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Venous Thromboembolism In Pregnancy

Venous Thromboembolism In Pregnancy. Dr: Galila Zaher MRCPath Consultant hematologist Assistant Professor KAUH. Epidemiology of venous thromboembolism. Incidence with pregnancy is unknown PE is leading cause of MM second only to bleeding

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Venous Thromboembolism In Pregnancy

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  1. Venous Thromboembolism In Pregnancy Dr: Galila Zaher MRCPath Consultant hematologist Assistant Professor KAUH

  2. Epidemiology of venous thromboembolism • Incidence with pregnancy is unknown • PE is leading cause of MM second only to bleeding • Pregnancy & puerperium are thrombophilic condition • Risk of VTE in pregnancy is 4 - 6 X > non pregnant • No preponderance to any trimester • Predisposition for DVT in left leg (90%) • Increased risk persists postpartum Mayo Clinic, Over the 30-year study period, the highest risk period for VTE and PE in particular is during the postpartum period (57% after delivery) • Risk is higher after CS (esp. emergency CS) • Additional risk factors.

  3. Pathogenesis of Venous Thromboembolism Hypercoagulability Venous stasis Virchow’s Triad Vascular Damage

  4. Procoagulant factors: VWF ,FVIII & FV TF VIIa IXa Fibroblast Propagation Xa Prothrombin Thrombin Thrombin Xa IXa XIa Prothrombin XIa VIIIa Platelet Activated platelets Amplification

  5. Tissue factor +Factor VIIa TFPI Factor IXa -FVIIIa Factor Xa +FVa Anti Thrombin Protein C& ProteinS Factor IIa (thrombin) Factor XIa Fibrinogen Fibrin

  6. Pregnancy is a “physiological” hypercoagulation state • Acquired Resistance APC & Protein S Imparied fibrinolysis : • Venous stasis end of 12w & peaks at 36w • Raised progeterone levels  reduced venous flow • Endothelial damage to pelvic vessels during delivery Special Risk Factors • Age > 35 yrs (doubled) Mortality from PE x100 in preg women > 40 years • Parity  3 • Prolonged immobility • Obesity • Operative delivery - 2-8 fold increase GA > epidural block Emergency CS  elective CS • Inherited thrombophilia

  7. Venous Thrombosis During Pregnancy • Diagnostic Challenge • Symptoms & signs of DVT & PE : physiologic changes • Concern about diagnostic procedures : radiation exposure • Thrombophilia testing • Safety of anti-coagulant during pregnancy

  8. Inherited Prothrombotic State

  9. Impact of Unconfirmed Diagnosis of VTE in Pregnancy: • Risk of anticoagulant therapy • Future pregnancy (ies): Thromboprophylaxis or not? • No large scale trials • Empirical recommendations based on extrapolation from studies in non-pregnant and small observational ones • Clinical Diagnosis Physiological changes mimicing symptoms of VTE Clinical diagnosis (pre test probability) lakes both the sensitivity & specificity(20-40%).

  10. D-DIMER (ELISA) • Highly sensitive, nonspecific screening test 95-99% NPV • Elevated in pregnancy, inflammation, advanced age and cancer • In pregnancy because its specificity was deemed too poor. • Sensitivity and specificity of SimpliRED assay in pregnant women Prospective study. Sensitivity :100%, specificity 60%, and NPV value was 100% • Normal result excludes DVT • Initial screen it reduce the imaging workload by 35%Clin Radiol 2000Jul:55(7):525-7 • Normal D-dimer level in low –inermediate clinical probability excludes DVT.Semin Thromb Hemos2000:26(6):65767 • Normal D-dimer test + normal CUS has a NPV of 99%.

  11. ULTRASOUND (Compression, Duplex, or Doppler) • Pro’s • Quick, cheap, and non-invasive • Con’s • highly operator dependent • negative in 10-30% distal DVT

  12. V/Q SCAN • Diagnosis based on pre-test probability • Rarely diagnostic (i.e. high or intermediate probability) • Unreliable in the setting of concomitant lung disease (e.g. pneumonia, cancer, COPD) or significant cardiac disease.

  13. High-Res CT SCAN • Quick, accurate, available, and relatively non-invasive. • Sensitivity(79%)Specificity(91%) • Valid only for main, lobar, or segmental artery occlusions. • Not an option in renal insufficiency.

  14. MRI for Diagnosis of PE • MRIGodolinium contrast crosses placenta • FDA “Safety of MRI devices when imaging the foetus has not been established”. Therefore, informed consent is required throughout pregnancy.

  15. ANGIOGRAPHY • Gold Standard for the diagnosis of VTE • It is invasive and has associated risks • Reserved when diagnosis of VTE cannot be established by less invasive tests • In indeterminate V-Q scan

  16. Estimated Radiation absorbed by foetus • CXR* < 10 Gy • V/Q* 10 – 50 GyTc-99 m sulphur colloid • PA* < 500 Gy brachial route • Total* < 50,000 • Expose of foetus to radiation <50,000 Gy (i.e. 5 rads) has not been associated with seg risk of foetal injury in most studies.

  17. Algorithm for the investigation of suspected DVT during pregnancy Suspected DVT CUS of proximal veins Clearly abnormal Normal Equivocal Treat Isolated Iliac DVT Suspected Venography or MRI Normal Abnormal No treatment Treat Yes No Serial CUS Pulsed Doppler with direct visualization of iliac vein Venography or MRI Normal Abnormal Abnormal Normal Normal Abnormal Treat No treatment No treatment Treat Serial CUS Treat or Confirm with Vernography or MRV Blood, 2002; 100: 3470-8

  18. Indications For Anticoagulant Therapy • Prevention and treatment of VTE • Prevention of pregnancy complications in APLAs • Prevention of pregnancy complications in thrombophilia • Recommendations are based largely on extrapolations from non pregnant patients

  19. Thrombo-Prophylaxis • Anticoagulant • Heparin & LMWH • Warfarin • Aspirin • Elastic compression

  20. Vitamin K Utilization Reduced Warfarin—Mechanism of Action Vitamin K Protein Half-Life Factor VII 4–6 hours Factor IX 24 hours Factor II 60 hours Factor X 48–72 hours Protein C 8 hours Protein S 30 hours Warfarin

  21. Elimination Half-Lives of Vitamin K-Dependent Proteins Protein Half-Life Factor VII 4–6 hours Factor IX 24 hours Factor II 60 hours Factor X 48–72 hours Protein C 8 hours Protein S 30 hours

  22. Warfarin Therapy • Cross placenta • Safe during first 6 ws of gestation • Embryopathy 6- 12 ws of gestation • CNS abnormalities : any trimester • Fatal or non-fatal hemorrhage • Necrosis of skin and other tissues • Less frequently include: • cholesterol microembolization • Alopecia • Purple toes syndrome, urticaria, dermatitis

  23. UFH Dose not cross placenta Major bleeding 2% (non pregnant) Inconvenient :frequent monitoring aPTT response to heparin is attenuated Painful to administer Osteoporosis Heparin-induced thrombocytopenia (HIT) LMWH Dose not cross placenta Major bleeding 2% Monitoring usually is not required : longer T1/2 Weight-adjusted dose BID preferable to OD Less Osteoporosis Less HIT As effective & safe as UFH Non-pregnant Expensive Anti- Xa 3 - 4 h post dose ( 0.5 - 1.2 U/mL) Long-term Heparins

  24. Nursing Mother • Heparin & LMWHs are not secreted into breast milk can be safe • Warfarin does not induce anticoagulant effect in breast-fed infant is also safe.

  25. Dose Definitions UFHSC BID • Minidose UFH 5,000 U • Moderate-dose adjusted anti-Xa 0.1 - 0.3 U/mL. • Adjusted-dose mid-interval aPTT 1.5-2.5 X control LMWH Enoxaparin • Prophylactic : 40 mg SC OD • Intermediate-dose 40 mg SC BID • Adjusted-dose weight-adjusted, 1 mg/kg OD or BID

  26. Treatment of VTE During Pregnancy • Many randomized trials & meta-analyses : in non-pregnant . • LMWH is at least as safe and effective as UFH. • Enoxaparin 1 mg/kg BID OR UFH 80 IU/Kg X 5 d • Enoxaparin 1 mg/kg BID OR Adjusted-dose UFH SC BID mid-interval aPTT 1.5-2.5 • Delivery : DC heparin 24 h before elective induction • Postpartum 4-6 ws Warfarin INR 2-3 • Graduated elastic stocking :ante &post-natal All are 1C except GES 2C

  27. Long-term Oral Anticoagulant Therapy Attempting pregnancy Replacement with UFH or LMWH when pregnancy is achieved Replacement with UFH or LMWH before conception is attempted. mid-interval aPTT 1.5-2.5 X control 1 mg/kg OD or BID Adjusted-dose UFH Or LMWH Reliable patient Increases heparinexposure Is costly Higher osteoporosis Assumes warfarin is safe first 4 - 6 ws (Grade 2C)

  28. Secondary Thrombo-prophylaxis • Single episode • Multiple (two or more) episodes and/or receiving long-term anticoagulants • Thrombophilia & No prior VTE

  29. VTE Thromboprophylaxis? No Yes

  30. Single Episode Transient risk factor • Antepartumclinical surveillance (Grade 1C) OR Graduated elastic compression • Postpartum warfarin 4- 6 W INR 2.5 (1C) Pregnancy / estrogen-related or additional risk factors (obesity) • Antepartum anticoagulant prophylaxis ( 2C) OR LMWH enoxaparin 40 mg SC OD OR UFH Minidose 5,000 U SC q12h OR Graduated elastic compression • Postpartum warfarin 4- 6 Ws INR 2.5(1C)

  31. Single Episode Idiopathic Or Strong Family History • Ante-partum • LMWH Prophylactic Or Intermediate-dose enoxaparin 40 mg SC OD Or BID • UFH Minidose Or Moderate-dose 5,000 U SC BID Or adjusted to anti-Xa 0.1 -0.3 U/mL. • Clinical surveillance & aggressive investigation with S&S of DVT or PE. • Ante-natal & postpartum GES • Postpartum warfarin 4 - 6 ws INR 2- 3 with initial heparin overlap until INR is 2.5 (All are 2C)

  32. Single episode VTE Thrombophilia confirmed by lab & not on long-term anticoagulants Or strong family history of VTE • High Risk :AT-deficient , compound heterozygotes & homozygotes : • History of VTE Antipartum & Postpartum moderate dose • No prior VTE Prophylactic dose LMWH Enoxaparin 40 mg SC All are 2C • Low Risk : • Surveillance • Enoxaparin 40 SC mg OD OR Minidose UFH 5000 IU SC BID • Postpartum warfarin 4 - 6 ws INR of 2- 3, with initial UFH or LMWH overlap until INR is 2.0 UFH: anti-Xa 0.1 - 0.3 U/mL or Enoxaparin 40 mg SC BID.

  33. Secondary prophylaxisMultiple episodes of VTE Or women receiving long-term anticoagulants • Antepartum • UFH SC BID adjusted mid-interval aPTT 1.5-2.5 • LMWH weight-adjusted, enoxaparin 1 mg/kg BID • Delivery DC heparin 24 h before elective induction • Postpartum warfarin 4-6W INR 2-3 • Antepartum & postpartum :Graduated elastic compression All are Grade 2C

  34. Thrombophilia &VTE *McColl et al73 Retrospective case control

  35. Labor & Adjusted-dose Heparin • Heparin be discontinued 24 h prior to elective induction or CS • Spontaneous labor careful monitoring of aPTT • Markedly prolonged near delivery, protamine sulfate • Bleeding complications very uncommon with LMWH • Very high risk of recurrent VTE • Proximal DVT within 2 weeks DC 4- 6 h prior to expected time of delivery &Temporary IVC filter • Postpartum anticoagulants for at least 6 weeks.

  36. Recurrent deep venous thrombosis • In order to estimate the rate of recurrent deep venous thrombosis • Retrospectively :1104 women with previous VTE • Recurrences during pregnancy 7.5% if first VTE was unprovoked, related to pregnancy or to oral contraceptive use • No recurrence occurred if the first VTE was related to other transient risk factors. • In puerperium, the rate of recurrence was 15.5% Mannuccio: Br J Haematol. 2006Nov;135(3):386-91.

  37. Combined oral contraceptives • The risk of VTE in women taking combined oral contraceptives (COCs) is attributed to changes in coagulation and fibrinolysis. • Women with hereditary deficiencies of PS,PC , or AT are at high risk of VTE during use of COCs, particularly when other thrombophilic defects are present.. • Oral contraceptive use and pregnancy/ post-partum period increased the risk of thrombosis in carriers of FVL Martinelli2003Semin Vasc Med. 2003Feb;3(1):47-60. • Presence of inherited thrombophilia increases the risk for VTE due to OCCs up to an absolute risk of 3 per 1000 person-years, in comparison with the baseline risk of 3 to 6 per 10000 person-years De Stefano V, Rossi E, Leone G..

  38. Thank you

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