Chemotherapy-Associated Thrombotic Microangiopathy

Abstract

Thrombotic microangiopathy (TMA) is a syndrome of microangiopathic hemolytic anemia and thrombocytopenia with end-organ dysfunction. Although the advent of plasma exchange, immunosuppression, and complement inhibition has improved morbidity and mortality for primary TMAs, the management of secondary TMAs, particularly drug-induced TMA, remains less clear. TMA related to cancer drugs disrupts the antineoplastic treatment course, increasing the risk of cancer progression. Chemotherapeutic agents such as mitomycin-C, gemcitabine, and platinum-based drugs as well as targeted therapies such as antiangiogenesis agents and proteasome inhibitors have been implicated in oncotherapy-associated TMA. Among TMA subtypes, drug-induced TMA is less well-understood. Treatment generally involves withdrawal of the offending agent and supportive care targeting blood pressure and proteinuria reduction. Immunosuppression and therapeutic plasma exchange have not shown clear benefit. The terminal complement inhibitor, eculizumab, has shown promising results in some cases of chemotherapy-associated TMA including in re-exposure. However, the data are limited, and unlike in primary atypical hemolytic uremic syndrome, the role of complement in the pathogenesis of drug-induced TMA is unclear. Larger multicenter studies and unified definitions are needed to elucidate the extent of the problem and potential treatment strategies.

Figure 1

KDIGO TMA diagnostic algorithm. The classifications of TMA and corresponding laboratory diagnoses are presented. The dashed line represents possible utility but insufficient evidence to recommend this evaluation. ACA, anticentromere antibody; aHUS, atypical hemolytic uremic syndrome; ANA antinuclear antibody; anti-Scl-70, antitopoisomerase I antibody; CMV, cytomegalovirus; DGKE, diacylglycerol kinase ε; EBV, Epstein-Barr virus; FACS, florescence-activated cell sorting; Hb, hemoglobin; Hep, hepatitis; HUS, hemolytic uremic syndrome; LDH, lactate dehydrogenase; MAHA, microangiopathic hemolytic anemia; MLPA, multiplex ligation-dependent probe amplification; PCR, polymerase chain reaction; Plts, platelets; STEC-HUS, Shiga toxin E. coli HUS; Stx, Shiga toxin; TA-TMA, transplant-associated thrombotic microangiopathy; TTP, thrombotic thrombocytopenic purpura. Adapted from Goodship et al. with permission from Kidney International.

Figure 2

Histologic findings in a patient with gemcitabine-associated thrombotic microangiopathy. Shown here is a kidney biopsy from a patient with gemcitabine-induced TMA. H&E stained light microscopy evaluation showing (A) a glomerulus (wide blue arrow) with intraglomerular thrombi, mesangiolysis, entrapped intraglomerular thrombi, and a vessel (black arrow) with luminal occlusion and intimal thrombi, (B) vessel (yellow arrow) with intimal edema and sclerosis. Nine of 37 glomeruli were globally sclerotic. (C) Electron microscopy showing mesangiolysis, diffuse endothelial swelling, and duplication of the glomerular basement membrane with expansion of the lamina rara interna (white arrow).

Figure 3

Proposed algorithm for evaluation of suspected chemotherapy-associated TMA. ADAMTS13, a disintegrin and metalloprotease with thrombospondin type 1 repeats, 13th member; BP, blood pressure; CBC, complete blood count; HTN, hypertension; MAHA, microangiopathic hemolytic anemia; RASi, renin angiotensin system inhibitor; TMA, thrombotic microangiopathy; TTP, thrombotic thrombocytopenic purpura. *Unexplained AKI, persistent despite volume optimization. **No proven benefit in cancer or chemotherapy-associated TMA. Consider only if etiology is uncertain or high index of suspicion for TTP.