DVT & Thrombophilia testing (Against)

1. DVT & Thrombophilia testing (Against) Evi Kalodiki MD BA DIC PhD FRCS Ealing Hospital & Imperial College, London

2. The evidence No need (or very selective) thrombophilia testing in DVT patients

3. Is it a rabbit or a duck?

4. Not to screen routinely • Cost • Low (+) tests • Clinically useful? • Anxiety/counselling

5. Laboratory Dx of thrombophilia • Genetic defects in hereditary antithrombin, PC & PS deficiencies are multiple & diverse. This makes routine DNA Dx impossible. • The FVL mutant can easily be diagnosed by highly sensitive & specific tests followed by DNA confirmation to differentiate between heterozygous & homozygous individuals • There is no functional test available for the prothrombin gene mutant G20210A variant. This can only be detected by a simple PCR-based DNA test Nicolaides et al, Int Angiol 2005; 24:1-26

6. Laboratory Dx of thrombophilia Detects quantitative or qualitative defects by the following three investigations: Functional Immunological Molecular

7. Functional & immunological tests • Phenotypic tests that study activity & antigen levels. • They are used for AT, PC & PS deficiency & FVL • Limitations: Variable sensitivity & specificity under different conditions such as • pregnancy, • liver insufficiency, • with certain medications. Tripodi & Mannucci. Clin Chem 2001; 47:1597-606

8. Molecular investigations • Are gene specific & therefore more accurate. • They are used for: • FVL & for Factor II mutant detection. • Advantage of good sensitivity • Drugs & external conditions do not affect specificity Tripodi & Mannucci. Clin Chem 2001; 47:1597-606

9. De Stefano et al, Haematologica2002; 87:1095-108 • The associated VTE risk is different according to genotype, being higher among the: - Carriers of natural anticoagulant deficiencies & - Homozygotes for FVL

10. De Stefano et al, Haematologica 2002; 87:1095-108 In the general population the overall prevalence of thrombophilic trait is 10% The probability of carrying multiple defects is not excessively rare with a further ↑ of risk of up to x 20

11. Clinical penetrance • Is heterogenous producing: - mild or severe VTE • unprovoked or associated with other risk factors • in either young or old - complications of pregnancy & puerperium De Stefano et al, Haematologica 2002; 87:1095-108

12. Conclusions • Inherited thrombophilia is a multicausal model The clinical event being the result of • gene-gene • gene-environment • age dependent interactions • Clinical manifestations can be heterogenous in • Severity • Event type (VTE or obstetric complication) • The criteria for screening Pts or Family should not be very stringent • Pt’s genotype could be the main determinant of prophylaxis.

13. Incidence of thrombophilia markers % 95% CI DVT 47/76 61 47-76 Recurrent 5/9 56 23-88 Calf 5/12 42 14-70 SVT 14/39 36 21-51 Caprini et al, EJVES 2005; 30:550-55

14. Incidence of thrombophilia markers 18/166 (10.8%, 95% CI 6-16%) had >1 defect (consider anticoagulation?) But selected patients Concluded that it is not recommended that all VTE pts should be screened Caprini et al, EJVES 2005; 30:550-55

15. Not to screen • Superficial thrombophlebitis • Isolated calf DVT Since we do not anticoagulate these pts Caprini et al, EJVES 2005; 30:550-55

16. Evidence-based screening indications - Selective in past VTE or family Hx - Only newly diagnosed antiphospholipid syndrome (since prolonged anticoagulation can avoid high incidence of recurrence) Lindhoff & Luxemburg VASA 2008; 37:19-30

17. Evidence-based screening indications Not in acute VTE as will not change duration of Rx Not for OCP as the absolute VTE incidence is very low Lindhoff & Luxemburg VASA 2008; 37:19-30

18. Thrombosis: Risk & Economic Assessment of Thrombophilia Screening To assess the: 1. Risk of clinical complications associated with thrombophilia 2. Effectiveness of prophylaxis 3. The relative cost-effectiveness of selective vs universal screening on pts with Hx of VTE Wu et al, Health Technol Assess 2006; 10:1-110

19. Thrombosis: Risk & Economic Assessment of Thrombophilia Screening Meta-analysis in 3 high-risk pt groups 1. Women using oral oestrogens (OCP & HRT) 2. Women during pregnancy 3. Pts undergoing major orthopaedic surgery Wu et al, Health Technol Assess 2006; 10:1-110

20. Risk of clinical complications

21. Risk of clinical complications • Prothrombin G20210A was significantly associated with postoperative PE But no ↑ risk in • Antithrombin deficiency • MTHFR • Hyperhomocysteinaemia

22. Effectiveness of prophylaxis In 8 studies Low dose aspirin & heparin were the most effective in preventing pregnancy loss in thrombophilic women

23. Cost-effectiveness • The most cost-effective was universal screening prior to HRT Rp While • The least cost-effective was universal screening prior to OCP Rp

24. Crowther et al, Intensive Care Med 2005; 31:48-55 • 197 ICU pts, prospective cohort • Hypercoagulability markers • 6 commercial D-dimer assays • Ultrasound compression scanning Neither baseline tests of molecular hypercoagualability nor D-dimer levels predict DVT in critically ill medical-surgical pts

25. Selective screening Only in personal or family Hx of idiopathic VTE For antiphospholipid syndrome

26. There is NO point to screen for thrombophilia • Superficial thrombophlebitis • Isolated calf DVT • Since we do not anticoagulate these pts • Cancer & VTE • Since Rx is long-term Anti-vitamin K • Routine pre-operatively • since a (+) result will not modify the prophylactic strategy in the majority of patients

27. Is it a rabbit or a duck?