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MANEJO DE LA GESTANTE CON SÍNDROME ANTIFOSFOLIPIDICO
(ANTICUERPOS, MANEJO OBSTÉTRICO, NUEVOS TRATAMIENTOS)
Ponentes: Diana Alecsandru, MD, PhD
IVI Madrid
www.ivi.es
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Santos et al. Reproduction. 2010
Macklon et al. Hum Reprod Update, 2002
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36,281 embryos with day-3 biopsies
1,750 embryos with day-5/6 biopsies
Abnormal embryos
0
20
40
60
80
100
120Tr D3 Tr D5/6
Percentage of abnormal embryos (38,031 embryos) embryos analyzed
Abnormal embryos
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30%
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Khamashta et al. Best Practice&Research Clinical Rheumatology 2016
APS -CRITERIA
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THROMBOPHILIA TESTS:
Heterogenous -Hereditary or Adquired:
Placenta mediated-complication –
individualized aproached-all risk
factors
Arterial/venous thrombosis
1st degree relatives-important trombophilic
disorders
Connors et al. Blood.2014.
Rambaldi et al. Reprod Sciences. 2014
TAILORED APPROACH FOR SUBSETS OF PATIENTS.
AUTOIMMUNE / THROMBOPHILIA TESTS
>30% of cases RM+RIF, no cause is identified
AUTOIMMUNE TESTS:
Antiphospholipid Antibodies :
RM
GOS: Pre-eclampsia,Placental insufficiency,
FGR, Stillbirth,Premature birth
Controversia-RIF (better studies are needed)
Others -Abs, Immune cells, Citokines:
-Autoimmune Disorders
-Immune system study
-Research
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Antibodies-RIF/RM association?
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We know everything about APS?
Criteria for Antifphospholipid Syndrome
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Endometrial fluid
miRNA gene
TRANSCRIPTION
Pri-miRNA
Pre-miRNA
PROCESSING
THROUGH
DROSHA
TRANSPORT TO
CYTOSOL THROUGH
EXPORTIN-5
PROCESSING
TROUGH DICER
MATURE
miRNA-30d
RISC
EXOSOMES
MIC
RO
VE
SIC
LE
S
RISC
FU
SIO
N
TRANSCRIPTOME
EFFECTS
mRNA TARGET
PROTEOME
EFFECTS
Itβ3
Itβ7
Cadh5
ENDOMETRIAL EPITHELIUM TROPHECTODERM
ADHESIVENESS
Vilella et all. Development. 2015 Hsa-miR-30d, secreted by the human endometrium, is taken up by the pre-implantation embryo and might
modify its transcriptome.
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Uterine
immune-tolerance
Uterine NK cells: active regulators at the maternal-fetal interface. Ashley Moffett and Francesco Colucci.The Journal of Clinical Investigation .2014
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EVT cross-talk: DSC dNK DC Ttreg cells Apoptosis ef LT
Arck and Hecher. Nature Medicine.2013
EVT-Maternal Uterine Immune System
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Meroni et al. Nature Reviews Rheumatology. 2011
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AUTOIMMUNE TESTS: Antiphospholipid Antibodies :
Khamashta et al. Best Practice&Research Clinical Rheumatology 2016
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Abs anti-phosphatidylserine, phosphatidylinositol and phosphatidic acid, Abs anti- phosphatidylethanolamine, Abs anti-proteins annexin V, protein C, protein S, thrombomodulin and oxidised LDL
Future: Abs antiD1 beta2GPI-accurate dg Abs phosphatidilserine-prothrombin or Abs antiPT (thrombotic risk) ACA, beta2GPI IgA- selected cases SLE + clinical signs and negative IgG, IgM
Antiphospholipid Antibodies :
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Pengo et al Blood 2011; Galli Me et al. Blood 2003. Khamashta et al. Best Practice&Research Clinical Rheumatology 2016; Sciascia et al. Rheumatology 2013; Pengo et al. Autoimmunity Review 2016
Category I
Category II
AUTOIMMUNE TESTS: Antiphospholipid Antibodies :
Thrombosis (29%/year without treatment)
Pregnancy morbidity
Pregnancy loss (80% LBR with treatment)
Increased Risk + autoimmune diseases or cardiovascular risk factors
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GAPSScore Antiphospholipid Antibodies :
Pengo et al Blood 2011; Khamashta et al. Best Practice&Research Clinical Rheumatology 2016; Sciascia et al. Rheumatology 2013; Pengo et al. Autoimmunity Review 2016
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AUTOIMMUNE / THROMBOPHILIA TESTS
Antiphospholipid Antibodies :
RM
GOS: Pre-eclampsia,
Placental insufficiency
FGR
Stillbirth
Premature birth
Uterine artery Doppler 2endT: uteroplacental insufficiency Uterine artery Doppler 1stT+maternal characteritics+biochemical biomarkers
Cnossen JS. Use of uterine artery Doppler ultrasonography to predict pre-eclampsia and FGR. CMAJ 2008 Velauthar L. First-trimester uterine artery Doppler and adverse pregnancy outcome. Ultrasound Obstet Gynecol 2014
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APS TREATMENT
WITH WITHOUT
LBR 70-80% 20-30%
APS Pregnancy morbidity
LDA + LMWH prophilactic doses
APS+Thrombotic event
LDA+LMWH therapeutic doses
The European Registry on obstetric antiphospholipid syndrom (EUROAPS). Autoimmun Rev 2015 Khamashta et al 2016. Best Practice&Research Clinical Rheumatology 2016
Heparin prevents: placental thrombosis; aPL binding to trophoblast; complement activation; block
inflammatory cell adhesion and migration through endotelial cells. Girardi. Nat Med.2004
APS-TREATMENT
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Increase heparin dosis Hydroxychloroquine Low-dose corticosteroids IVIG Apheresis Eculizumab
High-Risk Obstetric Antiphospholipid Syndrome
Ruffatti et al. Clin Rev Allerg Immunol.2016; Gomez-Puerta. Lupus 2013
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Ruffatti et al. Clin Rev Allerg Immunol.2016
Risk factors Refractory APS
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HCQ: pregnancy loss from 81% to 19%
HYDROXYCHLOROQUINE
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HYDROXYCHLOROQUINE
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Miscarriage rate: 30% to 9%
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Ruffatti et al. Clin Rev Allerg Immunol.2016
REFRACTORY APS
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Ruffatti et al. Clin Rev Allerg Immunol.2016
REFRACTORY APS
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Eculizumab (antiC5 monoclonal Ab)
Shapira I et al. Brief report: induction of sustained remission in recurrent catastrophic antiphospholipid
syndrome via inhibition of terminal complement with eculizumab. Arthritis Rheum 2012.
Canaud GD et al. Eculizumab improves posttransplant thrombotic microangiopathy due to
antiphospholipid syndrome recurrence but fails to prevent chronic vascular changes. Am J Transplant 2013.
Bakhtar O et al. A case of thrombotic microangiopathy associated with antiphospholipid
antibody syndrome successfully treated with eculizumab. Transplantation 2014
Lonze BE et al. Eculizumab prevents recurrent antiphospholipid antibody syndrome and enables
successful renal transplantation. Am J Transplant 2014.
Strakhan M et al. 36-year old female with catastrophic antiphospholipid syndrome treated with eculizumab:
a case report and review of literature. Case Rep Hematol 2014.
Zapantis E et al. Eculizumab in antiphospholipid antibody syndrome. Arthritis Rheum 2014
PROMISE Study (Predictors of pRegnancy Outcome: bioMarkers In APS and Systemic lupus Erythematosus) (clinicaltrials.gov#: NCT00198068), a prospective, multicenter
observational study, Open-label interventional phase II prevention trial (clinicaltrials.gov#: NCT01029587) eculizumab in
catastrophic APS+kidney transplant Open-label multicenter international phase Iia treatment trial (clinicaltrials.gov#: NCT02128269) intravenous
C5a inhibitor in persistently aPL-positive patients with at least one of the following non-criteria manifestations of APS: aPL-nephropathy, skin ulcers, and/or thrombocytopenia
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RM :
Aneuploidy-1st cause
POC >2 miscarriage
Tailored protocols – Patients Autoimmune disorders and thombophilia
GOS APS & Thrombophilia related
High- risk profile of APS
Conventional treatment 80% LBR
Consider additional treatment for high-risk, reflactory APS
Conclusions
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¡GRACIAS!
International IVI Congress
Reproductive Medicine and Beyond Bilbao, Spain May 11-13 2017