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In this phase 1 study, a chemically modified RNA interference therapy designed to target antithrombin was administered to participants with hemophilia A or B. Antithrombin levels decreased and the generation of thrombin increased.

Sickle cell disease (SCD) is an inherited monogenic disorder with high prevalence throughout sub-Saharan Africa, the Mediterranean basin, the Middle East, and India. Sources of SCD epidemiology remain scarce and fragmented. A systematic literature review (SLR) to identify peer-reviewed studies on SCD epidemiology was performed, with a search of bibliographic databases and key conference proceedings from 1 January 2010 to 25 March 2022 (congress abstracts after 2018). The SLR followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Meta-analyses, using a binomial normal random-effects model, were performed to estimate global and regional prevalence and birth prevalence. Of 1770 journal articles and 468 abstracts screened, 115 publications met the inclusion criteria. Prevalence was highest in Africa (~800/100,000), followed by the Middle East (~200/100,000) and India (~100/100,000), in contrast to ~30/100,000 in Europe. Birth prevalence was highest in Africa (~1000/100,000) and lowest in North America (~50/100,000) and Europe (~30/100,000). This SLR confirmed that sub-Saharan and North-East Africa, India, the Middle East, and the Caribbean islands are global SCD hotspots. Publications including mortality data were sparse, and no conclusions could be drawn about mortality. The identified data were limited due to gaps in the published literature for large parts of the world population; the inconsistent reporting of SCD genotypes, diagnostic criteria, and settings; and a sparsity of peer-reviewed publications from countries with assumed high prevalence. This SLR demonstrated a lack of systematic knowledge and a need to provide uniform data collection on SCD prevalence and mortality.

Density reversal of senescent red blood cells has been known for a long time, yet the identity of the candidate ion transporter(s) causing the senescent cells to swell is still elusive. While performing fractionation of RBCs from healthy individuals in Percoll density gradient and characterization of the separated fractions, we identified a subpopulation of cells in low-density fraction (1.02% ± 0.47) showing signs of senescence such as loss of membrane surface area associated with a reduction in band 3 protein abundance, and Phosphatidylserine (PS) exposure to the outer membrane. In addition, we found that these cells are overloaded with Na+ and Ca2+. Using a combination of blockers and activators of ion pumps and channels, we revealed reduced activity of Plasma membrane Ca2+ ATPase and an increase in Ca2+ and Na+ leaks through ion channels in senescent-like cells. Our data revealed that Ca2+ overload in these cells is a result of reduced PMCA activity and facilitated Ca2+ uptake via a hyperactive Piezo1 channel. However, we could not exclude the contribution of other Ca2+-permeable ion channels in this scenario. In addition, we found, as a universal mechanism, that an increase in intracellular Ca2+ reduced the initially high selectivity of Piezo1 channel for Ca2+ and allowed higher Na+ uptake, Na+ accumulation, and swelling.

Anaemia and iron deficiency are frequent in patients scheduled for cardiac surgery. This study assessed whether immediate preoperative treatment could result in reduced perioperative red blood cell (RBC) transfusions and improved outcome. In this single-centre, randomised, double-blind, parallel-group controlled study, patients undergoing elective cardiac surgery with anaemia (n=253; haemoglobin concentration (Hb) <120 g/L in women and Hb <130 g/L in men) or isolated iron deficiency (n=252; ferritin <100 mcg/L, no anaemia) were enrolled. Participants were randomly assigned (1:1) with the use of a computer-generated range minimisation (allocation probability 0·8) to receive either placebo or combination treatment consisting of a slow infusion of 20 mg/kg ferric carboxymaltose, 40 000 U subcutaneous erythropoietin alpha, 1 mg subcutaneous vitamin B12, and 5 mg oral folic acid or placebo on the day before surgery. Primary outcome was the number of RBC transfusions during the first 7 days. This trial is registered with ClinicalTrials.gov, number NCT02031289. Between Jan 9, 2014, and July 19, 2017, 1006 patients were enrolled; 505 with anaemia or isolated iron deficiency and 501 in the registry. The combination treatment significantly reduced RBC transfusions from a median of one unit in the placebo group (IQR 0–3) to zero units in the treatment group (0–2, during the first 7 days (odds ratio 0·70 [95% CI 0·50–0·98] for each threshold of number of RBC transfusions, p=0·036) and until postoperative day 90 (p=0·018). Despite fewer RBC units transfused, patients in the treatment group had a higher haemoglobin concentration, higher reticulocyte count, and a higher reticulocyte haemoglobin content during the first 7 days (p≤0·001). Combined allogeneic transfusions were less in the treatment group (0 [IQR 0–2]) versus the placebo group (1 [0–3]) during the first 7 days (p=0·038) and until postoperative day 90 (p=0·019). 73 (30%) serious adverse events were reported in the treatment group group versus 79 (33%) in the placebo group. An ultra-short-term combination treatment with intravenous iron, subcutaneous erythropoietin alpha, vitamin B12, and oral folic acid reduced RBC and total allogeneic blood product transfusions in patients with preoperative anaemia or isolated iron deficiency undergoing elective cardiac surgery. Vifor Pharma and Swiss Foundation for Anaesthesia Research.

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Nonacog beta pegol (N9‐GP) and recombinant factor IX‐Fc fusion protein (rFIXFc) are extended half‐life rFIX compounds. We report the first single‐dose pharmacokinetic trial of N9‐GP and rFIXFc. Paradigm 7 was a multicenter, open‐label, randomized, crossover trial in previously treated (>150 exposure days) adults with congenital hemophilia B (FIX activity ≤2%). Patients received single intravenous injections (50 IU/kg) of N9‐GP and rFIXFc with at least 21 days between doses. Plasma FIX activity, predose, and at serial time points up to 240 hours postdose, was measured using validated one‐stage clotting assays (SynthAFax for N9‐GP; Actin FSL for rFIXFc) and a chromogenic assay (ROX factor IX) with normal human plasma as calibrator. The primary endpoint was area under the FIX activity–time curve from 0 to infinity, dose‐normalized to 50 IU/kg (AUC0‐inf,norm). Fifteen patients received study treatment. Based on FIX activity results from the one‐stage clotting assays, estimated AUC0‐inf,norm was significantly greater for N9‐GP than rFIXFc (ratio: 4.39; P<0.0001, based on a two‐sided test on 5% significance level). In addition, N9‐GP had a longer terminal half‐life, two times higher incremental recovery at 30 minutes and maximum FIX activity (dose‐normalized to 50 IU/kg) and six times higher FIX activity at 168 hours than rFIXFc. These findings were largely comparable with the chromogenic assay data and are consistent with published data for each compound. In this comparison, N9‐GP demonstrated favorable pharmacokinetic characteristics versus rFIXFc, helping clinicians to understand differences between N9‐GP and rFIXFc. This trial is registered with clinicaltrials.gov (NCT03075670) and the European Clinical Trials Database (EudraCT: 2016‐001149‐25).

The objective of this scoping review is to summarize the current use of pharmacokinetics for tailoring prophylaxis in hemophilia patients switching between clotting factor products. Patients with hemophilia may require switching of clotting factor concentrates due to a variety of factors, but there have been perceived risks associated with switching, such as inhibitor development or suboptimal protection due to inadequate dosing while titrating treatment. Studies that look at patients switching from one clotting factor concentrate to another are categorized in terms of their primary and/or secondary objectives, notably biosimilarity and comparative pharmacokinetic studies and inhibitor development studies. Research on how best to switch concentrates with respect to dosing regimen are lacking, and currently a trial‐and‐error approach is used for dosing the new factor concentrate. In the future, studies looking at the predictability of pharmacokinetics (PK) of a new factor concentrate based on individual PK knowledge of the original factor concentrate may offer clinical benefit by providing a safer switching approach and protocol.