Studies on antibodies against phospholipids

Sammanfattning: The main clinical features of the antiphospholipid syndrome (APLS) are arterial andvenous thrombosis, repeated spontaneous abortions and thrombocytopenia. Diagnosedconcomitant with an underlying disease the designation is secondary APLS; otherwiseprimary APLS. The serological requirement for the diagnosis is the presence of antiphospholipidantibodies (APLA). These constitute closely related antibody specificities, as lupusanticoagulants (LA) and anticardiolipin antibodies (ACLA). The aim of this thesis was to study the prevalence of APLA in habitual abortionand chronic idiopathic thrombocytopenic purpura (ITP) and to investigate for immunologicaland metabolic derangements of potential relevance for disease manifestations in APLS. Of 99 women with habitual abortion, 42 had ACLA and the antibodies were presentin all IgG subclasses. Ten women with high antibody titers had low levels of thecomplement component C4 and fragmentation of C2 indicative of an ongoing complementactivation. Circulating immune complexes (CIC) were prevalent in the patients, andthus a factor potentially contributing to complement activation was present. A significant increase of thromboxane A2 (TXA2) was demonstrated in 31 subjectswith APLS by increased urine concentration of the metabolite 2,3-dinor-TxB2. TXA2is synthesized by activated platelets and has potent platelet aggregating and vasoconstrictiveproperties. Its actions are opposed by prostacyclin (PGI2) from endothelial cells(ETC). The PGI2 metabolite 2,3-dinor-6-keto-PGF1a was also increased but not to thesame extent. The disproportionate increase in TXA2 reflects platelet activation andmight be of pathogenic relevance in APLS. Twelve sera out of forty from patients with chronic ITP contained ACLA. Sera withthese antibodies from 12 non-ITP patients were studied for reactivity with plateletmembranes. Eight sera showed increased binding of IgG which was reduced in six afterabsorption with cardiolipin liposomes. Reactivity against phospholipids should thusbe considered when interpreting results suggestive of anti-platelet autoantibodies. CIC from five patients with APLA were isolated and antibody distribution betweenserum and CIC was determined. The relative concentration and avidity of the antibodieswas higher in CIC. This could have special implications with regard to the role ofCIC in platelet and complement activation and to thrombocytopenia and thrombophiliain APLS. The in vivo effect of a single oral dose of 500 mg of aspirin on the biosynthesisof TXA2 was studied in 7 subjects with IgG ACLA by monitoring the urine excretionof 2,3 dinor-TXB2 for at least seven days. The decrease in TXA2 formation was between46% and 85%, indicating a less inhibiting effect of aspirin than in healthy individuals.This might be of relevance for the dosage of aspirin in conditions in which plateletactivation is implicated as part of the pathogenic mechanism, as in the antiphospholipidsyndrome. Key words: Antiphospholipid syndrome, anticardiolipin antibodies, lupus anticoagulants,platelets, platelet activation, complement activation, endothelial cells, thromboxane,prostacyclin, acetylsalicylic acid. ISBN 91-628-2758-8