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Thrombophilia adverse pregnancy outcomes

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thrombophilia is claimed in many adverse pregnancy outcomes

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Thrombophilia adverse pregnancy outcomes

  1. 1. Thrombophilia and adverse pregnancy outcomes Dr. Mohammed Abdalla Egypt, Domiat General Hospital
  2. 2. Thrombophilia the tendency to thrombosis
  3. 3. The contact between placenta and maternal circulation is crucial for the success of pregnancy. Pro- thrombotic changes and thrombosis may interfere with these processes leading to adverse pregnancy outcomes at any gestational age
  4. 4. Thrombophilia Inherited Acquired The antiphospholipid syndrome. anticardiolipin antibodies  hyperhomocysteinemia (C677T) mutation ).  FV Leiden mutation (A506G) mutation ).  mutation in prothrombin (G 20210 A) .  The prothrombin II (PTII) mutation.  protein S deficiency.  Protein C deficiency. lupus anticoagulant antibodies
  5. 5. placental vasculopathy Placental pathologists use the term placental vasculopathy to describe pathological placental changes were found to be associated with some clinical conditions such as preeclampsia, IUGR, placental abruption and some cases of fetal loss and preterm labor .
  6. 6. villous infarcts. multiple infarcts. fibrinoid necrosis of decidual vessels. fetal stem vessel thrombosis. placental hypoplasia. spiral artery thrombosis . placental vasculopathy
  7. 7. antiphospholipid syndrome
  8. 8. In the antiphospholipid antibody syndrome the body recognizes phospholipids (part of a cell's membrane) as foreign and produces antibodies against them. antiphospholipid syndrome
  9. 9. APA syndrome is an acquired autoimmune thrombophilia in which vascular thrombosis and/or recurrent pregnancy losses occur in patients having laboratory evidence for antibodies against phospholipids or phospholipid-binding protein cofactors in their blood. antiphospholipid syndrome
  10. 10. Antiphospholipid antibodies are a family of approximately 20 antibodies directed against negatively charged phospholipid binding proteins. only the lupus anticoagulant and anticardiolipin antibodies (IgG and IgM subclass, but not IgA) have been shown to be of clinical significance. antiphospholipid syndrome
  11. 11. primary APS (PAPS) (53%) secondary APS (47%) . (37%) Secondary APS (SAPS) associated with SLE or SLE-like syndrome. Females are more frequently affected than males. It mainly affects the second and third decades of life. "Euro-Phospholipid Project Group". in a cohort of 1000 patients. Arthritis Rheum 2002; antiphospholipid syndrome
  12. 12. The mechanism of aPL-associated pregnancy loss is related to the adverse effect of these antibodies on embryonic implantation, trophoblast function and differentiation. and placental vasculopathy. antiphospholipid syndrome
  13. 13. PRINCIPAL PATHOGENIC MECHANISMS MEDIATED BY APL Interference with: protein C/S pathway inhibition; fibrinolysis inhibition a) soluble coagulation factors: induction of a pro-adhesive, pro- inflammatory and pro-coagulant endothelial phenotype; induction of a procoagulant phenotype in monocytes b) coagulation cells: Interference with: reduction of proliferation and differentiation; gonadotrophin secretion impairment a) trophoblast cells:
  14. 14. Sapporo criteria An International Consensus Conference held in Sapporo in 1998 stated that recurrent arterial and/or venous thrombosis and/or miscarriages in the persistent presence of a positive anti-phospholipid test are formal classification criteria for APS clinical criteria thrombosis, one or more confirmed episodes of venous, arterial, or small vessels disease . pregnancy criteria : one or more unexplained fetal deaths after ten weeks of pregnancy. one or more preeclampsia or placental insufficiencies occurring before 34 weeks .  three or more unexplained consecutive spontaneous abortions less than 10 weeks.
  15. 15. OBSTETRICAL AND FETAL MANIFESTATIONS IN THE COHORT OF 1,000 APS PATIENTS ENROLLED BY THE EUROPEAN APL FORUM %Obstetric manifestations 9Pre-eclampsia/eclampsia 3Toxemia 0.6Abruptio placentae 0.3Post-partum cardio-pulmonary syndrome Fetal manifestations 36Early fetal losses 17Late fetal losses
  16. 16. laboratory criteria The laboratory criteria are medium or high titer, not low titer, IgG or IgM anticardiolipin antibody, and/or a lupus anticoagulant on two or more occasions at least six weeks apart. When the aPTT is prolonged and not "correctable" by mixture with normal plasma, the presence of an "anticoagulant" or "inhibitor" should be suspected Sapporo criteria
  17. 17. Inherited Thrombophilia
  18. 18. three important inherited thrombophilias : mutation in factor V causing Resistance to activated protein C (responsible of 20–30% of venous thromboembolism events.) mutation in prothrombin (guanine 20210 adenine ) mutation in methylenetetrahydrofolate reductase (MTHFR) (cytosine 677 thymine (C677T) ) The mutation is responsible for reduced MTHFR activity and is the most frequent cause of mild hyperhomocysteinemia and can be found in 5–15% of the population. Inherited Thrombophilia
  19. 19. A high rate of protein S deficiency, APCR, hyperhomocysteinemia and aCL IgG or IgM was found in women with severe preeclampsia . Dekker et al Am J Obstet Gynecol 1995
  20. 20. higher prevalence of FV Leiden mutation in women with severe preeclampsia compared to controls. Nagy et al Clin genet 1998
  21. 21. 120 women with severe preeclampsia, (72% nulliparous) and 101 healthy matched for age and parity. 18.3% of preeclamptic women were carriers of the FV Leiden mutation compared to 3% in controls . Rigo et al Hypertens Pregnancy 2000
  22. 22. 110 healthy women who had during pregnancy severe preeclampsia, IUGR , severe abruptio placentae and stillbirth were enrolled in the study. The control group comprised 110 healthy matched women with normal pregnancies. All 220 patients were tested for all known thrombophilias at least 2 months after delivery. The total prevalence of all thrombophilias detected in the 110 women with complications was 65% compared to 18% in controls. Kupferminc et al N Eng J Med 1999
  23. 23. in USA tested the genetic thrombophilic mutations in 110 women with severe preeclampsia and 97 controls. Most women were nulliparous and 60% of them were African Americans. No difference was found in the prevalence of thrombophilias between the women with severe preeclampsia and control women groups, or in fetal genetic thrombophilias. Livingstone et al Am J Obstet Gynecol 2001
  24. 24. tested 113 nulliparous women with preeclampsia: 100 with severe disease, 13 with mild disease and 103 controls for the C677T polymorphism of the MTHFR gene. No difference in homozygosity for MTHFR was found between the 2 groups (preeclampsia 3% vs controls 6%) Laivuori et al in Finland Obstet Gynecol 2000,
  25. 25. factor V Leiden (A506G) mutation adenine 506 guanine (A506G) mutation in factor V (factor V Leiden) (a substitution of glutamine for arginine at amino acid 506 of factor V) Factor V Leiden (FVL) is a mutation in the factor V molecule, rendering it resistant to cleavage by activated protein C. Factor V remains a procoagulant and thus predisposes the carrier to clot formation. It has been linked with an increased risk for venous thromboembolism due to Resistance to activated protein C and is responsible of 20– 30% of venous thromboembolism events
  26. 26. The Factor V Leiden (FVL) mutation, present in 3- 8% of the general population, leads to less than normal anticoagulant response to activated protein C resulting in an increased risk for venous thrombosis. Individuals with one copy of the FVL gene mutation (heterozygotes) have a seven fold increased risk for thrombosis compared to the general population whereas homozygotes have an eighty fold increase. factor V Leiden (A506G) mutation
  27. 27. prothrombin (G20210A) mutation A change of G to A at position 20210 in prothrombin (prothrombin 20210A) elevates baseline prothrombin levels and thrombin formation.
  28. 28. MTHFR (C677T) mutation cytosine 677 thymine (C677T) mutation (a C to T change at position 677 of MTHFR) is responsible for reduced MTHFR activity results in decreased synthesis of 5-methyltetrahydrofolate, the primary methyl donor in the conversion of homocysteine to methionine and the resulting increase in plasma homocysteine concentrations ( Hyperhomocysteinemia ) is a risk factor for thrombosis Dietary restriction of folate and vitamin B12 remains the most common cause.
  29. 29. A homozygous methylenetetrahydrofolate reductase (MTHFR) mutation, present in 1-4% of the general population, is associated with a three fold increased risk for DVT or PE, as well as preeclampsia and placental abruption. MTHFR (C677T) mutation
  30. 30. Protein S deficiency Protein S deficiency (PSD), present in up to 2% of the general population, is found in approximately 15% of individuals with a DVT or PE and 6% of women with obstetrical complications including a relatively high risk for stillbirth.
  31. 31. Protein C deficiency Protein C deficiency (PCD), present in about 1.5% of the general population, is associated with a lower risk for obstetrical complications than PSD and is found in 3- 5% of individuals with a DVT or PE. Furthermore, PCD combined with a FVL mutation is a relatively common cause of DVTs and show a higher risk for thrombosis compared to FVL alone.
  32. 32. Antithrombin III deficiency Antithrombin III deficiency (ATIII), present in less than 0.5 % of the general population, as with PSD and PCD, may rarely result from mutational events Because of its relative rarity, actual risks for thrombotic events are difficult to estimate, but without question this entity contributes to thrombotic risks during pregnancy.
  33. 33. MANAGEMENT OF THROMBOPHILIC PREGNANT WOMEN
  34. 34. Obstetric management The gold standard therapy to prevent miscarriages and obstetrical complications is represented by the association of low-dose aspirin and heparin (unfractionated or low molecular weight heparin). Intravenous immunoglobulin has been used in pregnant women with APS, but a recent controlled study found no benefit in comparison to the aspirin-heparin treatment . The Pregnancy Loss Study Group. Am J Obstet Gynecol 2000; 182: 122-7
  35. 35. Recently, the Cochrane Collaboration reported a 15% reduction in the risk of preeclampsia (32 trials with 29,331 women) and a 14% reduction in fetal and/or neonatal death (30 trials with 30,093 women). This reduction in death was the greatest amongst high-risk women (4134 women). The combination of aspirin and heparin or low molecular weight (LMW) heparin is effective in recurrent fetal loss in APS syndrome and could be considered for women with inherited thrombophilias and history of severe preeclampsia, IUGR, abruptio placentae or fetal loss, although no controlled studies on the subject are currently available Antiplatelet drugs for prevention of pre-eclampsia and its consequences: Systematic review. BMJ 2001
  36. 36. Recurrent pre-eclampsia and/ or embryonic loss without history of thrombotic events 1) Standard heparin: 5,000 - 7,500 U every 12 hours in the first trimester; 5,000 - 10,000 U every 12 hours in the second and third trimesters. 2) Low molecular weight heparin: 1) Enoxaparin 40 mg/day or dalteparin 5,000 U/day or 2) Enoxaparin 30 mg every 12 hours or dalteparin 5,000 U every 12 hours.
  37. 37. Fetal death or severe early pre- eclampsia or severe placental insufficiency, without history of thrombotic events 1) Standard heparin: 7,500 - 10,000 U every 12 hours in the first trimester; 10,000 U every 12 hours in the second and third trimesters. 2) Low molecular weight heparin: 1) Enoxaparin 40 mg/day daily or dalteparin 5,000 U/day, or 2) Enoxaparin 30 mg every 12 hours or dalteparin 5,000 U every 12 hours
  38. 38. Anticoagulation treatment in women with previous thrombotic events 1) Standard heparin: 7,500 U every 8-12 hours adjusted to maintain the mid-interval heparin levels in the therapeutic range. 2) Low molecular weight heparin: 1) Weight-adjusted (e.g., enoxaparin 1 mg/kg every 12 hours or dalteparin 200 U/kg every 12 hours), or 2) Intermediate dosage (e.g., enoxaparin 40 mg/day or dalteparin 5,000 U/day until 16 weeks' gestation and every 12 hours from 16 weeks' gestation onwards)
  39. 39. Treatment should be prolonged for life if aPL positivity persists . Whether or not APS patients can be safely treated with intermediate-intensity warfarin treatment (INR range from 2.0 to 2.9) or with a high-intensity treatment (INR =3.0), is still a matter for debate due to the report of severe hemorrhagic complications associated with high-intensity anticoagulation therapy .
  40. 40. Thank you

thrombophilia is claimed in many adverse pregnancy outcomes

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