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Participants with hemophilia A received B-domain–deleted factor VIII gene therapy delivered in an AAV5 vector. A decrease in annualized bleeding rates was maintained for 2 years despite declining factor VIII levels.

Damoctocog alfa pegol (BAY 94-9027, Jivi ), is a site-specifically PEGylated, extended half-life recombinant factor VIII (FVIII) that is approved in several European and non-European countries for on-demand treatment and prophylaxis of bleeding in previously treated patients aged ≥ 12 years with hemophilia A. Reliable measurements can be obtained using most one-stage and chromogenic FVIII assays over a wide concentration range. The efficacy, safety and pharmacokinetics (PK) of damoctocog alfa pegol have been studied extensively in the PROTECT VIII clinical trials, and its long-term safety and effectiveness profile is continuing to build through observational and interventional real-world studies. The PK of damoctocog alfa pegol was shown to be improved as compared with that of sucrose-formulated rFVIII (rFVIII-FS, Kogenate ), and was also demonstrated to be non-inferior to and, for some variables, more favorable than rFVIII-Fc fusion protein, efmoroctocog alfa (Elocta ; NCT03364998), rurioctocog alfa pegol (BAX 855, Adynovate /Adynovi ; NCT04015492), and antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM, Advate ; NCT02483208). Damoctocog alfa pegol was generally well tolerated and none of the patients in any of the clinical trials, including the PROTECT VIII clinical program, HEM-POWR, or ongoing single-center studies, developed FVIII inhibitors. Efficacy for perioperative hemostasis has been demonstrated. Low bleeding rates were achieved across the studies, with twice weekly, every 5-day and every 7-day prophylaxis offering patients ≥ 12 years and their clinicians the chance to tailor treatment to individual needs and lifestyles, while maintaining long-term protection from bleeds and their consequences.

Rare, chronic diseases such as hemophilia and other congenital coagulation disorders require coordinated delivery of services for optimal outcomes. Hemophilia Treatment Centers (HTCs) are specialized, multidisciplinary health-care centers providing team-based care to meet the physical, psychosocial, and emotional needs of people with hemophilia (PWH) and may serve as a model for other rare coagulation disorders. Healthcare purchasers, as well as the general medical community, may not appreciate the breadth and quality of services provided by HTCs. They exemplify the acculturalization and actualization of integrated care by providing comprehensive diagnostic and treatment services that reduce morbidity, mortality, avoidable emergency room visits, hospitalizations, and overall costs, while promoting a longer lifespan and improved patient functioning and outcomes. This is accomplished by a team-based approach relying upon a shared decision-making model to effectively prevent complications and manage symptoms in PWH, who are dependent on high-cost treatments. This article provides a concise yet comprehensive description of the core components of an HTC and the regional and national networks in the United States, which together achieve their incomparable value for all stakeholders. Keywords: hemophilia, coagulation disorders, integrated care, patient-centered care, healthcare delivery network, multidisciplinary

We report long‐term follow‐up of a patient who underwent a tailored laparoscopic procedure for symptomatic cholelithiasis, massive splenomegaly, and a planned pregnancy. There were no complications, and the patient remained symptom‐free at the 5‐year follow‐up. We supplemented our case report with national surgical data demonstrating the safety of laparoscopic splenectomy. Laparoscopic splenectomy is a safe and effective approach for patients with immune thrombocytopenic purpura, even those with massive splenomegaly. We highlight the benefits of tailoring the surgical approach to address the patient's surgical needs.

Bleeding symptoms commonly seen by multiple physician specialties may belie undiagnosed congenital or acquired bleeding disorders. Acquired hemophilia is a potentially life-threatening cause of unexplained acute bleeding manifested by an abnormal activated partial thromboplastin time (aPTT) that does not correct with 1:1 mixing with normal plasma. Practicing physicians (hematology/oncology, emergency medicine, geriatrics, internal medicine, rheumatology, obstetrics and gynecology, critical care medicine, and general surgery) completed an online survey based on a hypothetical case scenario. Excluding surgeons and obstetrician/gynecologist respondents, 302 physicians (about 50 per specialty) were presented with an older adult woman complaining of recurrent epistaxis. Nearly 90% ordered a complete blood count and coagulation studies (aPTT, prothrombin time [PT]/international normalized ratio [INR]). Despite a prolonged aPTT of 42 seconds, <50% of nonhematologists would repeat the aPTT, and <45% would consult a hematologist; emergency medicine physicians were least likely (10%) and rheumatologists were most likely (43%) to consult. After presentation weeks later with bruising and abdominal/back pain, ≥90% of physicians within each specialty ordered a complete blood count or PT/INR/aPTT. Despite an aPTT of 63 seconds, the majority did not repeat the aPTT. At this point, approximately 75% of internal medicine and geriatric physicians indicated they would consult a hematologist, versus 47% in emergency medicine and 50% in critical care. All participants preferred abdominal computed tomography (80%-84%). After 12 hours of additional observation, 73% to 94% of respondents consulted a hematologist. Complete blood count revealed anemia and an aPTT twice the upper limit of normal; emergency medicine physicians remained least likely to request a consult. Determining the cause of an abnormal coagulation study result should carry equal weight as looking for the site of bleeding and could be facilitated by consultation with a hematologist. Insight from this survey highlights knowledge and practice gaps that could be the target of focused educational initiatives.

Lisa M Baumann Kreuziger,1 Tracy L Prosen,2 Mark T Reding1 1Division of Hematology, Oncology, and Transplantation, University of Minnesota, MN, USA; 2Obstetrics and Gynecology, Maternal Fetal Medicine Center, University of Minnesota, MN, USAWe read with great interest James et al's article \"Prevention and treatment of venous thromboembolism in pregnancy in patients with hereditary antithrombin deficiency.\" The authors reported a case series of six women with antithrombin (AT) deficiency treated with plasma derived antithrombin concentrate (pdAT; Thrombate III®, Grifols Therapeutics, Clayton, NC, USA).1 In contrast to these cases, we have managed three AT-deficient women over the past two years with low-molecular-weight-heparin during pregnancy and recombinant human antithrombin concentrate (rhAT; ATryn®, GTC Biotherapeutics, Framingham, MA, USA) at delivery. In the Phase III trial leading to approval of rhAT, pregnant women required frequent dose modifications, and an alternate dosing regimen is currently recommended by the manufacturer.2,3 The detailed information provided in these cases may assist future providers in managing pregnant patients with AT deficiency.View original paper by James and colleagues.

Liver sinusoidal endothelial cells are a major endogenous source of Factor VIII (FVIII), lack of which causes the human congenital bleeding disorder hemophilia A. Despite extensive efforts, gene therapy using viral vectors has shown little success in clinical hemophilia trials. Here we achieved cell type-specific gene targeting using hyaluronan- and asialoorosomucoid-coated nanocapsules, generated using dispersion atomization, to direct genes to liver sinusoidal endothelial cells and hepatocytes, respectively. To highlight the therapeutic potential of this approach, we encapsulated Sleeping Beauty transposon expressing the B domain-deleted canine FVIII in cis with Sleeping Beauty transposase in hyaluronan nanocapsules and injected them intravenously into hemophilia A mice. The treated mice exhibited activated partial thromboplastin times that were comparable to those of wild-type mice at 5 and 50 weeks and substantially shorter than those of untreated controls at the same time points. Further, plasma FVIII activity in the treated hemophilia A mice was nearly identical to that in wild-type mice through 50 weeks, while untreated hemophilia A mice exhibited no detectable FVIII activity. Thus, Sleeping Beauty transposon targeted to liver sinusoidal endothelial cells provided long-term expression of FVIII, without apparent antibody formation, and improved the phenotype of hemophilia A mice.

Background: Advances in treatment have enabled patients with haemophilia A to live longer and therefore may be subjected to comorbidities associated with ageing, in addition to disease-associated morbidities. There have been few reports to date on efficacy and safety of treatment specifically in patients with severe haemophilia A and comorbidities. Objective: To explore the efficacy and safety of damoctocog alfa pegol prophylaxis in patients with severe haemophilia A aged ⩾40 years with comorbidities of interest. Design: A post hoc analysis of data from the phase 2/3 PROTECT VIII study and its extension. Methods: Bleeding and safety outcomes were analysed in a subgroup of patients aged ⩾40 years with ⩾1 comorbidity receiving damoctocog alfa pegol (BAY 94-9027; Jivi®) prophylaxis. Results: Thirty-four patients with severe haemophilia A were included in this analysis, with a mean age of 49.4 years at time of enrolment. The most prevalent comorbidities were hepatitis C (n = 33; chronic, n = 23), hepatitis B (n = 8) and hypertension (n = 11). Four patients had human immunodeficiency virus. All received damoctocog alfa pegol prophylaxis for the entire study [median (range) time in study = 3.9 (1.0–6.9) years]. During the main study and extension, median total annualised bleeding rates (ABRs) (Q1; Q3) were 2.1 (0.0; 5.8) and 2.2 (0.6; 6.0), respectively; median joint ABRs were 1.9 (0.0; 4.4) and 1.6 (0.0; 4.0), respectively. Mean adherence with prophylaxis schedule was greater than 95% throughout the study. No deaths or thrombotic events were reported. Conclusion: Efficacy, safety and adherence of damoctocog alfa pegol were confirmed in patients aged ⩾40 years with haemophilia A and one or more comorbidities, with data for up to 7 years supporting its use as a long-term treatment option in this group. Plain language summary Advances in treatment mean that people with haemophilia A are now living longer and, as a result, may have additional medical conditions that occur with ageing. We aimed to investigate the efficacy and safety of the long-acting replacement factor VIII damoctocog alfa pegol in people with severe haemophilia A who had additional medical conditions. To do this, we investigated the recorded information about patients aged 40 years of age or older who had been treated with damoctocog alfa pegol in a previously completed clinical trial. We found that the treatment was well-tolerated; no deaths or thrombotic events (undesirable clotting events) were reported. Treatment was efficacious in reducing bleeding in this group of patients. The findings support the use of damoctocog alfa pegol as a long-term treatment for older patients with haemophilia A and coexisting conditions. Graphical Abstract This is a visual representation of the abstract.

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.