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Thrombophilia Where angels fear to tread

Thrombophilia Where angels fear to tread. Andrew McDonald Division of Haematology GSH. n. CASE 1 40 year old female (physician) 3 years ago: episode of severe diarrhoea / dehydration swollen calf  U/S “calf vein” DVT 2 weeks full dose clexane, then nothing no further events

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Thrombophilia Where angels fear to tread

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  1. ThrombophiliaWhere angels fear to tread Andrew McDonald Division of Haematology GSH

  2. n • CASE 1 • 40 year old female (physician) • 3 years ago: • episode of severe diarrhoea / dehydration • swollen calf  U/S “calf vein” DVT • 2 weeks full dose clexane, then nothing • no further events • Tests herself: • Homozygous Factor V Leiden (FVL) • Would you anticoagulate her? • If so, how long? • n NO Not applicable

  3. n CASE 2 52 year old female from a family with VTE history Heterozygous FVL, no personal history of thrombosis Asymptomatic daughter tested pre OC use: – heterozygous FVL positive Would you have done this? Do you advise longterm anticoagulation? She falls pregnant – do you anticoagulate? Would you test her 2 asymptomatic brothers? • n Probably not NO NO NO

  4. n CASE 2 Her 26 year old bother develops insidious onset dyspnoea CT shows massive multiple pulmonary emboli Pulmonary hypertension is present – resolves on anticoagulation Was the decision not to test him wrong? How long would you anti-coagulate? Would you now test him for FVL? Would you now test the other brother? • n NO Lifelong NO NO

  5. n CLINICAL Thrombophilia: “an inherited or acquired disorder which increases the risk of Venous Thrombo-embolism” VTE is the DISEASE NOT thrombophilia • n

  6. n • CLINICAL MANIFESTATIONS of THROMBOPHILIA • Family history of VTE • Spontaneous VTE at younger age • Recurrent VTE • Unusual sites (splanchnic, cerebral venous sinus, upper limb) • Warfarin skin necrosis • Neonatal purpura fulminans • Resistance to therapy • [Obstetric complications (fetal loss, GPH / HELLP, IUGR)] • [Arterial thrombosis] • n

  7. n CLINICAL RISK FACTORS • n • ACUTE • Immobility (>3 days) • Surgery • Pregnancy • Medical diseases (TB) • Indwelling catheters • Medical diseases (CCF, Stroke, COPD exacerbation, HIV) • CHRONIC • Obesity • OC and HRT • Hypertension • Smoking • Cancer +/- therapy

  8. n THROMBOPHILIA Genetic AT deficiency PC deficiency FVL Prothrombin 20210A FV Cam / HK FV HR2 haplotype FVII 10976A FXIII Val34Leu Fibrinogen mutations TAFI 438A TM 127A ACE intron 16 FSAP 1601A PAI-1 polymorphisms tPA intron h Apolipoprotein E polymorphism Mixed / Unknown PS deficiency APC resistance  FVIII  IX  XI  Fibrinogen Elevated homocysteine (MTHFR C677T) Sticky platelet syndrome Acquired APLS PNH MPD / JAK2V617F • n

  9. n What is the most prevalent “thrombophilic” risk factor? • n Heit et al 2001

  10. n Relative risk of VTE • n

  11. n Absolute risk of VTE in asymptomatic carriers • n

  12. FVL X FVL + X FVL X n EVENTS VTE event multifactorial: gene-gene interaction gene-environment interaction 50-80% “thrombophilic events” have a laboratory abnormality • n

  13. n RISK FACTOR ANALYSIS ARTERIAL VENOUS Risk factor predictive of events YESYES “Exclusion” other causes YES NO Risk factor modifiable YESNO Modifies prevention strategy YES ? Modifies disease therapy YES NO • n

  14. n Decision analysis post VTE event Post first VTE event, does the presence of a thrombophilic defect influence the: intensity of therapy? NO duration of therapy? NO, except: AT deficiency homozygous FVL? APLS ?? • n

  15. n LEIDEN THROMBOPHILIA STUDY • n Christiansen et al 2005

  16. n RISK STRATIFICATION for VTE RECURRENCE Provoked VTE – 0-1% recurrence Baglin 2003 Stop after 3-6 months (Grd 1A) Idiopathic VTE Dfn: No recent surgery (within 3 months) No plaster cast No malignancy in past 5 years No immobilisation for 3/7 Usual therapy with OAC for 6-12 months Recurrence rates: 5-10% first year 5% second year 2-3% / year thereafter • n

  17. n • n

  18. n RISK STRATIFICATION for VTE RECURRENCE Catch up effect Agnelli 2001 - OAC Rx - Early stop - Late stop Stratify: 3% recurrence risk = acceptable >9% recurrence risk = unacceptable • n

  19. n RISK STRATIFICATION for VTE RECURRENCE Clinical Decision Rules for stopping therapy Risk Stratification: D-dimer – good at PPV, but not NPV Paoreti 2002, 2006 Residual DVT – proven but difficult Prandoni ISTH 2007 Male gender – OR 1.6 for recurrence Elevated FVIII Age Thrombophilia • n

  20. n RISK STRATIFICATION for VTE RECURRENCE REVERSE[REcurrent VEenous thromboembolism Risk Stratification Evaluation] Clinical findings of Hyperpigmentation Edema Redness MEN: HER+ 21% annual recurrence rate, HER- 7.9% recurrence risk WOMEN: Also factor in d-dimer, obesity (BMI>30), age >65 years, ( chol) HER DOO 0 or 1 score 1.6% recurrence risk (half of all women) HER DOO 2 or more 14.1% annual recurrence rate Kovacs et al ISTH 2007 • n

  21. n Screening Asymptomatic Individuals Screen first degree family members of an index case? No evidence for long term prophylaxis prior to VTE Bleeding risk outweighs incidence rate of VTE events FATAL 0.25% / year SERIOUS 1% / year Short term prophylaxis Standard indications and strategy similar ? More aggressive prophylaxis in “low risk” situations • n

  22. n Family history Family history: EDITH study – case control in 1st VTE event Family history  OR for VTE of 2.7 (95%CI 1.8-3.8) FVL / II 20210A mutation OR 3.6 (1.2-4) No mutation OR 2.6 (1.7-3.8) Positive family history increases risk for DVT irrespective of 2 common mutations Noboa et al 2008 Treat all patients with family history as high risk, irrespective of thrombophilic status • n

  23. n Screening Asymptomatic Individuals Universal screening prior to longer term risk situations? • n N.Baartman - personal communication 2008

  24. n • OC and Thrombophilia • OC  risk of thrombosis by 3-4x • Combination with “thrombophilic” defect synergistic • FVL + OC  risk ~30x • Studies confirm increased risk • No indication to screen general population for thrombophilia (FVL) prior to OC initiation • TREATS • ICER £202 402 for universal screening pre OC • Wu et al 2005 • Prevent 1 in 200 000 deaths by screening • n

  25. n • OC and Thrombophilia • OR 4.9 (1.92-12.6 95%CI) for VTE event in women with lowest quartile of APC function (all negative for FVL and other mutations) Legnani et al 2004 • Screen first degree relatives of known carriers? • May prevent DVT • BUT consider: • Anxiety • False reassurance of negative test • Other contraceptives not as good • Insurance • n

  26. n FVL and Insurance Asymptomatic FVL+ve <30 years 75% load re mortality no income protection / critical illness / lumpsum disability. >30 years 50% load on mortality no income protection Positive VTE and FVL No cover O’Mahoney 2008 – personal communication • n

  27. n Traveler’s thrombosis: • n

  28. n • Practical testing tips • DON’T test functional assays during acute event or inflammatory process • No antithrombin (and ?LAC) on UF heparin / LMWH • No Protein C and S (and ?LAC) on warfarin (washout 2-4 weeks) • Repeat all abnormal functional assays (high cv) • Serological and clotting assays for APLS • - Repeat positive APLS studies after 12 weeks • Do ALL appropriate tests • n

  29. n • SUMMARY • CURRENT • Utility of thrombophilia testing largely questionable • Consider cost-benefit ratio • Do in context of: • Trials • Changing management strategy • FUTURE • New global coagulation tests for screening? • Newer anticogulants? • n

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