Chronic thrombocytopenia is induced in dogs by development of cross reacting antibodies to the MpL ligand

Abstract

The MpL ligand (ML) is a potent stimulus for thrombocytopoiesis. To create an in vivo model of ML deficiency, we injected dogs with a recombinant human ML (rhML) to determine whether cross-reacting antibodies would develop and cause thrombocytopenia. RhML was administered subcutaneously for 8 weeks to three normal dogs (mean platelets, 197 ± 5.5 x 103/μL). Within 5 days their platelet counts were twice baseline and greater than 4 times baseline by day 21. Then, uniformly, chronic thrombocytopenia developed. At 1 week after terminating rhML, mean platelets were 0.5 times baseline and at 2 months 0.25 times baseline. Early in treatment, marrow biopsies showed increased megakaryocyte number and ploidy, which decreased as platelets declined. Paralleling these changes, high filer anti-rhML antibodies developed. Autologous 51Cr-labeled platelet recovery and survival measurements indicated that the thrombocytopenia was principally due to decreased production. Infusion of plasma from the thrombosytopenic dogs into two normal dogs and one dog previously made thrombocytopenic with rhML caused platelet counts to fall gradually. These studies show that dogs with anti- rhML antibodies develop thrombocytopenia, presumably because the cross- reacting antibodies neutralize endogenous canine ML. The results strongly suggest that ML plays an essential role in maintaining normal platelet levels.