Avatrombopag is an orally-administered small molecule thrombopoietin receptor agonist. It was the third thrombopoietin receptor agonist approved for the treatment of immune thrombocytopenia and the first approved to treat periprocedural thrombocytopenia in patients with chronic liver disease (thereby providing an alternative to blood transfusions for these patients). Unlike eltrombopag, avatrombopag does not require a 4 hr food-restricted window around its use and it has not been associated with hepatotoxicity in ITP patients or portal vein thrombosis in patients with chronic liver disease. In ITP patients it can often be dosed less frequently than once daily. It is overall well-tolerated with a side-effect profile similar to placebo in randomized clinical trials. This article will review the clinical development, efficacy, safety, and pharmacology of avatrombopag for use in patients with ITP and thrombocytopenia of chronic liver disease.

Background Complement may contribute to platelet destruction in immune thrombocytopenia (ITP), but serum complement levels of ITP patients are not well defined. This study characterized C3, C4, and CH50 levels from 108 ITP patients in comparison with 120 healthy subjects. Methods Results of complement testing performed using commercially available turbidimetric immunoassays were retrospectively analyzed. Mean complement levels in patients with ITP were compared with levels from a sample of 120 healthy subjects, and subgroups of ITP patients were compared. Regression analyses evaluated for relations between low complement levels and disease severity and response to ITP treatments. Results One hundred eight patients with ITP were included. Mean C3, C4, and CH50 were significantly lower in patients with ITP compared with healthy subjects, largely driven by the 32% of patients with ITP with substantial reductions in one or more assays. Patients requiring treatment had lower mean C4 (18.1 vs 23.1 mg/dL; P = .042) and CH50 (50.4 vs 63.0 mg/dL; P = .004). Mean C3 was higher in splenectomized versus nonsplenectomized patients (120.6 vs 101.0 mg/dL; P = .035). In multivariable analyses, reduced complement did not predict treatment response to corticosteroids, intravenous immunoglobulin, or thrombopoietin receptor agonists but low C4 levels did predict more severe ITP (relative to nonsevere disease, odds ratio for severe/refractory disease: 6.28; 95% confidence interval, 0.75‐52.54; P = .090). Complement levels in patients with ITP were generally consistent over repeat measurements. Conclusions Complement levels are reduced in one‐third of patients with ITP and are associated with more severe disease. Additional study is needed to evaluate if hypocomplementemia is predictive of response to emerging complement‐directed therapies.

Fluoride ion channels of the Fluc family selectively export F− ions to rescue unicellular organisms from acute F− toxicity. Crystal structures of bacterial Fluc channels in complex with synthetic monobodies, fibronectin-derived soluble β-sandwich fold proteins, show 2-fold symmetric homodimers with an antiparallel transmembrane topology. Monobodies also block Fluc F− current via a pore blocking mechanism. However, little is known about the energetic contributions of individual monobody residues to the affinity of the monobody—channel complex or whether the structural paratope corresponds to functional reality. This study seeks to structurally identify and compare residues interacting with Fluc between two highly similar monobodies and subjects them to mutagenesis and functional measurements of equilibrium affinities via a fluorescence anisotropy binding assay to determine their energetic contributions. The results indicate that the functional and structural paratopes strongly agree and that many Tyr residues at the interface, while playing a key role in affinity, can be substituted with Phe and Trp without large disruptions.

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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.

To the Editor: Imagine that a medical student quickly checks his email while studying for his fast-approaching United States Medical Licensing Examination (USMLE) Step 1. He sees the dreaded words informing of his exam cancellation due to the pandemic with no information on rescheduling. To avoid having to cancel his upcoming clinical rotation, he pays for cancelation fees, flights, and accommodations to take his exam 600 miles away. This story exemplifies the experiences of U.S. medical trainees since the COVID-19 pandemic began, with over 17,000 exam cancellations before June 2020 alone. 1 Funding/Support: None reported.