MANEJO DE LA GESTANTE CON SÍNDROME ANTIFOSFOLIPIDICO

(ANTICUERPOS, MANEJO OBSTÉTRICO, NUEVOS TRATAMIENTOS)

Ponentes: Diana Alecsandru, MD, PhD

IVI Madrid

Diana.alecsandru@ivi.es

www.ivi.es

Santos et al. Reproduction. 2010

Macklon et al. Hum Reprod Update, 2002

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

30%

Khamashta et al. Best Practice&Research Clinical Rheumatology 2016

APS -CRITERIA

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

Antibodies-RIF/RM association?

We know everything about APS?

Criteria for Antifphospholipid Syndrome

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.

Uterine

immune-tolerance

Uterine NK cells: active regulators at the maternal-fetal interface. Ashley Moffett and Francesco Colucci.The Journal of Clinical Investigation .2014

EVT cross-talk: DSC dNK DC Ttreg cells Apoptosis ef LT

Arck and Hecher. Nature Medicine.2013

EVT-Maternal Uterine Immune System

Meroni et al. Nature Reviews Rheumatology. 2011

AUTOIMMUNE TESTS: Antiphospholipid Antibodies :

Khamashta et al. Best Practice&Research Clinical Rheumatology 2016

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 :

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

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

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

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

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

Ruffatti et al. Clin Rev Allerg Immunol.2016

Risk factors Refractory APS

HCQ: pregnancy loss from 81% to 19%

HYDROXYCHLOROQUINE

HYDROXYCHLOROQUINE

Miscarriage rate: 30% to 9%

Ruffatti et al. Clin Rev Allerg Immunol.2016

REFRACTORY APS

Ruffatti et al. Clin Rev Allerg Immunol.2016

REFRACTORY APS

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

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

¡GRACIAS!

International IVI Congress

Reproductive Medicine and Beyond Bilbao, Spain May 11-13 2017