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Title: The Impact of Antiphospholipid Antibodies on Trophoblast Biology
Author: Bose, Patrick
ISNI:       0000 0001 3471 2522
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2008
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Recurrent miscarriage is a devastating condition which in the U.K. is defined as spontaneous loss of three or more consecutive pregnancies before the fetus has reached viable gestation. The observed rate of 'Recurrent Miscarriage' is approximately 'I %, threefold higher than the theoretical expected risk. The epidemiology suggests a possible underlying cause and one such candidate is the presence of auto-immune antiphospholipid antibodies (aPL). aPL are a heterogeneous group of auto-antibodies directed against membrane phospholipids or phospholipid binding proteins. Prevalence of t'aPL is 15% in women with recurrent miscarriage compared with 2% in women with no history of miscarriage. Women with untreated aPL have a prospective foetal loss of 90%, the majority of miscarriages occurring during the first trimester. Current literature suggests a potential association between aPL and deficient syncytial fusion in placental trophoblast. Syncytial fusion utilises similar molecular steps to those employed in the apoptosis cascade, such as activation of initiator caspases. Initiator caspases influence trophoblast cells to externalise phosphatidylserine from the inner to the outer leaflet of the plasma membrane, thus not only serving as a signal for syncytial fusion but also exposing a potential target for antiphospholipid antibodies. Disruption in the rates of syncytial fusion in the presence of aPL was demonstrated using a novel 'Fusion Assay'. Syncytin, a recently discovered envelope protein of a human endogenous retrovirus is expressed by human trophoblast during syncytial fusion. Northern blot analysis illustrated reduced syncytin expression in the presence' of aPL, and further corroborated the hypothesised association between aPL and deficient syncytial fusion. Morphological studies of villous trophoblast have been restricted to late 15 \ 2nd and 3rd trimester placentas. Specific enumeration of cytotrophoblast and syncytiotrophoblast nuclei using differential immunohistochemical staining techniques enabled estimation of the nuclear cytotrophoblast to nuclear syncytiotrophoblast ratio (nuclear CT:ST ratio), an index of proliferation versus differentiation in growing tissues. Placental tissue from aPL mediated miscarriages exhibited major deviations from the normal patterns seen in healthy pregnancies. The clear therapeutic benefits of heparin and aspirin in the treatment of recurrent miscarriage has meant that the purported roles of heparin and aspirin as anticoagulants have yet to be challenged. Clinical ultrasound studies refuting the onset of a maternal blood supply until ten weeks suggest an alternative mechanism of action in early gestation: The influence of heparin, and to a lesser extent aspirin, was clearly demonstrated in attenuation of placental apoptosis, promotion of villous invasion and increased proliferation of cytotrophoblast. The direct effect of heparin on trophoblast viability demonstrated an alternative biological function and raises the possibility that anomalous trophoblast development may be therapeutically regulated.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available