Can Hiprex (methenamine) or EDTA (ethylenediaminetetraacetic acid) cause thrombocytopenia?/nBackgro

Fråga: Can Hiprex (methenamine) or EDTA (ethylenediaminetetraacetic acid) cause thrombocytopenia?

Background: A 76-year-old man with angina pectoris is also suffering from thrombocytopenia of unknown aetiology. It was first recognised 1.5 years ago shortly after the start of treatment with methenamine, which was given for three months. During this period platelet counts fell from 124 to 34 (reference value > 150) millions per ml. The patient developed purpuric lesions and was referred to the Hematology Clinic for further investigation but no explanation was found. However, during the following half-year, platelet counts normalised, but recently it was discovered that platelets again had dropped, down to 90 millions per ml. The patient has not taken methenamine, but now informs the questioner about an on-going treatment against atherosclerosis at a private clinic with EDTA-infusions every 6th week since many years. The patient is not taking any other drugs.

Sammanfattning: There is no evidence that methenamine or EDTA could trigger thrombocytopenia. However, in the present case it is not possible to rule out any of these two agents in the aetiology of thrombocytopenia. We recommend that EDTA-treatment is stopped to evaluate possible beneficial effects on platelet counts.

Svar: The temporal association between the start of methenamine and onset of thrombocytopenia, as well as recovery of platelets after methenamine was discontinued, together indicate a drug-induced adverse effect. Importantly though, thrombocytopenia re-occurred in the absence of the drug one year later. Moreover, there is no documentation in the scientific literature supporting that methenamine could cause blood dyscrasias, and there is no Swedish case of blood cell or bone marrow toxicity reported (1, 2). In the international WHO-database on adverse drug reactions, 2 cases of methenamine-associated thrombocytopenia are found, but the causality assessment is unknown (3). Taken together, in the present case, the causality of methenamine appears possible but far from probable.

EDTA-treatment against atherosclerosis is highly controversial and not an approved therapy in Sweden. Despite a high number of treated patients worldwide, there are surprisingly few controlled clinical trials published in the literature, most commonly not showing any effect compared to placebo in peripheral or cardiovascular disease (4, 5). EDTA is not metabolized but rapidly excreted unchanged in urine. EDTA is a divalent metal ion chelator, but the pharmacological action, if any, is unknown (4, 5). Adverse reactions to EDTA appear to be limited, but the documentation is poor. Most importantly, EDTA has been associated with kidney toxicity but there is no data on thrombocytopenia (4-6).

Interestingly, EDTA used as an anticoagulant in blood sampling tubes, has been found in some rare samples to cause in vitro-aggregation of platelets and pseudothrombocytopenia. This laboratory artefact was found to depend on the presence of serum antibodies that only react with platelet surface antigen in the absence of calcium, ie chelated by EDTA in the test tube (7). It is unclear if such antibodies also would react with platelets in vivo during treatment with EDTA, but probably plasma levels of calcium would still be sufficiently high to prevent these antibodies from causing platelet aggregation in vivo. Moreover, the antibody reaction appears to be triggered only at temperatures lower than in vivo (8). Possible further investigations might include clinical immunological analysis of serum anti-platelet antibodies, as well as testing in the absence or presence of calcium and EDTA (7).

A report to SADRAC, the Swedish Adverse Drug Reactions Advisory Committee, is recommended for further evaluation. 1 Drugline no 04216 (year 1984) 2 Swedis (The Swedish Drug Information System) 3 Intdis (International Drug Information System): WHO:s adverse drug reactions database 4 Grier NT, Meyers DG: So much writing, so little science: a review of 37 years of literature on edetate sodium chelation therapy. Ann Pharmacother 1993; 27: 1504-1509 5 Elihu N, Anandasbapathy S, Frishman WH: Chelation therapy in cardiovascular disease: ethylenediaminetetraacetic acid, deferoxamine, and dexrazoxane. J Clin Pharmacol 1998; 38: 101-105 6 Meltzer LE, Kitchell JR, Palmon F JR: The long term use, side effects, and toxicity of sodium ethylenediamine tetraacetuc acid (EDTA). Am J Med Sci 1961; p 51-57 7 Kosugi S, Tomiyama Y, Shiraga M, Kashiwagi H, Mizutani H, Kanakura Y, Kurata Y, Matsuzawa Y: Platelet-associated anti-glycoprotein (GP) IIb-IIIa auto-antibodies in chronic immune thrombocytopenic purpura mainly recognize cation-dependent conformations: Comparison with the epitopes of serum autoantibodies. Thromb Haemost 1996; 75: 339-45 8 Bizarro N, Brandalise M: EDTA-dependent pseudothrombocytopenia. Association with antiplatelet and antiphospholipid antibodies. Am J Clin Pathol 1995; 103: 103-107