Molecular characterization of the variable domains of an αIIbβ3-specific immunoglobulin M κ platelet cold agglutinin in a follicular lymphoma patient with treatment refractory autoimmune thrombocytopenia:: idiotypic overlap between αIIbβ3 integrin antibodies

BACKGROUND: Cold hemagglutinins are generally immunoglobulin M (lgM) K antibodies reactive at temperatures below 37 degrees C and if of high titer may cause hemolysis. Platelet (PLT) cold agglutinins (CAs) are rare and poorly characterized. A detailed molecular characterization of the variable domains of a pathologic, PLT-reactive, CA is presented. CASE REPORT A 70-year-old woman was admitted with rectal bleeding accompanied by widespread petechiae, bruising, tongue and buccal mucosa bleeding, and epistaxes and proved refractory to HLA- and HPA-matched PLTs. Detailed investigation showed monoclonal heavy-chain gene rearrangement with an lgM paraprotein of 3.3 g per L and a trace of K Bence Jones protein in the urine, compatible with a diagnosis of secretory B-cell non-Hodgkin's lymphoma (B-NHL). PLT antibody (PAlg) investigations revealed a potent lgM K PLT CA. Sequencing of the rearranged variable domain genes of the malignant clone together with idiotype-specific antibodies obtained by DNA-based immunization of rabbits and matrix-assisted laser desorption/ionization-time-of-flight analysis of the PAlgM provided a irrefutable link between the thrombocytopenia, the lgM paraprotein, and the PAlgM against alpha llb beta 3. The thrombocytopenia and bleeding were refractory to standard treatment and PLT transfusion, but treatment with rituximab resulted in a recovery of the PLT count and a complete remission of B-NHL. CONCLUSION: The lgM K paraprotein derived from the malignant B-cell clone was a potent and clinically significant CA against alpha llb beta 3. The testing for PLT CAs in patients with a paraprotein and refractory to matched PLTs may aid the selection of appropriate treatment.