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Haemophilia 2022 Jun 29. Epub 2022 Jun 29.

Department of Medicine, Division of Hematology/Oncology, University of California San Diego, San Diego, California, USA.

Introduction: Persons with haemophilia (PWH) have a higher prevalence of hypertension compared to the general population, which cannot be explained entirely by the usual cardiovascular risk factors. Neutralizing antibodies (inhibitors) against clotting factors might have some relation to cardiovascular disease in PWH. However, whether inhibitors facilitate hypertension is unknown. Read More

Res Pract Thromb Haemost 2022 May 3;6(4):e12705. Epub 2022 Jun 3.

University of Southampton Southampton UK.

Background: Gene therapy shows promise as a potential "cure" for hemophilia A and B. Adeno-associated virus (AAV) vectors are the leading platform to deliver modified genetic code of factor VIII or IX to the liver effecting endogenous production. Patient exposure to wild-type AAV leads to the formation of neutralizing factors, which can prevent successful transduction. Read More

Front Immunol 2022 11;13:880829. Epub 2022 May 11.

Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta/Emory University School of Medicine, Atlanta, GA, United States.

Humoral immunity to factor VIII (FVIII) represents a significant challenge for the treatment of patients with hemophilia A. Current paradigms indicate that neutralizing antibodies against FVIII (inhibitors) occur through a classical CD4 T cell, germinal center (GC) dependent process. However, clinical observations suggest that the nature of the immune response to FVIII may differ between patients. Read More

Eur J Dent 2022 May 2. Epub 2022 May 2.

Department of Conservative Dentistry and Endodontics, Poznan University of Medical Sciences, Poznan, Poland.

Objectives:  The objective of our study was to assess the current knowledge, the oral health status, and the pro-health needs of patients with hemophilia.

Materials And Methods:  The study included 77 patients with known hemophilia. The study included the assessment of dental indicators related to caries incidence (decayed, missing, and filled teeth [DMFT] and decayed, missing, and filled permanent teeth or surfaces [DMFS]), caries treatment (treatment index), oral hygiene status (Approximal Plaque Index [API] and simplified oral hygiene index [OHI-S]), and periodontal status (bleeding on probing [BoP]). Read More

World Allergy Organ J 2022 Mar 7;15(3):100627. Epub 2022 Apr 7.

Department of Immunology, Barts Health NHS Trust, London, United Kingdom.

Hereditary Angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical. This revision and update of the global WAO/EAACI guideline on the diagnosis and management of HAE provides up-to-date guidance for the management of HAE. For this update and revision of the guideline, an international panel of experts reviewed the existing evidence, developed 28 recommendations, and established consensus by an online DELPHI process. Read More

J Matern Fetal Neonatal Med 2022 Apr 12:1-6. Epub 2022 Apr 12.

Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medicine/New York Presbyterian Hospital, New York, NY, USA.

Background: Pregnancy, peripartum management, and outcomes of mild hemophiliacs and hemophilia carriers in the United States are not well established.

Aim: To describe the management and outcomes of mild hemophiliacs and hemophilia carriers during assisted conception, pregnancy, peripartum and post-partum period at our hemophilia treatment center (HTC).

Methods: Retrospective review of electronic medical records of pregnant women with mild hemophilia A or B (Factor VIII [FVIII] or Factor IX [FIX] level <0. Read More

Blood Adv 2022 Apr 12. Epub 2022 Apr 12.

U.S. Food and Drug Administration, Silver Spring, Maryland, United States.

Hemophilia B is a blood clotting disorder caused by deficient activity of coagulation factor IX (FIX). Multiple recombinant FIX proteins are currently approved to treat hemophilia B and several gene therapy products are currently being developed. Codon optimization is a frequently used technique in the pharmaceutical industry to improve recombinant protein expression by recoding a coding sequence using multiple synonymous codon substitutions. Read More

Gac Med Mex 2022 ;158(1):11-15

Hematology Department, "Dr. Gaudencio González Garza" General Hospital, High Specialty Medical Unit, Centro Médico Nacional La Raza, Instituto Mexicano del Seguro Social, Mexico City, Mexico.

Background: Joint ultrasound examination using the HEAD-US method in the detection of early arthropathy is poorly studied in our country.

Objective: To compare the clinical and ultrasound evaluation of the joints in haemophilia.

Method: Longitudinal, prospective and descriptive study with paediatric patients with haemophilia A and B evaluated with the HJHS 2. Read More

Front Genome Ed 2022 11;4:785698. Epub 2022 Mar 11.

International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.

Many inborn errors of metabolism require life-long treatments and, in severe conditions involving the liver, organ transplantation remains the only curative treatment. Non-integrative AAV-mediated gene therapy has shown efficacy in adult patients. However, treatment in pediatric or juvenile settings, or in conditions associated with hepatocyte proliferation, may result in rapid loss of episomal viral DNA and thus therapeutic efficacy. Read More

Hemasphere 2022 Apr 21;6(4):e694. Epub 2022 Mar 21.

Center for Benign Haematology, Thrombosis and Haemostasis, Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Predicting individual effects of switching from standard half-life (SHL) to extended half-life (EHL) FVIII/FIX concentrates is pivotal in clinical care, but large-scale individual data are scarce. The aim of this study was to assess individual changes in terminal half-life (THL) after switching to EHL concentrates and identifying determinants of a clinically relevant THL extension in people with severe hemophilia. Data from participants with pharmacokinetic studies on both SHL and EHL were extracted from the Web-Accessible Population Pharmacokinetics Service (WAPPS) database and stratified according to hemophilia type and age groups (children/adults). Read More

Quant Imaging Med Surg 2022 Feb;12(2):886-893

Division of Haematology, Department of Medicine, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Szeged, Hungary.

Background: Hemophilia is an X-linked inherited disorder primarily affecting males, its major types are type A (deficiency in factor VIII) and B (deficiency in factor IX), and is considered to be the most common severe congenital coagulation factor deficiency. The present study was designed to test whether any differences in left ventricular (LV) rotational mechanics could be demonstrated between male patients with hemophilia and healthy controls using three-dimensional speckle-tracking echocardiography (3DSTE)-derived virtual LV models.

Methods: The present study consisted of 17 patients with hemophilia, however, 3 patients were excluded due to insufficient image quality. Read More

Haemophilia 2022 Mar 7;28(2):239-246. Epub 2022 Jan 7.

Van Creveldkliniek, University Medical Center, Utrecht, The Netherlands.

Aim: The aim of this study was to investigate if prophylactic treatment in severe haemophilia impact on bone mineral densisty (BMD) in adults with haemophilia A/B.

Methods: Subjects with haemophilia (n = 120) underwent bone-density measurement and clinical data was collected. BMD in subjects with severe haemophilia on high-dose prophylaxis (n = 41) was compared to BMD in subjects with mild haemophilia (n = 33) and to severe haemophilia treated with intermediate-dose prophylaxis (n = 32) or on-demand replacement therapy (n = 14). Read More

J Manag Care Spec Pharm 2022 Apr 27;28(4):449-460. Epub 2021 Dec 27.

Division of Hematology-Oncology, Boston Children's Hospital/Harvard Medical School, Boston, MA.

Standard of care for patients with severe hemophilia A (HA) is life-long prophylaxis with factor VIII (FVIII) concentrate or other hemostatic agents. Published literature highlights a wide range of treatment costs for patients with HA. To estimate average annual health care costs and resource utilization for a cross-section of adult patients managed with FVIII concentrate prophylaxis using recent data from a large US commercial claims database. Read More

Br J Oral Maxillofac Surg 2022 02 31;60(2):157-161. Epub 2021 Mar 31.

Department of Oral and Maxillofacial Surgery I of the School of Dentistry of Buenos Aires University, Marcelo T de Alvear 2142, C1122AAH, CABA, Argentina.

Haemophilia is a recessive congenital hereditary haemorrhagic disorder characterised by the decrease in, or absence of, the functional activity of factor VIII (Haemophilia A) or factor IX (Haemophilia B). The haematological medical treatment for these patients is systemic replacement therapy with factor VIII or factor IX concentrates. Dental implants are considered the gold standard for the replacement of missing teeth. Read More

Hematology Am Soc Hematol Educ Program 2021 12;2021(1):206-214

Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, University of Utah, Salt Lake City, UT.

The current mainstay of therapy for hemophilia is to replace the deficient clotting factor with the intravenous administration of exogenous clotting factor concentrates. Prophylaxis factor replacement therapy is now considered the standard of care in both pediatric and adult patients with hemophilia with a severe phenotype to protect musculoskeletal health and improve quality of life. Heterogeneity in bleeding presentation among patients with hemophilia due to genetic, environmental, and treatment-related factors has been well described. Read More

Appl Clin Genet 2021 23;14:445-454. Epub 2021 Nov 23.

Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA.

Hemophilia B (HB) is a bleeding disorder caused by deficiency of or defect in blood coagulation factor IX (FIX) inherited in an X-linked manner. It results from one of over 1000 known pathogenic variants in the FIX gene, ; missense and frameshift changes predominate. Although primarily males are affected with HB, heterozygous females may have excessive bleeding due to random or non-random X chromosome inactivation; in addition, homozygous, compound heterozygous, and hemizygous females have been reported. Read More

Blood Coagul Fibrinolysis 2022 Jan;33(Suppl 1):S12-S14

Banc de Sang iTeixits.

Von Willebrand disease (VWD) is the most frequent inherited bleeding disorder caused by quantitative or qualitative defects of von Willebrand factor (VWF). This protein far from simplicity constitutes a very complex molecular model, remaining unravelled yet many aspects of it, even though the VWF gene (VWF) was cloned already in 1985 and the structure of VWF well defined. VWD diagnosis is difficult to achieve in a significant proportion of patients due to both disease heterogeneity and limitations in existing test processes. Read More

Haemophilia 2022 Jan 10;28(1):91-96. Epub 2021 Nov 10.

Division of Haematology/Oncology, The Hospital for Sick Children, University of Toronto, Department of Nursing, Toronto, ON, Canada.

Introduction: The COVID-19 pandemic has resulted in lifestyle changes for children. The aim of this study was to evaluate the impact of the pandemic on weight/BMI in children with severe bleeding disorders.

Methods: We conducted a retrospective review of patients age 3-18 years with severe bleeding disorders on prophylactic therapy treated at SickKids Hospital (Toronto, Canada) between February 01, 2018 and March 31, 2021. Read More

Plast Reconstr Surg 2022 Jan;149(1):117-129

From the Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine.

Background: Gene therapy is a promising treatment for protein deficiency disorders such as hemophilia B. However, low tissue selectivity and efficacy are limitations of systemic vector delivery. The authors hypothesized that selective transfection of rat superficial inferior epigastric artery flaps could provide systemic delivery of coagulation factor IX, preventing the need for systemic vector administration. Read More

Haemophilia 2022 Jan 28;28(1):125-137. Epub 2021 Oct 28.

Institute of Haematology and Immunology, Havana, Cuba.

Introduction: In several countries, molecular diagnosis of haemophilia A (HA) and B (HB) is hampered by a lack of resources for DNA analysis. The advent of next-generation sequencing (NGS) has enabled gene analysis at a reasonable cost.

Aim: Describe a collaboration between Cuban and Spanish researchers to identify candidate variants and investigate the molecular epidemiology of 106 Cuban haemophilia patients using NGS. Read More

Blood Coagul Fibrinolysis 2021 Dec;32(8):584-590

Gene Therapy Center.

Subclinical bleeding is a haemorrhage event not clinically detected in haemophilia, and no reliable method is available for predicting subclinical bleeding. We investigated whether haemophilia mice have subclinical haemorrhage and evaluated potential biomarkers including multiple cytokine changes to predict subclinical haemorrhage. Plasma from naïve FVIII-/- and FIX-/- mice and their wild-type counterparts (FVIII WT and FIX WT, respectively) were measured for prothrombin fragment 1 + 2 (F1 + 2) and multiple cytokines. Read More

Hum Gene Ther 2022 02 6;33(3-4):119-130. Epub 2022 Jan 6.

Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Glucocorticoids have anti-inflammatory and immunosuppressive functions and have commonly been used for preventing liver toxicity after the systemic application of a high dose of adeno-associated virus (AAV) vector for gene therapy. Clinical studies have reported that glucocorticoids have rescued factor IX (FIX) expression in patients with hemophilia B who showed a reduced FIX expression at 6 to 10 weeks post-AAV vector administration. In this study, we explored whether glucocorticoids could affect transgene expression in AAV targeted livers in animal models. Read More

Thromb Haemost 2022 May 29;122(5):755-766. Epub 2021 Sep 29.

State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine at Shanghai, Pôle Sino-Français des Sciences du Vivant et Genomique, Collaborative Innovation Center of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Platelet-targeted FVIII gene therapy can efficiently recover bleeding phenotype for hemophilia A (HA), yet characteristics of thrombus formation with this ectopic expression of factor VIII (FVIII) in platelets remain unclear. Here, we generated 2bF8 mice restrictively expressing human B-domain-deleted FVIII (hBDD FVIII) in platelets on a hemophilic (FVIII) mice background. The results showed no statistical difference in clot strength and stability between wild-type (WT) and 2bF8 mice, but with a prolonged reaction time (R-time), by thromboelastography. Read More

Haemophilia 2021 Nov 29;27(6):1045-1050. Epub 2021 Sep 29.

American Thrombosis and Hemostasis Network, Rochester, New York, USA.

Background: Several studies have reported that haemophilia carriers have a bleeding tendency independent of factor activity. However, investigations have been fraught with methodological concerns. The ATHNdataset houses the largest data set of haemophilia carriers in the world. Read More

Blood Adv 2021 10;5(20):4314-4325

Department of Pediatric Hematology and Oncology, Erasmus MC Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands; and.

The accuracy of pharmacokinetic (PK)-guided dosing depends on the clinical and laboratory data used to construct a population PK model, as well as the patient's individual PK profile. This review provides a detailed overview of data used for published population PK models for factor VIII (FVIII) and factor IX (FIX) concentrates, to support physicians in their choices of which model best suits each patient. Furthermore, to enhance detailed data collection and documentation, we do suggestions for best practice. Read More

Zhonghua Kou Qiang Yi Xue Za Zhi 2021 Aug 9;56(8):785-790. Epub 2021 Aug 9.

National Center for Children's Health & Department of Hematology, Beijing Children's Hospital, Capital Medical University, Beijing 100045, China.

To provide clinical references for the diagnosis and treatment of hemophilic pseudotumor (HPT) in maxillofacial region. Fourteen cases of HPT in maxillofacial region from the Department of Stomatology, Beijing Children's Hospital from Jan 2009 to Jan 2019 were collected. Two cases were lost for follow-up and 12 patient,all boys, were finally followed up and included in the study. Read More

J Oral Maxillofac Res 2021 Apr-Jun;12(2):e1. Epub 2021 Jun 30.

Dental Implant Centre "Stilus Optimus", KaunasLithuania.

Objectives: The systematic literature review aims to assess patients' dental extraction with inherited bleeding disorders, to understand the type, dosage, and modality of administration of the haemostatic agents for safe intra- and postoperational results.

Material And Methods: The search was undertaken in MEDLINE (PubMed) databases and Cochrane library for articles published in English from 1 January, 2010 till 31 October, 2020. Before the full-text articles were considered, titles and abstracts were screened. Read More

Exp Ther Med 2021 Sep 14;22(3):995. Epub 2021 Jul 14.

Department of Pathophysiology, Morfo-Functional Sciences (II), Faculty of Medicine, 'Grigore T. Popa' University of Medicine and Pharmacy, 700115 Iasi, Romania.

Hemophilia is a hereditary coagulopathy caused by factor VIII (hemophilia type A) or by coagulation factor IX (hemophilia type B) dysfunction, characterized by an increased bleeding predisposition, which is either spontaneous or secondary to minimal trauma. Currently, hemophilia may also be considered an 'orthopedic' condition, due to the fact that it affects the musculoskeletal system of most hemophilic patients. In recent years, constant prophylaxis using coagulation factors has led to a significant improvement in the hemophilic patient's quality of life, by reducing both life-threatening hemorrhagic phenomena, as well as the occurrence of chronic complications. Read More

Haemophilia 2021 Sep 26;27(5):769-782. Epub 2021 Jul 26.

uniQure Inc, Lexington, Massachusetts, USA.

Introduction: Gene therapy has shown promise in clinical trials for patients with haemophilia, but patient preference studies have focused on factor replacement treatments.

Aim: We conducted a discrete choice experiment (DCE) to investigate the relative importance and differential preferences patients provide for gene therapy attributes.

Methods: We surveyed male adults with haemophilia in the United States recruited from patient panels including the National Hemophilia Foundation Community Voices in Research platform using an online survey over 4 months in 2020/21. Read More

Hum Genet 2021 Sep 26;140(9):1329-1342. Epub 2021 Jun 26.

i3S, Instituto de Investigação e Inovação em Saúde, Population Genetics and Evolution Group, Universidade do Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal.

A non-negligible proportion of human pathogenic variants are known to be present as wild type in at least some non-human mammalian species. The standard explanation for this finding is that molecular mechanisms of compensatory epistasis can alleviate the mutations' otherwise pathogenic effects. Examples of compensated variants have been described in the literature but the interacting residue(s) postulated to play a compensatory role have rarely been ascertained. Read More