Introduction: Complement activation contributes to platelet destruction in immune thrombocytopenia (ITP). Autoantibodies bound to platelets fix complement (Naiaoui et al. 2011) and ITP platelets have increased cell surface-bound C3 and C4 (Kurata et al. 1985). Despite this known pathophysiology there is very little published data describing serum complement levels in ITP patients and no data describing a possible relation of complement levels to disease characteristics. Therapeutics targeting the complement system are now emerging for the treatment of ITP, including an ongoing clinical trial of the C1 esterase inhibitor sutimlimab (BIVV009). ITP patients with major complement-mediated platelet destruction as revealed by low serum complement levels may be more likely to respond to anti-complement therapies. With this background, we aimed to characterize the serum complement levels of C3, C4, and total hemolytic complement (CH50) in a large cohort of ITP patients and explore the relation of these levels to clinical features in 108 adults with ITP. Complement measurements from 120 healthy adult subjects were used for comparison. ITP patient data was collected retrospectively as standard clinical serum complement evaluation has been a routine part of initial patient evaluation at our ITP center for the past two years.

Methods: Serum C3, C4, and CH50 were measured using a commercially-available turbidimetric assay (Optilite System, Binding Site, Birmingham, UK). Reference ranges were: C3, 81.1-157.0 mg/dL; C4, 12.9-39.2 mg/dL; CH50, 41.7-95.1 U/mL. Data collected for analysis included dates and results of complement testing (including disease status and platelet count at time of testing), patient demographics, and disease characteristics. Satisfaction of the 2011 American Society of Hematology (ASH) ITP diagnostic criteria were required for ITP patient inclusion and ASH ITP guideline definitions of disease severity and treatment response were used. Patients with other disorders known to reduce complement (e.g. systemic lupus) were excluded. Wilcoxon rank-sum tests and t-tests were used to compare groups. Multivariate logistic regression was used to model the probability of low complement levels based on disease severity and platelet count as well as model the probability of treatment response based on complement levels.

Results: A total of 98 C3 assays, 97 C4 assays, and 102 CH50 assays from 108 ITP patients (92 patients had all three assays performed) were collected and compared with results from 120 healthy subjects obtained from the assay manufacturer. Of ITP patients, mean (range) age was 53 (18-89) years, 54% were female, 16% were splenectomized, and 52% were receiving ITP-directed treatment at the time of complement testing. 32% of patients had levels of one or more complement assay below the reference range and 10% had low levels of all three assays. Mean serum C3, C4 and CH50 were significantly lower in ITP patients relative to healthy subjects (Table 1, Figure). On subgroup analysis, patients requiring treatment for ITP had significantly lower serum C4 and CH50 and splenectomized patients had significantly higher serum C3 (Table 2). Multivariate logistic regression analyses including age, sex, splenectomy status, disease severity, platelet count at time of complement assay, and results of complement testing demonstrated a relation between low C4 levels and presence of severe or refractory disease (relative to non-severe disease, OR for severe/refractory disease 6.28, 95% CI 0.75 to 52.54, P=0.090) and low C3 levels and platelet count (odds ratio (OR) for low C3 per 10×109/L reduction in platelet count, 1.04, 95% CI, 0.99 to 1.08, P=0.057). Multivariate logistic regression models including age, sex, splenectomy status, platelet count, treatment response, and results of complement testing did not demonstrate a relation between complement levels and response to corticosteroids, IVIG, or thrombopoietin receptor agonists.

Conclusions: ITP patients have significantly lower serum C3, C4, and CH50 than healthy subjects, with the overall difference driven by the one-third of ITP patients with substantial reductions. We observed a relation between low C4 and more severe disease and low C3 and reduced platelet counts. Patients requiring treatment had significantly lower C4 and CH50 relative to those not requiring treatment, and splenectomized patients had significantly higher C3.

Disclosures

Kuter:Protalix: Consultancy, Honoraria; Zafgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Shinogi: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Up-to-Date: Consultancy, Honoraria, Patents & Royalties: 3 Up-to-Date chapters; Up-to-Date: Consultancy, Honoraria, Patents & Royalties: 3 Up-to-Date chapters; Zafgen: Consultancy, Honoraria; Protalex: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Shinogi: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; UCB: Consultancy, Honoraria; Dova: Consultancy, Honoraria; Dova: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; UCB: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Kezar: Research Funding; Pfizer: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; Kezar: Research Funding; Platelet Disorder Support Association: Consultancy, Honoraria; Principia: Consultancy, Honoraria, Research Funding; Principia: Consultancy, Honoraria, Research Funding; Protalex: Consultancy, Honoraria, Research Funding; Rigel: Consultancy, Honoraria, Research Funding; Protalix: Consultancy, Honoraria; Rigel: Consultancy, Honoraria, Research Funding. Al-Samkari:Moderna: Consultancy; Dova: Consultancy, Research Funding; Agios: Consultancy, Research Funding.

Author notes

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Asterisk with author names denotes non-ASH members.