PATHOGENESIS OF ANTIPHOSPHOLIPID ANTIBODIES WHICH RECOGNIZE KININOGENS IN PATIENTS WITH THROMBOSIS AND PREGNANCY LOSSES

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We have published that certain aPE are not specific for phosphatidylethanolamine (PE) per se, but are directed to PE-binding plasma proteins, e.g., kininogens (Blood, 86, 3083, 1995). We recently reported that 31.7% of patients with early recurrent pregnancy losses (RPL) were positive for aPE and 90.5% of the PE-binding protein dependent IgG aPE positive sera were kininogen-dependent (Fertil Steril, 71, 1061, 1999). Kininogens bind to platelets and inhibit thrombin-induced platelet aggregation. Kininogen domain 3 was found responsible for this activity. We demonstrated that kininogen-dependent aPE augments thrombin-induced platelet aggregation (Thromb Res, 84, 97, 1996). Therefore, is it possible that certain aPE recognize kininogen domain 3? By using synthetic peptides that span the third kininogen domain, we observed that some kininogen-dependent aPE from RPL patients recognized the Cys333-Lys345 peptide, which encompasses both the cell binding and cysteine protease inhibitory sites. … More Other RPL aPE patient sera recognized Pro258-Ala277 or Gly235-Glu259, which contain the thrombin inhibitory sequence (Leu271-Ala277) and cysteine protease inhibitory site, respectively, Inhibition of platelet cysteine protease, i.e., calpain, results in inhibition of thrombin-induced platelet aggregation. Our data support an hypothesis that kininogen-dependent aPE may promote thrombosis in vivo due to disruption of the normal antithrombotic effects of kininogen.aPA have been described in patients with thrombosis, thrombocytopenia, and RPL.We recently reported that a strong association between RPL and antiphosphatidylethanolamine antibodies (aPE) exists (Fertil Steril, 71, 1060, 1999) ; and that kininogen-dependent aPE augmented thrombin-induced platelet aggregation in vitro (Thromb Res, 84, 97, 1996). Historically, conventional aggregometers, which measure the changes in light transmission of a platelet suspension, have a limited ability to detect SSAF.Our earlier attempts showed that older instruments were not sufficiently sensitive to detect SSAF in RPL patients. By using a newly developed aggregometer based on laser light scattering (PA-20, Kowa, Tokyo, Japan), we looked again for platelet aggregation in 30 non-pregnant RPL patients. Twenty of the 30 RPL patients were positive for aPA, such as aPE, anticardiolipin antibodies and antiphosphatidylserine antibodies. SSAF was observed in 12/30 RPL patients, all of whom were positive for aPA.Among the 18 patients negative for SSAF, 8 patients (44.4%) were positive for aPA.None of the 10 RPL patients without aPA was found to have SSAF.Our data show a statistically significant association between SSAF and aPA (p=0.0016) in patients with RPL. Less