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.