Thrombotic Microangiopathy, Drugs



Thrombotic Microangiopathy, Drugs


Neeraja Kambham, MD










The glomerulus demonstrates extensive duplication of basement membranes image associated with endothelial swelling image and mild mesangiolysis. TMA in this 13 year old with renal allografts is attributed to sirolimus.






GBM duplication and mesangial cell interposition image is seen in a 64 year old with TMA. The patient received aflibercept (VEGF trap) for prostate carcinoma. Fibrin image is also seen in the urinary space.


TERMINOLOGY


Abbreviations



  • Thrombotic microangiopathy (TMA)


Definitions



  • Atypical hemolytic uremic syndrome (HUS) caused by drugs


ETIOLOGY/PATHOGENESIS


Mechanism of TMA Induction



  • Direct endothelial injury due to dose-related toxicity


  • Immune-mediated with induction of autoantibodies


Implicated Drugs



  • > 60 drugs reportedly associated with TMA, but often difficult to establish causative role


  • Chemotherapeutic agents



    • Mitomycin-C



      • Dose-dependent endothelial toxicity


      • Median time from last dose to development of TMA is 75 days


    • Gemcitabine



      • Endothelial damage causes TMA


      • Median time from initiation of therapy to development of TMA is 6-8 months


    • Other agents include bleomycin, cisplatin, daunorubicin, vinblastine, deoxycoformycin


  • Anti-vascular endothelial growth factor (VEGF) therapy



    • VEGF receptor blockers (bevacizumab, VEGF trap)



      • VEGF synthesis by podocytes is needed for survival of glomerular endothelial cells that express VEGF receptors


      • TMA due to endothelial damage can occur from 1 week to 9 months after initiation of therapy


      • Symptoms can occur after discontinuation of drug


    • Sunitinib



      • Inhibits receptor tyrosine kinases such as VEGF


      • Endothelial damage causes TMA


  • Immunomodulators



    • Calcineurin inhibitors (CNi)



      • Cyclosporine and tacrolimus are associated with TMA


      • Direct endothelial toxicity due to reduced prostacyclin synthesis or reduced formation of activated protein C


      • Toxicity often seen in 1st 6 months after transplantation


    • Sirolimus



      • Mammalian target of rapamycin (mTOR) regulates production of VEGF in addition to its effects on cell cycle


      • Inhibition of VEGF results in endothelial damage


      • Toxicity is exacerbated by concomitant calcineurin inhibitors


  • Antiplatelet drugs of thienopyridine family



    • Ticlopidine and clopidogrel



      • TMA occurs within 1st month (or even within 1st week) of exposure


      • Cause direct endothelial toxicity


      • ADAMTS13 levels can be severely deficient (< 5%) in some cases, and inhibitor to ADAMTS13 has been detected


  • Miscellaneous drugs

Jul 7, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Thrombotic Microangiopathy, Drugs
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