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INHERITED THROMBOPHILIA

INHERITED THROMBOPHILIA. Anticoagulant Profibrinolytic. Procoagulant Antifibrinolytic. Anticoagulant Profibrinolytic. Procoagulant Antifibrinolytic. There Are Five Proven Independent Genetic Risk Factors for VTE. 4 are defects in physiologic anticoagulant pathways.

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INHERITED THROMBOPHILIA

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  1. INHERITED THROMBOPHILIA

  2. Anticoagulant Profibrinolytic Procoagulant Antifibrinolytic

  3. Anticoagulant Profibrinolytic Procoagulant Antifibrinolytic

  4. There Are Five Proven Independent Genetic Risk Factors for VTE 4 are defects in physiologic anticoagulant pathways • Antithrombin deficiency • Protein C deficiency • Protein S deficiency • Factor V Leiden 1 causes increased production of procoagulant • Prothrombin G20210A gene mutation • Many other genes affect coagulation – the relative contributions of mutations in these genes to thrombotic risk are unknown

  5. Polymorphism eliminates a preferred protein C cleavage site, slows inactivation of factor Va by protein C Factor Vaprocoagulant activity not affected Not a “deficiency” Same genotype responsible for all cases Diagnosed by DNA testing Very common About 5% of US population heterozygous, 0.05% homozygous High allele frequency implies evolutionary advantage FACTOR V LEIDENA highly prevalent inherited risk factor for thrombosis

  6. FACTOR V LEIDEN Prevalence in different ethnic groups Allele frequency Heterozygote frequency Homozygote frequency Group European 4.4% 8.6% 0.2% Asia Minor 0.6 1.2 0.004 African 0 0 0 SE Asian 0 0 0 Native American 0 0 0 Lancet 1995;346:1133

  7. Polymorphism in 3' untranslated (non-coding) part of prothrombin gene No effect on prothrombin structure or function Heterozygotes have 5-10% higher plasma levels of prothrombin, 2-3 fold relative risk of venous thromboembolism About 1-2% of population heterozygous Diagnosis: DNA testing PROTHROMBIN G20210A GENE POLYMORPHISM

  8. Typically 30-60% of normal plasma activity of affected protein Dominant inheritance Genetically heterogeneous Thrombotic risk differs with different mutations Together account for approximately 10-15% of cases of inherited thrombophilia THROMBOPHILIA DUE TO DEFICIENCY OF ANTICOAGULANT PROTEIN Antithrombin, Protein C, Protein S

  9. Plasma levels of anticoagulant proteins are poor predictors of inherited deficiency Likelihood that a gene mutation is present if measured protein activity is 50% of normal: • Antithrombin = 75% • Protein C =60% • Protein S = 25% ThrombHaemost 2012; 108: 247

  10. Genetic testing for thrombophilia

  11. Clinical Features Venous thromboembolism Much less evidence for increased risk of arterial thrombosis Onset often in 20s and 30s About half of VTE episodes unprovoked Increased risk of pregnancy loss INHERITED THROMBOPHILIA

  12. Thrombotic risk varies with type of thrombophilia Proportion of individuals from thrombophilic families who have an episode of VTE by age 50: • Protein C, protein S or antithrombin deficiency: 40-50% • Factor V Leiden or prothrombin polymorphism: 10-15% AT PS PC FVL PT Blood 2009;113:5314

  13. Relative risk of thrombosis 95% CI Low plasma protein S (general population) 0.7 0.3-1.8 Protein S mutation in thrombophilic family 11.5 4.3-30.6 Koster et al, Blood 1995;85:2756 Relative risk of VTE in individuals with low plasma protein S vs known protein S mutation • Family history and (if possible) genotype should be taken into account when interpreting the results of thrombophilia testing Simmonds et al, Ann Intern Med 1998;128:8

  14. 0.6 0.6 0.5 0.5 0.4 0.4 N (% population) Risk of VTE 0.3 0.3 0.2 0.2 0.1 0.1 0 0 # Prothrombotic Alleles VTE is a multigenic disease

  15. EFFECT OF GENE DOSE Relative risk of thrombosis in heterozygous and homozygous factor V Leiden Genotype Relative Risk Normal 1 Heterozygous 7 Homozygous 80 Rosendaal et al, Blood 1995;85:1504

  16. Homozygotes have more severe disease PHENOTYPE IN HOMOZYGOTES CONDITION Antithrombin III deficiency lethal? Protein C deficiency neonatal purpural fulminans neonatal purpural fulminans (? - rare) Protein S deficiency FVL Prothrombin mutation Premature thrombosis in many (most?) - some asymptomatic

  17. HOMOZYGOUS PROTEIN C DEFICIENCY WITH NEONATAL PURPURA FULMINANS

  18. Mutations have additive effects Co-inheritance of protein C deficiency and factor V Leiden within a family Thrombosis present (%) Thrombosis absent (%) Gene Mutation Protein C and Factor V 16 (73) 6 (27) Protein C 5 (31) 11 (69) Factor V 2 (13) 11 (87) None 0 11 (100) Koeleman et al, Blood 1994;84:1031

  19. 0.6 0.6 0.6 0.6 Genetic Risk Genetic + Acquired Risk 0.5 0.5 0.5 0.5 0.4 0.4 0.4 0.4 N (% population) N (% population) Risk of VTE 0.3 0.3 Risk of VTE 0.3 0.3 0.2 0.2 0.2 0.2 0.1 0.1 0.1 0.1 0 0 0 0 # Prothrombotic Alleles # Prothrombotic Alleles Genetic and acquired risk are additive

  20. FACTOR V LEIDEN + ORAL CONTRACEPTIVE RELATIVE RISK OF THROMBOSIS RISK FACTOR Oral contraceptive 4 Factor V Leiden 8 Both 35 Vandenbroucke et al, Lancet 1994;344:1453

  21. FACTOR V LEIDEN + ESTROGEN REPLACEMENT RELATIVE RISK OF THROMBOSIS RISK FACTOR Estrogen replacement 3.5 Factor V Leiden 4.6 Both 11 Rosendaal, 2001

  22. IS THE MANAGEMENT OF PATIENTS WITH VTE AFFECTED BY THE RESULTS OF THROMBOPHILIA TESTING?

  23. Idiopathic VTE Other risk factor Postop VTE The risk of recurrent venous thromboembolism is higher in patients with idiopathic events Lancet 2003; 362: 523–26

  24. The risk of recurrent VTE is not significantly affected by the presence of inherited thrombophilia Lancet 2003; 362: 523–26 Hazard ratio 1.50 (95% CI = 0.82-2.77) p=0.187

  25. Idiopathic VTE is a strong independent predictor of recurrence risk, and so is a potential indication for long-term anticoagulation The presence of inherited thrombophilia is not a good predictor of VTE recurrence risk and so should not generally be used as the basis for prolonging therapy The presence of inherited thrombophilia does not usually affect treatment of patients with VTE

  26. Warfarin-induced skin necrosis in a protein C-deficient patient Compound heterozygote for FVL and protein C deficiency Day 5 of warfarin treatment, on heparin Concomitant bilateral adrenal hemorrhagic infarction

  27. WARFARIN LOWERS LEVELS OF PROTEIN C FASTER THAN LEVELS OF PROCOAGULANT VITAMIN K-DEPENDENT PROTEINS Prothrombin Protein C Transient hypercoagulability?

  28. WHAT ARE THE IMPLICATIONS OF A POSITIVE TEST FOR THROMBOPHILIA IN AN ASYMPTOMATIC PERSON?

  29. RELATIVE RISK OF VENOUS EVENTS IN RELATIVES OF PATIENTS WITH THROMBOPHILIA Vossen et al, J Thromb Haemost 2004;2:1526

  30. THE ABSOLUTE RISK OF VENOUS EVENTS IN ASYMPTOMATIC RELATIVES OF THROMBOPHILIC PATIENTS IS LOW Vossen et al, J Thrombos Haemost 2005;3:459 Bleeding risk with long term anticoagulation estimated at 1-3%/year

  31. Laboratory evidence of thrombophilia does not predict thrombotic risk in the absence of a family hx of VTE Thromb Haemost 2011;106:646

  32. INCIDENCE OF FIRST VTE EVENTS IN SPECIFIC RISK SITUATIONS IN THROMBOPHILIC INDIVIDUALS Vossen et al, J Thrombos Haemost 2005;3:459 Analysis restricted to individuals not given prophylaxis

  33. INCREASED RISK OF FETAL LOSS IN WOMEN WITH HERITABLE THROMBOPHILIA European Prospective Cohort on Thrombophilia (1384 women) Lancet 1996;348:913 RR OF STILLBIRTH RR OF MISCARRIAGE CONDITION 95% CI 95% CI ANTITHROMBIN DEFICIENCY 5.2 1.5-18.1 1.7 1.0-2.8 PROTEIN C DEFICIENCY 2.3 0.6-8.3 1.4 0.9-2.2 PROTEIN S DEFICIENCY 3.3 1.0-11.3 1.2 0.7-1.9 FACTOR V LEIDEN 2 0.5-7.7 0.9 0.5-1.5 COMBINED DEFECTS 14.3 2.4-86.0 0.8 0.2-3.6 ALL THROMBOPHILIA 1.4-9.4 1.27 0.94-1.71 3.6

  34. BUT…

  35. There is no evidence that anticoagulant (LMWH) or antiplatelet (ASA) prophylaxis improves pregnancy outcomes in women with inherited thrombophilia

  36. Inherited thrombophilia is more likely if a patient with VTE Is young Has a family history of VTE Had unprovoked VTE Had warfarin-induced skin necrosis (protein C) Acute thrombosis and antithrombotic therapy may affect blood levels of AT, PC, PS Testing should be done only if the result will affect patient management WHO TO TEST?

  37. Is there benefit to testing family members of a thrombophilic patient? • Negative tests do not rule out genetic risk • Positive test may create undue anxiety or lead to inappropriate intervention by physicians • Chronic anticoagulation not warranted in asymptomatic individuals who test positive • Testing may be warranted in families with a thrombotic phenotype and high-risk thrombophilia (AT, PC, PS)

  38. Family history predicts thrombotic risk just as well as laboratory testing for thrombophiliaA case-control study Arch Intern Med 2009;169:610

  39. SHOULD ORAL CONTRACEPTIVES BE WITHHELD FROM ASYMPTOMATIC WOMEN WITH FACTOR V LEIDEN?PREDICTED OUTCOMES WITH ALTERNATIVE CONTRACEPTIVE METHODS Blood 2011;118:2055

  40. Antiphospholipid syndrome Hyperhomocysteinemia (may be inherited) Inflammatory bowel disease Cancer Nephrotic syndrome Myeloproliferativedisorders Pregnancy Oral contraceptive/estrogen Hyperviscosity ACQUIRED THROMBOPHILIA

  41. HOMOCYSTEINE

  42. SEVERE (plasma levels 5-10 x normal) homozygous cystathione beta-synthase deficiency (1:250,000) homozygous methylenetetrahydrofolate reductase deficiency MILD OR MODERATE heterozygous CBS deficiency (0.3-1.4% of population) C677T polymorphism in MTHFR (10% of population homogyzous) B12, folate or B6 deficiency Aging Chronic renal failure CAUSES OF HYPERHOMOCYSTEINEMIA

  43. HIGHER HOMOCYSTEINE LEVELS ARE ASSOCIATED WITH VASCULAR RISK Meta-analysis BMJ 2002;325:1202

  44. BUT…

  45. LOWERING HOMOCYSTEINE DOES NOT DECREASE VASCULAR RISK • VISP trial (JAMA 2004): Moderate reduction in HC had no effect on vascular risk during 2 yrfollowup • HOPE 2 trial (NEJM 2006): Vitamin supplements lowered HC levels but had no effect on vascular risk • NORVIT trial (NEJM 2006): More aggressive vitamin supplementation associated with increased vascular risk • VITRO study (Blood 2007): Lowering HC did not prevent recurrent VTE • Note – these studies did not include individuals with very high plasma HC levels

  46. Is testing for MTHFR mutations useful? • Very common C677T polymorphism in MTHFR associated with modest elevations in homocysteine in some individuals • Several studies have shown that this MTHFR mutation is NOT an independent risk factor for thrombosis NOT USEFUL

  47. Antiphospholipid Syndrome

  48. Antiphospholipid Antibodies • Lupus anticoagulant • Cardiolipin antibodies (IgG, IgM) • Beta-2 glycoprotein I antibodies (IgG, IgM) • Thrombotic risk associated with higher antibody levels, positive tests for more than one type of antibody • “Triple positive” patients appear to be at highest risk

  49. Who has antiphospholipid antibodies? APPROX INCIDENCE PATIENT GROUP ANTIBODY TYPE SLE LAC 30% SLE aCL 40% Blood donors aCL 2% Healthy elderly aCL 52% Love and Santoro, Ann Intern Med 1990

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