Cianidanol and its metabolites bind tightly to red cells and are responsible for the production of auto‐ and/or drug‐dependent antibodies against these cells

Abstract

Cianidanol ((+)-2-(3,4-dihydroxyphenyl)-3, 5, 7-chromantriol) is a flavonoid which has been associated with severe immune haemolysis by as yet unclear mechanisms. We report six patients who developed haemolysis while receiving the drug. The disorder was episodic in all patients and resolved after discontinuing the drug. The causative antibodies could be demonstrated in all six cases, even when the haemolytic episode was more than 1 year prior to this study. One patient had developed drug-independent IgG autoantibodies, another simultaneously developed autoantibodies and drug-dependent antibodies (ddab) of the IgG class, while the remaining four patients had only ddab of the IgM and/or the IgG classes. All ddab were reactive with red blood cells (RBC) in the presence of the drug and/or its metabolites (ex vivo antigens), and, quite unexpectedly, also with RBC coated with the drug (metabolites) in vitro or in vivo. This reactivity did not change either by preincubating the antibodies with the drug or by adding large amounts of the drug to the mixture of drug-coated cells plus antibody. It seems that the stable association of cianidanol with RBC generates antigenic sites against which a heterogeneous immune response is elicited giving rise to long-lasting drug-dependent antibodies as well as autoantibodies.

Hemolytic Anemia and Thrombocytopenia Induced by Cyanidanol

“…The results herein presented are similar to those re ported by Salama and Mueller-Eckhardt [8] and Casaril et al [12] in patients with cyanidanol-induced immune he molysis. The IgG autoantibodies could not be distin guished serologically from those observed in warm au toimmune hemolytic anemia; the hematological findings were also normal after suspending cyanidanol.…”

“…Several authors have demonstrated the pres ence of drug-dependent antibodies against red blood cells [4][5][6][7][8], In particular, Salama and Mueller-Eckhardt [8] showed that cyanidanol strongly combines with erythro cyte membranes, thus inducing the development of drugdependent antibodies and autoantibodies.…”

Safety Evaluation of a Combination, Defined Extract of Scutellaria Baicalensis and Acacia Catechu

“…However, all rat blood samples exhibited very high, potentially lethal potassium levels (Table 5). Ciandanol and its metabolites, (+)-catechin-related compounds, have been implicated in at least six cases of hemolysis in humans (Salama and Mueller-Eckhardt 1987). In vitro hemolysis, however, can also occur in a blood sample owing to prolonged storage or storage in incorrect conditions (Cox 1981).…”

The first example of a patient with etoricoxib‐induced immune hemolytic anemia

“…1 Sometimes the causative drugs appear to bind strongly to RBCs, for example, cianidanol, diclofenac, cefotetan, and piperacillin, and can also lead to acute and intravascular hemolysis. [1][2][3] During the acute phase of hemolysis, the DAT is not only positive for C3d, but also for IgG or, less frequently, IgM antibodies. These antibodies, unlike those in autoimmune hemolytic anemia (AIHA) of warm type, do not solely react with RBCs, but in combination with the drug.…”