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INHERITED THROMBOPHILIA

INHERITED THROMBOPHILIA. Defects in physiologic anticoagulant pathways. Increased production of procoagulant. Antithrombin deficiencyProtein C deficiencyProtein S deficiencyFactor V Leiden (APC resistance). Prothrombin G20210A gene mutation. Many other genes affect coagulation the contribution

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INHERITED THROMBOPHILIA

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    1. INHERITED THROMBOPHILIA

    4. THE PROTEIN C SYSTEM A negative feedback loop that degrades factors Va, VIIIa

    5. 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 Va procoagulant 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 LEIDEN A highly prevalent inherited risk factor for thrombosis

    7. FACTOR V LEIDEN

    8. Increased risk of VTE associated with high levels of factors II, VIII, XI (+others?) Prothrombin G20210A mutation causes increased prothrombin level Causes of elevated levels of other factors unknown Probably both inherited and acquired THROMBOPHILIA DUE TO HIGH PLASMA PROCOAGULANT ACTIVITY

    9. 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

    10. GENETIC RISK FACTORS FOR THROMBOSIS

    11. CLINICAL FEATURES OF INHERITED THROMBOPHILIA

    12. INHERITED THROMBOPHILIA

    14. Venous thromboembolism No convincing evidence of increased risk of arterial thrombosis Onset often in 20s and 30s Many remain asymptomatic to advanced age About half of VTE episodes associated with other risk factors, half "idiopathic" Increased risk of pregnancy loss INHERITED THROMBOPHILIA

    15. RISK OF VTE HIGHER WITH ANTICOAGULANT PROTEIN DEFICIENCY THAN FVL, PROTHROMBIN MUTATION

    17. Genetic heterogeneity 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

    18. PROTEIN S DEFICIENCY IS A POOR PREDICTOR OF THROMBOSIS RISK IN THE GENERAL POPULATION The 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) Half of those who carried protein S mutation had at least one episode of thrombosis by age 30 Free protein S measurements correlated better with presence of mutation than total protein S PROTEIN S DEFICIENCY IS A STRONG PREDICTOR OF THROMBOTIC RISK IN A FAMILY WITH A KNOWN MUTATION

    20. Family history predicts thrombotic risk just as well as laboratory testing for thrombophilia A case-control study

    21. Age-specific incidence of VTE in individuals with and without a history of VTE in a sibling

    22. Younger age at onset of VTE predicts higher incidence of VTE in relatives

    23. The presence of thrombophilia does not predict thrombotic risk in the absence of a family hx of VTE

    24. RISK OF THROMBOSIS IN INHERITED THROMBOPHILIA

    25. EFFECT OF GENE DOSE

    26. EFFECT OF GENE INTERACTIONS

    27. INTERACTION WITH ACQUIRED RISK FACTORS

    28. INTERACTION WITH ACQUIRED RISK FACTORS

    29. FACTOR V LEIDEN INCREASES RISK OF VENOUS, BUT NOT ARTERIAL, THROMBOSIS

    30. WHAT IS THE RISK OF THROMBOSIS IN ASYMPTOMATIC INDIVIDUALS WITH INHERITED THROMBOPHILIA?

    31. RELATIVE RISK OF VENOUS EVENTS IN RELATIVES OF PATIENTS WITH THROMBOPHILIA

    32. THE ABSOLUTE RISK OF VENOUS EVENTS IN ASYMPTOMATIC RELATIVES OF THROMBOPHILIC PATIENTS IS LOW

    33. INCIDENCE OF FIRST VTE EVENTS IN SPECIFIC RISK SITUATIONS IN THROMBOPHILIC INDIVIDUALS

    36. THROMBOPHILIA AND PREGNANCY

    37. INCREASED RISK OF FETAL LOSS IN WOMEN WITH HERITABLE THROMBOPHILIA

    38. LATE FETAL LOSS IN THROMBOPHILIA

    39. RECOMMENDATIONS FOR DIAGNOSIS AND TREATMENT

    40. WHO TO TEST? 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) Presence or absence of inherited thrombophilia does not usually determine the type or duration of treatment for VTE

    41. WHEN TO TEST? 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

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

    43. VTE PROPHYLAXIS DURING PREGNANCY 2012 ACCP 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

    44. VTE PROPHYLAXIS DURING PREGNANCY 2012 ACCP 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

    45. SHOULD ORAL CONTRACEPTIVES ROUTINELY BE WITHHELD FROM WOMEN WITH FACTOR V LEIDEN? PREDICTED OUTCOMES WITH ALTERNATIVE CONTRACEPTIVE METHODS

    46. The presence of inherited thrombophilia does not usually affect treatment of patients with VTE In the presence of reversible risk factor (eg, postop VTE) there is no evidence that presence of inherited thrombophilia is an indication for prolonged or more intense anticoagulation Idiopathic VTE is potential indication for long-term anticoagulation even in the absence of known thrombophilia

    49. ACQUIRED THROMBOPHILIA Antiphospholipid syndrome Hyperhomocysteinemia (may be inherited) Cancer Myeloproliferative disorders Nephrotic syndrome Pregnancy Oral contraceptive/estrogen Hyperviscosity

    50. HOMOCYSTEINE

    51. SEVERE homozygous cystathione beta-synthase deficiency (1:250,000) homozygous methylenetetrahydrofolate reductase deficiency MILD OR MODERATE heterozygous CBS deficiency (0.3-1.4% of population) thermolabile variant of MTHFR (5% of population) B12, folate or B6 deficiency Aging Chronic renal failure CAUSES OF HYPERHOMOCYSTEINEMIA

    53. BUT…

    54. VISP trial (JAMA 2004): Moderate reduction in HC had no effect on vascular risk during 2 yr followup 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

    55. ANTIPHOSPHOLIPID ANTIBODIES

    56. 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

    57. INCIDENCE OF ANTIPHOSPHOLIPID ANTIBODIES

    58. Thrombosis (arterial and venous) Recurrent fetal loss Hematologic abnormalities: Immune thrombocytopenia Immune hemolytic anemia CLINICAL CONDITIONS ASSOCIATED WITH ANTIPHOSPHOLIPID ANTIBODIES The “antiphospholipid syndrome”

    60. 1% or less of APL patients Generalized vasculopathy (?thrombotic or inflammatory) Livedo reticularis Multiple organ system involvement Renal failure Hypertension ARDS CNS Rapid progression; sudden death in some patients Treatment: anticoagulation, plasma exchange, ?immunosuppresion CATASTROPHIC ANTIPHOSPHOLIPID SYNDROME

    61. In study of 22000 male physicians: aCL titer above 95th percentile associated with 5-fold increase in relative risk of DVT No significant increase in ischemic stroke risk ANTIPHOSPHOLIPID ANTIBODIES AND THROMBOSIS IN HEALTHY PEOPLE

    62. IgG Anticardiolipin Antibodies and Risk of Recurrence or Death in Patients with VTE After Stopping Anticoagulation

    63. Incidence of first thromboembolic events in asymptomatic “high-risk” individuals with antiphospholipid antibodies

    64. ANTIPHOSPHOLIPID SYNDROME CLINICAL CRITERIA One or more documented episodes of arterial, venous, or small vessel thrombosis (other than superficial venous thrombosis) in any tissue or organ Thrombosis must be confirmed by objective validated criteria For histopathologic confirmation, thrombosis should be present without significant evidence of inflammation in the vessel wall Pregnancy morbidity One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with normal fetal morphology documented by ultrasound or by direct examination of the fetus, or One or more premature births of a morphologically normal neonate before the 34th week of gestation because of: (i) eclampsia or severe pre-eclampsia defined according to standard definitions, or (ii) recognized features of placental insufficiency, or Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded

    65. ANTIPHOSPHOLIPID SYNDROME LABORATORY CRITERIA Lupus anticoagulant (LAC) present in plasma, on two or more occasions at least 12 weeks apart, detected according to the guidelines of the International Society on Thrombosis and Haemostasis (Scientific Subcommittee on LACs/phospholipid- dependent antibodies) Anticardiolipin antibody (aCL) of IgG and/or IgM isotype in serum or plasma, present in medium or high titer (i.e., > 40 GPL or MPL, or > the 99th percentile), on two or more occasions at least 12 weeks apart, measured by a standardized ELISA Anti-ß2 glycoprotein-I antibody of IgG and/or IgM isotype in serum or plasma (in titer >the 99th percentile), present on two or more occasions at least 12 weeks apart, measured by a standardized ELISA, according to recommended procedures APL syndrome considered present if at least one of the clinical and one of the laboratory criteria are present

    66. TREATMENT OF PATIENTS WITH ANTIPHOSPHOLIPID ANTIBODIES Asymptomatic: no treatment History of thrombosis: Consider prolonged treatment in selected patients Recurrent or unprovoked thrombosis (arterial or venous) Persistently high antibody levels More than 1 APL antibody test positive Most patients can be treated with standard anticoagulant regimen Two RCTs have shown inferior outcomes with high intensity warfarin treatment A few patients exhibit warfarin failure – consider long term LMWH treatment

    67. ANTIPHOSPHOLIPID ANTIBODIES AND FETAL LOSS Antiphospholipid antibodies associated with lower live birth rates in unselected “low-risk” pregnancies Live birth rates in untreated women with APL and at least one fetal loss have ranged from 10-85% in published studies Aspirin and heparin have been associated with higher live-birth rates in several studies, but most of these did not include a placebo-treated arm

    68. ANTIPHOSPHOLIPID ANTIBODIES AND FETAL LOSS Testing for APL should be restricted to women with at least three consecutive miscarriages Other causes of pregnancy loss (especially abnormal karyotypes) should be ruled out If criteria for obstetric APL syndrome met, treat with aspirin and/or LMWH during pregnancy and postpartum period

    69. ANTICOAGULATION IN WOMEN WITH RECURRENT PREGNANCY LOSS 2012 ACCP CONSENSUS RECOMMENDATIONS Women who meet lab and clinical criteria for obstetric APLA: Antepartum prophylactic or intermediate-dose LMWH plus low dose ASA For other women with recurrent pregnancy loss, whether or not they have thrombophilia: No antithrombotic therapy recommended

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