Summary
Immune-mediated platelet activation is emerging as an important pathogenic mechanism
of thrombosis. In vitro studies have suggested two distinct pathways for immune-mediated
platelet activation; one involving clustering of platelet FcyRIIa, the other involving
platelet-associated complement activation. HLA-related antibodies have been shown
to cause platelet aggregation, but the mechanism has not been clarified. We evaluated
the mechanism of platelet aggregation induced by HLA-related antibodies from nine
patients. Antibody to platelet FcyRIIa failed to block platelet aggregation with 8/9
samples, indicating that engagement of platelet FcyRIIa is not necessary for the platelet
aggregation induced by HLA-related antibodies. In contrast, platelet aggregation was
blocked by antibodies to human C8 (5/7) or C9 (7/7). F(ab’)2 fragments of patient
IgG failed to induce platelet activation although they bound to HLA antigen on platelets.
Intact patient IgG failed to aggregate washed platelets unless aged serum was added.
The activating IgG could be adsorbed by incubation with lymphocytes and eluted from
the lymphocytes. These results indicate that complement activation is involved in
the aggregation response to HLA-related antibodies. This is the first demonstration
of complement-mediated platelet aggregation by clinical samples. Five of the patients
developed thrombocytopenia in relationship to blood transfusion and two patients developed
acute thromboembolic disease, suggesting that these antibodies and the complement-dependent
pathway of platelet aggregation may be of clinical significance.
