

52. FRR No benefit % tested OR for recurrent VT (tested vs not- tested) Recurrent VT (cases) No recurrent VT (controls) all35301.2 (0.8-1.8) women41351.4 (0.7-2.9) First VT with OC use 60323.4 (1.3-8.6) Positive family history for VT 47391.5 (0.7-3.1) (Coppens, J Throm Haemost 2008)

53. FRR Psychological impact (Cohn, J Throm Haemost 2008)

54. FRR Impact of testing – my e-mails “I personally have a chronically elevated factor VIII activity (186%, 242%, and 192%), an elevated Factor XI activity (212%), as well as being heterozygous for MTHFR A1298C. …… After researching the literature and finding a sparcity of information reguarding my problem, I believe the only hope for finding advice and guidance in my care is to personally ask the experts leading the research in the field of hypercoagulability. Please attempt to share your wisdom and advice with me.”

55. FRR More consultations “I recently discovered I am heterozygous for Factor II G20210A and Factor V Leiden. I have never had a DVT. ….. I would like to get the best estimate I can of my risk, and how to monitor and reduce it. …… My daughter was on birth control because she had an ovarian cyst. She has tested positive for Factor II and has stopped birth control—need she do so? Should I have my son tested?... From the genomics service, the reported risk of a first DVT based on my Factor II and V results is 57% over the next 14 years, ie until I turn 74, and the likelihood increases sharply thereafter with a lifetime estimated risk of 90%. ”

56. FRR Conclusion our knowledge of genetics has not positively affected clinical care testing seems mainly psychotherapeutic studies in patients inconclusive studies in physicians not performed

57. FRR Conclusion: we test too much! Seems natural ‘to want to know’ Wanting to know not always a good idea (film: Troy, 2004)