When cold complicates: the impact of cryoglobulins and pre-analytical conditions on monoclonal protein analysis

Cryoprecipitation of monoclonal protein in two patients from separate hospitals led to falsely reduced concentrations. In one case, this was only later discovered because the hematology analyzer falsely flagged the cryoglobulins as abnormal platelets and lymphocytosis. This resulted in the generation of a peripheral blood smear in which the cryoprecipitation was microscopically identified. In both cases, initially unnoticed discrepancies existed between the total immunoglobulin and albumin concentrations derived from the general chemistry analyzer and those from serum protein electrophoresis analysis, which is what later alerted staff to the second case. These cases highlight the significant risk cryoglobulins pose in the diagnosis and accurate follow-up of plasma cell dyscrasias. We therefore propose several measures to improve laboratory detection and prevention of such discrepancies. These include; performing total immunoglobulin and albumin measurements alongside the protein electrophoresis analysis; implementation of a cross reference alarm in the laboratory information system for the discrepancies; consequent visual inspection of all samples prior to analysis; pre-warming of samples with a visible cryoprecipitate prior to serum protein electrophoresis; and the implementation of adequate operating procedures for handling samples from patients with known cryoglobulins to prevent pre-analytical loss caused by precipitation. Finally, we provide insight into the stability of immunoglobulins and monoclonal proteins at room temperature, which may be helpful to determine the optimal sample storage temperature in order to reduce the risk of unwanted cryoprecipitation.