1. THROMBOPHILIA IN PREGNANCY Rukset Attar, MD, PhD Obstetrics and Gynecology Department

2. Hypercoagulability in Pregnancy During pregnancy, there is a marked increase in the procoagulant activity by elevation of fibrinogen, factors II, V, VII, VIII, IX, X, XII and the von Willebrand factor. Fibrinogen levels increase up to two fold. It is unclear why factor XI decreases. The physiological anticoagulant system becomes less efficient because of an increased resistance to activated protein C in the second and third trimester and a reduced protein S activity, due to estrogen induced decreases in total protein S. higher concentrations of plasminogen activator inhibitors (PAI), and an increased tendency to platelet aggregation Overall fibrinolytic activity is impaired during pregnancy

3. Risk factors for thrombotic complications Pregnancy-related risk factors for VTE include increasing maternal age (35 years), Caesarean section (especially emergency sections), thrombophilia, a family or personal history of thrombosis and obesity The puerperium itself is a risk factor (the most probable trigger for that is delivery itself, because vessel trauma can cause thrombosis, and systemic coagulation activation in the mother’s circulation can easily occur. Immobilisation after delivery can substantially add to this risk.

4. Risk factors for thrombotic complications An individual assessment of the thrombotic risk should be undertaken, ideally before or in early pregnancy. There is an increased risk of thrombosis in pregnant patients with thrombophilia depending on the severity of thrombophilia

5. Thrombophilia in Pregnancy Inherited thrombophilias Acquired thrombophilias Non-thrombotic pregnancy complications and thrombophilias

6. Inherited thrombophilias genetic conditions with an increased thrombotic risk depending on additional risk factors frequent causes of inherited thrombophilia are heterozygosity for Factor V Leiden (FVL) and G20210A mutation of the prothrombin gene; rarer are antithrombin, protein C and S deficiency Hyperhomocysteinemia due to genetic defects (homozygosity for a thermolabile mutant of methylenetetrahydrofolate reductase MTHFR) is controversially discussed as a cause of hereditary thrombophilia.

7. Inherited thrombophilias Rare thrombophilic mutations, such as gene polymorphisms of plasminogen activator inhibitor-1, factor XIII or apolipoprotein B do not generally transfer an independent risk for thrombosis

8. Acquired thrombophilias Antiphospholipid antibodies, such as the lupus anticoagulant or anticardiolipin and b-2-glycoprotein I antibodies are directed against glycoproteins in concert with phospholipids and are associated with thromboembolism and/or obstetrical complications. Antiphospholipid antibodies (aPL) are found in about 5% of the reproductive population and antiphospholipid syndrome (APS) in 15–17% of women with recurrent pregnancy loss

9. Non-thrombotic pregnancy complications and thrombophilias Maternal thrombophilias are not associated with pregnancy loss prior to 8–10 weeks of gestation, explained by the embryogenetic development of the vascular system Before 8 weeks of gestation in the embryo there is only yolk sac vasculature, and thereafter a contact between the maternal and fetal circulation develops. Therefore, it seems unlikely, that maternal thrombophilia can impair embryonic development at that earliest gestational stage.

10. Non-thrombotic pregnancy complications and thrombophilias Women with thrombophilia show an increased risk for pregnancy loss at the end of the first and in the second trimester those with FVL or prothrombin gene variant show a higher risk of late pregnancy loss (24 weeks) Recurrent pregnancy loss has been linked to inherited thrombophilia particularly with protein C and S deficiency,FVL and a prothrombin gene variant A significant association with increased risk for placental abruption was only observed with heterozygous FVL and the prothrombin gene variant IUGR Pre-eclampsia

11. Management of thrombotic disorders during pregnancy Risk-assessment for VTE Major known risk factors for VTE in pregnancy and in the postpartum period are C-section, obesity, Prolonged bed rest, immobility, pre-eclampsia, Nephrotic syndrome, current infection and recent surgery previous VTE and thrombophilia. In women at high risk LMWH prophylaxis should be continued for 4–6 weeks postpartum

12. Management of thrombotic disorders during pregnancy Anticoagulan Therapy coumarin-derivates Unfractionated heparin (UFH) low-molecular-weight heparins (LMWH) and aspirin The choice of the anticoagulant depends on the maternal or fetal complications. UFH and LMWH do not cross the placenta and are safe for the fetus. Maternal bleeding complications appear to be uncommon with LMWH.

13. Management of thrombotic disorders during pregnancy Prevention of VTE LMWH is the prophylaxis of choice in pregnancies at risk for VTE No laboratory monitoring is required. All women with previous VTE or a thrombophilia should be additionally encouraged to wear elastic compression stockings throughout their pregnancy and for 6–12 weeks after delivery.

14. Management of thrombotic disorders during pregnancy Women with prior VTE These women should have a postpartum prophylaxis for 6 weeks Two options have been proposed: no routine prophylaxis during pregnancy, but clinical surveillance and immediate investigation in cases with clinical suspicion of VTE- due to transient risk factor ACCP Guidelines, Chest 2008 prophylaxis starting during the first trimester (ideally before 10 gestational weeks) in women with an increased risk for VTE (thrombophilia or a history of a severe thrombotic event like PE or extended deep vein thrombosis, VTE during previous pregnancy, or during HRT)- ACCP Guidelines, Chest 2008

15. Management of thrombotic disorders during pregnancy Treatment of VTE Acute DVT or PE during pregnancy should be managed initially as in non-pregnant women UFH or LMWH have to be given until the diagnosis is confirmed. The first line treatment remains intravenous UFH (70 IU/kg as bolus, followed by 350 IU/kg/24 h as continuous infusion) to rapidly achieve an aPTT at 1.5–2.5 times the control value. Therapeutic doses of LMWH may be started once the patient is hemodynamically stable

16. Management of thrombotic disorders during pregnancy Weight-adjusted subcutaneous LMWH is to be preferred and administered once daily at a therapeutic dose (200 IU/kg/d) throughout pregnancy. Twice-daily administration (100 IU/kg q12 h) might be preferable for obese patients to achieve more stable factor Xa-levels in plasma, Therapeutic anticoagulation should be continued throughout pregnancy and for at least 6 month after thrombosis

17. Patients with recurrent trombosis attacks without trombophilia shoud be on life-long anticoagulan therapy Patients with recurrent trombosis attacks without trombophilia shoud be on life-long anticoagulan therapy Pro with UFH/LMWH during pregnancy and + postpartum period is advised for these patients (Grade 1A) Prophylaxis with UFH/LMWH during pregnancy and + postpartum period is advised for these patients (Grade 1A)

18. Management of thrombotic disorders during pregnancy APS Pregnant women with APS and previous thrombosis should receive antepartum and postpartum thromboprophylaxis with LMWH in a therapeutic dose UFH combined with ASS significantly reduced pregnancy loss compared to ASS alone A typical combined treatment regimen includes aspirin (75–85 mg/day), beginning with attempts at conception, and unfractionated heparin (5,000– 10,000 subcutaneous twice daily), beginning at first indication of pregnancy. A typical combined treatment regimen includes aspirin (75–85 mg/day), beginning with attempts at conception, and unfractionated heparin (5,000– 10,000 subcutaneous twice daily), beginning at first indication of pregnancy.

19. Operations not related to malignancies, lasting no longer than 30 minutes don’t require any prophylaxis unless there is another risk factor. Early mobilisation and IPC is advised for them (Grade 1A) Operations not related to malignancies, lasting no longer than 30 minutes don’t require any prophylaxis unless there is another risk factor. Early mobilisation and IPC is advised for them (Grade 1A) No prophylaxis for laparoskopic procedures unless there is another risk factor (Grade 1B) No prophylaxis for laparoskopic procedures unless there is another risk factor (Grade 1B)

20. Routin trombosis prophylaxis must be done in major gynecologic operations (Grade 1A) Routin trombosis prophylaxis must be done in major gynecologic operations (Grade 1A) With no other risc factor and not related to malignancy- LMWH (Grade 1A) or unfractunated heparin (Grade 1A) or IPC (Grade 1B) With no other risc factor and not related to malignancy- LMWH (Grade 1A) or unfractunated heparin (Grade 1A) or IPC (Grade 1B) With another risk factor or operation for malignancy- heparin + IPC (Grade 1C) With another risk factor or operation for malignancy- heparin + IPC (Grade 1C)

21. Sectio One risk factor besides pregnancy and sectio - heparin prophylaxis or (IPC, GCS) during hospital stay (Grade 2C) One risk factor besides pregnancy and sectio - heparin prophylaxis or (IPC, GCS) during hospital stay (Grade 2C) multipl risk factors- heparin prophylaxis or (IPC, GCS) (Grade 2C) multipl risk factors- heparin prophylaxis or (IPC, GCS) (Grade 2C) patients with high risk - prophylaxis for 6 weeks patients with high risk - prophylaxis for 6 weeks

22. Routin trombosis prophylaxis should be started before the major gynecologic operations Routin trombosis prophylaxis should be started before the major gynecologic operations Should continue during hospital stay (Grade 1A) Should continue during hospital stay (Grade 1A) İf it was a cancer surgery or if the patient had a VTE before LMWH should be continued for 28 days after discharge from the hospital (Grade 2C) İf it was a cancer surgery or if the patient had a VTE before LMWH should be continued for 28 days after discharge from the hospital (Grade 2C)

23. Acute trombosis in pregnancy UFH heparin (IV bolus, then infusion, aPTT measurement every 4 hours) or LMWH ( twice a day, s.c.) at least for 5 days (Grade 1A) UFH heparin (IV bolus, then infusion, aPTT measurement every 4 hours) or LMWH ( twice a day, s.c.) at least for 5 days (Grade 1A) Then prophylactic dosage Then prophylactic dosage Should continue thoroughout pregnancy (Grade 1B) and 6 weeks postpartum (Grade 2C) Should continue thoroughout pregnancy (Grade 1B) and 6 weeks postpartum (Grade 2C) Should be stopped 24 hours before delivery (Grade 1C) if delivered at therapeutic dosage Should be stopped 24 hours before delivery (Grade 1C) if delivered at therapeutic dosage

25. Unfractunated Heparin 3000- 30.000 Da 3000- 30.000 Da Binds to antitrombin, FIX, FX, FXI ve FXII Binds to antitrombin, FIX, FX, FXI ve FXII Also binds to beta tromboglobulin, PF4, histidin rich protein, vitronektin, platelets, osteoblasts and endothelial cells Also binds to beta tromboglobulin, PF4, histidin rich protein, vitronektin, platelets, osteoblasts and endothelial cells IV IV followed with aPTT measurements x1.5-2.5 followed with aPTT measurements x1.5-2.5 neutralised with Protamin neutralised with Protamin

26. LMWH 2000- 9.000 Da 2000- 9.000 Da Exreacted from UH via chemical and enzimatic procedures Exreacted from UH via chemical and enzimatic procedures İnhibits Fxa İnhibits Fxa Low affinity for endothelial cells, osteoblasts and PLT Low affinity for endothelial cells, osteoblasts and PLT Sc Sc monitorised via antiXa- anti-Xa level should be 0.5-1.2 U/ml monitorised via antiXa- anti-Xa level should be 0.5-1.2 U/ml neutralisation with Protamin is low neutralisation with Protamin is low

27. Whom should receive prohylaxis with heparin during pregnancy? Whom should receive prohylaxis with heparin during pregnancy? Those with valvular dieases or ritm disorders who are already on anticoagulation therapy Those with valvular dieases or ritm disorders who are already on anticoagulation therapy Recurrent VTE attacks- who are already on anticoagulation therapy Recurrent VTE attacks- who are already on anticoagulation therapy Patients with one VTE + trombophilia Patients with one VTE + trombophilia Patients with VTE during previous pregnancy or HRT Patients with VTE during previous pregnancy or HRT

28. Trombosis risks FV Leiden heterozigotx 4-7 FV Leiden homozigotx 80 P-20210 Ax 2-5 Hiperhomosisteinemiax 2-6 OC x 4 FVL+ P-20210 Ax 20 FVL+ hiperhomosisteinemiax 21.6 FVL+ OCx 35 FVL+ smoking x 30

29. FV Leiden mutation FV Leiden mutation Protrombin G20210A Protrombin G20210A Protein C activity Protein C activity Protein S activity Protein S activity AT activity AT activity Fasting homosistein level Fasting homosistein level Lupus anticoagulant Lupus anticoagulant ACA IgG ve IgM ACA IgG ve IgM Anti-B2 GPI IgG ve IgM Anti-B2 GPI IgG ve IgM ANA, anti-DNA ANA, anti-DNA