Donohoe, Siobhan; (1999) An investigation of antiphospholipid antibody associated obstetric complications. Doctoral thesis (Ph.D.), UCL (University College London).

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Abstract

I aimed to assess the involvement of 'phospholipid antibodies' (aPL) in the pathology of antiphospholipid syndrome (aPS), with an emphasis on pregnancy complications and placental pathology. Using an immunofluorescent technique I demonstrated binding of affinity purified aPL to normal term placenta; further experiments suggested binding to placental proteins. I established assays for prothrombin (aPT) and β2Glycoprotein-I (a-β2GPI) antibodies, and studied a variety of non pregnant patients (PAPS, SLE, and infection). An associations between IgG and IgM a-β2GPI with aPS was demonstrated, but aPT were less specific. In serial samples from aPS patients with thrombotic/ neurological events, a-β2GPI levels were reasonably constant. In pregnant aPS patients, the antibody levels fluctuated. Women who became aPL negative before 12 weeks, proceeded with normal pregnancies. Other women having mixed pregnancy outcomes, had a peak in aPL levels, and the overall trend was that aPL remained positive at =20 weeks gestation. In a low risk pregnant population, the prevalence of aCL was approximately 3%, a-β2GPI 3.5% and aPT 3-6%. aPL were not always associated with an adverse outcome and are unsuitable preclinical markers of pregnancy complications in general obstetric populations. Women with persistent abnormal uterine artery Doppler in mid-gestation, were more likely to express aCL than healthy controls. There was no increase in the prevalence of aPL in pregnancies with unexplained biochemical markers of obstetric problems. In non-pregnant PAPS and SLE patients, thrombin generation, FVIIa and FXIIa were significantly increased, and this was ameliorated by oral anticoagulants (except FXIIa). Increased activation markers were observed in normal and aPS pregnancies, despite heparin and aspirin prophylaxis. β2GPI and annexin V (AV) were expressed by the placenta, from the 7th week, and throughout gestation, in normal, and aPS pregnancies. The immuno localisation of β2GPI and AV in term aPS pregnancies was similar to normal, but abnormal staining patterns were detected in aborted first trimester aPS placentas. Extractable β2GPI was reduced in term aPS placentas. The villous placenta and placenta bed are both exposed to maternal circulation during pregnancy, thus allowing access of aPL to target antigens. aPL are associated with coagulation activation, and arc capable of binding to cellular antigens. In pregnancy, the aPL antibody spectrum, individual cellular response to challenge, and the procoagulant environment probably interact to determine the clinical consequence of aPL.

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