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JHEP Rep 2021 Aug 30;3(4):100300. Epub 2021 Apr 30.

Gene Therapy Area, Foundation for Applied Medical Research, University of Navarra, IdisNA, Pamplona, Spain.

Gene therapy is becoming an increasingly valuable tool to treat many genetic diseases with no or limited treatment options. This is the case for hundreds of monogenic metabolic disorders of hepatic origin, for which liver transplantation remains the only cure. Furthermore, the liver contains 10-15% of the body's total blood volume, making it ideal for use as a factory to secrete proteins into the circulation. Read More

J Thromb Haemost 2021 Jun 17. Epub 2021 Jun 17.

Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA.

New modified coagulation factor VIII (FVIII) and factor IX (FIX) products have been designed to improve the treatment of individuals with hemophilia A and B by increasing the interval between dosing. Although these FVIII and FIX molecules have been structurally modified to improve the circulation time, the changes have also influenced their behavior in functional assays in comparison with traditional plasma-derived or recombinant coagulation factors. The assignment of potencies for these products can be problematic because discordance in factor activity values between the commonly used one-stage clotting (OC) and chromogenic substrate (CS) assays is often observed. Read More

Haemophilia 2021 Jun 12. Epub 2021 Jun 12.

Indiana Haemophilia and Thrombosis Centre, Indianapolis, Indiana, USA.

Introduction: Inhibitors develop less frequently in haemophilia B (HB) than haemophilia A (HA). However, when present, the success of tolerization by immune tolerance induction (ITI) therapy is lower and the risk of complications higher.

Aim: To evaluate the use and outcome of ITI in patients with HB and inhibitors. Read More

Calcif Tissue Int 2021 Jun 12. Epub 2021 Jun 12.

Medical Research Service, Portland Veterans Affairs Health Care System, 3710 SW US Veterans Hospital Road, Portland, OR, 97239, USA.

Osteopenia and osteoporosis have increasingly become a recognized morbidity in those persons with hemophilia (PwH) receiving inadequate prophylactic clotting factor replacement. Animal models can control or eliminate genetic and environmental factors and allow for invasive testing not clinically permissible. Here, we describe the skeletal phenotype of juvenile and adult male mice with a genetically engineered deficiency in coagulation factor IX (FIX KO). Read More

Br J Haematol 2021 Jun 9. Epub 2021 Jun 9.

Department of Life Sciences and Biotechnology and LTTA Centre, University of Ferrara, Ferrara, Italy.

The short half-life of coagulation factor IX (FIX) for haemophilia B (HB) therapy has been prolonged through fusion with human serum albumin (HSA), which drives the neonatal Fc receptor (FcRn)-mediated recycling of the chimera. However, patients would greatly benefit from further FIX-HSA half-life extension. In the present study, we designed a FIX-HSA variant through the engineering of both fusion partners. Read More

Int J Surg Case Rep 2021 May 21;83:105995. Epub 2021 May 21.

Department of Orthopedics, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand. Electronic address:

Introduction And Importance: Flexion contracture following total knee arthroplasty (TKA) in patients with hemophilia is not uncommon, and this complication reduces knee range of motion and produces morbidity for the patient. This report states the success of treatment of flexion contracture after primary TKA in a patient with hemophilia; by open soft tissue contracture releasing and serial casting.

Case Presentation: A 20-year-old-man presented with hemophilia type A. Read More

Haemophilia 2021 May 22. Epub 2021 May 22.

Department of Orthopedic Surgery, The First Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, China.

Introduction: Clinical practice showed that patients with haemophilia (PwH) with bony ankylosed end-stage haemophilic arthropathy knees reported milder pain than those with not bony ankylosed knees.

Aim: To compare the differences in pain sensation and the histopathological differences in synovial samples of affected knee joints between PwH with bony ankylosed end-stage haemophilic arthropathy knees and those with not bony ankylosed knees.

Methods: From January 2011 to December 2019, the synovial samples of knee joints were collected during total knee arthroplasty (TKA) surgery for end-stage haemophilic arthropathy. Read More

J Family Med Prim Care 2021 Jan 30;10(1):295-299. Epub 2021 Jan 30.

Department of Pathology, IMS, BHU, Varanasi, Uttar Pradesh, India.

Context: Inherited bleeding disorders are common in India and hemophila and von Willebrand diseases are the most common among them. These patients can present in any department including paediatrics, medicine, orthopaedics and even gynaecology so knowledge about hemophilias and facilities for specialized tests for diagnosis are required. Few centres of north-eastern part of India perform these tests so hemophilias remain an underdiagnosed and underreported disease. Read More

Open Life Sci 2021 3;16(1):431-441. Epub 2021 May 3.

Animal Genetics, Breeding and Reproduction, College of Animal Science and Technology, Guangxi University, Nanning, 530004, China.

A new approach is adopted to treat primary immunodeficiency disorders, such as the severe combined immunodeficiency (SCID; e.g., adenosine deaminase SCID [ADA-SCID] and IL-2 receptor X-linked severe combined immunodeficiency [SCID-X1]). Read More

Res Pract Thromb Haemost 2021 Mar 14;5(3):390-394. Epub 2021 Mar 14.

Hemostasis and Thrombosis Unit Division of Hematology Cliniques Universitaires Saint-Luc Université Catholique de Louvain (UCLouvain) Brussels Belgium.

Background: While the number of individuals with hemophilia who are expected to be or have already been included in gene therapy trials has been regularly reported, the number of unscreened or excluded individuals, in addition to the reasons for exclusion, is mostly not reported.

Methods: We conducted an eligibility assessment of all people with severe hemophilia for gene therapy trials in one large Belgian hemophilia treatment center based on patient selection criteria of gene therapy trials and patients' profiling.

Results: Among 87 adult patients with severe hemophilia A and B, 11 aged ≥65 years and two women were excluded from analysis. Read More

Gesundheitswesen 2021 Apr 8;83(4):282-290. Epub 2021 Apr 8.

Institut für Medizinische Psychologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Deutschland.

Background And Objectives: Chronic diseases, such as inherited bleeding disorders (IBD) are often associated with high costs of medical care. COVID-19 containment measures, including isolation and triage, led to restrictions in the health care of chronically ill patients. The aim of the present study was to investigate the effects of the COVID-19 pandemic on the health care of IBD patients. Read More

Haemophilia 2021 May 29;27(3):332-339. Epub 2021 Mar 29.

Department of Biology, UNC-Chapel Hill, Chapel Hill, NC, USA.

Introduction: The majority of clotting factor IX (FIX) resides extravascularly, in the subendothelial basement membrane, where it is important for haemostasis.

Aim: We summarize preclinical studies demonstrating extravascular FIX and its role in haemostasis and discuss clinical observations supporting this. We compare the in vivo binding of BeneFIX and the extended half-life FIX, Alprolix , to extravascular type IV collagen (Col4). Read More

Hum Gene Ther 2021 May 26;32(9-10):506-516. Epub 2021 Apr 26.

Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Department of Basic Medical Sciences, Hangzhou Normal University School of Medicine, Hangzhou, China.

Targeting the coagulation factor IX (FIX) expression in platelets has been shown to be effective in ameliorating bleeding in hemophilia B (HB) mice. To improve the therapeutic effects and evaluate the safety of this gene therapy strategy, we generated a transgenic mouse model on an HB background with FIX Padua target expressed in platelets. The transgenic mice exhibited stable expression and storage of FIX Padua in platelets. Read More

Br J Oral Maxillofac Surg 2021 04 12;59(3):341-346. Epub 2020 Oct 12.

Department of Oral and Maxillofacial Surgery, Nara Medical University, Kashihara, Japan.

Many guidelines and studies describe haemostatic management protocols for patients with haemophilia, but few have evaluated the risk factors for post-extraction bleeding. This retrospective cohort study was performed to investigate these risks among this group of patients. We used medical records to identify patients with haemophilia who underwent tooth extraction(s) between April 2006 and April 2019 in the Department of Oral and Maxillofacial Surgery at Nara Medical University Hospital, Nara, Japan, and conducted logistic regression analyses to identify risk or protective factors for post-extraction bleeding in procedures involving factor replacement therapy. Read More

Blood Adv 2021 03;5(5):1324-1332

Divsion of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA.

The high-specific-activity factor IX (FIX) variant Padua (R338L) is the most promising transgene for hemophilia B (HB) gene therapy. Although R338 is strongly conserved in mammalian evolution, amino acid substitutions at this position are underrepresented in HB databases. We therefore undertook a complete 20 amino acid scan and determined the specific activity of human (h) and canine (c) FIX variants with every amino acid substituted at position 338. Read More

Thromb Haemost 2021 Feb 13. Epub 2021 Feb 13.

Octapharma AG, Lachen, Switzerland.

Introduction:  FVIII inhibitor development is the most serious contemporary treatment complication in haemophilia A, particularly in previously untreated patients (PUPs). No inhibitors developed in clinical trials in previously treated patients treated with simoctocog alfa (Nuwiq), a fourth-generation recombinant FVIII produced in a human cell line.

Methods:  The NuProtect study investigated the immunogenicity of simoctocog alfa in PUPs. Read More

Blood 2021 May;137(21):2970-2980

Integrated Drug Discovery, Sanofi, Waltham, MA.

Interaction of factor VIII (FVIII) with von Willebrand factor (VWF) is mediated by the VWF D'D3 domains and thrombin-mediated release is essential for hemostasis after vascular injury. VWF-D'D3 mutations resulting in loss of FVIII binding are the underlying cause of von Willebrand disease (VWD) type 2N. Furthermore, the FVIII-VWF interaction has significant implications for the development of therapeutics for bleeding disorders, particularly hemophilia A, in which endogenous VWF clearance imposes a half-life ceiling on replacement FVIII therapy. Read More

J Thromb Haemost 2021 04 24;19(4):967-975. Epub 2021 Mar 24.

Catalyst Biosciences, South San Francisco, California, USA.

Background: Dalcinonacog alfa (DalcA), a next-generation, recombinant human factor IX (FIX) variant, was developed using a rational design approach for increased procoagulant activity and longer duration of action to be administered subcutaneously (SC) for prophylaxis of hemophilia B bleeding episodes.

Objectives: To investigate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of DalcA.

Methods: This multicenter, phase 1/2a study (NCT03186677) was conducted in 11 males aged 12 to 65 years with severe hemophilia B. Read More

Semin Thromb Hemost 2021 Feb 1;47(1):84-89. Epub 2021 Feb 1.

Regional Reference Center for Inherited Bleeding Disorders, University Hospital, Parma, Italy.

Considering the profound influence exerted by the ABO blood group system on hemostasis, mainly through the von Willebrand factor and factor VIII (FVIII) complex, we have conducted a study evaluating the possible role of blood type on the risk of inhibitor development in hemophilia A. A total of 287 consecutive Caucasian patients with severe hemophilia A (202 without FVIII inhibitors and 85 with FVIII inhibitors) followed at seven Italian Hemophilia Treatment Centers belonging to the Italian Association of Hemophilia Centers (AICE) were included in the study. A higher prevalence of O blood group was detected in patients without inhibitors as compared in inhibitor patients (55 vs. Read More

Blood 2021 May;137(18):2532-2543

Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA.

Mechanisms thought to regulate activated factor VIII (FVIIIa) cofactor function include A2-domain dissociation and activated protein C (APC) cleavage. Unlike A2-domain dissociation, there is no known phenotype associated with altered APC cleavage of FVIII, and biochemical studies have suggested APC plays a marginal role in FVIIIa regulation. However, the in vivo contribution of FVIIIa inactivation by APC is unexplored. Read More

BMJ Open 2021 01 13;11(1):e042283. Epub 2021 Jan 13.

Inserm CIC 1408, Saint-Etienne University Hospital Center, Saint-Etienne, Rhône-Alpes, France.

Introduction: Two meta-analyses showed lower bone mineral density (BMD) in patients with haemophilia (haemophilia type and severity were often not specified) compared with healthy controls. This finding could be related to reduced mobility and sedentary lifestyle, and/or hepatitis C or HIV infection. The aim of this study is to determine osteoporosis prevalence in patients with haemophilia classified in function of the disease type (A or B) and severity, and to evaluate the potential role of regular prophylactic factor replacement (early vs delayed initiation) in preserving or restoring BMD. Read More

Blood Res 2020 Dec;55(4):246-252

Global Patient safety Evaluation, Takeda Pharmaceutical Company Ltd, Cambridge, MA, USA.

Background: Rixubis (recombinant factor IX, nonacog gamma) is indicated for the control and prevention of bleeding episodes, perioperative management, and routine prophylaxis in hemophilia B patients. This real-world, postmarketing surveillance study aimed to evaluate the safety and effectiveness of Rixubis in adult and pediatric hemophilia B patients in South Korea.

Methods: This prospective, observational, multicenter study (clinicaltrials. Read More

J Exp Med 2021 Mar;218(3)

Pediatric Department A and Immunology Service, Jeffrey Modell Foundation Center, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel.

The T cell receptor (TCR) signaling pathway is an ensemble of numerous proteins that are crucial for an adequate immune response. Disruption of any protein involved in this pathway leads to severe immunodeficiency and unfavorable clinical outcomes. Here, we describe an infant with severe immunodeficiency who was found to have novel biallelic mutations in SLP76. Read More

Blood Coagul Fibrinolysis 2021 Jan;32(1):8-15

Hematology Department.

Hereditary hemophilias are X-linked inherited bleeding disorders defined as deficiencies of the coagulation factors VIII or IX. They are characterized by easy to provoke or spontaneous bleeding. HIV infection in hemophilic patients is a risk factor for the reduction of CD4+ T cells. Read More

Res Pract Thromb Haemost 2020 Oct 11;4(7):1114-1120. Epub 2020 Aug 11.

Division of Laboratory Medicine, Coagulation Department of Clinical Chemistry and Pharmacology University and Regional Laboratories Region Skåne Malmö Sweden.

Background: Monitoring hemophilia treatment with extended half-life products is challenging for coagulation laboratories since factor assays may show substantial differences between results obtained with the one-stage assay (OSA) and the chromogenic substrate assay (CSA).

Objectives: The aim of this study was to evaluate and compare different factor assays and global coagulation methods.

Methods: Factor VIII (FVIII) and IX (FIX) activities and global assay parameters were analyzed in pre- and postinfusion samples (5 patients 2 samples/product/method). Read More

Biotechnol Lett 2021 Jan 1;43(1):143-152. Epub 2020 Nov 1.

Department of Clinical, Toxicological and Food Science Analysis, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.

Objective: To develop recombinant factor IX (FIX) variants with augmented clotting activity.

Results: We generated three new variants, FIX-YKALW, FIX-ALL and FIX-LLW, expressed in SK-Hep-1 cells and characterized in vitro and in vivo. FIX-YKALW showed the highest antigen expression level among the variants (2. Read More

Clin Med Insights Blood Disord 2020 6;13:2634853520962467. Epub 2020 Oct 6.

IPS-Especializada, Bogotá, Colombia.

Background: The appearance of inhibitory antibodies against antihemophilic factors is one of the most serious complications related to hemophilia.

Objective: The objective of this study was to identify variables and factors related to the development of inhibitory antibodies in a group of patients undergoing antihemophilic therapy in Colombia.

Methods: A case-control study in patients with hemophilia treated in Specialized Healthcare Provider Institutions (IPS-E) in 21 cities of Colombia of any age and with a diagnosis of inhibitory antibodies against factor VIII or IX during 2016. Read More

Haemophilia 2020 Nov 16;26(6):e291-e299. Epub 2020 Sep 16.

Sanofi Genzyme, Bridgewater, NJ, USA.

Introduction: Long-acting products are changing the haemophilia A treatment landscape by giving patients and caregivers treatment options with varying product attributes.

Aim: A discrete choice experiment (DCE) was used to elicit treatment attribute preferences among patients with haemophilia A and caregivers of children with haemophilia A.

Materials & Methods: A survey of sociodemographics and preferences was completed by an online panel of adult patients with haemophilia A and caregivers of children (<18 years) with haemophilia A. Read More

Haemophilia 2020 Nov 15;26(6):e272-e281. Epub 2020 Sep 15.

Paediatric Haemostasis and Thrombosis Unit, Department of Paediatrics, Paediatric Haemophilia Centre, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany.

Background: The worldwide pandemic spread of SARS-CoV-2 can lead to either respiratory infection or containment-associated isolation with possible higher impact on chronic diseases such as inherited bleeding disorders (IBD). The aim of the study was to evaluate the impact of COVID-19 on patients and caregivers of IBD patients regarding their concerns and worries related to own health, access to treatment and availability of factor concentrates and their experiences related to medical care.

Methods: Multicentre, cross-sectional study evaluating the impact of COVID-19 on mental health of IBD patients. Read More

Haemophilia 2020 Sep 25;26(5):898-906. Epub 2020 Aug 25.

Center for Bleeding Disorders and Coagulation, Careggi University Hospital, Firenze, Italy.

Introduction: Haemophilia (H) is frequently associated with a multifactorial reduction in bone mineral density (BDM), but little is known about possible differences between HA and HB according to their severity.

Aim: To evaluate the association between low bone mineral density (BMD), 25-hydroxyvitamin D [25(OH)D] concentrations and bone turnover markers in patients with HA and HB younger or older than 50 years.

Methods: In 78 patients <50 years and 33 patients >50 years with severe (S) or moderate (M) HA and HB, BMD was measured by dual-energy X-ray absorptiometry at femoral neck (FN) and lumbar spine and then correlated to annual bleeding rate (ABR), World Federation of Haemophilia orthopaedic joint scale (WFH score), 25(OH)D concentrations, parathyroid hormone (PTH), amino-terminal telopeptide of type 1 collagen (NTx), urinary pyridinolines, osteocalcin and bone-specific alkaline phosphatase. Read More