Anatomic Pathology: Vascular Pathology

• The patient in the scenario with liver dysfunction in combination with small vessel vasculitis likely has cryoglobulinemia, potentially in the setting of hepatitis C infection. Cryoglobulinemia likely has also resulted in glomerulonephritis (often type I membranoproliferative glomerulonephritis) causing hematuria and proteinuria.

• The clinical detection of cryoglobulins is complex and involves the following steps. Blood is drawn into warmed collection tubes at 37° C that do not contain anticoagulants (anticoagulants may produce false-positive results). Tubes are transported at 37° C. After clotting at 37° C (for 0.5 to 1 hour), the serum is separated by centrifugation at 37° C, placed in a graduated tube, and refrigerated (4° C) to allow the precipitation of cryoglobulin.

• Note: In type I cryoglobulin, precipitates are often seen within 24 hours, but 3 to 5 days are usually needed for complete precipitation, especially for the mixed cryoglobulins (types II and III).

• The precipitate is washed multiple times in cold saline solution (to reduce the possibility of precipitated salts or other proteins) and redissolved in saline at 37° C to confirm the warm solubility of the cryoglobulins. At this time, cryoglobulin protein concentration can be determined, and further characterization can be accomplished by immunofixation or enzyme-linked immunosorbent assay.

• Because the testing is complex and requires attention to detail, erroneously “negative” tests as illustrated in the present case do occur. If the clinicopathologic suspicion is high for cryoglobulinemic vasculitis in the setting of a negative cryoglobulin test, repeat testing should be performed at a reputable laboratory.