Case reports and two prospective, controlled trials document the efficacy of anti-C5 monoclonal antibody eculizumab in the treatment of refractory atypical hemolytic uremic syndrome (aHUS) as well as in aHUS patients requiring chronic plasma exchange. It has shown efficacy in the presence and absence of defects in complement (C) and C regulatory proteins. However, eculizumab has not been previously used in TTP associated with low ADAMTS13 activity, despite the many shared clinical and pathologic features of TTP with aHUS.
A 27 y.o. white male with a history of inflammatory bowel disease presented with fever, thrombocytopenia, and microangiopathic hemolytic anemia, and rapidly developed renal failure, seizures, and coma. ADAMTS13 activity was <5% of normal (IgG anti-ADAMTS13 inhibitor titer of 160), and LDH, 476 on presentation, steadily rose to 1321 by day 8 (Figure). Daily plasma exchange, initiated on hospital day 1, produced no improvement in platelet count, LDH, creatinine, schistocyte levels on peripheral blood smear, mental status, or seizure activity through day 8. Admission stress dose steroids were then increased to 60mg/day prednisone, and vincristine, N-acetylcysteine, and weekly rituximab infusions were initiated, with no change in clinical or laboratory status (Figure). Skin biopsies on day 21 revealed intense granular deposits of C3d, C4d, and the terminal membrane attack complex C5b-9 within and around vessels, including endothelium and pericytes, suggesting a role for local vascular C activation. Hence, eculizumab (900mg IV once a week for 4 weeks, with two supplemental weekly doses of 600mg to adjust for some loss of antibody with plasma exchange, and a final 1200mg dose) was added to the treatment regimen. Platelets increased to 71 and LDH declined to 293 by day 31, and ADAMTS13 activity normalized by day 54 (85%). Plasma exchange and eculizumab were discontinued, and a steroid taper initiated on day 56 when the platelet count was 213K, LDH 145, and creatinine 1.07. The beginning of a rapid decent in platelet count was noted on day 85, accompanied by a decrease in ADAMTS13 activity to 9%. Eculizumab alone (900mg) was restarted. Platelet count, Hb, and creatinine returned to normal within 9 days.
Figure and C1q and complement regulatory proteins: factors H, I, and B: normal.
In remission four months after initial presentation, receiving biweekly eculizumab infusions as an outpatient.
Eculizumab was associated with remission induction in a patient with classic idiopathic TTP refractory to plasma exchange. Although multiple, overlapping initial therapies obfuscate assignment of efficacy to a single agent during initial treatment, remission obtained with eculizumab alone on relapse suggests its efficacy. Eculizumab should be considered in patients with refractory TTP. Eculizumab treatment is ongoing in this patient, but the duration of the treatment period remains to be elucidated. Our study also emphasizes that vascular C activation, possibly triggered by endothelial cell injury, may be a critical factor in at least some cases of TTP. C5b-9 induces a secretory response in endothelium to elaborate ultra high molecular weight von Willebrand factor multimers which would be ineffectually cleaved in patients with antibodies to ADAMTS13. This could lead to a dysregulated thrombotic microangiopathy. Blocking C5 formation may thus address a critical upstream pathway relevant to TTP as well as aHUS.
Off Label Use:Eculizumab treatment of TTP is an off-label use.
Asterisk with author names denotes non-ASH members.