Cp Rounds Factor V Leiden & Pregnancy

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Cp Rounds Factor V Leiden & Pregnancy

  1. 1. Factor V Leiden & Pregnancy Karl Robstad, MD Albany Medical Center Department of Pathology
  2. 2. Causes of inherited thrombophilia <ul><li>Factor V Leiden (40-50%) </li></ul><ul><li>Prothrombin mutation (10-20%) </li></ul><ul><li>Deficiency of: </li></ul><ul><ul><li>Protein C </li></ul></ul><ul><ul><li>Protein S </li></ul></ul><ul><ul><li>Antithrombin </li></ul></ul>
  3. 3. Demographics <ul><li>First described in 1993 in Leiden, Netherlands </li></ul><ul><li>Factor V Leiden is the most common hereditary blood coagulation disorder in the United States. </li></ul><ul><li>Factor V Leiden increases the risk of venous thrombosis: </li></ul><ul><ul><li>Heterozygous: 3-8 fold </li></ul></ul><ul><ul><li>Homozygous: 30-140 fold </li></ul></ul><ul><li>Mean age of onset: </li></ul><ul><ul><li>Homozygous: 31 years </li></ul></ul><ul><ul><li>Heterozygous: 44 years </li></ul></ul>
  4. 4. Sequellae <ul><li>Venous thrombosis and Pulmonary embolism (PE) </li></ul><ul><li>Stillbirth or recurrent unexplained miscarriage </li></ul><ul><li>Preeclampsia and/or ecclampsia (toxemia while pregnant) </li></ul>
  5. 5. Additional risk factors <ul><li>Tobacco use, smoking </li></ul><ul><li>Obesity, BMI over 30 </li></ul><ul><li>Hyperlipidemia </li></ul><ul><li>Varicose veins </li></ul>
  6. 6. <ul><li>Relative risk for first episode of venous thrombosis </li></ul>0.02 2.8 Prothrombin mutation 0.02 2.5 Hyperhomocysteinemia 0.5 – 1.0 80 FVL homozygous 0.29 35 FVL heterozygous + OCP 0.03 4 Oral contraceptive pills 0.06 7 Factor V Leiden heterozygous 0.008 1 Normal Incidence (% per year) Relative risk Condition
  7. 7. Normal Physiology <ul><li>Factor V is a proenzyme that is activated to Factor Va, whose function is to catalyze the activation of prothrombin to thrombin. </li></ul><ul><li>Remember, activated Protein C along with Protein S inactivates both Factor Va and VIIIa. </li></ul>
  8. 8. Coagulation cascade: schematic
  9. 9. Factor V Leiden Protein C
  10. 10. Genetics <ul><li>Substitution mutation (Arg506Gln) at one of t he three APC cleavage sites in the factor Va molecule. </li></ul><ul><li>Substantially reduces anticoagulant response to activated protein (APC), because Factor V Leiden is inactivated ~10X slower than normal Factor V. </li></ul><ul><li>Leads to increased Factor V levels, increased thrombin generation and hypercoagulability. </li></ul>
  11. 11. Recommendations for Testing <ul><li>VT under age 50 </li></ul><ul><li>VT in unusual sites such as hepatic, mesenteric, and cerebral veins) </li></ul><ul><li>Recurrent VT </li></ul><ul><li>Strong family history of thrombotic disease </li></ul><ul><li>VT in pregnant women or women taking oral contraceptives. </li></ul><ul><li>Myocardial infarction in female smoker under age 50 </li></ul>
  12. 12. Consideration for Testing <ul><li>VT, age >50, except when malignancy is present </li></ul><ul><li>Relatives have factor V Leiden mutation </li></ul><ul><li>May influence management of pregnancy and oral contraceptive use. </li></ul><ul><li>Women with: </li></ul><ul><ul><li>Recurrent pregnancy loss </li></ul></ul><ul><ul><li>U nexplained severe preeclampsia </li></ul></ul><ul><ul><li>Placental abruption </li></ul></ul><ul><ul><li>Intrauterine fetal growth retardation </li></ul></ul><ul><li>Mutation identification may influence management of future pregnancies </li></ul>
  13. 13. Screening for Factor V Leiden <ul><li>Random screening not recommended . </li></ul><ul><li>Routine testing is also not recommended for: </li></ul><ul><ul><li>Patients with a family history of arterial thrombotic disorders except for MI in young female smokers </li></ul></ul><ul><ul><li>Prenatal testing </li></ul></ul><ul><ul><li>Routine newborn screening </li></ul></ul>
  14. 14. Factor V Leiden: Treatment <ul><li>Initial venous thrombosis event: </li></ul><ul><ul><li>heparin (UFH or LMWH) followed by 6-12 months of warfarin (goal INR 2.0-3.0) </li></ul></ul>
  15. 15. Factor V Leiden: Treatment <ul><li>Risk of recurrent venous thrombosis is unclear in Factor V Leiden </li></ul><ul><li>Indefinite anticoagulation? </li></ul><ul><ul><li>More than one inherited thrombophilia </li></ul></ul><ul><ul><li>Severe clot (clot in cerebral, mesenteric, or portal vein or life-threatening PE) </li></ul></ul><ul><ul><li>Recurrent clot </li></ul></ul>
  16. 16. FVL and Pregnancy <ul><li>Blood clot during pregnancy or after delivery </li></ul><ul><li>Fetal loss </li></ul><ul><li>Pre-eclampsia </li></ul><ul><li>Intrauterine growth retardation </li></ul><ul><li>Abruption </li></ul>
  17. 17. Pregnancy <ul><li>Pregnancy alone is associated with a 5 to 6 fold increase in risk of VTE. </li></ul><ul><ul><li>Increases in factors I, II, VII, VIII, IX, XII </li></ul></ul><ul><ul><li>Decreases in Protein S </li></ul></ul><ul><ul><li>Increased resistance to Protein C </li></ul></ul><ul><li>Has been postulated as a natural mechanism to reduce PP bleeds. </li></ul>
  18. 18. Pregnancy <ul><li>Women who are pregnant and heterozygous for FVL mutation are at a 5 to 10 fold increased risk for VTE. </li></ul><ul><li>Women who are pregnant and homozygous for FVL mutation are at a 50 to 100 fold increased risk for VTE. </li></ul>
  19. 19. Case Study <ul><li>KH is a 34 year-old G5P2022 female who delivered her third live child. </li></ul><ul><li>She is known to be heterozygous for the FVL mutation. </li></ul><ul><li>After an uncomplicated delivery by caesarean secetion, multiple units of cryo, plasma and packed red cells were ordered. </li></ul><ul><li>Transfusion audit was called. </li></ul>
  20. 20. Treatment in Pregnancy <ul><li>Homozygotes should be fully anticoagulated with heparin </li></ul><ul><ul><li>Low Molecular Weight until 36 weeks. </li></ul></ul><ul><ul><li>Unfractionated after. </li></ul></ul><ul><ul><ul><li>Reduces risk of epidural hematoma associated with regional anesthesia. </li></ul></ul></ul><ul><li>One case report of FVL heterozygote during pregnancy: </li></ul><ul><ul><li>heparin started at time of diagnosis </li></ul></ul><ul><ul><li>Discontinued the day prior to delivery </li></ul></ul><ul><ul><li>Restarted the day after </li></ul></ul><ul><ul><li>Continued for 6 weeks post-partum </li></ul></ul>
  21. 21. Treatment in Pregnancy <ul><li>Heparin is discontinued immediately before delivery. </li></ul><ul><li>Heparin and coumadin started immediately post-partum </li></ul><ul><li>After achieving a target INR of 2-3, heparin is discontinued. </li></ul><ul><li>Warfarin is continued for 6-12 months. </li></ul>
  22. 22. References <ul><li>Cotran, Kumar, Collins. Robbins Pathologic Basis of Disease. 6 th ed.1999. </li></ul><ul><li>Diuguid, D. Laboratory Diagnosis of Hypercoaguable states. http://www.columbia.edu/itc/hs/medical/selective/ AdvClinicalPathology/2005/lecture/LabDxProthromboticDisordersBW_Diuguid.pdf </li></ul><ul><li>Jones, S. Clinical Laboratory Pearls. 2001. </li></ul><ul><li>Langan, R. Factor V Leiden Mutation and Pregnancy. JABFP. July 2004. </li></ul><ul><li>Pollack, E. Protein C Deficiency. http://www.emedicine.com/MED/topic1923.htm </li></ul><ul><li>Valentino, L. Factor V Leiden: Patient Education and Genetic Counseling. http://www.rush.edu/Rush_Document/ Factor%20V%20Leiden%20presentation,0.pdf. </li></ul>

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