Recurrent Arterial Thrombosis Linked to Autoimmune
Antibodies Enhancing von Willebrand Factor Binding to Platelets and
Inducing Fc
RII Receptor-Mediated Platelet Activation
Marc F. Hoylaerts,
Chantal Thys,
Jef Arnout, and
Jos Vermylen
From the Center for Molecular and Vascular Biology, Katholieke
Universtiteit Leuven, Leuven, Belgium.
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 for further investigation. Coronary angiography was normal.
Antinuclear factor, lupus anticoagulant, anticardiolipin antibodies,
and other thrombophilia parameters were negative, but there was
moderate hyperthyroidism with positive thyroid peroxidase antibodies.
Platelet numbers and von Willebrand factor (vWF) were normal. Her
platelets showed spontaneous aggregation that disappeared with aspirin
intake. However, aggregation 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 (GPIb) and anti-vWF antibodies. The
monoclonal anti-Fc
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 µg/mL), purified patient Igs dose-dependently
enhanced ristocetin (0.15 mg/mL)-induced aggregation between 0 and 500 µg/mL, an effect that disappeared again above 1 mg/mL. Aggregation
was dependent on the vWF concentration and was blocked by IV.3 or
neutralizing anti-GPIb or anti-vWF antibodies. The spontaneous
aggregation of normal platelets resuspended in patient plasma could be
inhibited totally by IV.3 and partially by neutralizing anti-GPIb or
anti-vWF antibodies. Perfusion with normal anticoagulated blood,
enriched with 10% of control or patient plasma, over surfaces coated
with vWF showed increased platelet adhesion and activation in the
presence of patient antibodies. Treatment of the patient with the
antithyroid drug thiamazol and temporary corticosteroids, aspirin, and
ticlopidine did not correct the platelet hypersensitivity to
ristocetin. These observations suggest that some autoantibodies to vWF
may both enhance vWF binding to platelets and cause platelet activation through binding to the FcRII receptor, and thereby may be
responsible for a new form of antibody-mediated thrombosis.
Blood, Vol. 91 No. 8 (April 15), 1998:
pp. 2810-2817
© 1998 by The American Society of Hematology.
