Proteasome inhibitor associated thrombotic microangiopathy


Yui JC, Van Keer J, Weiss BM, Waxman AJ, Palmer MB, D'Agati VD, Kastritis E, Dimopoulos MA, Vij R, Bansal D, et al. Proteasome inhibitor associated thrombotic microangiopathy. American Journal of Hematology [Internet]. 2016;91(9):E348 - E352.


A variety of medications have been implicated in the causation of thrombotic microangiopathy (TMA). Recently, a few case reports have emerged of TMA attributed to the proteasome inhibitors (PI) bortezomib and carfilzomib in patients with multiple myeloma. The aim of this case series was to better characterize the role of PI in the etiology of drug-induced TMA. We describe eleven patients from six medical centers from around the world who developed TMA while being treated with PI. The median time between medication initiation and diagnosis of TMA was 21 days (range 5 days to 17 months). Median laboratory values at diagnosis included hemoglobin—7.5 g dL−1, platelet count—20 × 109/L, LDH—698 U L−1, creatinine—3.12 mg dL−1. No patient had any other cause of TMA, including ADAMTS13 inhibition, other malignancy or use of any other medication previously associated with TMA. Nine patients had resolution of TMA without evidence of hemolysis after withdrawal of PI. Two patients had stabilization of laboratory values but persistent evidence of hemolysis despite medication withdrawal. One patient had recurrence of TMA with rechallenge of PI. There is a strong level of evidence that PI can cause DITMA. In evaluating patients with suspected TMA, PI use should be recognized as a potential etiology, and these medications should be discontinued promptly if thought to be the cause of TMA. Am. J. Hematol. 91:E348–E352, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.


Cited By :1Export Date: 18 February 2017References: George, J.N., Nester, C.M., Syndromes of thrombotic microangiopathy (2014) N Engl J Med, 371, pp. 654-666;Reese, J.A., Bougie, D.W., Curtis, B.R., Drug-induced thrombotic microangiopathy: Experience of the Oklahoma registry and the bloodcenter of Wisconsin (2015) Am J Hematol, 90, pp. 406-410; Kojouri, K., Vesely, S.K., George, J.N., Quinine-associated thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: Frequency, clinical features, and long-term outcomes (2001) Ann Intern Med, 135, pp. 1047-1051; Bennett, C.L., Connors, J.M., Carwile, J.M., Thrombotic thrombocytopenic purpura associated with clopidogrel (2000) N Engl J Med, 342, pp. 1773-1777; Pham, P.T., Peng, A., Wilkinson, A.H., Cyclosporine and tacrolimus-associated thrombotic microangiopathy (2000) Am J Kidney Dis, 36, pp. 844-850; Humphreys, B.D., Sharman, J.P., Henderson, J.M., Gemcitabine-associated thrombotic microangiopathy (2004) Cancer, 100, pp. 2664-2670; Chan, K.L., Filshie, R., Nandurkar, H., Thrombotic microangiopathy complicating bortezomib-based therapy for multiple myeloma (2015) Leuk Lymph, 56, pp. 2185-2186; Mehta, N., Saxena, A., Niesvizky, R., Bortezomib-induced thrombotic thrombocytopaenic purpura (2012) BMJ case Rep, 10, p. 1136; Salmenniemi, U., Remes, K., Thrombotic microangiopathy associated with bortezomib treatment in a patient with relapsed multiple myeloma (2012) Hematol Rep, 4; Moore, H., Romeril, K., Multiple myeloma presenting with a fever of unknown origin and development of thrombotic thrombocytopenic purpura post-bortezomib (2011) Inter Med J, 41, pp. 348-350; Morita, R., Hashino, S., Shirai, S., Thrombotic microangiopathy after treatment with bortezomib and dexamethasone in a patient with multiple myeloma (2008) Int J Hematol, 88, pp. 248-250; Lodhi, A., Kumar, A., Saqlain, M.U., Thrombotic microangiopathy associated with proteasome inhibitors (2015) Clin Kidney J, 8, pp. 632-636; Sullivan, M.R., Danilov, A.V., Lansigan, F., Carfilzomib associated thrombotic microangiopathy initially treated with therapeutic plasma exchange (2015) J Clin Apher, 30, pp. 308-310; Qaqish, I., Schlam, I.M., Chakkera, H.A., Carfilzomib: A cause of drug associated thrombotic microangiopathy (2016) Transfus Apher Sci, 54, pp. 401-404; Siegel, R.L., Miller, K.D., Jemal, A., Cancer statistics, 2015 (2015) CA Cancer J Clin, 65, pp. 5-29; Palumbo, A., Anderson, K., Multiple myeloma (2011) N Engl J Med, 364, pp. 1046-1060; Richardson, P.G., Sonneveld, P., Schuster, M.W., Bortezomib or high-dose dexamethasone for relapsed multiple myeloma (2005) N Engl J Med, 352, pp. 2487-2498; Richardson, P.G., Barlogie, B., Berenson, J., A phase 2 study of bortezomib in relapsed, refractory myeloma (2003) N Engl J Med, 348, pp. 2609-2617; Vij, R., Siegel, D.S., Jagannath, S., An open-label, single-arm, phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been previously treated with bortezomib (2012) Br J Haematol, 158, pp. 739-748; Siegel, D.S., Martin, T., Wang, M., A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma (2012) Blood, 120, pp. 2817-2825; Siegel, D., Martin, T., Nooka, A., Integrated safety profile of single-agent carfilzomib: Experience from 526 patients enrolled in 4 phase II clinical studies (2013) Haematologica, 98, pp. 1753-1761; Field-Smith, A., Morgan, G.J., Davies, F.E., Bortezomib (Velcadetrade mark) in the treatment of multiple myeloma (2006) Ther Clin Risk Manag, 2, pp. 271-279; Al-Nouri, Z.L., Reese, J.A., Terrell, D.R., Drug-induced thrombotic microangiopathy: A systematic review of published reports (2015) Blood, 125, pp. 616-618; George, J.N., Raskob, G.E., Shah, S.R., Drug-induced thrombocytopenia: A systematic review of published case reports (1998) Ann Inter Med, 129, pp. 886-890; Izzedine, H., Anti-VEGF cancer therapy in nephrology practice (2014) Int J Nephrol, 2014, p. 143426; Xiao, X., Zhong, H.Y., Zhang, G.S., Thrombotic thrombocytopenic purpura as initial and major presentation of multiple myeloma (2013) J Thromb Thrombolysis, 36, pp. 422-423; Yao, H., Monge, M., Renou, M., Thrombotic thrombocytopenic purpura due to anti-ADAMTS13 antibodies in multiple myeloma (2014) Clin Nephrol, 81, pp. 210-215