The antiphospholipid/cofactor syndromes: A primary variant with antibodies to β2-glycoprotein-I but no antibodies detectable in standard antiphospholipid assays,

Background Most systemic lupus erythematosus (SLE) patients with two or more clinical manifestations of the antiphospholipid syndrome (APS) and negative antiphospholipid antibodies (aPL) have antibodies to β2-glycoprotein-I (aβ2GP-I). Herein we describe a similar set of circumstances, but in patients without evidence of SLE. Patients and methods We studied 6 patients with recurrent venous and/or arterial thromboses without aPL as detected by routine assays nor clinical or serological evidence of other autoimmune disease. Immunogloublin (Ig) G and IgM antibodies to bovine and human phospholipid-free β2GP-I were studied by Western blot test and by enzyme-linked immunosorbent assay (ELISA) utilizing radiated and nonirradiated plates. We also tested antibodies to cardiolipin, phosphatidylserine, and phosphatidylethanolamine by ELISA. As controls, 54 normal sera were studied. Results All 6 patients had recurrent arterial and/or venous thromboses. Three also had thrombocytopenia, 1 had livedo reticularis, and 2 had valvular heart disease. None of the patients had aPL, but all had serum IgG reactivity against human and bovineβ2GP-I (P< 0.001 versus controls for both). Titers of antibovine β2GP-I were higher when studied in irradiated plates but were also higher than normal in nonirradiated plates (P< 0.001). These antibodies did not recognize human or bovine β2GP-I bound to cardiolipin in solid phase. We confirmed by Western blot that these autoantibodies recognize human β2GP-I. We found no IgM aβ2GP-I. Conclusions We describe a primary condition akin to the antiphospholipid syndrome with negative aPL, but with serum IgG antibodies to human and bovine β2GP-I. These antibodies recognize β2GP-I epitopes that are not accessible when β2GP-I is bound to cardiolipin.