Terminal Complement Inhibitor Eculizumab Improves Complement-Mediated Platelet Consumption and Thrombocytopenia in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)

PNH is a hematopoietic stem cell disorder in which unregulated activation of the complement system leads to significant morbidities with shortened lifespan. Life threatening thromboembolism (TE) is the most feared complication of PNH, accounting for 45% of patient deaths.  Approximately 40% of PNH patients experience a clinically evident TE and 60% of patients without clinically diagnosed TE demonstrate TE by high-sensitivity MRI, indicating the ongoing thrombotic risk in PNH patients. Thrombocytopenia is found in 25-50% of PNH patients at presentation.  PNH platelets are extremely sensitive to terminal complement activation, and circulating platelets are activated in thrombocytopenic PNH patients without clinically diagnosed TE.  Eculizumab, a monoclonal antibody targeted to complement C5, blocks the production of both C5a and C5b-9, and has been demonstrated to reduce TE events by up to 92% in PNH patients.  Eculizumab has also been shown to beneficially impact several prothrombotic processes in PNH patients including hemolysis, nitric oxide consumption, thrombin generation, tissue factor pathways, and inflammation. We hypothesized that terminal complement activation of PNH platelets contributes to ongoing platelet activation, which is reflected by platelet consumption, contributing to chronic thrombocytopenia defined as platelets <100x10⁹/L.  This hypothesis was tested by examining whether chronic inhibition of terminal complement activation with eculizumab increases platelet counts in thrombocytopenic PNH patients.  The study population was comprised of the 49 thrombocytopenic PNH patients identified from the total 195 patients in the SHEPHERD, TRIUMPH, and Phase 2 eculizumab trials.  Platelet counts were measured at baseline, 26 and 52 weeks of eculizumab treatment. At baseline the median platelet count in the thrombocytopenic group was 68x10⁹/L (range 23 to 97).  Patients with thrombocytopenia were more likely to have a history of TE than patients with normal platelet counts (45% vs 27%; P<0.022). Treatment with eculizumab markedly inhibited terminal complement activity in all thrombocytopenic patients, as measured by a significant reduction in LDH at 26 and 52 weeks (median values at baseline, 26 weeks, and 52 weeks: 1746 IU/L, 290 IU/L, 286 IU/L, respectively, UNL 220 U/L); P<0.00001 for each time point vs. baseline). Chronic terminal complement inhibition with eculizumab significantly increased platelet counts to a non-thrombocytopenic level in 33% (95% CI: 20-48%) and 36% (95% CI: 22-51%) of thrombocytopenic patients at 26 and 52 weeks, respectively, of treatment.  By inhibiting C5 activity, the median platelet counts significantly increased in thrombocytopenic patients from 68x10⁹/L at baseline to 80 and 85x10⁹/L (P<0.001) at 26 and 52 weeks, respectively.  Eculizumab treatment significantly increased platelet counts in both thrombocytopenic patients with a history of TE and no history of TE (P<0.05 vs baseline in both groups). Treatment with eculizumab significantly increased platelet counts at 52 weeks in this thrombocytopenic patient population irrespective of a history of bone marrow failure (P<0.05 vs baseline for each group). As expected, there was no apparent impact of terminal complement inhibition on marrow blood cell production as measured by no change in absolute neutrophil count at 26 and 52 weeks. This suggests that the mechanism of platelet increase may be due to inhibition of terminal complement-mediated consumption of platelets in thrombocytopenic patients with PNH.  The present study indicates that thrombosis in PNH patients is more frequent in patients with thrombocytopenia.  Terminal complement deposition on PNH platelets results in platelet activation which in turn would be expected to result in platelet consumption, suggestive of a chronic prothrombotic state, in PNH patients. Earlier studies have shown that chronic terminal complement inhibition with eculizumab reduces thrombotic risk in patients with PNH. The current study shows that chronic terminal complement inhibition with eculizumab treatment improves pre-existing thrombocytopenia in a significant proportion of patients with PNH. These clinical findings warrant further investigation and suggest that terminal complement C5 activity contributes to platelet activation and consumption with subsequent thrombocytopenia and an increased thrombotic risk in patients with PNH.