Thrombophilia and ٍٍRecurrent Pregnancy Loss
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review the evidence (RCT & meta-analyses) concerning the best practices in contemporary Recurrent Pregnancy Loss and Thrombophilia depending on Eshre guideline 2017 and other EBM sources.
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Thrombophilia and ٍٍRecurrent Pregnancy Loss
- 1. Thrombophilia and Recurrent Pregnancy Loss www.marwanalhalabi.com Marwan Alhalabi Professor of Reproductive Medicine and Infertility, Damascus University Head of Assisted Reproduction Unit, Orient Hospital President of Middle East Fertility Society President of Syrian Society of Obstetricians and Gynecologists Homs 2018
- 3. • To review the evidence (RCT & meta- analyses) concerning the best practices in contemporary Recurrent Pregnancy Loss and Thrombophilia depending on Eshre guideline 2017 and other EBM sources. Objectives
- 4. Outlines • Definition • Risk Factors • Investigation • Treatment • Conclusion www.marwanalhalabi.com
- 11. Grade of Recommendation • There is good evidence to support the recommendation, either for or against. Grade A • There is fair evidence to support the recommendation, either for or against. Grade B • There is insufficient evidence to support the recommendation, either for or against. Grade C
- 12. Strength of Recommendation • Most individuals should receive the intervention Strong: S • Different choices will be appropriate for individual Conditional: C • based on the clinical experience of the guideline development group Good practice point: GPP
- 14. Causes
- 15. Anatomical AETIOLOGY Infectious ? Genetic Immunologic Endocrine ? Thrombophilia Allo-Immunity Unexplained Causes - Biggest DILEMMAS
- 16. Inherited ØActived Protein C resistance Factor V Leiden. ØProthrombin Mutation. Ø(MTHFR) Hyperhomocystenemia. ØProtein C deficiency ØProtein S deficiency ØAnti Thrombin deficiency Acquired ØAntiphospholipid synd ØAdvancing age ØMalignancy ØImmobilization ØTrauma, Postoperative ØPregnancy ØEstrogen use ØHematologic diseases ØNephrotic syndromeCombined: ØHyperhomocystenemia Thrombophilia
- 18. Girardi,Redecha,Salmon. Nature Med 10:1222-1226, 2005 • Inhibit hCG release from placental explants • Block of in vitro trophoblast migration &invasion • Inhibit formation of giant, multinucleated cell • Inhibit of trophoblast cell adhesion molecules (alpha 1 and 5 integrins, E and VE cadherins) • Activate complement on the trophoblast surface inducing an inflammatory response Pathophysiology of aPL It’s not just anticoagulation !
- 21. Strong Evidence the patient should have two positive tests at least six weeks apart for either lupus anticoagulant, anticardiolipin antibodies or Anti-β2-glycoprotein I of IgG and/or IgM class S Eshre Guidelines, 2017 Screening for aPL antibodies
- 22. Conditional Evidence Prophylactic therapies such as aspirin, heparin in pregnancy and 6 to 8 weeks postpartum Women with APS without a history of thrombotic events (most women with RPL) C Eshre Guidelines, 2017 Treatment of aPL Syndrom
- 24. Strong Evidence their use may provoke significant maternal and fetal morbidity Neither corticosteroids nor intravenous immunoglobulin therapy improve the live birth rate of women with recurrent pregnancy loss associated with APL. S Eshre Guidelines, 2017 Treatment of aPL Syndrom
- 25. Treatment of aPL Syndrom www.marwanalhalabi.com How to manage APS with RPL?
- 27. Inherited ØActived Protein C resistance Factor V Leiden. ØProthrombin Mutation. Ø(MTHFR) Hyperhomocystenemia. ØProtein C deficiency ØProtein S deficiency ØAnti Thrombin deficiency Acquired ØAntiphospholipid synd ØAdvancing age ØMalignancy ØImmobilization ØTrauma, Postoperative ØPregnancy ØEstrogen use ØHematologic diseases ØNephrotic syndromeCombined: ØHyperhomocystenemia Thrombophilia
- 28. Factor V Leiden mutation protein C deficiency Protein S deficiency Antithrombin III deficiency Hyperhomocysteinaemia Prothrombin gene mutation Green-top Guideline April 2009 Inherited thrombophilic defects (Hypercoagulable state)
- 29. • Antithrombin deficiency • Abnormalities in protein C and protein S system - protein C deficiency - protein S deficiency - abnormal thrombomodulin • Resistance to activated protein C (FV Leiden, FV Cambridge) Inherited thrombophilic states (1)
- 30. • Hyperprothrombinemia (prothrombin variant G20210A) • Dysfibrynogeneimia • Abnormalities in fibrinolytic system - hypo- or dysplasminogenemia - elevated plasminogen activator inhibitor - decreased tissue plasminogen activator • Hyperhomocysteinemia • Heparin cofactor II defciency • Elevated histidine-rich glycoprotein • Factor XII deficiency Inherited thrombophilic states (2)
- 32. Inherited Thrombophilia 1965 AT mutation identified [Egeberg et al] 1967 Dysfunctional fibrinogen [Egeberg et al] 1981 Protein C [Griffin et al] 1984 Protein S [Comp et al]] 1993/4 aPCR/FV L [Dalhback/Bertina et al] 1996 Prothrombin mutation [Poort et al]
- 36. Pregnancy-Associated Changes in Haemostatic and Fibrinolytic Proteins Increase in Clotting Factors: • 20 to 200% increase in levels of fibrinogen, factors II, VII, VIII, IX, X. • Progressive platelet activation 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 www.marwanalhalabi.com
- 40. • Protein C and Protein S are vitamin K dependent proteins produced in liver • Protein C is activated by thrombin/ thrombomodulin on endothelial cells • Protein S is a co-factor • Activated protein C + protein S destroys factor Va and factor VIIIa - blocking coagulation Protein C System
- 41. • Protein C deficiency. • Protein S deficiency. • Mutation of factor V cleavage site (activated protein C resistance). Protein C System - 3 abnormalities
- 44. • Homocysteine- intermediary amino acid formed by the conversion of methionine to cysteine. • Cofactors: folate, vitamin B12, vitamin B6. Hyperhomocystinemia
- 45. RPL Patients Controls 30% 61% 2% 0% MTHER C677T gene Heterozygous MTHER C677T gene Homozygous Al Halaki et al, 2016 MTHFR (C677T) mutation
- 47. Prevalence of factor V Leiden mutation and its relation with recurrent spontaneous pregnancy loss in a group of Syrian women Mohammad Motee Abbas Mohammad * Marwan Gamil Al-Halabi, Ph.D. † Fawza Mohammad Sharif Monem, PhD. ‡ Faculty of Pharmacy, and faculty of Medicine Damascus University, Damascus, Syria ABSTRACT Objective: The aim of our study was to investigate the prevalence of factor V Leiden and its relation with RPL in a group of Syrian women. Materials and Methods: The study group included 35 women with a history of recurrent pregnancy loss (two or more abortions before 20th week of gestation) were referred to Orient hospital for obstetrics, gynecology and assisted reproduction, Damascus, Syria, for investigation between December 2005 and July 2006. All women with known causes of pregnancy loss after convenient investigations were excluded. The control group included 45 healthy women from the same ethnic background, who had at least one successful pregnancy, and none of them had a history of fetal loss or complicated pregnancy. FVL mutation was screened by Real-time PCR method. Results: The results show that 10 women out of 35 with RPL and 4 women out of 45 controls had FVL mutation (28.6 versus 8.9 %,P=0.022, Odds ratio 4.1, 95% CI: 1.16-14.4). From the 25 women who were primary RPL, eight patients had the factor V Leiden (32 versus 8.9%, P=0.014, OR: 4.8, 95%CI: 1.2, 18.17). From the 10 women who were secondary RPL, two patients had the factor V Leiden (20 versus 8.9%, P=0.30, OR: 2.5, 95% CI: 0.4-16.4). All patients and controls carrying the factor V Leiden were heterozygote. Conclusion: Our results revealed that the prevalence of FVL was significantly higher in women with RPL in comparison with controls, particularly in the subgroup with primary RPL, and there is an association between factor V Leiden mutation and recurrent pregnancy loss. Key Words: Factor V Leiden mutation, recurrent pregnancy loss, Prevalence, Syrian women Middle East Fertility Society Journal Vol. 12, No. 3, 2007 Copyright Middle East Fertility Society
- 51. Management
- 52. High Risk www.marwanalhalabi.com • Antiphospholipid syndrome • Anti-thrombin deficiency 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) Low Risk • Heterozygosity for Factor V Leiden mutation • Heterozygosity for PT G20210A mutation
- 54. Good Practice Point and dehydration should be avoided Regardless of their risk of VTE, immobilization of women during pregnancy, labour and the puerperium should be minimized GPP RPL: Inherited Thrombophilia
- 55. Fair Evidence For elevated homocysteinemia without thrombosis history (Supplementation with Vitamin B6, B12 and folic acid) (Heparin anticoagulation for history of thrombosis) Women with second- trimester pregnancy loss should be screened for inherited thrombophilias including factor V Leiden and prothrombin gene mutation. B RCOG guidelines 2011 , In 2014; de Jesús et al., RPL: Inherited Thrombophilia
- 57. Advantages of LMWH over UFH • No need for laboratory monitoring • Higher bioavailability - 90% vs 30% • Longer plasma half-life (4 to 6 hours vs 0.5 to 1 hour) • Less inhibition of platelet function • Lower incidence of thrombocytopenia and thrombosis (HIT syndrome) • low risk in result in osteoporosis and fractures. www.marwanalhalabi.com current guidelines still recommend checking the platelet count one week after starting LMWH
- 58. Treatment with LMWH 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 postnatal 100 units/kg/12 hourly 175 u/kg/daily (antenatal and postnatal)
- 59. Final Treatment • There are no specific therapies to reverse most hypercoagulable states. • Recombinant factor concentrates of antithrombin and APC. • Gene transfer to correct a particular genetic defect. • Attempts to eliminate APA by plasmapheresis or • immunosuppressive therapy have not been very successful. www.marwanalhalabi.com
- 60. one unexplained fetal deaths after ten weeks of pregnancy one preeclampsia or placental insufficiencies occurring before 34 weeks One previous preterm birth one or more confirmed episodes of venous or arterial thrombosis. any of these must invite a big question mark ?
- 62. • Pregnancy itself is a thrombogenic condition. • Every woman should be assessed for risk factors. • Decision for thromboprophylaxis should be individualized. • LMWH is the drug of choice. Conclusions
- 66. 66 Thank you
- 69. Molecular basis of inherited thrombophilia caused by impaired anticoagulant mechanisms Genetic defect No. of different mutations Most frequent mutations AT deficiency PC deficiency >79 >160 Type I: whole or partial gene deletions (<10% of cases) Short insertions or deletions Single nucleotide changes Type II: missense mutations (leading to amino acids substitutions) Type I: frameshift mutations, nonsense, missense mutations Type II: missense mutations
- 70. Molecular basis of inherited thrombophilia caused by impaired anticoagulant mechanisms Genetic defect No. of different mutations Most frequent mutations PS deficiency APC-resistance >13 2 Type I: gene deletions, frameshift mutations, nonsense mutation, missense mutations Type II: missense mutations Missence mutation in the factor V molecule