Pregnancy Loss in the Antiphospholipid-Antibody Syndrome — A Possible Thrombogenic Mechanism

Rand, Jacob H.; Wu, Xiao‐Xuan; Andree, Harry A. M.; Lockwood, Charles J.; Guller, Seth; Scher, Jonathan; Harpel, Peter C.

doi:10.1056/nejm199707173370303

Cited by 497 publications

(286 citation statements)

References 25 publications

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“…This disorder is characterized by recurrent thrombosis and fetal loss in the presence of pathogenic autoantibodies reacting against phospholipid-binding proteins (mainly ␤ 2 -glycoprotein I) (21)(22)(23). Passive infusion of human aPL was shown to induce fetal loss in pregnant naïve mice by triggering a local inflammatory and necrotic process at the placental level (21,23). Passive transfer to pregnant mice of IgG fractions from healthy women had no effect on pregnancy, whereas aPL-containing Ig fractions from APS patients induced a significant rate of fetal loss ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The second fetal-loss model was based on the injection of antiphospholipid (aPL) autoantibodies purified from patients affected by the antiphospholipid syndrome (APS) (20,21). This disorder is characterized by recurrent thrombosis and fetal loss in the presence of pathogenic autoantibodies reacting against phospholipid-binding proteins (mainly ␤ 2 -glycoprotein I) (21)(22)(23). Passive infusion of human aPL was shown to induce fetal loss in pregnant naïve mice by triggering a local inflammatory and necrotic process at the placental level (21,23).…”

Section: Resultsmentioning

confidence: 99%

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Protection against inflammation- and autoantibody-caused fetal loss by the chemokine decoy receptor D6

Torre

Buracchi

Borroni

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

169

204

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Fetal loss in animals and humans is frequently associated with inflammatory conditions. D6 is a promiscuous chemokine receptor with decoy function, expressed in lymphatic endothelium, that recognizes and targets to degradation most inflammatory CC chemokines. Here, we report that D6 is expressed in placenta on invading extravillous trophoblasts and on the apical side of syncytiotrophoblast cells, at the very interface between maternal blood and fetus. Exposure of D6 ؊/؊ pregnant mice to LPS or antiphospholipid autoantibodies results in higher levels of inflammatory CC chemokines and increased leukocyte infiltrate in placenta, causing an increased rate of fetal loss, which is prevented by blocking inflammatory chemokines. Thus, the promiscuous decoy receptor for inflammatory CC chemokines D6 plays a nonredundant role in the protection against fetal loss caused by systemic inflammation and antiphospholipid antibodies.trophoblast ͉ leukocyte ͉ placenta

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Protection against inflammation- and autoantibody-caused fetal loss by the chemokine decoy receptor D6

Torre

Buracchi

Borroni

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

169

204

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“…Reported direct effects of aPL on trophoblasts have included inhibition of the intercytotrophoblast fusion process (31), of human chorionic gonadotropin (hCG) or placental lactogen secretion (31,32), and/or of trophoblast invasiveness (31). Furthermore, whole IgG fractions from APS patient sera or xenogenic murine anti-PS mAb have been shown to displace annexin V from trophoblasts (and endothelial cell surfaces in the case of human IgG), thus creating conditions favorable to procoagulant state in vitro (31,33).…”

mentioning

confidence: 99%

Antiphospholipid antibodies affect trophoblast gonadotropin secretion and invasiveness by binding directly and through adhered β2-glycoprotein I

Simone

Meroni

Papa

et al. 2000

Arthritis & Rheumatism

295

179

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Objective. To investigate the in vitro ability of antiphospholipid antibodies (aPL) to bind human trophoblast cells and to affect gonadotropin secretion and invasiveness.Methods. Antiphospholipid antibody IgG from women with recurrent miscarriages, ␤ 2 -glycoprotein I (␤ 2 GPI)-independent IgG aPL human monoclonal antibody (mAb) (519), and IgM anti-␤ 2 GPI human mAb (TM1G2) were investigated for their binding to trophoblasts cultured for various amounts of time, their ability to affect invasiveness of Matrigel-coated filters, and their release of human chorionic gonadotropin (hCG).Results. Polyclonal IgG aPL, as well as mAb 519 and TM1G2, bound to trophoblasts, the highest binding being found when cells displayed the greatest amount of syncytium formation. TM1G2 binding was found to be ␤ 2 GPI dependent. Both polyclonal and monoclonal aPL, but not the controls, significantly reduced hCG release and Matrigel invasiveness.Conclusion. These findings suggest that aPL recognition of both anionic PL and adhered ␤ 2 GPI on trophoblast cell structures might represent a potential pathogenetic mechanism for defective placentation in women with the antiphospholipid syndrome.

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“…It is defined as the presence of lupus anticoagulant (LAC) and/or anticardiolipin antibodies (aCL) with recurrent miscarriage (RM), thrombosis, preeclampsia, IUGR and placental abruption. The most specific clinical features are thrombosis (both venous and arterial thrombosis), RM and fetal loss in the second and third trimester and autoimmune thrombocytopenia [27][28][29].The APS is associated with placental vascular thrombosis, decidual vasculopathy, intervillous fibrin deposition, and placental infarction [21,30]. These pathological changes in the placenta may result in miscarriage, IUGR, stillbirth, and early severe preeclampsia.…”

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confidence: 99%

Thrombophilia and pregnancy

Brenner¹

2005

Eur J Clin Investigation

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Pregnancy is hypercoagulable state. The field of thrombophilia; the tendency to thrombosis, has been developed rapidly and has been linked to many aspects of pregnancy. It is recently that severe pregnancy complications such as severe preeclampsia intrauterine growth retardation abruptio placentae and stillbirth has been shown to be associated with thrombophilia. Recurrent miscarriage and has also been associated with thrombophilia. Finally, thromboembolism in pregnancy as in the non-pregnant state is linked to thrombophilia. In this review all aspects of thrombophilia in pregnancy are discussed, and also all prophylactic and therapeutic implications.Thrombophilias are inherited or acquired conditions which predispose an individual to thromboembolism. Deficiencies of protein S C and antithrombin are rare and each of them is found in about 3% of patients with thrombosis. Recently, three important inherited thrombophilias were discovered which are responsible of the majority of thromboembolic events in patients with otherwise no apparent risk for thrombosis. Resistance to activated protein C caused by an adenine 506 guanine (A506G) mutation in factor V (factor V Leiden) has been linked with an increased risk for venous thromboembolism [1][2][3]. Heterozygosity for the factor V (FV) Leiden mutation is found in about 5% of the population and the mutation is responsible of 20-30% of venous thromboembolism events. A recently described guanine 20210 adenine mutation in prothrombin is associated with higher plasma prothrombin concentrations and increased risk for venous thromboembolism [4] and cerebral-vein thrombosis [5]. Homozygosity for the cytosine 677 thymine (C677T) mutation in methylenetetrahydrofolate reductase (MTHFR) results in decreased synthesis of 5-methyltetrahydrofolate, the primary methyl donor in the conversion of homocysteine to methionine and the resulting increase in plasma homocysteine concentrations is a risk factor for thrombosis [6,7]. The mutation is responsible for reduced MTHFR activity and is the most frequent cause of mild hyperhomocysteinemia and can be found in 5-15% of the population.Homocysteine is an independent risk factor for atherosclerosis, stroke, peripheral vascular disease and cardiovascular diseases [8,9]. Homocysteine concentrations are affected by nutrition. A deficiency in folate, B-6, and/or B-I2 causes elevation of homocysteine. Homocysteine concentrations are also affected by genetics such as cystathionine beta-synthase deficiency (10) and C677T MTHFR gene mutation [7]. Hyperhomocysteinemia promotes vascular damage by several mechanisms. Many of the endothelial vascular changes associated with hyperhomocysteinemia can be found in preeclampsia [11][12][13][14][15]. thrombophilia is substantially increased. The risk of VTE in pregnant women may be further amplified by the type of underlying genetic predisposition, like, homozygosity for a mutation, the presence of multiple mutations (multigenic defects) or thrombophilic anomalies [16][17][18][19].Thrombophilia and ad...

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Pregnancy Loss in the Antiphospholipid-Antibody Syndrome — A Possible Thrombogenic Mechanism

Cited by 497 publications

References 25 publications

Protection against inflammation- and autoantibody-caused fetal loss by the chemokine decoy receptor D6

Protection against inflammation- and autoantibody-caused fetal loss by the chemokine decoy receptor D6

Antiphospholipid antibodies affect trophoblast gonadotropin secretion and invasiveness by binding directly and through adhered β2-glycoprotein I

Thrombophilia and pregnancy

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