LM and colleagues had previously shown that dengue virus infection elicits E-specific antibodies that cross-react with a 19-amino-acid peptide derived from the sequence of plasminogen known to bear similarity to a domain in E. It was subsequently shown that there was a statistical association between the development of bleeding in DF and in DHF/DSS and the detection of plasminogen cross-reactive antibodies. The cross-reactive antibodies were not associated with DHF or with thrombocytopenia. Cross-reactive antibodies were not detected in association with a flavivirus infection not associated with bleeding (Japanese encephalitis). In vitro studies started a few years ago and completed by LM this year showed that the IgG fraction of sera from patients previously shown to have developed high titers of plasminogen-peptide cross-reactive antibodies could inhibit plasmin activity in vitro. This inhibitory effect was synergistically enhanced in the presence of alpha-2-antiplasmin, the physiologic inhibitor of plasmin activity. In contrast, IgG from flavivirus seronegative controls had no such effect. This provided the first evidence that plasmiongen-peptide cross reactive antibodies could actually bind plasmin and suggested that such antibodies might play a role in bleeding in both DF and DHF. These results are being submitted for publication in the Journal of Infectious Diseases.
