Thrombotic microangiopathy with targeted cancer agents

Abstract

Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are clinically similar disorders characterized by microvascular thrombosis, hemolysis, thrombocytopenia, and end-organ damage. Although they may present with overlapping symptoms, multiple etiologies have been proposed for these thrombotic microangiopathies (TMA). Chemotherapy-induced TMA, which has been described with the use of mitomycin, gemcitabine, and other drugs, has a poor prognosis. Recently, reports of TMA associated with targeted cancer agents have surfaced in the literature. We discuss the clinical presentation, outcome, and etiology of TMA reported with the use of immunotoxins, monoclonal antibodies, and tyrosine kinase inhibitors. A search of PubMed and meeting abstracts was conducted for cases of TMA with the use of targeted cancer agents. The defining symptoms, laboratory values, time to onset, and patient outcomes were compiled. Consistent definitions of TMA and grading of severity in these cases are lacking. However, presentation of TMA in these cases revealed the importance of monitoring for renal toxicity, hemolysis, and thrombocytopenia. Patient outcomes seem to differ from those seen in cases of chemotherapy-induced TMA and may reflect a different underlying etiology. Little is known about the pathogenesis of TMA with targeted cancer agents. In contrast to chemotherapy-induced TMA, partial to full reversibility may be a common outcome. However, further research is warranted into optimal management of patients diagnosed with TMA following treatment with targeted agents.

Figure 1. Proposed pathophysiology of thrombotic microangiopathies

Formation of pathogenic thrombi in TMA may arise from reduced ADAMTS13 activity as shown in Panel A. ADAMTS13 bound to the surface of endothelial cells can cleave ultralarge multimers of Von Willebrand’s Factor (vWF). When the activity of ADAMTS13 is reduced due to anti-ADAMTS13 antibodies or an inherited deficiency, the uncleaved multimers of vWF induce platelet aggregation. In atypical HUS (Panel B), mutations in complement proteins lead to unregulated formation of C5a and C5b-9 (membrane-attack complex). Recruitment of neutrophils, endothelial cell injury, and exposure of the subendothelium results in a prothrombotic state. Drug cytotoxicity (Panel C) can also result in direct injury to the endothelium and lead to TMA. The exact pathogenesis of TMA in these cases is unknown, but may involve decreased levels of prostacyclin, secretion of vWF, or exposure of the subendothelium leading to thrombus formation.