Abstract
Introduction
We present a case of TTP refractory to usual therapies treated successfully with eculizumab.
Case presentation
A 64 year-old African American female with history of diabetes and hypertension presented with left sided weakness and seizure-like activity preceded by 2 days of headaches and 2 weeks of easy bruising. On admission her vital signs and physical exam were unremarkable. Her basic metabolic panel, ANA panel, hepatitis panel, HIV, and anti-phospholipid panel was negative. Her hemoglobin was 9.0 g/dL, platelets were 13K/uL, LDH was 954IU/L, haptoglobin <30 mg/dL, eGFR was 50, and blood smear showed 4-5 schistocytes/high power field. ADAMTS13 activity was <5% and there was an inhibitor level of 1.1BU. C3 level was 75.3 (normal range 90-180mg/dL), C4 was <10 mg/dL (normal range 15-45 mg/dL). On day 1, she was started on oral prednisone (1mg/kg/day) and daily plasma exchange (TPE). changes. After 6 days of TPE without signs of improvement, the first dose of rituximab 375 mg/msq/dose was given on day 7. During the second week of hospitalization, patient also developed delirium and mental status changes. Vincristine 2 mg was given on day 13 for refractory TTP. Due to clinical worsening of microangiopathy and mental status, a decision was made to administer eculizumab 900 mg on day 17. Within a few hours of eculizumab administration, her platelets improved from 8k/uL to 21k/uL and to 47k/uL 12 hours later. After the second dose of eculizumab on day 24, platelets improved to 117k/uL and continued to rise. Eculizumab 900 mg was given weekly for 4 weeks, at which time ADAMTS13 activity was 75% and ADAMTS13 inhibitor was undetectable. Eculizumab 1200 mg was then given every two weeks, for a total of 3 more doses, during which the CBC, LDH, and haptoglobin remained in the normal range. Eculizumab was stopped, and after four months of close follow up, platelets, LDH, renal function and mental status were still normal range. C3 level was 203 (normal range 90-180 mg/dl), C4 was 35 mg/dl (normal range 15-45 mg/dl), ADAMTS 13 activity assay is >100% and there is no inhibitor.
Discussion
TTP and aHUS are both thrombotic microangiopathies (TMA). TTP is caused by acquired or inherited deficiency of the ADAMTS 13 protein or due the formation of an inhibitor to the ADAMTS13 protein. aHUS results, in most cases, from a genetic mutation in complement factor H in the alternative pathway of the complement cascade. Recent studies have described the importance of the complement system in all forms of TMA (Update on the role of the complement system in the pathogenesis of thrombotic microangiopathies. Prilozi. 2014;35(1):115-22). While plasma exchange is the cornerstone of TTP treatment, complement inhibition with drugs such as eculizumab is the treatment of choice for aHUS. The use of complement inhibiting drugs has not yet been studied in TTP.
We report an unusual case of TTP, with confirmed ADAMTS 13 inhibitor and low activity, which did not respond to conventional treatment for TTP. Theorizing that this patient either had concurrent aHUS or had TTP with a dysregulated alternate complement pathway, we used eculizumab, to which the patient had a remarkable and persistent response.
There are other reports in literature of patients with aHUS having reduced levels of ADAMTS13 protein; however, these patients did not have an inhibitor as was seen in our patient (Partial ADAMTS13 deficiency in atypical hemolytic uremic syndrome. Blood. 2013 Aug 22;122(8):1487-93). There is one other case in the literature where TTP was treated successfully with eculizumab. In that case, discontinuation of eculizumab was associated with a relapse of TTP and so had to be continued (Eculizumab in the treatment of refractory idiopathic thrombocytopenic purpura. Br J Haematology. 2012 June;157 (6):772-4). To our knowledge, we report the first case of a confirmed diagnosis of TTP treated successfully with eculizumab with remission continuing 3 months after discontinuation of the drug.
The use of eculizumab and the role of the complement pathway in TTP deserves further study.
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Disclosures
No relevant conflicts of interest to declare.
Plasma exchange in thrombotic microangiopathies (TMAs) other than thrombotic thrombocytopenic purpura (TTP)