ANTIPHOSPHOLIPID ANTIBODIES AND RECURRENT PREGNANCY LOSS

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Lupus anticoagulant (LAC) is an acquired immunoglobulin inhibitor of phospholipid dependent coagulation tests that is associated with recurrent pregnancy loss, early and severe pregnancy-induced hypertension, intrauterine growth retardation, thrombocytopenia, and deep venous and arterial thrombosis. It is identified when the patient's plasma demonstrates prolongation of in vitro phospholipid-depencent coagulation, without correction by the addition of an equal volume of normal plasma. The inhibition of coagulation is by the binding of the autoantibody to the phospholipid portion of the prothrombin-prothrombinase complex; thus, the anitcoagulatn is identified as an antiphospholip antibody (APA). Other antibodies against phospholipids, such as antibodies against cardiolipin and phosphatidylserine, have also been associated with the same clinical problems, and may, in fact, be indentical with LAC. Very little is known about the specificity of the antibody or the possible mechanism(s) for reproductive failure. The aims of our proposal are: 1) to characterize LAC and other antibodies against phospholipids, 2) determine the specific phospholipid(s) against which LAC is directed, and 3) to evaluate the possible mechanism(s) of LAC- and APA- associated pregnancy loss. Methodology will include analysis of APA specificity using serologic reactivity in enzyme immunoassays, purification of the phospholipid antigen by thin-layer chromatography, the production and use of antibodies of know specificity either by chromatographic purification of polyclonal antibodies of known specificity or by the production of monoclonal human and mouse monoclonal antibodies, and the evaluation of the affects of these antibodies on in vitro prostacyclin and thromboxane generation and of their activities in mouse and rabbit models of pregnancy loss.