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1987 year – Antiphospholipid Syndrome G.Houghes

Thrombophilia and issues of modern perinatology A.D.Makatsariya Professor, Head of department of obstetrics and gynecology of Sechenov Moscow State Medical University, head of obstetrical clinic. 1987 year – Antiphospholipid Syndrome G.Houghes

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1987 year – Antiphospholipid Syndrome G.Houghes

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  1. Thrombophilia and issues of modern perinatologyA.D.MakatsariyaProfessor, Head of departmentof obstetrics and gynecology ofSechenov Moscow State Medical University,head of obstetrical clinic

  2. 1987 year – Antiphospholipid Syndrome G.Houghes Formation of autoantibodies to phospholipid determinants in platelets, endothelium and neural tissue 2002 year - APSis systemic process Taormina, Sicilia Formation of autoantibodies to phospholipid determinants of majority organs and tissues

  3. Catastrophic APS 1992 year – Ronald Asherson gavethe determination of catastrophic form of APS

  4. CAPS – rare, an unusual and most severe variant of APS, develops in 1% of patients. • Manifests with multiple thrombosis of vital organswith the development of multi-organ failure. • CAPS is a life-threatening condition which requires urgent therapy.

  5. More often in women (2:1) • The mortality is almost 50%despite the therapy gets (more from cardiac or pulmonary insufficiency and cerebral vascular complications) • Optimal therapy is not developed yet

  6. CAPS may underlie the pathological conditions, such as • Septic shock • HELLP-syndrome • Severe preeclampsia • Hemolytic UremicSyndrome • DIC-syndrome • Systemic Inflammatory Response Syndrome • Thrombotic Thrombocytopenic Purpura

  7. After 1992 – the discovery of FV Leiden and Pt G20210А mutations Rogier M. Bertina Björn Dahlbäck

  8. EARLY AND LATE MISCARRIAGES • ANTENATAL FETAL DEATH • IUGR • STAGNANT PREGNANCY • STILLBIRTH • INFERTILITY • EARLY PREEMBRIONIC LOSSES • PREECLAMSIA • ABRUPTIO PLACENTAE • THROMBOEMBOLISM CATASTROPHIC APS, SEPTIC SHOCK THROMBOPHILIA APS METABOLIC SYNDROME ENDOTHELIOPATHY SYSTEMIC INFLAMMATORY RESPONSE SYNDROME DIC-SYNDROME OXIDATIVE STRESS THROMBOTIC COMPLICATIONS OF OC THROMBOTIC COMPLICATIONS OF HRT • IVF FAILURE IVF-associated thrombosis IVF-associated obstetrical complications

  9. Genotype Fenotype ? = Pregnancyis an EXAM! for the presence of hidden thrombophilia

  10. Changes in hemostasis system during the pregnancy

  11. Genetic thrombophilia Physiological changes in pregnancy Antiphospholipid antibody Hyperhomocysteinemia Inflammation

  12. Thrombophilia and venous thrombosis Lim W, Eikelboom JW, Ginsberg JS. Inherited thrombophilia and pregnancy associated venous thromboembolism. BMJ. 2007 Jun 23;334(7607):1318-21.

  13. Thrombophilia and risk of pregnancy losses Vossen CY et al. Hereditary thrombophilia and fetal loss: a prospective follow-up study. J Thromb Haemost. 2004 Apr;2(4):592-6. Brenner B. Thrombophilia and fetal loss. Semin Thromb Hemost. 2003 Apr;29(2):165-70.

  14. APS and venous/аrterial thromboembolism,pregnancy losses, preeclampsia, IUGR Strong association! Robertson, L. and Wu, O. and Langhorne, P. and Twaddle, S. and Clark,P. and Lowe, G.D.O. and Walker, I.D. and Greaves, Greer, I.A. (2006) Thrombophilia in pregnancy: a systematic review. British Journal of Haematology 132(2):pp. 171-196.

  15. What is typically occurs in patients with thrombophilia? • History of obstetric complications (thromboembolism, severe preeclampsia, abruption placenta, intrauterine growth restriction, preterm labor, miscarriages, IVF failures) • MASSIVE OBSTETRIC BLEEDING associated with DIC-syndrome • Idiopathic thrombosis • Repeated thrombosis especially in the young age under 50 years • History of family thromboembolism • Thrombosis of unusual sites: • Budd-Chiari Syndrome • mesenterial thrombosis • cerebral veins thrombosis • Thrombotic complications of OC or HRT • Ovarian Hyperstimulation Syndrome and thrombosis as IVF complications • Skin necrosis after oral contraceptive use

  16. Laboratory criteria of thrombophilia • FV Leiden mutation G1691A • Prothrombin gene mutation G22010A • Antiphospholipid syndrome • Hyperhomocysteinemia • АТ III, Pr C, PrS deficiency • Combined forms

  17. The thrombotic effects of thrombophilia can not explain all complications in pregnancy! Antiphospholipid syndrome Thrombophilia Thrombotic effects Genetic thrombophilia Hyperhomocysteinemia Non-thrombotic effects

  18. Hypercoagulation ‍ mediators of coagulation, hyperproduction of fibrin, activation of complement, platelet’s activation Thrombosis blood clot formation, platelet’s aggregation, deposition of fibrin Inflammation cytokines molecules of adhesion growth factors Early and late pregnancy losses Vascular complications

  19. Thrombotic and nonthrombotic effects of hyperhomocysteinemia Proliferation of smooth myocytes Oxidized low density lipoproteins DNA damage Oxidative stress Trombomodulin Tissue factor NO Antithrombin III Platelet activation, TXA2 Hyperhomocysteinemia MTHFR C677T Hypercoagulation, hyperaggregation, vasoconstriction, endothelial dysfunction, inflammation, genetic defects, Immunologic maladaptation • Chromosomal aberrations • Congenital birth defects • Spontaneous abortions • IUGR, preeclampsia, abruptio placentae • Antenatal death • Venous and arterial thrombosis

  20. Microparticles and vascular complications of pregnancy Participate in formation of thrombosis, inflammation, endothelial dysfunction and angiogenesis Preeclampsia, HELLP-syndrome Placental abruption Fetal los syndrome IUGR Multiple pregnancy complications • Simplify the intercellular interactions • Transfer proteins and mRNA among cells • Induction of cellular signals and influence on expression of proteins in target cells Expression of TF, Р-selectin, negatively charged phospholipids, activation of extrinsic pathway of coagulation Microparticles derived from trophoblast, platelets and endothelium

  21. Non-thrombotic effects of APL and placentation defects Cells damage • Apoptosis induction • Proliferation inhibition (inhibit expression of heparin binding EGF on trophoblast) • Chorionic gonadotropin suppression • Defective trophoblast invasion • (integrins and cadherins function) • Defects of endometrium differentiation

  22. APL and progesterone deficiency Progesterone deficiency Defects of implantation, throphoblast invasion and placentation Fetal loss syndrome Infertility IVF failure Early pre-embrionic losses Anti-hCG-effects of APA Treatment? LMWH Induction of trophoblastic invasionin vitro1 1 Di Simone et al.Low-molecular weight heparin induces in vitro trophoblast invasiveness: role of matrix metalloproteinases and tissue inhibitors. Placenta. 2007 Apr;28(4):298-304

  23. Thrombotic and proinflammatory effects of APL • Elevated levels of anti β2-GPI and annexin V antibodies • Annexin barries disruption • APC resistence • Widespread thrombosis • Placental infarctions • Imbalance of Th1/Th2 • Complement deposition (С5а activates TF expression and polymorphonuclear leukocyte recruitment; inhibition of DAF/CD55 expression) • Neutrophils and monocytes activation • Hyperexpression of TNF-аlfa, chemokines • Defects of chemokines degradation (deficiency of D4 receptor)

  24. АPA: «tripleblow» on hemostasis system: inhibition of anticoagulant system, fibrinolysis and coagulation activation PC TМ ERPC Extrinsic way TF TFPI activation XIIa inhibition Intrinsic way VIIa XIa IXa АPА Xa protrombin АPА ATIII Plasminogen Fibrin t-PA Plasmin

  25. ADAMTS 13 – молекулярные механизмы тромбоза • С дефектами фермента ADAMTS 13 связан недостаточный протеолиз мультмеров фактора фон Виллебранда, которые обладают высокой способностью активировать тромбоциты • С тромботической тромбоцитопенической пурпурой (ТТП) связаны более 70 мутаций гена ADAMTS 13 (Wyrick-GlatzelJ., Laboratory med., 2007) • Септический шок, тяжелая преэклампсия, HELLP-синдром, HUS могут маскировать картину ТТП • В большинстве случаев дефицит • ADAMTS 13 является приобретеннымОбусловлен АФС? – ДА!

  26. ADAMTS 13 – молекулярные механизмы тромбоза Дефицит активности ADAMTS 13 или образование ингибиторов Протеолиз Тир1605-мет 1606 в WVF Варианты ADAMTS 13, обуславливающие повышенную протеолитическую активность Мультимеры WVF Связывание VWF с GР Ib тромбоцитов Тромботическая тромбоцитопеническая пурпура Картина болезни Виллебранда Гиперагрегация тромбоцитов

  27. Thrombin Influence on angiogenesis Pro-coagulant properties Anticoagulant properties

  28. Fetal loss, IUGR, Fetal death, Placental abruption Non-thrombotic effects of thrombin Decidua Thrombin + Il-1β +TNF-α Thrombin  sFlt, ↓VEGF, ↓PIGF  MCPs   Macrophags  ↓Vascular remodeling ↓Angiogenesis ↓Throphoblast invasion Placental Hypoxia Systemic  sFlt, ↓VEGF, ↓PIGF, ↓Angiogenesis Microparticles Fetal signs Preeclampsia Maternal signs

  29. Preeclampsia Fetal loss syndrome Placental abruption IUGR Maternal hereditary thrombophilia APL Fetal hereditary thrombophilia, APL ↓Vascular remodeling Impaired trophoblast invasion Vasoconstriction Endothelial dysfunction Increase of blood coagulation potential Activation of systemic pro-inflammatory response Maladaptation in fetal-maternal complex Inadequate maternal-placental blood flow Noncurable condition Placental perfusion (ischemia)

  30. RESEARCHES SHOWED POSITIVE EFFECTS OF LOW MOLECULAR WEIGHT HEPARINS IN PROPHYLAXIS OF PREGNANCY COMPLICATIONS IN PATIENTS WITH THROMBOPHILIA

  31. Fetal Loss Syndrome Brenner 2000 50 Ogueh 2001 24 Grandone 2002 25 Padias 2004 41 Gris 2004 160 Brenner 2004 183 Ghosh 2008 25 Ogueh 2001 24 Gris 2004 160 Kupferminc 2011 87 Tormene 2012 416 (LMH+LDA)

  32. LMWH Micronized progesterone Effective not only due to its anticoagulant effects! • LMWH blocks endothelial expression of TF, induced by proinflammatory cytokines (TNF-, IL-1b) • LMWH increases t-PA activity both in intact and cytokine-induced endothelium Anticoagulant and antiinflammatory effect anti-hCG antiphospholipid antibodies Inhibit progesterone production by corpus luteum, which is essential for pregnancy maintenance PIBF ->balance Th1/Th2 Anti-inflammatory effects Doesn’t induce hypercoagulation Favorable effects for implantation, trophoblast invasion Counteract with thrombotic and nonthrombotic effects of genetic thrombophilia and APA

  33. Therapy was started after the development of clinical symptoms of preeclampsia • Pts with recurrent fetal loss syndrome: n=400 • Pts with history of VTE: n=80 Antithrombotic prophylaxis from the fertile cycle and during pregnancy • Pts with antenatal death • n=100 • Pts with placental abruption: n=100 • Pts with preeclampsia: Group I: Ia: 44 women with history of ≥2 severe preeclampsia Ib: 42 women with history of 1 severe preeclampsia n=160 Group II: 74 primagravida with preeclampsia during present pregnancy • Control group: 500 women with normal pregnancy

  34. Maternal thrombophilia, % * Patients with thrombophilia, % RR in fetal loss =3.23 [2.33; 4.48] RR in recurrent preeclampsia = 4.79 [3.44; 6.67]RR in one preeclampsia= 3.13 [2.06; 4.75] ** *p<0.05 vs. group Ia and II ** p<0.05 vs. other groups

  35. Prophylaxis of recurrent pregnancy complications in women with thrombophilia I trimester • LMWH Folic acid (up to 4 mg) • Natural progesterone Omega-3 • Polyvitamins for pregnant • Aspirin 50-81 mg • II – III trimester • Correction of LMWH dose • Iron drugs (+/-) • Folic acid • Natural progesterone (+/-) (before 32 weeks) Aspirin 50-81 mg (before 36 weeks) Postpartum • LMWH 10-30 days • Polyvitamins Iron drugs (+/-) Fertile cycle • Aspirin 50-81 mg* • LMWH (+/-) • (omega 3 acids) • Folic acid (up to 4 mg) • Natural progesterone • Polyvitamins for pregnant (vitamins of B group B1, B6, B12) * Aspirin was used in patients with platelet hyperfunction and APA-circulation

  36. Alive babies – 96% No thrombosis Mild preeclampsia – 16% No moderate or severe preeclampsia Moderate preeclampsia – 27 pts (49%) Severe preeclampsia – 28 pts (51%) Results • Recurrent fetal loss syndrome: • VTE • Antenatal death Antithrombothic prophylaxis from the fertile cycle and during pregnancy No antenatal death • Placental abruption No plactental abruption Ia: women with history of ≥2 preeclampsia Ib: women with history of 1 preeclampsia Therapy was started after the development of clinical symptoms of preeclampsia Primagravida with preeclampsia in present pregnancy

  37. The Barker theory and thrombophilia Genetic thrombophilia Antiphospholipid syndrome DIC-syndrome SIRS Preeclampsia Placental insufficiency IUGR Dysadaptation in adults: atherosclerosis, arterial hypertension, hyperholesterinemia, atherothrombosis, insulin resistance Causes of chronic diseases determine during the intrauterine period(Barker D.J.P. A model for origins of chronic disease. Med. Health Care and philos. 2001; 4: 31-35. The processes of adaptation to unfavourable conditions Abnormal maturation of one structures (placenta, kidneys) in favour of more important, for example, brain IUGR

  38. Systemic Syndromes and severe obstetrical complications Genetic Thrombophilia APS DIC-syndrome SIRS Metabolic Syndrome • SEVERE PRE-ECLAMPSIA • ABRUPTIO PLACENTA • SEPSIS AND SEPTIC SHOCK • THROMBOEMBOLISM • GEMORRHAGIC SHOCK • AND OTHERS Maternal Mortality

  39. Should all pregnant women be routinely investigated for thrombophilia? • Would it be appropriate to routinely use LMWH in patients with history of the syndrome of fetal loss, PE and IUGR?

  40. Conclusions • Routine screening for thrombophilia is not recommended. • Investigation for thrombophilia should be performed in: • a) patients with fetal loss syndrome when excluded the well-known causes of miscarriage (chromosomal, hormonal, infectious, etc.); • b) patients with recurrent PE, IUDR and PA); • c) patients with complicated personal and family history of thromboses. • Patients with recurrent complications of pregnancy should be investigated for genetic forms of thrombophilia, antiphospholipid antibodies and high levels of homocysteine. • Patients with thrombophilia require an early start of pathogenetic therapy during future pregnancies.

  41. Conclusions • Preventive treatment with LMWH combined with natural progesterone is highly effective for the prophylaxis of recurrent fetal loss and pre-eclampsia (moderate and severe) in patients with thrombophilia. • In patients with the history of thrombophilia and obstetric complications, low molecular weight heparin therapy should be started at early stages of pregnancy (ideally during the preconception period in order to reduce thrombinemia, if the latter is diagnosed prior to pregnancy and throughout gestation. • As thrombophilia is associated with a high risk of VTE in the postpartum period, the prophylaxis with LMWH should be continued in this period.

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