Gemcitabine-induced thrombotic microangiopathy: a systematic review.

Thrombotic microangiopathy (TMA) is a microvascular occlusive disorder characterized by predominantly platelet thrombi in the renal and/or systemic circulations. Haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are the clinical entities comprising TMA, with predominantly renal manifestations in the former, while the latter more often presents with systemic and neurological findings. In some cases, TMA includes de novo hypertension and pulmonary or central nervous system symptoms. TMA is a rare condition, which is severe and may be fatal. Globally, two biological abnormalities explain TMA, namely: ADAMTS13 (A Disintegrin-like And Metalloprotease with ThromboSpondin type 1 repeats) deficiency and various complement component deficiencies. Studies aimed at determining these deficiencies in cases of chemotherapy-induced TMA were not systematically available in the articles reviewed. Gemcitabine was approved by the US Food and Drug Administration (FDA) in 1996 for the treatment of patients with metastatic pancreatic cancer and is currently used for the treatment of a wide range of malignancies, including lymphoma, lung, bladder and breast cancer. Casper et al. [1] first linked TMA to gemcitabine therapy in 1994, during a phase II trial of pancreatic cancer patients receiving this agent. The reported incidence of gemcitabine-associated TMA in the literature is very low, with a manufacturer’s estimate of 0.015% (range 0.008–0.078%) according to adverse event reports in 1997 [2], contrasting with the apparent frequency of patients with gemcitabineassociated TMA at local institutions [3,4]. Since most gemcitabine-treated patients presenting with TMA have far advanced disease and some have received other agents known to be associated with TMA, the exact role of the underlying disease and chemotherapeutic agents is not easily delineated. Although microangiopathy caused by disseminated cancer and chemotherapy-associated TMA may represent two distinct syndromes, and distinguishing clinical and histological features have been identified for these two conditions, there may be more similarities than differences. Nevertheless, clinical improvement after gemcitabine withdrawal in some cases and the result from re-exposure to the drug strongly suggest gemcitabine to be causative for TMA. We report three patients who developed gemcitabine-associated TMA from January 2001 to December 2005, and we undertook a retrospective review to investigate the clinical manifestations and outcomes associated with this condition in case reports and Phase II/III trials.