Thrombotic Thrombocytopenic Purpura Associated with Pazopanib

Abstract

A 76-year-old male with metastatic renal carcinoma on day 24 of pazopanib was admitted with complaints of emesis, confusion, and hematuria. Laboratory testing showed acute kidney injury, hyperbilirubinemia, and thrombocytopenia. Scattered schistocytes were seen on peripheral smear, and he was diagnosed with thrombotic microangiopathy (TMA). He was started on daily, one-volume plasma exchange with rapid improvement in thrombocytopenia. ADAMTS13 activity returned as undetectably low with no inhibitor detected. After cessation of plasmapheresis, repeat ADAMTS13 activity returned as normal. Unfortunately, his platelet count started to downtrend within four days after developing septicemia thought to be due to a catheter-associated infection. He was placed on comfort care measures after discussion with his family. An autopsy listed the major cause of death as metastatic renal cell carcinoma. According to two separate systematic reviews, there have been no cases of proven drug-induced TMA where decreased ADAMTS13 activity was the identified mechanism. While pazopanib is also associated with TMA, this unique case suggests a novel potential mechanism for TMA associated with pazopanib and brings forth “drug-induced thrombotic thrombocytopenic purpura” that quickly responds to plasmapheresis as a possible new diagnostic entity requiring prompt recognition and treatment.

An Update in Drug-Induced Thrombotic Microangiopathy

“…Two cases of TMA, one in a patient receiving the immune checkpoint inhibitor ipilimumab, and one in a patient treated with multi-targeted receptor tyrosine kinase inhibitor pazopanib have also been reported. However, these reports differ from other DITMAs, due to the severe ADAMTS13 deficiency (7,16).…”

“…It is important to exclude any other diagnosis before attributing TMA to a drug. For example, in some cases such as these of ipilimumab, pazopanib, ustekinumab, and golimumab severe ADAMTS13 deficiency was found, plasma exchange was effective and no drug-dependent antibody inhibition of ADAMTS13 activity was reported, making drug-indused causal relationship unlikely (7,(16)(17)(18).…”

“…Plasma exchange and immunosuppressive therapy may be a reasonable treatment option, especially when the diagnosis is uncertain. Although rarely described in DITMA, patients with severe ADAMTS13 deficiency respond to plasma exchange (7,(16)(17)(18)(82)(83)(84). However, these reports should be interpreted with caution, since severe ADAMTS13 deficiency indicates TTP as a more likely diagnosis.…”

“…Drug-induced thrombotic microangiopathy (DITMA) is a life-threatening complication that is often under-recognized and under-reported (1). Despite recent systematic reviews published in 2015 (2) and 2018 (3), the list of drugs implicated in TMA continues to expand (4)(5)(6)(7)(8)(9). In addition, novel reports have unraveled potential new mechanisms that might contribute to a targeted therapy of this syndrome.…”

Thrombotic Microangiopathy Associated with Pazopanib in a Kidney Transplant Recipient

“…The second case was of a 76-year-old male, who was managed with pazopanib for 4 months following RCC diagnosis; he presented with acute kidney injury, hyperbilirubinaemia, and schistocytes on film, and was diagnosed with TMA on clinical grounds. This patient had low ADAMTS13 activity, which was probably the driving mechanism, rather than VEGF inhibition; enzyme activity increased following cessation of pazopanib and 1 week of plasmapheresis ( 20 ).…”