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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

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slide2

(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 š›½-hCGsecretion and decrease in fusion

(2) Mechanisms on endometrial cells

(i) Angiogenesis inhibition

(ii) Decrease in VEGF secretion

(iii) NFšœ…B activation inhibition.

slide4

Anti-Ī²2GPI antibodies react with decidual cells

Induction of a proinflammatory phenotype

Main Effects of aPL on Placenta

Fetal Blood

Vessels

Umbilical Cord

Intravillous space

Mtaernal Blood vessels

Blood Vessels

Trophoblast

Decidua

aPL induced placental thrombosis

Monocyte, Platelet, endothelial cell activation, annexin 5 sheild abnormality

Anti-Ī²2GPI antibodies react with trophoblasts

Inhibition of proliferation, differentiation;

induction of apoptosis

future targeted therapeutic agents
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),

slide9

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

deļ¬brotide),

slide10

Inhibitors of expression of adhesion molecules (statins),

Anti-cytokine agents (statins, anti-TNF agents and anti IL-6

agents),

slide11

Speciļ¬c inhibitors of GPIIbIIIa (abciximab and HCQ),

And at the level of production of aPL (Rituximab)

aspirin
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
  • 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 antiš›½2GP1 Abs on trophoblast migration
  • Heparin may also block tissue factor-mediated placental bed immunopathology
  • low dose heparin prevented aPL associated fetal loss by inhibiting complement activation
slide14

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

slide15
HCQ
  • HCQ reduces the binding of antiš›½2GP1 Abs at the surface of trophoblastic cells
  • The expression of annexin A5 is reduced by antiš›½2GP1 Abs. HCQ has been shown to restore its expression, preventing the pathological activation of the trophoblastic cells
  • HCQ decreased TLR 4 expression
statin
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

slide17
IVIG
  • Intravenous immune globulinĀ ā€”Ā 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
  • PlasmapheresisĀ ā€”Ā 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
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.