Thrombophilia screening and ascertained alterations
Gualtiero Palareti and Marino Golinelli from University Hospital S Orsola Malpighi Bologna, Italy discuss inherited and acquired thrombophilic alterations, including antithrombin, protein C and S deficiencies, FV Leiden and prothrombin mutations, LAC, and anti-phospholipid antibodies.
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1. Thrombophilia screening Gualtiero Palareti Dept. Angiology & Blood Coagulation “Marino Golinelli” University Hospital S. Orsola-Malpighi Bologna, Italy
2. Ascertained t h rombo ph ilic alterations Inherited • A ntithrombin d efici ency Reduced anticoagulation • Protein C d efici ency “ “ • Protein S d efici ency “ “ • Mut. R506Q (FV Leiden) Activated PC resistance • Mut. G20210A (Prot h rombin) Increased prot h rombin levels Mixed • Increased F . VIII levels Acquired • Lupus Anticoagulant (LAC) Anti ph os ph olipid Ab
3. Prevalen ce of t h rombo ph ilic alterations in the general population Year Prevalen ce Antit h rombin 1965 0.05-0.2% Protein C 1981 0.2-0.3% Protein S 1984 ? Mut. R506Q (FV Leiden) 1993-94 3-7% Mut. G20210A (Prot h rombin) 1996 1-3% LAC ---- 3-5% Increased F . VIII levels ---- 10%
4. Prevalen ce of t h rombo ph ilic alterations in subjects with VTE events Prevalen ce RR Antit h rombin 1% 5-50 Protein C 3% 7-10 Protein S 1-2% 6-10 Mut. R506Q (FV Leiden) 15-20% 7-10 Mut. G20210A (Prot h rombin) 6% 2-3 Increased F . VIII levels 25% 4 LAC 5% 9
5. May Thrombophilia Screening affect the initial treatment of DVT? NO!!
6. May Thrombophilia Screening affect the choice of the initial anticoagulant drug? Not now In future, an immediately active anticoagulant that does not need antithrombin (AT) may be preferred when AT is reduced
7. May results of Thrombophilia Screening be useful to assess the risk of recurrence?
8. From Baglin et al. Lancet 2003
10. Ho et al, Arch Intern Med 2006 Risk of recurrence in common thrombophilia
11. Recurrence in subjects with/without thrombophilia (Palareti et al. Circulation 2003)
12. D-d carried out 1 month after OAT interruption and recurrences (Palareti et al., Circulation 2003)
13. Cumulative probability of VTE recurrence according to the plasma levels of Factor VIII in patients with a first unprovoked VTE. Legnani et al, Br J Haematol 2004
14. Not all the thrombophilic defects carry the same risk
15. Risk of recurrent venous thromboembolism in patients with hereditary deficiency of either protein S, protein C or antithrombin (Brouwer et al. Thromb Haemost 2009) Conclusions : These patients have a high absolute risk of recurrence. Th e risk is increased after a first spontaneous event, and by concomitance of other thrombophilic defects.
16. What are annualised recurrence rates for unselected patients with AT, PC, PS deficiency and homozygotes and compound heterozygotes of FVL/ F2 G20210A ? Trevor Baglin, Joseph Emmerich, Clive Kearon, Gualtiero Palareti, Paolo Prandoni, Sam Schulman
17. AT, PC, PS deficiency, all patients n = 223 recurrence by deficiency p = ns AT PC PS Annualised recurrence rates recurr follow up AT 16/46 (35%) 150 pt-yrs 10.7% (6.2 – 16.7) PC 21/75 (28%) 321 pt-yrs 6.6% (4.1 – 9.9) PS 25/102 (25%) 286 pt-yrs 8.7% (5.7 – 12.6)
18. recurrence by defect p = ns FVL hom FVL F2 comp F2 hom Annualised recurrence rates recurr follow up FVL/ 10/23 (43%) 90 pt-yrs FVL 11.1% (5.5 – 19.5) FVL/ 12/45 (27%) 176 pt-yrs F2 6.8% (3.6 – 11.6) F2/ 3/12 (25%) 55 pt-yrs F2 5.5% (1.1 – 15.1) FVL & F2 G20210A, all patients n = 80
19. May results of Thrombophilia Screening influence the duration of anticoagulation? An indefinite anticoagulation can be suggested in carriers of AT, PC, PS deficiency or combined defects whose 1st event was idiopathic
20. May Thrombophilia Screening be useful in particular groups of patients ? Examples: • Women with 1 st VTE during pregnancy • Children with 1 st VTE
21. Does thrombophilia screening help us manage patients with a history of VTE during pregnancy? American College of Obstetricians and Gynecologists Int J Gynaecol Obstet 2001;75:203-12.
22. Pregnant subjects with previous VTE (ACOG 2001) Pregnant patients with a history of thrombosis found to be antithrombin III deficient, homozygous for the factor V Leiden mutation or prothrombin G20210A mutation, or heterozygous for both mutations should be given therapeutic anticoagulation for the duration of their pregnancy and in the postpartum period. All other patients are candidates for prophylactic anticoagulation in the antepartum and postpartum period.
25. .. compared with children with the FV mutation or no thrombophilia, children with the FII variant are at increased risk for recurrent VTE. This may have significant implications on outcome and possibly treatment modalities.
26. May results of Thrombophilia Screening of a pt with DVT be useful for relatives? Yes , for asymptomatic carriers • To reduce exposition to other risk factors • To offer appropriate prophylaxis in high- risk situations
28. Synergic effect of some risk factors Risk • Gene-gene interaction Mut. R506Q (FV Leiden) heteroz. Mut. R506Q (FV Leiden) homoz. 7-10 70-90 • Gene-environment interaction Pill Mut. R506Q (FV Leiden) Pill + Mut. R506Q (FV Leiden) 3-4 7-10 35-40
30. Hypothesis: Positive results may influence p atient management such as : - prolonged anticoagulant treatment or - intensified prophylaxis in high-risk situations. Testing for inherited thrombophilia does not reduce the recurrence of venous thrombosis Coppens et al. , J Thromb Haemost 2008; 6: 1474–7 Results: The OR for recurrence was 1.2 [95% CI 0.9 - 1.8] for tested vs. non-tested patients.
31. Anxiety significantly (p ≤ 0.05) decreased in the altered group and a non - significant improvement in perceived health status after TS result communication was recorded in both altered and normal result subjects
32. (from Mazzolai, EJVES 2007)
33. Final comments: Thrombophilia screening in pts with DVT - No influence on initial treatment - Risk of recurrence - Prolonged duration of anticoagulation in very high-risk subjects - Possible information on selected groups (women/pregnancy; children) - Useful for relatives, but only if associated with appropriate counseling