Drug‐induced thrombotic microangiopathy: An updated systematic review, 2014‐2018
Authors: Rabia Saleem, Jessica A. Reese, James N. George
Journal: American Journal of Hematology (2018)

In 2015, we reported our systematic review of publications, 1946-March 2014, describing patients with drug-induced thrombotic microangiopathy (DITMA) and defining criteria for levels of evidence supporting a causal association of the drug with TMA. We identified 78 drugs that were reported to cause TMA; 22 of the 78 drugs had definite evidence for a causal association with TMA.1 We also reported the DITMA experience of the Oklahoma Registry and the BloodCenter of Wisconsin.2 In March 2018, we updated our systematic review (Table S1, Supporting Information). Fifty-nine articles reported evaluable data for 111 individual patients with TMA attributed to 24 drugs; 2 articles reported group data on 3 drugs (Table S2). Twenty of the 59 articles presented data on 8 drugs (41 patients) that provided definite evidence supporting a causal association with TMA. Table 1 summarizes the data for these 8 drugs. Opioids: oxymorphone-extended release (Opana-ER) and oxycodone-extended release (oxycontin). Nine reports described 28 patients with Opana-ER-induced TMA, all from the United States. Our previous review1 identified only one report of Opana-ER-induced TMA. That report was the initial epidemiologic description by the Centers for Disease Control, however their data only supported a probable causal association with TMA. One of the 9 reports identified by our current literature search described 18 episodes of TMA in 15 patients from one hospital for 14 months.3 Another report4 described 3 patients and definitively documented the etiology of Opana-ER-induced TMA. In 2012, extended-release oxymorphone tablets were reformulated to contain a crush resistant, insoluble inert ingredient containing high molecular weight (~7 000 000 Da) polyethylene oxide (PEO). The goal of this reformulation was to deter the intravenous abuse that involved crushing the tablets and solubilizing the oxymorphone. Hunt et al.4 determined that the cause of TMA was the PEO, not the oxymorphone. Their initial clue was the presence of gelatinous material that occluded the apheresis tubing during therapeutic plasma exchange. Using the same process that the patients used to solubilize Opana-ER tablets, they estimated that the patients' plasma concentration of PEO would be ~5 μg/mL. This concentration of PEO in guinea pigs recapitulated the pathologic features of TMA. PEO altered blood flow causing vessel wall shear stress and mechanical red cell damage; the intense hemolysis caused kidney injury.4 Oxycodone tablets were similarly reformulated with PEO to produce long-acting, tamper-resistant oxycontin, which was approved in Australia in 2014. Three reports, from Australia, 2015-2017, provided definite evidence for a causal association of oxycontin with TMA, presumably also caused by the PEO. These data illustrate a new aspect of the global opioid epidemic. Clinicians evaluating patients with clinical features of TMA must be alert for IV opioids as a potential etiology. Proteasome inhibitors. Recognition of proteasome inhibitors as a cause of TMA was also increased in our current review. Our previous review identified 3 reports of describing bortezomib-induced TMA, but the evidence only supported a possible or unlikely causal association.1 In this review, there were 5 reports with definite evidence supporting a causal association for bortezomib (1 patient), carfilzomib (4 patients), and ixazomib (1 patient). The authors suggested that proteasome inhibitors as a class may have a risk for acute kidney injury with the hematologic abnormalities of TMA.5 Clinicians must be alert for the clinical features of TMA with the use of these 3 drugs and also the new proteasome inhibitors, marizomib, and oprozomib, currently in clinical trials. Palbociclib, a selective inhibitor of cyclin-dependent kinases, CDK4 and CDK6, received FDA approval in 2015 for advanced ER+, HER-2-negative breast cancer. The principal previously reported adverse effects were neutropenic infections and thrombocytopenia. Our review identified the report of one patient who developed hemiparesis and fluctuating aphasia with microangiopathic hemolysis, thrombocytopenia, and acute kidney injury after 2 weeks of daily oral palbociclib. Two weeks after palbociclib was stopped, her hematocrit and platelet count recovered but her neurologic and kidney abnormalities persisted. Intravenous immunoglobulin (IVIg). Although IVIg has been previously associated with venous thrombosis and kidney injury, these adverse effects are uncommon and may be related to specific IVIg products. The 2 patients, reported from Australia, had a failure of their kidney allografts and were treated with IVIg for BK virus infection. The patients became febrile and oliguric following the infusion; increased serum creatinine, thrombocytopenia, and anemia occurred during the next several days. Both patients had kidney biopsies documenting TMA; both recovered. The authors speculated that the TMA may be related to the specific brand of IVIg used in these 2 patients, which was different from the brand they usually used. Valproic acid commonly causes thrombocytopenia by dose-dependent marrow suppression. This patient had received valproic acid for many years for epilepsy. Because of recurrent seizures and severe emesis, he was hospitalized and treated with IV valproic acid which reached a toxic level for 16 hours, when he suddenly developed thrombocytopenia, hemolytic anemia, and acute kidney injury. These abnormalities resolved during the following 5 days. We previously described two mechanisms for DITMA, dose-dependent toxicity and immune (antibody-mediated) reactions.1 The distinction between these 2 mechanisms is imprecise. For some drugs, such as Opana-ER, the mechanism for dose-dependent toxicity has been clearly defined.4 The distinct dose-dependent mechanisms of bevacizumab and interferons for causing TMA have also been clearly defined. The mechanisms for immune-mediated DITMA have been defined for quinine.6 Quinine-induced TMA is caused by enhancing antibody binding to target cells. Quinine binds to the complementarity-determining region of naturally occurring weak antibodies creating a hybrid paratope that increases their binding affinity 10 000-fold.6 Although drug-dependent antibodies have been documented in many patients with quinine-induced TMA, they have documented in only two other patients: one with oxaliplatin-induced TMA and one with vancomycin-induced TMA.2 The goal of our continuing systematic reviews is to increase awareness of DITMA and to identify additional drugs that can cause DITMA. The authors have no conflict with this topic or these data. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.