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Characterization of blood proteins for clinical purposes was initiated in the middle of the nineteenth century and serum protein electrophoresis was first developed in the 1930s by a Swedish biochemist Arne Tiselius. Today, clinical analysis of human serum proteins by the electrophoretic method that evolved from the original fluid method of Tiselius, through paper electrophoresis, cellulose acetate, agarose, high-resolution agarose gel electrophoresis, capillary electrophoresis to total serum protein electrophoresis with immunofixation is widely and commonly used in clinical diagnostic laboratories. Although screening for monoclonal gammopathies has evolved over the last five decades and resulted in highly specific and sensitive techniques and standardized testing algorithms, new treatment modalities for monoclonal gammopathies have recently brought new and unexpected challenges for clinical diagnostics laboratories. Therefore, the more sophisticated techniques of immunofixation, isoelectric focusing, improved gel resolution, serum free light chains, heavy/light analysis and quantification of immunoglobulins are important in the diagnostic work-up of a patient with suspected plasma cell dyscrasias.