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Thrombophilia & Thromboembolism in Pregnancy & Puerperium


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Thrombophilia & Thromboembolism in Pregnancy & Puerperium

  1. 1. THROMBOPHILIA & THROMBOEMBOLISM DURING PREGNANCY & PUERPERIUM-PREVENTION & MANAGEMENT Dr. Jagannath Mishra Chair-Person-Dr. Sasmita Swain, Associate Prof. Dept. of O&G Co-chairperson-Dr. Utkal Naik, SR, Dept. of O&G
  2. 2. DEFINITIONS • Homeostasis- Process that maintain blood in a fluid, clot-free state. • Thrombosis- the formation of blood clot (thrombus) within vessels. • Embolus- Dislodged thrombus within vessels. • Thrombophilia- Group of inherited and acquired disorders that has increased risk of thrombosis.
  3. 3. The Three Factors……
  4. 4. Anticoagulant and Fibrinolytic Pathways IXXI / platelets IXa VIIIa Xa X TF/ VII - )APC/S( X TFPI- Va IIIIa - )APC/S( FDP FXIII Fibrin Fibrinogen +tPA Plasmin - Antithrombin PAI-1 Antiplasmin - - 5
  5. 5. VTE in Pregnancy Epidemilogy 1.Affects 1 in 100,000 women of child bearing age. 2.10 times more common in pregnancy. 3.Age <35 = 1/1000 pregnancy 4.Age >35 = 2.4/1000 pregnancy 5.10%-20% of VTE are PE
  6. 6. Mortality • PE remains third most common cause of maternal death after hypertension and hemorrhage. • Most common direct cause maternal death in devloped countries. • 62% of women with fatal VTE die in 1st trimester although highest risk is immediately after delivery.
  7. 7. Risk Factors…..
  8. 8. 1. Pregnancy
  9. 9. Pregnancy-Associated Changes in Haemostatic and Fibrinolytic Proteins 1. Increase in Clotting Factors: • 20 to 200% increase in levels of fibrinogen, • factors II, VII, VIII, IX, X and • vWF • Progressive platelet activation
  10. 10. Pregnancy-Associated Changes in Haemostatic and Fibrinolytic Proteins 2. Decrease in Anticoagulant and Fibrinolytic Activity: • Protein S levels (free and total) decrease by 60% to 70% • PAI-1 and PAI-2 levels increase two to three-fold in pregnancy
  11. 11. • Some women are at even higher risk during pregnancy because they have one or more additional risk factors
  12. 12. Additional risk factors for venous thromboembolism (VTE) Pre-existing risk factors • Previous recurrent VTE • Family history of VTE • Known thrombophilia
  13. 13. Pre-existing risk factors-contd.. • Medical co-morbidities(e.g. heart or lung disease, SLE, cancer, inflammatory conditions, nephritic syndrome, sickle cell disease, intravenous drug user, Surgical procedure, • Age (> 35 years) • Obesity • Smoker • Gross varicose veins
  14. 14. Obstetric risk factors • Parity ≥3 • Pre-eclampsia • Dehydration/ hyper emesis/ OHSS • Multiple pregnancy • Caesarean section in labor • Elective caesarean section • Prolonged labor (> 24 hours) • PPH (>1 liter or transfusion)
  15. 15. Acute presentation DVT • Usually U/L, most commonly left leg. • a red and hot swollen leg. • swelling in entire leg or just part of it. • pain and/or tenderness • or it may just feel heavy.
  16. 16. PE • sudden unexplained difficulty in breathing • tightness in the chest or chest pain • Haemoptysis • Faintness or collapse • Tachypnoea • Raised JVP • ABG= Hypoxemia
  17. 17. Diagnosis • Compression duplex ultrasound • Chest x-ray • Ventilation-perfusion lung scan • Computed tomography pulmonary angiogram Note: D-dimer testing was considered but not recommended.
  18. 18. MANAGEMENT Offer either: • proximal leg vein ultrasound scan (within 4 hours) or • if proximal leg vein scan not available within 4 hours, D-dimer test and an interim 24-hour dose of a parenteral anti-coagulant followed by proximal leg vein ultrasound within 24 hours . NICE
  19. 19. • Repeat proximal leg vein ultrasound scan 6–8 days later for all patients with positive D-dimer test and negative proximal leg vein ultrasound scan. NICE
  20. 20. FOR ACUTE PRESENTATION Choice is LMWH- as soon as possible except in 1.Renal failure 2.High risk of bleeding 3.Hemodynamic instability • In these conditions UFH is safer than LMWH NICE
  21. 21. For patients with hemodynamic unstability • Urgent CTPA within one hour but t/t shouldn’t be delayed • Thrombolysis if possible (Golden period=1st hour) • IV UFH 5000iu bolus followed by 1000- 2000iu/hr infusion with daily monitoring of aPTT • Gradually switch over to LMWH
  22. 22. Confirmed PE or proximal DVT Continue LMWH for remainder of pregnancy + 6 weeks post- partum. NICE
  23. 23. Mechanical interventions Temporary inferior vena caval filters: •offer to patients with proximal DVT or PE who cannot have anticoagulation treatment. •consider for patients with recurrent proximal DVT or PE despite adequate anticoagulation treatment. NICE
  24. 24. Mechanical interventions Offer below-knee graduated compression stockings (ankle pressure greater than 23 mmHg) to patients with proximal DVT a week after diagnosis or when swelling is reduced sufficiently, and: •advise patients to continue wearing the stockings for at least 2 years •ensure that the stockings are replaced 2 or 3 times per year •advise patients that the stockings need to be worn only on the affected leg or legs. NICE
  26. 26. • Women at high risk of VTE, including those with previous confirmed VTE, should be offered pre-pregnancy counseling with a prospective management plan. Pre-pregnancy Counseling
  27. 27. • Is important because thrombotic risk exists from the beginning of the first trimester and often the antenatal booking visit is at the end of the first trimester.
  28. 28. • All women should undergo an assessment of risk factors for VTE in early pregnancy or before pregnancy. C
  29. 29. • A retrospective comparison of the overall risk of recurrence of VTE during pregnancy and the non-pregnant period revealed risks of 10.9% during and 3.7% outside pregnancy. Evidence level III
  30. 30. • However, the risk was higher if the woman had thrombophilia or if the previous VTE was in an unusual site. Evidence level III
  31. 31. scenarios 1. Women with previous VTE and no thrombophilia 2. Women with previous VTE who have thrombophilia 3. Women without previous VTE or thrombophilia
  32. 32. •Women with a previous VTE and no thrombophilia
  33. 33. Women with a previous VTE and no thrombophilia • Women with single previous VTE and no thrombophilia should be offered prophylaxis with low molecular weight heparin (LMWH) for six weeks after delivery. • Whether they also require antenatal thromboprophylaxis is controversial.
  34. 34. • Although pregnancy may be associated with a more than three-fold increase in the risk of recurrent VTE, the evidence is conflicting.
  35. 35. • It may be reasonable not to use antenatal thromboprophylaxis with heparin in women with a single previous VTE associated with a temporary risk factor that has now resolved. C
  36. 36. Women who have had : 1. more than one previous episode of VTE, 2. who have had one episode and in addition have a family history of VTE in a first degree relative or 3. whose episode of VTE was in an unusual site should be considered for antenatal thromboprophylaxis with LMWH and for at least six weeks postpartum.
  37. 37. Women with a previous VTE who have thrombophilia
  38. 38. Women with a previous VTE who have thrombophilia • Women with thrombophilias have an increased risk of VTE in pregnancy, but this risk varies depending upon the specific thrombophilia.
  39. 39. High Risk • Antiphospholipid syndrome • Anti-thrombin deficiency
  40. 40. Medium Risk • Protein C deficiency • Protein S deficiency • Homozygosity for Factor V Leiden mutation • Homozygosity for PT G20210A mutation • Combined heterozygosity (Factor V Leiden and PT 20210A)
  41. 41. Low Risk • Heterzoygosity for Factor V Leiden mutation • Heterozygosity for PT G20210A mutation
  42. 42. WHO DO WE SCREEN ? • Studies suggests that all patients with a history of prior venous thrombotic events and those with adverse pregnancy events such as fetal loss, abruptions, severe intra- uterine growth restriction and early onset severe preeclampsia, should be evaluated for thrombophilias. • Screening tests for inherited and acquired thrombophilias
  43. 43. LABORATORY TESTS FOR TROMBOPHILIAS SCREENING A. Acquired Thrombophilias • Lupus anticoagulants •Anticardiolipin antibodies •ß2-glycoprotein antibodies •Anti-nuclear antibodies
  44. 44. LABORATORY TESTS FOR TROMBOPHILIAS SCREENING B. Inherited Thrombophilias •Activated protein C resistance (APCR) •Protein S •Protein C •Ant thrombin III (AT III) •Factor V Leiden mutation •Prothrombin gene mutation
  45. 45. • Women should be stratified according to the level of risk associated with their thrombophilia. • Since the risk of VTE is lower in women with no history of VTE, antenatal thromboprophylaxis is not always necessary, except in: 1. those with combined defects, 2. those homozygous for defects or 3. those with anti-thrombin deficiency. Women with a previous VTE who haveWomen with a previous VTE who have inherited thrombophiliainherited thrombophilia
  46. 46. Women with acquired thrombophilia (antiphospholipid syndrome)
  47. 47. Antiphospholipid syndrome (APS) is defined as: the presence of lupus anticoagulant or anticardiolipin antibodies of medium–high titer on two occasions 12 weeks apart, found in association with a history of: • Thrombosis (arterial or venous) or • Adverse pregnancy outcome : 1. Three or more unexplained miscarriages before ten weeks of gestation, 2. Fetal death after ten weeks of gestation or 3. Preterm birth {less than 34 weeks} due to severe pre-eclampsia or intrauterine growth restriction.
  48. 48. • The risk of recurrent thromboses in women with APS is up to 70% and may be even higher in pregnancy. • Therefore, pregnant women with APS and previous thromboses should receive antenatal and postnatal thromboprophylaxis with LMWH.
  49. 49. • Low-dose aspirin has been shown to improve pregnancy outcome in APS and is recommended for all women with APS.
  50. 50. Women without previous VTE or thrombophilia
  51. 51. • The combination of either of (Age over 35 years and BMI greater than 30/body weight greater than 90 kg )with any other risk factor for VTE (such as pre-eclampsia or immobility) or • The presence of two other persisting risk factors should lead the clinician to consider the use of LMWH for three to five days postpartum. GPP Women without previous VTE or thrombophilia
  52. 52. Timing and duration of thromboprophylaxis
  53. 53. Ante partum • As VTE during pregnancy has an equal distribution throughout gestation , if a decision is made to initiate thromboprophylaxis antenatally, this should begin as early in pregnancy as practical.
  54. 54. • Once antenatal treatment is initiated it should continue until- 1.Labour pain occurs 2.Elective induction of labour starts
  55. 55. BEFORE LSCS • last heparin injection should be 24 hours before the planned caesarean delivery. • If by emergency caesarean section within 24 hours of last injection Need general anesthesia
  56. 56. Very High Risk • Women with recurrent VTE associated with either 1. On long term oral anti-coagulation 2. Anti-thrombin deficiency or 3. Antiphospholipid syndrome Requires antenatal prophylaxis with LMWH (high dose 40 mg 12-hourly)
  57. 57. High Risk • Women with 1. Single previous VTE with a)Thrombophilia or family history b) Unprovoked/estrogen-related 2. Previous recurrent VTE (> 1) require thromboprophylaxis with LMWH antenatally
  58. 58. Intermediate Risk Women with 1.Single previous VTE with no family history or thrombophilia 2.Thrombophilia without VTE 3.Medical co-morbidities LMWH prophylaxis can be considered antenatlly
  59. 59. • Age > 35 years, Obesity (BMI > 30kg/m2) • Parity ≥ 3, Pre-eclampsia • Smoker • Gross varicose veins, Immobility • Dehydration/hyper emesis/OHSS • Multiple pregnancy or ART -More than 3 risk factors- consider LMWH antenatally -Less than 3 risk factors- do not require LMWH antenatally ( mobilization & prevention of dehydration)
  60. 60. Postpartum • Postpartum thromboprophylaxis should be given as soon as possible after delivery, provided that there is no postpartum hemorrhage. • Those with postpartum hemorrhage should be fitted with thromboembolic deterrent stockings.
  61. 61. • If the woman has been given regional analgesia, LMWH should be withheld until four hours after insertion or removal of the epidural catheter (or six hours if either insertion or removal were traumatic). Postpartum
  62. 62. • The combined oral contraceptive pill should not be prescribed during the first three months postpartum for women with other risk factors for VTE.
  63. 63. High Risk • Any previous VTE • Anyone requiring antenatal LMWH At least 6 weeks postnatal prophylactic LMWH
  64. 64. Intermediate Risk • Caesarean section in labor • Asymptomatic thrombophilia • BMI > 40 kg/m2 • Medical co-morbidities At least 7 days postnatal prophylactic LMWH
  65. 65. • Age > 35 years, Obesity (BMI > 30kg/m2) • Parity ≥ 3, Pre-eclampsia • Smoker • Elective caesarian section • Gross varicose veins, Immobility • Prolonged labor (> 24 hours) • PPH > 1 liter or blood transfusion -2 or more risk factors-At least 7 days postnatal prophylactic LMWH -Less than 2 risk factors-Mobilization and avoidance of dehydration
  66. 66. Agents for thromboprophylaxis
  67. 67. • Regardless of their risk of VTE, immobilization of women during pregnancy, labour and the puerperium should be minimized and dehydration should be avoided. Good Practice Point (GPP)
  68. 68. Low molecular weight heparin • Low molecular weight heparins are the agents of choice for antenatal thromboprophylaxis. • They are as effective as and safer than unfractionated heparin in pregnancy. B
  69. 69. Advantages of LMWH over UFH 1. No need for laboratory monitoring- -Experience indicates that, provided that the woman has normal renal function, monitoring of anti-Xa levels is not required when LMWH is used for thromboprophylaxis.
  70. 70. Continued…….. 2.Higher bioavailability - 90% vs 30% 3.Longer plasma half-life – 4 to 6 hours vs 0.5 to 1 hour – renal (slower) vs hepatic clearance 4. Less inhibition of platelet function – potentially less bleeding risk, but not shown in clinical use
  71. 71. Continued…… 5.Lower incidence of thrombocytopenia and thrombosis (HIT syndrome) – less interaction with platelet factor 4 – fewer heparin-dependent IgG antibodies current guidelines still recommend checking the platelet count one week after starting LMWH
  72. 72. 6. Prolonged unfractionated heparin use during pregnancy may result in osteoporosis and fractures but this risk is low with LMWH. Continued……
  73. 73. • Experience of enoxaparin in the puerperium reports no adverse effects on the baby resulting from breastfeeding. Low molecular weight heparin
  74. 74. Thromboprophylactic doses for antenatal and postnatal LMWH Weight (kg) Enoxaparin Dalteparin Tinzaparin <50 20 mg daily 2500U daily 3500U daily 50-90 40 mg daily 5000U daily 4500U daily 90-130 60 mg daily 7500U daily 7000U daily >130 80 mg daily 10,000U daily 9000U daily High prophylactic 40 mg 12- hourly 5000 units 12- hourly 4500 units 12- hourly Treatment dose 1 mg/kg/12 hourly antenatal;1.5 mg/kg/daily 100 units/kg/12 hourly 175 u/kg/daily (antenatal and postnatal)
  75. 75. Low-dose aspirin • Low-dose aspirin is safe in pregnancy, although its use for thromboprophylaxis in this setting has never been assessed by a controlled trial.
  76. 76. • The use of low-dose aspirin (75 mg daily) may be appropriate in situations where the risk of VTE is increased but is not deemed high enough to warrant the use of antenatal LMWH. Low-dose aspirin
  77. 77. Warfarin • Warfarin should be avoided if possible during pregnancy, especially between 6 and 12 weeks of gestation, because it is associated with an up to : 1. 5% risk of teratogenesis and 2. increases the risk of miscarriage, 3. fetal and maternal hemorrhage, 4. neurological problems in the baby and stillbirth.
  78. 78. • Warfarin is safe after delivery and for breastfeeding, although it requires : 1. Close monitoring, 2. Frequent visits to an anticoagulant clinic Warfarin
  79. 79. Warfarin carries an increased risk of: 1. Postpartum hemorrhage and 2. Perineal hematoma compared with LMWH. Warfarin
  80. 80. Dextran Dextran should not be used primarily because of the risk of anaphylaxis, which has killed fetuses by causing : • Massive histamine release and • Uterine hyper tonus.
  81. 81. Graduated elastic compression stockings • There are no trials to support such practice but the British Society for Hematology guidelines give a grade C recommendation (evidence level IV) that: All women with previous VTE or a thrombophilia should be encouraged to wear class-II graduated elastic compression below knee stockings throughout their pregnancy and for 6–12 weeks after delivery.