pathogenesis of antiphospholipid antibodies in pregnancy

Pathogenesis of Antiphospholipid Antibodies in Pregnancy

(1) Mechanisms on placental cell (i) Thrombosis (a) Aspecific mechanism (ii) Inflammation (a) Complement activation (iii) Immunomodulations (a) TLR 4 activation by aPL (iv) Defective placentation (a) Migration: decrease in IL-6 and STAT3 expression (b) Invasion: decrease in integrin expression (c) Differentiation: decrease in -hCG secretion and decrease in 𝛽

fusion (2) Mechanisms on endometrial cells (i) Angiogenesis inhibition (ii) Decrease in VEGF secretion (iii) NF B activation inhibition.𝜅

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Intravillous space

Umbilical Cord Fetal Blood Vessels

Decidua TrophoblastMtaernal Blood vessels Blood Vessels

aPL induced placental thrombosisMonocyte, Platelet, endothelial cell activation,

annexin 5 sheild abnormality

Anti-β2GPI antibodies react with trophoblastsInhibition of proliferation, differentiation;

induction of apoptosis

Anti-β2GPI antibodies react with decidual cellsInduction of a proinflammatory phenotype Main Effects of aPL on Placenta

Future targeted therapeutic agents

This includes complement inhibitors: Eculizumab, ahumanized monoclonal antibody directed against complement protein C5(Anti C5a antibodies), P38MAPK inhibitors (SB203580), NF-kB inhibitors (MG132),

Blockers of aPL binding to its target cell (anti-annexin A antibody, TLR-4 mutations, TIFI, HCQ), Inhibitors of TF expression (ACEI, statins, dilazep and defibrotide),

Inhibitors of expression of adhesion molecules (statins), Anti-cytokine agents (statins, anti-TNF agents and anti IL-6 agents),

Specific inhibitors of GPIIbIIIa (abciximab and HCQ), And at the level of production of aPL (Rituximab)

ASPIRIN

• Aspirin could decreasethromboxaneA2 production and prostaglandin I2 formation.

• Aspirin has also been shown to upregulate interleukin-3 (IL-3) production.This molecule seems necessary for trophoblast invasion and placental formation

HEPARIN

• Heparin as LMWH are anticoagulant molecules that prevent clot formation, they have also been shown to be antiinflammatory and anti-apoptotic molecules.

• Neither heparin nor LMWH could reverse the effects of anti 2GP1 Abs on trophoblast migration𝛽

• Heparin may also block tissue factor-mediated placental bed immunopathology

• low dose heparin prevented aPL associated fetal loss by inhibiting complement activation

• Second-line treatments include steroids, hydroxychloroquine (HCQ), intravenous immunoglobulin injections, and plasmaphereses

HCQ

• HCQ reduces the binding of anti 2GP1 Abs at the surface of 𝛽trophoblastic cells

• The expression of annexin A5 is reduced by anti 2GP1 Abs. 𝛽HCQ has been shown to restore its expression, preventing the pathological activation of the trophoblastic cells

• HCQ decreased TLR 4 expression

STATIN

• Statins prevented aPLmediated endothelial cell activation, inhibited the thrombogenic and inflammatory properties of aPL and inhibited TF up-regulation in aPL-treated endothelial cells

• A significant reduction in VEGF (vascular endothelial growth factor), serum TF and TNF-a in the serum of APS patients treated with fluvastatin for 30 days compared with

the control group

IVIG

• Intravenous immune globulin — Intravenous gamma globulin (IVIG) (0.4 g/kg per day for five days each month during the next attempted pregnancy) is one alternative treatment that has been proposed

PLASMAPHERESIS

• Plasmapheresis — Plasmapheresis has been used to treat pregnant women with documented APS when first line therapy (aspirin and/or heparin) failed to prevent pregnancy loss

• Exchanges of approximately three to four treatments per week starting at the 14th week of pregnancy and continuing until cesarean delivery at 34 weeks; another performed a total of six exchanges beginning at the 24th week followed by cesarean delivery at week 29. Both documented a reduction in antibody titers following apheresis

New oral anticoagulants

• Apixaban and rivaroxaban are specific inhibitors of factor Xa, while dabigatran inhibits factor IIa.

• These agents do not require monitoring, and display minimal drug or dietary interactions.

• Evaluation and management of bleeding complications may be difficult, as there is no standardized coagulation test and no specific antidotes to reverse the anticoagulation effects of these new drugs.