Eculizumab in the treatment of refractory idiopathic thrombotic thrombocytopenic purpura (2012)

Thrombotic thrombocytopenic purpura (TTP) is an acute thrombotic microangiopathy with a high morbidity and mortality if untreated. Refractory TTP represents a unique clinical challenge, and few therapies have proven long-term efficacy in these cases. A related thrombotic microangiopathy, atypical haemolytic uraemic syndrome (aHUS), has been successfully treated with the anti-C5 monoclonal antibody eculizumab in both the refractory setting and in patients requiring chronic plasma exchange (Waters & Licht, 2011). However, complement-based therapy has not been explored in TTP, despite many of its shared pathological features with aHUS. We report a 27-year-old white male with severe idiopathic TTP characterized by thrombocytopenia, microangiopathic haemolytic anaemia, renal failure, seizures, and coma. Stool cultures for Shiga toxin-producing Escherichia coli were negative. Plasma ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity was <5% and the ADAMTS13 IgG inhibitor titre was elevated at 6·4 units (normal <0·4). Analysis of complement and complement regulatory proteins did not reveal abnormalities in protein levels of Factor H and Factor B, and mutational analysis revealed normal alleles in CD46 and Factor I. Daily plasma exchanges produced no improvement in clinical symptoms or laboratory values and the patient's clinical condition continued to deteriorate (Fig 1A). The plasma lactate dehydrogenase (LDH) rose, from 476 u/l on presentation to 2230 u/l by day 11. Vincristine, rituximab, steroids, and N-acetylcysteine, utilized because of its effect on high molecular weight von Willebrand factor (VWF) multimers (Chen et al, 2011), were all ineffective over several weeks. A skin biopsy performed on day 20 revealed endothelial deposition of C3d, C4d, and C5b-9, the terminal membrane attack complex (MAC) (Fig 1B). Because of the heavy complement deposition seen in the perivasculature and the patient's critical illness, unresponsive to multiple modalities, emergency institutional review board approval was obtained to administer eculizumab. Platelet counts increased following eculizumab administration by day 29, and creatinine and LDH decreased to normal levels (Fig 1A). ADAMTS13 activity normalized to 85% by day 54. Plasma exchange and eculizumab were discontinued, and steroids were tapered starting at hospital discharge (day 57). Four weeks later, his platelet count and haemoglobin dropped rapidly, creatinine rose, and ADAMTS13 activity fell to 8·6%. Reinstituting eculizumab alone restored normal platelet, haemoglobin, and creatinine levels within 9 d, and this response was sustained for 6 weeks on bi-weekly eculizumab infusions. Two further disease flares occurred, manifested by declines in platelet counts and rises in creatinine levels, each time reversed by eculizumab. Complement dysregulation is well characterized in aHUS. Excessive MAC and complement C5a formation that is triggered by inflammation in aHUS can initiate endothelial damage, platelet activation, and secretion of ultra-large molecular weight VWF multimers (Roumenina et al, 2011). In the setting of impaired complement regulation, endothelial cell damage and thrombosis continues unabated. Mutations in complement regulatory proteins Factor I, CD46, and Factor H along with complement C3 and Factor B account for disease susceptibility in up to 60% of cases (Sanchez-Corral & Melgosa, 2010; Roumenina et al, 2011; Waters & Licht, 2011). Antibodies against Factor H have also been described in paediatric cases of aHUS, suggesting that acquired defects in alternative pathway regulation participate in thrombotic microangiopathies (Mache et al, 2009). Complement or complement regulatory factor abnormalities have not been identified in all cases of aHUS, however, and do not predict clinical response to eculizumab treatment (Mache et al, 2009; Waters & Licht, 2011). Complement regulatory factor mutations have not been systematically examined in TTP patients. In this patient with idiopathic TTP, analysis of four of such factors, those most important in aHUS, did not reveal abnormalities, although other complement and complement regulatory factor abnormalities could have been present. Multiple lines of evidence for complement participation in TTP pathology do exist, however. For example, a Factor H mutation was described in one patient with TTP and a familial ADAMTS13 deficiency; this patient had a clinical presentation distinct from than her sister, who suffered only the ADAMTS13 mutation (Noris et al, 2005). In addition, endothelial cell injury can be recapitulated in vitro by exposing microvascular endothelial cells to TTP plasma or serum, which results in MAC deposition, a process that is reversible by complement blockade (Mitra et al, 1997; Ruiz-Torres et al, 2005). Generation of MAC and C5a leads to endothelial cell damage in aHUS, resulting in endothelial apoptosis that leads to complement activation, platelet activation, and release of VWF (Dragon-Durey & Fremeaux-Bacchi, 2005; Raife, 2005). These downstream effects further enhance thrombosis and up-regulate the complement cascade, creating a positive feedback system, whereby endothelial cell damage and apoptosis further perpetuate thrombotic microangiopathy, and reducing complement regulatory proteins. A similar system may exist in, at least, some patients with TTP; the elaboration of VWF multimers in cases of injury may overwhelm an impaired ADAMTS13 system. This case suggests that eculizumab should be investigated in patients with refractory TTP. Further consideration should also be given to determining the prevalence of complement and complement regulatory factor mutations in patients with TTP. The authors declare no conflict of interest; this report received no financial support. Drs Laurence and Weksler provided direct clinical care for this patient and wrote to the IRB to request eculizumab use, Dr Magro performed the dermatological biopsy and analysis and created the figures, Dr Chapin provided clinical care for the patient and drafted the manuscript. Alexion Pharaceuticals provided eculizumab on a compassionate use basis. All authors contributed equally to the editing and revisions of the manuscript.