RECURRENT ARTERIAL THROMBOSIS LINKED TO AUTOIMMUNE ANTIBODIES ENHANCING VON-WILLEBRAND-FACTOR BINDING TO PLATELETS AND INDUCING FC-GAMMA-RII RECEPTOR-MEDIATED PLATELET ACTIVATION

A patient with a history of recurrent late fetal loss associated with multiple placental infarcts and cerebrovascular ischemia at the age of 36, followed a year later by a myocardial infarction, was referred fo r further investigation. Coronary angiography was normal. Antinuclear factor, lupus anticoagulant, anticardiolipin antibodies, and other thr ombophilia parameters were negative, but there was moderate hyperthyro idism with positive thyroid peroxidase antibodies. Platelet numbers an d von Willebrand factor (VWF) were normal. Her platelets showed sponta neous aggregation that disappeared with aspirin intake, However, aggre gation still was induced by low levels of ristocetin (0.3 to 0.5 mg/mL ), The low-dose ristocetin aggregation in patient platelet-rich plasma (PRP) was completely blocked by neutralizing antiglycoprotein Ib (GPI b) and anti-vWF antibodies. The monoclonal anti-Fc gamma RII receptor antibody IV.3 inhibited partly, which suggests that PRP aggregation by low-dose ristocetin was elicited by vWF-immunoglobulin (Ig) complexes . Upon addition to washed human platelets, with vWF (10 mu g/mL), puri fied patient Igs dose-dependently enhanced ristocetin (0.15 mg/mL)-ind uced aggregation between 0 and 500 mu g/mL, an effect that disappeared again above 1 mg/mL. Aggregation was dependent on the VWF concentrati on and was blocked by IV.3 or neutralizing anti-GPIb or anti-vWF antib odies. The spontaneous aggregation of normal platelets resuspended in patient plasma could be inhibited totally by IV.3 and partially by neu tralizing anti-GPIb or anti-vWF antibodies. Perfusion with normal anti coagulated blood, enriched with 10% of control or patient plasma, over surfaces coated with VWF showed increased platelet adhesion and activ ation in the presence of patient antibodies. Treatment of the patient with the antithyroid drug thiamazol and temporary corticosteroids, asp irin, and ticlopidine did not correct the platelet hypersensitivity to ristocetin, These observations suggest that some autoantibodies to vW F may both enhance vWF binding to platelets and cause platelet activat ion through binding to the Fc gamma RII receptor, and thereby may be r esponsible for a new form of antibody-mediated thrombosis. (C) 1998 by The American Society of Hematology.