Platelet autoantibodies in the bone marrow of patients with immune thrombocytopenia

Autoantibodies cause platelet destruction in patients with immune thrombocytopenia (ITP); yet only 50% to 60% of patients have detectable platelet autoantibodies in peripheral blood. We hypothesized that in some ITP patients, platelet autoantibodies are sequestered in the bone marrow where pathological immune reactions target megakaryocytes or newly formed platelets. In this study, we modified the platelet glycoprotein-specific assay to test bone marrow aspiration samples for free platelet autoantibodies or antibodies bound to bone marrow cells in aspirate fluid from patients with ITP (n = 18), patients with nonimmune thrombocytopenia (n = 3), and healthy donors (n = 6). We found that 10 (56%) of 18 patients with ITP had autoantibodies in the bone marrow, including 5 (50%) of 10 with autoantibodies in bone marrow only, and 5 (50%) of 10 with autoantibodies in bone marrow and peripheral blood. In comparison, 6 (33%) of 18 ITP patients had autoantibodies in peripheral blood, most of whom (5 [83%] of 6) also had autoantibodies in bone marrow. Bone marrow autoantibodies were not detected in patients with nonimmune thrombocytopenia or healthy donors; however, peripheral blood autoantibodies were detectable in 1 (33%) of 3 patients with nonimmune thrombocytopenia. The sensitivity of platelet autoantibodies for the diagnosis of ITP increased from 60% (peripheral blood testing) to 72% (peripheral blood and bone marrow testing). Immune reactions limited to the bone marrow may be characteristic of certain subsets of ITP patients.

Platelet antibodies in immune thrombocytopenia and related conditions

Platelet autoantibodies are a common finding in immune thrombocytopenia (ITP) and in rare cases of antibody-mediated platelet function (“acquired thrombasthenia”). In drug-induced immune thrombocytopenia, antibodies react with platelets only in the presence of the offending drug. Alloantibodies reacting with platelets are induced by transfusion of cellular blood products or during pregnancy. They are responsible for fetal/neonatal alloimmune thrombocytopenia (FNAIT), they are able to cause febrile, nonhemolytic transfusion reactions and they give rise to insufficient platelet increments following platelet transfusions. Two rare transfusion reactions: post-transfusion purpura (PTP) and passive alloimmune thrombocytopenia (PAT) are triggered by platelet alloantibodies. This review discusses the clinical value of tests for platelet antibodies in various clinical situations related to insufficient primary hemostasis.

Prediction of Response to Fostamatinib Based on the Presence of Plasma Platelet Autoantibodies in Adult Patients with Immune Thrombocytopenia (ITP) — Exploratory Analyses from Phase 3 Studies

Background: Initial results of an analysis of anti-platelet autoantibodies in patients with ITP from two phase 3 studies showed that patients were more likely to respond to treatment with the SYK inhibitor fostamatinib if they were positive for anti-platelet autoantibodies. Stable platelet responses to fostamatinib were reported in 36% of 28 patients who tested positive for anti-platelet autoantibodies and in 9% of 32 patients who tested negative (p<0.02). This analysis has been expanded to include 85 patients and to evaluate various platelet antigens. Methods: Plasma samples from 85 patients in the phase 3 studies were collected with informed consent at 2 weeks after the first dose of fostamatinib. Samples were analyzed for anti-platelet autoantibodies via Luminex beads-based PakLx assayand FACS-based indirect platelet immunofluorescence test (iPIFT) using platelets from healthy volunteers. Results: Of 85 patient samples, 38 (45%) were positive for one or more anti-platelet autoantibodies and 19 (22%) were from patients with a stable platelet response to fostamatinib. Of 38 patients positive for autoantibodies, 13 (34%) had stable platelet responses. Of 47 patients negative for autoantibodies, 6 (13%) had stable platelet responses. Conclusions: The presence of anti-platelet autoantibodies appeared to be associated with a stable platelet response to fostamatinib. This exploratory analysis provides support for the hypothesis that fostamatinib prevents platelet loss through inhibition of autoantibody-directed platelet destruction in ITP. Further studies are ongoing. Disclosures Markovtsov: Rigel: Employment, Equity Ownership. Yi:Rigel: Employment, Equity Ownership. Young:Rigel: Employment, Equity Ownership. Duliege:Rigel: Employment, Equity Ownership. Masuda:Rigel Pharmaceuticals: Employment, Equity Ownership.