A B s T R A C T To define the pathophysiologic mechanisms of cold agglutinin disease, we investigated a human model of this syndrome in normal volunteers and in patients with diminished levels of serum complement. Subjects received intravenous injections of autologous, chromated (mCr) erythrocytes which had been exposed in vitro to purified cold agglutinin preparations and to fresh autologous serum (as a source of complement). In vitro tests confirmed that such cells were coated with activated complement components (C3b), but not with immunoglobulin.Studies of erythrocyte clearance and simultaneous organ scanning showed that erythrocytes sensitized with low levels of cold agglutinin primarily undergo reticuloendothelial sequestration by the liver rather than intravascular hemolysis. After the initial sequestration of C3b-coated erythrocytes, a fraction of the cells are released back into the circulation and survive nornmally thereafter. Both phenomena are dose dependent and closely follow the sequestration and release pattern observed with IgM isoagglutinin sensitization.Experiments that used heated autologous serum as a source of C3 inactivator demonstrated that functionally intact C3b is required for hepatic sequestration. Erythrocytes coated with C3d were not cleared from the circulation. In vitro assays that used human macrophage monolayers suggested that the intrahepatic conversion of C3b to C3d is responsible for the release of sensitized erythrocytes back into the circulation.The clearance of cold agglutinin-sensitized erythrocytes was compared to the clearance mediated by IgM isoagglutinin. We found that the rate of complement

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