Molecular characterization of the variable domains of an alphaIIbbeta3-specific immunoglobulin M kappa platelet cold agglutinin in a follicular lymphoma patient with treatment refractory autoimmune thrombocytopenia: idiotypic overlap between alphaIIbbeta3 integrin antibodies.
BACKGROUND
Cold hemagglutinins are generally immunoglobulin M (IgM) kappa 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.


METHODS
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 IgM paraprotein of 3.3 g per L and a trace of kappa Bence Jones protein in the urine, compatible with a diagnosis of secretory B-cell non-Hodgkin's lymphoma (B-NHL). PLT antibody (PAIg) investigations revealed a potent IgM kappa 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 PAIgM provided a irrefutable link between the thrombocytopenia, the IgM paraprotein, and the PAIgM against alphaIIbbeta3. 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.


CONCLUSIONS
The IgM kappa paraprotein derived from the malignant B-cell clone was a potent and clinically significant CA against alphaIIbbeta3. The testing for PLT CAs in patients with a paraprotein and refractory to matched PLTs may aid the selection of appropriate treatment.
Jennings
Nicola S
NS
Department of Haematology, University of Cambridge and National Blood Service, Cambridge, UK.
Harmer
Ian J
IJ
Campbell
Kate
K
Stafford
Prachi
P
Smith
Graham A
GA
Metcalfe
Paul
P
Benton
M Ann
MA
Marsh
Judith C W
JC
Ouwehand
Willem H
WH
D000368:Aged; D000595:Amino Acid Sequence; D000888:Antibodies, Anti-Idiotypic / Q000378:metabolism; D016824:Antigens, Human Platelet / Q000276:immunology; D001483:Base Sequence; D003429:Cross Reactions; D003450:Cryoglobulins / Q000235:genetics; D005260:Female; D006801:Humans; D007075:Immunoglobulin M / Q000235:genetics* / Q000378:metabolism; D007135:Immunoglobulin Variable Region / Q000235:genetics* / Q000378:metabolism; D008224:Lymphoma, Follicular / Q000150:complications / Q000235:genetics / Q000276:immunology*; D008969:Molecular Sequence Data; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000276:immunology*; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000150:complications / Q000235:genetics / Q000276:immunology*; D012689:Sequence Homology, Nucleic Acid
D000888:Antibodies, Anti-Idiotypic; D016824:Antigens, Human Platelet; D003450:Cryoglobulins; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C029443:cold agglutinins