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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 - PowerPoint PPT Presentation
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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 fusion 𝛽 (2) Mechanisms on endometrial cells (i) Angiogenesis inhibition (ii) Decrease in VEGF secretion (iii) NF B activation inhibition.𝜅
4
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 𝛽
trophoblastic cells • The expression of annexin A5 is reduced by anti 2GP1 Abs. 𝛽
HCQ 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.