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INHERITED THROMBOPHILIA

INHERITED THROMBOPHILIA. INHERITED THROMBOPHILIA. Defects in physiologic anticoagulant pathways. Antithrombin deficiency Protein C deficiency Protein S deficiency Factor V Leiden (APC resistance). Increased production of procoagulant. Prothrombin G20210A gene mutation.

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INHERITED THROMBOPHILIA

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  1. INHERITED THROMBOPHILIA

  2. INHERITED THROMBOPHILIA Defects in physiologic anticoagulant pathways • Antithrombin deficiency • Protein C deficiency • Protein S deficiency • Factor V Leiden (APC resistance) Increased production of procoagulant • Prothrombin G20210A gene mutation • Many other genes affect coagulation – the contribution of mutations in these genes to thrombotic risk is important but presently difficult to quantify

  3. THE ANTITHROMBIN SYSTEM Antithrombin inhibits thrombin, Xa, IXa, XIa

  4. THE PROTEIN C SYSTEMA negative feedback loop that degrades factors Va, VIIIa Vi VIIIi Va VIIIa APC P S IIa P C IIa TM E C

  5. Antithrombin, Protein C, Protein S Typically 30-60% of normal plasma activity of affected protein Genetically heterogeneous Type 1: low antigen and activity Type 2: normal antigen, low activity (missense mutations) Thrombotic risk varies from family to family Together account for approximately 10-15% of cases of inherited thrombophilia THROMBOPHILIA DUE TO DEFICIENCY OF ANTICOAGULANT PROTEIN

  6. Missense mutation changes amino acid 506 of factor V from arginine to glycine Mutation is at preferred protein C cleavage site, slows inactivation of factor Va by protein C Factor Vaprocoagulant activity not affected Not a “deficiency” Single mutation responsible for all cases Usually diagnosed by DNA testing Very common About 5% of US population heterozygous, 0.05% homozygous FACTOR V LEIDENA highly prevalent inherited risk factor for thrombosis

  7. 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

  8. Mutation 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 Heterozygotes have 2-3 fold risk of venous thromboembolism About 1-2% of population heterozygous; 5-7% of young patients with DVT/PE Diagnosis: DNA testing PROTHROMBIN G20210A GENE MUTATION

  9. GENETIC RISK FACTORS FOR THROMBOSIS Approximate prevalence in thrombophilia Phenotype Number of genotypes Antithrombin deficiency 5% or less Many Protein C deficiency about 5% Many Protein S deficiency 5% or less Many Factor V Leiden 40-50% One Prothrombin G20210A 5-7% One

  10. CLINICAL FEATURES OF INHERITED THROMBOPHILIA

  11. INHERITED THROMBOPHILIA Clinical findings in homozygous state CLINICAL FINDINGS 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

  12. HOMOZYGOUS PROTEIN C DEFICIENCY WITH NEONATAL PURPURA FULMINANS

  13. Clinical Features in Heterozygotes Venous thromboembolism No convincing evidence of increased risk of arterial thrombosis Onset often in 20s and 30s Many carriers are asymptomatic throughout life About half of VTE episodes associated with other risk factors, half "idiopathic" Increased risk of pregnancy loss INHERITED THROMBOPHILIA

  14. No defect PT FVL PC AT PS RISK OF VTE HIGHER WITH INHERITED ANTICOAGULANT PROTEIN DEFICIENCY THAN FVL, PROTHROMBIN MUTATION Thrombosis-free survival in relatives of patients with thrombophilia Blood 2009;113:5314

  15. CONTROLS FVL CONTROLS FVL INCREASED THROMBIN GENERATION IN HETEROZYGOUS FACTOR V LEIDEN Can such testing help predict risk of thrombosis?

  16. Diagnosing anticoagulant protein deficiency Genetic heterogeneity – mutation detection more difficult than for FVL, PT mutations Blood levels affected by other conditions, drugs Heparin lowers antithrombin levels Warfarin lowers protein C, protein S levels Liver disease lowers all three Pregnancy, inflammation, contraceptives decrease free protein S Some mutations affect protein activity, not antigen Measurements of anticoagulant protein levels in unselected patients have low predictive value INHERITED THROMBOPHILIA

  17. Likelihood that a gene mutation is present if measured protein activity is 50% of normal: • Antithrombin = 75% • Protein C =60% • Protein S = 25% Low blood level ≠ inherited deficiency ThrombHaemost 2012; 108: 247

  18. Relative risk of thrombosis 95% CI Low total protein S (one measurement) 0.7 0.3-1.8 Low total protein S (two measurements) 0.8 0.2-3.0 1.6 0.6-4.0 Low free protein S Low free and total protein S 1.7 1.0-4.7 Koster et al, Blood 1995;85:2756 LOW PROTEIN S LEVEL IS A POOR PREDICTOR OF THROMBOSIS RISK IN THE GENERAL POPULATIONThe Leiden Thrombophilia Study

  19. Subjects: 122-member protein S-deficient family, 44 of whom carried Gly295-Val mutation Diagnosis of protein S deficiency established by DNA testing Hazard ratio for thrombosis associated with carriage of protein S mutation was 11.5 (95% CI = 4.33-30.6) PROTEIN S DEFICIENCY IS A STRONG PREDICTOR OF THROMBOTIC RISK IN A FAMILY WITH A KNOWN MUTATION Simmonds et al, Ann Intern Med 1998;128:8

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

  21. The presence of thrombophilia does not predict thrombotic risk in the absence of a family hx of VTE Thromb Haemost 2011;106:646

  22. RISK OF THROMBOSIS IN THROMBOPHILIA

  23. 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

  24. EFFECT OF GENE INTERACTIONS 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

  25. INTERACTION WITH ACQUIRED RISK FACTORS Oral contraceptive RELATIVE RISK OF THROMBOSIS RISK FACTOR Oral contraceptive 4 Factor V Leiden 8 Both 35 Vandenbroucke et al, Lancet 1994;344:1453

  26. INTERACTION WITH ACQUIRED RISK FACTORS Estrogen replacement RELATIVE RISK OF THROMBOSIS RISK FACTOR Estrogen replacement 3.5 Factor V Leiden 4.6 Both 11 Rosendaal, 2001

  27. Ridker et al, NEJM 1995;332:912 P = 0.02 12 10 8 P = 0.9 P = 0.7 6 % Heterozygotes P = 0.4 4 MI or Stroke DVT or PE 2 None MI Stroke 0 Type of thrombosis FACTOR V LEIDEN INCREASES RISK OF VENOUS, BUT NOT ARTERIAL, THROMBOSIS Physicians' Health Study (15,000 subjects)

  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. 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

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

  33. Counseling/reassurance Prophylaxis in high-risk situations Carefully consider risk/benefit ratio and alternatives when prescribing oral contraceptives or HRT MANAGEMENT OF ASYMPTOMATIC INDIVIDUALS WITH INHERITED THROMBOPHILIA

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

  35. 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 be used as the basis for prolonging therapy The presence of inherited thrombophilia does not usually affect treatment of patients with VTE

  36. 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

  37. 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

  38. A diagnosis of thrombophilia does not affect overall survival after an episode of VTE ThrombHaemost 2013;1:79 Median followup time = 5 yrs

  39. 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

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

  41. THROMBOPHILIA AND PREGNANCY

  42. 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

  43. LATE FETAL LOSS IN THROMBOPHILIA Due to factor V or prothrombin mutation % of women with late fetal loss % of women with normal pregnancy Mutation RR (95% CI) Factor V or prothrombin 16 6 3.3 (1.4-7.8) Factor V Leiden 7 3 3.2 (1.0-10.9) Prothrombin 9 3 3.3 (1.1-10.3) NEJM 2000;343;1015

  44. BUT…

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

  46. ANTICOAGULATION IN WOMEN WITH RECURRENT PREGNANCY LOSS2012ACCP CONSENSUS RECOMMENDATIONS • For women with recurrent pregnancy loss and no evidence of antiphospholipid syndrome, whether or not they have inherited thrombophilia: • No antithrombotic therapy recommended CHEST 2012; 141:e691S

  47. VTE PROPHYLAXIS DURING PREGNANCY2012ACCP CONSENSUS RECOMMENDATIONS • Women homozygous for FVL or prothrombin mutation, no prior VTE • If positive FH: antepartum prophylaxis (LWMH) and postpartum prophylaxis x 6 weeks (warfarin or LMWH) • If no FH: antepartum “clinical vigilance” and postpartum prophylaxis x 6 weeks CHEST 2012; 141:e691S

  48. VTE PROPHYLAXIS DURING PREGNANCY2012ACCP CONSENSUS RECOMMENDATIONS • All other forms of thrombophilia, no prior VTE • If positive FH: antepartum “clinical vigilance” and postpartum prophylaxis x 6 weeks (LMWH, warfarin OK if not protein C or S deficient) • If no positive FH: clinical vigilance only CHEST 2012; 141:e691S

  49. 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) Test results rarely affect patient management! WHO TO TEST?

  50. FVL, prothrombin mutation: any time (not informative after liver transplantation) Antithrombin: Not during acute thrombosis Not during pregnancy or estrogen/OCP use Off heparin/LMWH at least 2 weeks Protein C: Off warfarin (preferable), or on stable warfarin dose at least 2 weeks Preferably not during acute thrombosis Protein S: As for protein C Not during pregnancy, OCP use or acute inflammation Neonatal period, DIC, liver disease, asparaginase Rx can all cause acquired deficiency of AT, PC, PS Testing should usually be done in the outpatient setting WHEN TO TEST?

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