697 results match your criteria Hemophilia Type B


Tissue factor pathway inhibitor is the main determinant of thrombin generation in haemophilic patients.

Haemophilia 2019 Jan 28. Epub 2019 Jan 28.

INSERM, U1059, SAINBIOSE, Université de Lyon, UJM-Saint-Etienne, Saint-Etienne, France.

The thrombin generation (TG) assay evaluates haemostatic balance, which is influenced by the levels of many coagulation factors and inhibitors. Our objective was to identify the determinant factors of TG in haemophilia A (HA) and haemophilia B (HB) patients and to compare them to those in healthy controls. Coagulation factor and inhibitor levels, and TG, were measured in platelet-poor plasma from 40 patients with HA, 32 patients with HB and 40 healthy subjects. Read More

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http://dx.doi.org/10.1111/hae.13679DOI Listing
January 2019
1 Read

Viral Vector-Based Delivery of CRISPR/Cas9 and Donor DNA for Homology-Directed Repair in an In Vitro Model for Canine Hemophilia B.

Mol Ther Nucleic Acids 2018 Dec 20;14:364-376. Epub 2018 Dec 20.

Institute for Virology and Microbiology, Center for Biomedical Education and Research (ZBAF), Department of Human Medicine, Faculty of Health, Witten/Herdecke University, 58453 Witten, Germany. Electronic address:

Gene therapy represents an attractive alternative to treat hemophilia B. Here we established three hepatocyte-derived cell lines based on Huh7, PLC/PRF/5, and Hep3B cells stably carrying a mutated canine FIX (cFIXmut) transgene containing a single point mutation in the catalytic domain. Based on these in vitro models resembling a commonly used canine large animal model, the tetracycline-controlled transcriptional activator (Tet-on)-inducible CRISPR/Cas9 system and an optimized donor were used to correct mutated cFIX gene through homology-directed repair (HDR). Read More

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http://dx.doi.org/10.1016/j.omtn.2018.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356096PMC
December 2018
1 Read

Comparative accuracy of optical sensor-based wearable system for non-invasive measurement of blood glucose concentration.

Clin Biochem 2019 Jan 7. Epub 2019 Jan 7.

Maale Carmel Mental Health Center Affiliated to Bruce Rappaport Medical Faculty, Technion, Tirat Carmel, Israel.

Non-invasive biosensors for indirect evaluation of routinely-measured blood components by sweat analysis have broad potential clinical applications. This trial tested a wrist-borne non-invasive glucose monitor (NIGM) to measure blood glucose (BG) levels using photoplethysmographic (PPG) optical sensors. Our aim was to determine the accuracy of the device in comparison with a standard, invasive clinical method for blood glucose monitoring. Read More

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http://dx.doi.org/10.1016/j.clinbiochem.2018.12.014DOI Listing
January 2019
7 Reads

AAV8 Gene Therapy for Crigler-Najjar Syndrome in Macaques Elicited Transgene T Cell Responses That Are Resident to the Liver.

Mol Ther Methods Clin Dev 2018 Dec 5;11:191-201. Epub 2018 Dec 5.

Gene Therapy Program, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Systemic delivery of adeno-associated viral (AAV) vectors has been evaluated for the treatment of several liver diseases, including homozygous familial hypercholesterolemia, ornithine transcarbamylase deficiency, and hemophilia. Here, we evaluated this approach for the treatment of Crigler-Najjar syndrome. We administered wild-type rhesus macaques with 1. Read More

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http://dx.doi.org/10.1016/j.omtm.2018.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282099PMC
December 2018
2 Reads

Factor VIII with a 237 amino acid B-domain has an extended half-life in F8-knockout mice.

J Thromb Haemost 2019 Feb 25;17(2):350-360. Epub 2019 Jan 25.

Novo Nordisk A/S, Novo Nordisk Park, Måløv, Denmark.

Essentials Factor (F)VIII with an intermediate-length B-domain showed higher levels in murine gene therapy. FVIII with different B-domain lengths were analysed. FVIII variants with B-domains between 186 and 240 amino acids (aa) have extended half-life in mice. Read More

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http://dx.doi.org/10.1111/jth.14355DOI Listing
February 2019
1 Read

Potential limits of AAV-based gene therapy with the use of new transgenes expressing factor IX fusion proteins.

Haemophilia 2019 Jan 6;25(1):e11-e18. Epub 2018 Dec 6.

Research Department of Haematology, University of London Cancer Institute, London, UK.

Introduction: The variety of treatment for haemophilia B (HB) has recently improved with the emergence of both AAV-based gene therapy and bioengineered human factor IX (hFIX) molecules with prolonged half-life due to fusion to either albumin (Alb) or immunoglobulin Fc fragment (Fc).

Aim: Adeno-associated viral vectors (AAV) mediating expression of hFIX-Alb and hFIX-Fc fusion proteins was investigated for gene therapy of HB to explore if their extended half-life translates to higher plasma levels of FIX.

Methods: Single-stranded cross-packaged AAV2/8 vectors expressing hFIX-Alb, hFIX-Fc and hFIX were evaluated in vitro, and in mice. Read More

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http://dx.doi.org/10.1111/hae.13651DOI Listing
January 2019
2 Reads

Fusion of Factor IX to Factor XIII-B Sub-Unit Improves the Pharmacokinetic Profile of Factor IX.

Thromb Haemost 2018 Dec 19;118(12):2053-2063. Epub 2018 Nov 19.

EA4609-Hemostase et Cancer, Universite Claude Bernard Lyon I, Lyon, France.

Prophylaxis is currently considered the optimal care for severe haemophilia. For patients and their families one of the major difficulties with prophylaxis is the need for frequent venipunctures. The half-life of standard factor IX (FIX) concentrates is approximately 18 hours, which requires 2 or 3 intravenous infusions per week to achieve bleeding prevention in patients with severe haemophilia B. Read More

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http://www.thieme-connect.de/DOI/DOI?10.1055/s-0038-1675787
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http://dx.doi.org/10.1055/s-0038-1675787DOI Listing
December 2018
10 Reads

Paired CRISPR/Cas9 Nickases Mediate Efficient Site-Specific Integration of into rDNA Locus of Mouse ESCs.

Int J Mol Sci 2018 Oct 5;19(10). Epub 2018 Oct 5.

Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410000, China.

Hemophilia B (HB) is an X-linked recessive bleeding disorder, caused by gene deficiency. Gene therapy combined with the CRISPR/Cas9 technology offers a potential cure for hemophilia B. Now the Cas9 nickase (Cas9n) shows a great advantage in reducing off-target effect compared with wild-type Cas9. Read More

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http://www.mdpi.com/1422-0067/19/10/3035
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http://dx.doi.org/10.3390/ijms19103035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213315PMC
October 2018
4 Reads

Impact of Exercise/Sport on Well-being in Congenital Bleeding Disorders.

Semin Thromb Hemost 2018 Nov 4;44(8):796-801. Epub 2018 Oct 4.

Unità Operativa Complessa Medicina Trasfusionale, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.

Physical activity provides many benefits in patients with congenital bleeding disorders. Patients with hemophilia are encouraged to participate in exercise and sports, especially those patients receiving prophylaxis. Several publications and guidelines have explored this issue in hemophilia patients, evaluating in particular the impact of physical activity on patients' well-being and quality of life. Read More

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http://www.thieme-connect.de/DOI/DOI?10.1055/s-0038-1673628
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http://dx.doi.org/10.1055/s-0038-1673628DOI Listing
November 2018
12 Reads

The elevated prevalence of risk factors for chronic liver disease among ageing people with hemophilia and implications for treatment.

Medicine (Baltimore) 2018 Sep;97(39):e12551

Department of Haematology, Oslo University Hospital.

Chronic liver disease (CLD) is frequently seen in the hemophilia population. The ADVANCE Working Group conducted a cross-sectional study in which people with hemophilia (PWH) aged ≥40 years were included. This study aimed to assess the associations between CLD and its risk factors using data from the H3 study, and to suggest implications for optimal care. Read More

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http://Insights.ovid.com/crossref?an=00005792-201809280-0007
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http://dx.doi.org/10.1097/MD.0000000000012551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6181599PMC
September 2018
2 Reads

Long-Term Outcome after Joint Bleeds in Von Willebrand Disease Compared to Haemophilia A: A Post Hoc Analysis.

Thromb Haemost 2018 Oct 1;118(10):1690-1700. Epub 2018 Oct 1.

Department of Epidemiology, Van Creveldkliniek and Julius Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Long-term outcome after joint bleeds in von Willebrand disease (VWD) (von Willebrand factor activity ≤ 30 IU/dL) could differ from moderate or severe haemophilia A (HA) (factor VIII [FVIII] 1-5 IU/dL or FVIII < 1 IU/dL). We performed a post hoc analysis on Haemophilia Joint Health Score (HJHS, 0-124), X-ray Pettersson scores (PS, 0-13/joint) and the Haemophilia Activities List (HAL, 0-100), using multivariable regression to adjust for age (rate ratio [RR] or odds ratio [OR] [95% confidence interval]). We included 48 VWD (median age, 47 years, type 3 VWD,  = 19), 39 moderate HA (median, 39 years) and 59 severe HA patients (median, 25 years) with documented joint bleeds. Read More

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http://dx.doi.org/10.1055/s-0038-1670704DOI Listing
October 2018
9 Reads

Anti-ADAMTS13 Autoantibodies against Cryptic Epitopes in Immune-Mediated Thrombotic Thrombocytopenic Purpura.

Thromb Haemost 2018 Oct 20;118(10):1729-1742. Epub 2018 Sep 20.

Laboratory for Thrombosis Research, IRF Life Sciences, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by severe ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13) deficiency, the presence of anti-ADAMTS13 autoantibodies and an open ADAMTS13 conformation with a cryptic epitope in the spacer domain exposed. A detailed knowledge of anti-ADAMTS13 autoantibodies will help identifying pathogenic antibodies and elucidating the cause of ADAMTS13 deficiency. We aimed at cloning anti-ADAMTS13 autoantibodies from iTTP patients to study their epitopes and inhibitory characteristics. Read More

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http://dx.doi.org/10.1055/s-0038-1669459DOI Listing
October 2018
14 Reads

The frequency of joint hemorrhages and procedures in nonsevere hemophilia A vs B.

Blood Adv 2018 Aug;2(16):2136-2144

Department of Medicine, University of Minnesota, Minneapolis, MN.

Data are needed on minimal factor activity (FA) levels required to prevent bleeding in hemophilia. We aimed to evaluate associations between hemophilia type and FA level and joint bleeding and orthopedic procedures using longitudinal data. Data were collected over an 11-year period on males with nonsevere hemophilia A or B without inhibitors who were receiving on-demand factor replacement therapy. Read More

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http://dx.doi.org/10.1182/bloodadvances.2018020552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113607PMC
August 2018
5 Reads

Optimizing outcome measurement with murine ferric chloride-induced thrombosis.

Blood Coagul Fibrinolysis 2018 Nov;29(7):636-643

McAllister Heart Institute.

: The murine FeCl3 model is a widely used model for studying arterial thrombosis, yet provides limited information from each mouse, often only a single time point for the onset of occlusion (defined as the time to occlusion; TTO). To optimize data from the murine ferric chloride model of thrombosis. FeCl3 injury was induced in the carotid arteries of wild-type and Factor IX (FIX) knockout mice, with infusion of recombinant FIX (rFIX) to normalize FIX deficiency at various times around FeCl3 injury. Read More

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http://dx.doi.org/10.1097/MBC.0000000000000768DOI Listing
November 2018
12 Reads

Novel assays in the coagulation laboratory: a clinical and laboratory perspective.

Transfus Apher Sci 2018 Aug 20;57(4):480-484. Epub 2018 Jul 20.

University of Toronto, Department of Medicine, Toronto, Canada; St. Michael's Hospital Hemostasis and Thrombosis Laboratory, Toronto, Canada; Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada.

The ability to monitor Factor VIII (FVIII) and Factor IX (FIX) levels is integral to the clinical management of hemophilia A and B patients, respectively. Factor activity levels are checked during regular follow-up, post-infusion of factor concentrates, during pre- and post-operative assessments, and when the presence of an inhibitor is suspected. However, the ability to accurately and reproducibly measure factor activity levels with standard coagulation assays has been challenging due to the emergence of recombinant factor concentrates with extended half-lives. Read More

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http://dx.doi.org/10.1016/j.transci.2018.07.008DOI Listing
August 2018
39 Reads

Real-world comparative analysis of bleeding complications and health-related quality of life in patients with haemophilia A and haemophilia B.

Haemophilia 2018 Sep 9;24(5):e322-e327. Epub 2018 Aug 9.

Irish Haemophilia Society, Dublin, Ireland.

Introduction: Clinical severity and impact of haemophilia on quality of life have been generally considered to be lower for haemophilia B (HB) compared with haemophilia A (HA) patients.

Aims: To compare annual bleeding rate (ABR), target joint development and health-related quality of life (HRQoL) between adult (≥18 years) severe HA and HB patients using recent data from the Cost of Haemophilia in Europe: a Socioeconomic Survey (CHESS) study.

Methods: Multivariate generalized linear models (GLM) were constructed to assess the relationship between haemophilia type, ABR, HRQoL (derived from EQ-5D index scores) and the presence of target joints while controlling for covariates. Read More

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http://dx.doi.org/10.1111/hae.13596DOI Listing
September 2018

Effect of ABO blood group on haemostatic parameters in severe haemophilia A patients performing acute moderate-intensity exercise.

Blood Coagul Fibrinolysis 2018 Nov;29(7):626-635

CHU Sainte-Justine.

: The primary objective was to assess the effect of ABO blood group on von Willebrand factor (VWF) rise induced by four bouts of moderate-intensity physical activity, on pharmacokinetics of a B-domain-deleted recombinant FVIII (BDD-rFVIII), and haemostatic parameters in severe haemophilia A patients with a null mutation. The secondary objective was to compare the response to exercise according to infused product type in a subgroup of patients who previously participated to the same exercise protocol, while treated with a full length recombinant FVIII (FL-rFVIII). Twenty patients had two visits (rest and exercise). Read More

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http://dx.doi.org/10.1097/MBC.0000000000000762DOI Listing
November 2018
2 Reads

Evaluation of early musculoskeletal disease in patients with haemophilia: results from an expert consensus.

Blood Coagul Fibrinolysis 2018 Sep;29(6):509-520

Van Creveldkliniek, UMC, Utrecht, the Netherlands.

: Early joint damage in patients with haemarthrosis often escapes diagnosis because of insufficient investigation of biomechanical changes. Arthropathy in haemophilia requires complex assessment with several tools. Considering the increased emphasis on an integrated approach to musculoskeletal (MSK) outcomes, re-evaluation of MSK assessment to address individual patient needs is warranted. Read More

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http://Insights.ovid.com/crossref?an=00001721-201809000-0000
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http://dx.doi.org/10.1097/MBC.0000000000000767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125749PMC
September 2018
5 Reads

Factor XI promotes hemostasis in factor IX-deficient mice.

J Thromb Haemost 2018 Oct 16;16(10):2044-2049. Epub 2018 Aug 16.

Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.

Essentials Mice lacking factor IX (FIX) or factor XI (FXI) were tested in a saphenous vein bleeding model. FIX-deficient mice displayed a hemostatic defect and FXI-deficient mice were similar to wild type mice. Infusion of FXI or over-expression of FXI in FIX-deficient mice improved hemostasis. Read More

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http://dx.doi.org/10.1111/jth.14243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173617PMC
October 2018
6 Reads

The chaperone-like sodium phenylbutyrate improves factor IX intracellular trafficking and activity impaired by the frequent p.R294Q mutation.

J Thromb Haemost 2018 Oct 9;16(10):2035-2043. Epub 2018 Aug 9.

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

Essentials Missense mutations often impair protein folding, and thus intracellular trafficking and secretion. Cellular models of severe type I hemophilia B were challenged with chaperone-like compounds. Sodium phenylbutyrate improved intracellular trafficking and secretion of the frequent p. Read More

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http://dx.doi.org/10.1111/jth.14236DOI Listing
October 2018
5 Reads

Advantages, disadvantages and optimization of one-stage and chromogenic factor activity assays in haemophilia A and B.

Int J Lab Hematol 2018 Dec 6;40(6):621-629. Epub 2018 Jul 6.

Department of Pathology, University of New Mexico, Albuquerque, NM, USA.

Haemophilia A and B diagnosis and disease severity classification are determined on the basis of results from factor VIII (FVIII) and factor FIX (FIX) activity assays, respectively. These assays are also used for potency labelling, postinfusion monitoring of factor replacement products and testing for FVIII/FIX inhibitors. This review focuses on activated partial thromboplastin time (APTT)-based one-stage assays (OSAs) and two-stage chromogenic substrate assays (CSAs). Read More

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http://dx.doi.org/10.1111/ijlh.12877DOI Listing
December 2018
20 Reads

Coagulation factor 9-deficient mice are protected against dextran sulfate sodium-induced colitis.

Biol Open 2018 Jul 25;7(7). Epub 2018 Jul 25.

Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany

Patients with inflammatory bowel disease (IBD) are susceptible to thromboembolism. Interestingly, IBD occurs less frequently in patients with inherited bleeding disorders. Therefore, we analyzed whether -deficiency is protective against the onset of acute colitis in a genetic hemophilia B mouse model. Read More

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http://dx.doi.org/10.1242/bio.034140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6078354PMC
July 2018
6 Reads

Relevance of Abusive Head Trauma to Intracranial Hemorrhages and Bleeding Disorders.

Pediatrics 2018 May;141(5)

Blood Disorders, Centers for Disease Control and Prevention, Atlanta, Georgia.

Background: Bleeding disorders and abusive head trauma (AHT) are associated with intracranial hemorrhage (ICH), including subdural hemorrhage (SDH). Because both conditions often present in young children, the need to screen for bleeding disorders would be better informed by data that include trauma history and are specific to young children. The Universal Data Collection database contains information on ICH in subjects with bleeding disorders, including age and trauma history. Read More

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http://dx.doi.org/10.1542/peds.2017-3485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985662PMC
May 2018
6 Reads

Acquired von Willebrand Disease Associated with Mantle Cell Lymphoma.

Case Rep Hematol 2018 30;2018:7973297. Epub 2018 Jan 30.

Department of Hematology, Radboud University Medical Center, Nijmegen, Netherlands.

We present a rare case of acquired von Willebrand syndrome (AVWS) caused by a mantle cell lymphoma. A 61-year-old male suffered from recurrent bleeding symptoms since a few months. Initially, physical examination was normal. Read More

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http://dx.doi.org/10.1155/2018/7973297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830951PMC
January 2018
8 Reads

Human iPS Cell-based Liver-like Tissue Engineering at Extrahepatic Sites in Mice as a New Cell Therapy for Hemophilia B.

Cell Transplant 2018 02;27(2):299-309

1 Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.

Instead of liver transplantation or liver-directed gene therapy, genetic liver diseases are expected to be treated effectively using liver tissue engineering technology. Hepatocyte-like cells (HLCs) generated from human-induced pluripotent stem (iPS) cells are an attractive unlimited cell source for liver-like tissue engineering. In this study, we attempted to show the effectiveness of human iPS cell-based liver-like tissue engineering at an extrahepatic site for treatment of hemophilia B, also called factor IX (FIX) deficiency. Read More

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http://journals.sagepub.com/doi/full/10.1177/096368971775173
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http://dx.doi.org/10.1177/0963689717751734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5898695PMC
February 2018
6 Reads

Designer nuclease-mediated gene correction via homology-directed repair in an in vitro model of canine hemophilia B.

J Gene Med 2018 May 3;20(5):e3020. Epub 2018 May 3.

Institute of Virology and Microbiology, Center for Biomedical Education and Research (ZBAF), Department of Human Medicine, Faculty of Health, Witten/Herdecke University, Witten, Germany.

Background: Gene correction at specific target loci provides a powerful strategy for overcoming genetic diseases. In the present study, we aimed to use an in vitro model for canine hemophilia B containing a single point mutation in the catalytic domain of the canine coagulation factor IX (cFIX) gene. To correct the defective gene via homology-directed repair (HDR), we designed transcription-activator like effector nucleases and clustered regularly interspaced short palindromic repeats including Cas9 (CRISPR/Cas9) for introduction of double-strand breaks at the mutation site. Read More

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http://dx.doi.org/10.1002/jgm.3020DOI Listing
May 2018
5 Reads

In Utero Transplantation of Placenta-Derived Mesenchymal Stromal Cells for Potential Fetal Treatment of Hemophilia A.

Cell Transplant 2018 01;27(1):130-139

1 Department of Surgery, Surgical Bioengineering Laboratory, UC Davis School of Medicine, Research II, University of California, Davis, Sacramento, CA, USA.

Hemophilia A (HA) is an X-linked recessive disorder caused by mutations in the factor VIII ( FVIII) gene leading to deficient blood coagulation. The current standard of care is frequent infusions of plasma-derived FVIII or recombinant B-domain-deleted FVIII (BDD-FVIII). While this treatment is effective, many patients eventually develop FVIII inhibitors that limit the effectiveness of the infused FVIII. Read More

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http://dx.doi.org/10.1177/0963689717728937DOI Listing
January 2018
7 Reads

Factor Xa and VIIa inhibition by tissue factor pathway inhibitor is prevented by a monoclonal antibody to its Kunitz-1 domain.

J Thromb Haemost 2018 May 6;16(5):893-904. Epub 2018 Apr 6.

Global Research, Novo Nordisk A/S, Måløv, Denmark.

Essentials Activated FVII (FVIIa) and FX (FXa) are inhibited by tissue factor pathway inhibitor (TFPI). A monoclonal antibody, mAb2F22, was raised against the N-terminal fragment of TFPI (1-79). mAb2F22 bound exclusively to the K1 domain of TFPI (K ∼1 nm) and not to the K2 domain. Read More

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http://dx.doi.org/10.1111/jth.14000DOI Listing
May 2018
2 Reads

Suppressive Role of Tissue Factor Pathway Inhibitor-α in Platelet-Dependent Fibrin Formation under Flow Is Restricted to Low Procoagulant Strength.

Thromb Haemost 2018 03 16;118(3):502-513. Epub 2018 Feb 16.

Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.

Tissue factor pathway inhibitor-alpha (TFPI-α) is a Kunitz-type serine protease inhibitor, which suppresses coagulation by inhibiting the tissue factor (TF)/factor VIIa complex as well as factor Xa. In static plasma-phospholipid systems, TFPI-α thus suppresses both factor Xa and thrombin generation. In this article, we used a microfluidics approach to investigate how TFPI-α regulates fibrin clot formation in platelet thrombi at low wall shear rate. Read More

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http://dx.doi.org/10.1055/s-0038-1627453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880031PMC
March 2018
8 Reads

FVIII proteins with a modified immunodominant T-cell epitope exhibit reduced immunogenicity and normal FVIII activity.

Blood Adv 2018 02;2(4):309-322

Bloodworks Northwest Research Institute, Seattle, WA.

Factor VIII (FVIII)-neutralizing antibodies (inhibitors) are a serious complication in hemophilia A (HA). The peptide FVIII contains an immunodominant HLA-DRA*01-DRB1*01:01 (DRB1*01:01)-restricted epitope recognized by CD4 T-effector cells from HA subjects. The aim of this study was to identify amino acid substitutions to deimmunize this epitope while retaining procoagulant function and expression levels comparable to those of wild-type (WT) FVIII proteins. Read More

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http://dx.doi.org/10.1182/bloodadvances.2017013482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5858479PMC
February 2018
10 Reads

Molecular mechanisms of missense mutations that generate ectopic N-glycosylation sites in coagulation factor VIII.

Biochem J 2018 03 6;475(5):873-886. Epub 2018 Mar 6.

Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute, Cleveland, OH, U.S.A.

N-glycosylation is a common posttranslational modification of secreted and membrane proteins, catalyzed by the two enzymatic isoforms of the oligosaccharyltransferase, STT3A and STT3B. Missense mutations are the most common mutations in inherited diseases; however, missense mutations that generate extra, non-native N-glycosylation sites have not been well characterized. Coagulation factor VIII (FVIII) contains five consensus N-glycosylation sites outside its functionally dispensable B domain. Read More

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http://dx.doi.org/10.1042/BCJ20170884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5957299PMC
March 2018
9 Reads
4.400 Impact Factor

Anticoagulant Protein S Targets the Factor IXa Heparin-Binding Exosite to Prevent Thrombosis.

Arterioscler Thromb Vasc Biol 2018 04 1;38(4):816-828. Epub 2018 Feb 1.

From the Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, New Orleans (W.E.P., V.S.S.P., R.C., R.M.); Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill (B.C.C., T.G., D.P., W.B.); and Department of Medicine/Hematology-Oncology, University of Wisconsin School of Medicine and Public Health, Madison (P.R.W., J.P.S.).

Objective: PS (protein S) is a plasma protein that directly inhibits the coagulation FIXa (factor IXa) in vitro. Because elevated FIXa is associated with increased risk of venous thromboembolism, it is important to establish how PS inhibits FIXa function in vivo. The goal of this study is to confirm direct binding of PS with FIXa in vivo, identify FIXa amino acid residues required for binding PS in vivo, and use an enzymatically active FIXa mutant that is unable to bind PS to measure the significance of PS-FIXa interaction in hemostasis. Read More

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http://dx.doi.org/10.1161/ATVBAHA.117.310588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5982114PMC
April 2018
9 Reads

Secretion of wild-type factor IX upon readthrough over F9 pre-peptide nonsense mutations causing hemophilia B.

Hum Mutat 2018 05 17;39(5):702-708. Epub 2018 Feb 17.

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

Pre-peptide regions of secreted proteins display wide sequence variability, even among highly homologous proteins such as coagulation factors, and are intracellularly removed, thus potentially favoring secretion of wild-type proteins upon suppression of nonsense mutations (translational readthrough). As models we selected F9 nonsense mutations with readthrough-favorable features affecting the pre-peptide and pro-peptide regions of coagulation factor IX (FIX), which cause hemophilia B (HB). Only the p. Read More

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http://dx.doi.org/10.1002/humu.23404DOI Listing
May 2018
15 Reads

Management of Hemophilic Cysts and Pseudotumors of the Hand in Bleeding Disorders: A Case Series.

J Hand Surg Am 2018 May 18;43(5):486.e1-486.e9. Epub 2017 Dec 18.

Department of Hematology, Christian Medical College & Hospital, Vellore, Tamil Nadu, India.

Purpose: Hemophilic cysts and pseudotumors (HCPTs) of the hand are rare and are secondary to bleeding disorders such as hemophilia A and B. This is a report of our experience in the management of this rare condition.

Patients And Methods: Seven male patients with hemophilia A presenting with progressive swelling of the hand were treated between 2004 and 2013 at a tertiary referral hospital. Read More

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http://dx.doi.org/10.1016/j.jhsa.2017.10.035DOI Listing
May 2018
7 Reads

Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B.

Blood 2018 Mar 15;131(9):1022-1031. Epub 2017 Dec 15.

Erasmus University Medical Centre, Rotterdam, The Netherlands.

Gene therapy for hemophilia B aims to ameliorate bleeding risk and provide endogenous factor IX (FIX) activity/synthesis through a single treatment, eliminating the requirement for FIX concentrate. AMT-060 combines an adeno-associated virus-5 (AAV5) vector with a liver-specific promoter driving expression of a codon-optimized wild-type human FIX gene. This multinational, open-label study included 10 adults with hemophilia B (FIX ≤2% of normal) and severe-bleeding phenotype. Read More

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http://dx.doi.org/10.1182/blood-2017-09-804419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833265PMC
March 2018
25 Reads

Evaluation of bone mineral density (BMD) and indicators of bone turnover in patients with hemophilia.

Bosn J Basic Med Sci 2018 May 20;18(2):206-210. Epub 2018 May 20.

Department of Internal Medicine, Faculty of Medicine, Selcuk University, Konya, Turkey.

A decrease in bone mass is observed in hemophilic patients. The aim of this study was to evaluate bone mineral density (BMD), parathyroid hormone (PTH), 25-hydroxy vitamin D (vitamin D), and a bone formation and resorption marker, procollagen type I N-terminal propeptide (PINP) and urinary N-terminal telopeptide (uNTX) respectively, in hemophilic patients and healthy controls. Laboratory parameters related to the pathogenesis of bone loss such as neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) were also evaluated. Read More

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http://dx.doi.org/10.17305/bjbms.2018.2335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988541PMC
May 2018
5 Reads

[Dermatologic surgery, hemophilia and Von Willebrand disease].

Ann Dermatol Venereol 2018 Apr 14;145(4):233-239. Epub 2017 Nov 14.

Service de dermatologie, centre Tarnier, hôpital Cochin, AP-HP, 89, avenue d'Assas, 75006 Paris, France; Université Paris 5, 15, rue de l'École-de-Médecine, 75006 Paris, France. Electronic address:

Background: Von Willebrand disease (VWD) and hemophilia A and B are the most common types of hereditary coagulation-factor deficiencies. The frequency and type of complications of skin surgery in these patients are unknown. The increasing incidence of skin cancer prompted us to reflect upon this issue. Read More

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http://dx.doi.org/10.1016/j.annder.2017.10.009DOI Listing
April 2018
5 Reads

European guidelines on perioperative venous thromboembolism prophylaxis: Patients with preexisting coagulation disorders and after severe perioperative bleeding.

Eur J Anaesthesiol 2018 Feb;35(2):96-107

From the Department of Anaesthesia, Glenfield Hospital, University Hospitals of Leicester NHS Trust, Leicester, UK (AA), Sigmund Freud Private University and Department of Anaesthesia and Intensive Care, Evangelical Hospital Vienna, Vienna, Austria (SKL), Université catholique de Louvain, CHU UCLNamur, Namur Thrombosis and Hemostasis Center, Namur, Belgium (FM), Department of Clinical Haematology, Oxford University Hospitals, Oxford, UK (SP), and Division of Haematology, Haemostasis and Thrombosis Unit and Haemophilia Centre of Saint-Luc University Hospital, Bruxelles, Belgium (CH).

: In patients with inherited bleeding disorders undergoing surgery, we recommend assessment of individual risk for venous thromboembolism, taking into account the nature of the surgery and anaesthetic, type and severity of bleeding disorder, age, BMI, history of thrombosis, the presence of malignancy and other high-risk comorbidities. Venous thromboembolism risk should be balanced against the increased bleeding risk associated with anticoagulant use in patients with known bleeding disorders (Grade 1C). In these patients undergoing major surgery, we recommend against routine postoperative use of pharmacological thromboprophylaxis, especially for patients with haemophilia A and B (Grade 1B). Read More

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http://dx.doi.org/10.1097/EJA.0000000000000725DOI Listing
February 2018
24 Reads

Engineering of a membrane-triggered activity switch in coagulation factor VIIa.

Proc Natl Acad Sci U S A 2017 11 6;114(47):12454-12459. Epub 2017 Nov 6.

Global Research, Novo Nordisk A/S, DK-2760 Maaloev, Denmark;

Recombinant factor VIIa (FVIIa) variants with increased activity offer the promise to improve the treatment of bleeding episodes in patients with inhibitor-complicated hemophilia. Here, an approach was adopted to enhance the activity of FVIIa by selectively optimizing substrate turnover at the membrane surface. Under physiological conditions, endogenous FVIIa engages its cell-localized cofactor tissue factor (TF), which stimulates activity through membrane-dependent substrate recognition and allosteric effects. Read More

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http://dx.doi.org/10.1073/pnas.1618713114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5703266PMC
November 2017
16 Reads

Long-term results of total elbow arthroplasty in patients with hemophilia.

J Shoulder Elbow Surg 2018 Jan 3;27(1):126-132. Epub 2017 Nov 3.

Department of Orthopedics, Balgrist University Hospital, University of Zürich, Zürich, Switzerland.

Hypothesis: It was hypothesized that the long-term survivorship and clinical outcome are reasonable, justifying total elbow arthroplasty (TEA) in patients with end-stage hemophilic arthropathy.

Methods: From 2002 to 2012, 13 primary TEAs (Coonrad-Morrey design) were implanted in 9 consecutive patients with an average age of 55 (range, 39-76) years. Type A hemophilia was diagnosed in 7 patients and type B hemophilia in 2 patients. Read More

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http://dx.doi.org/10.1016/j.jse.2017.09.009DOI Listing
January 2018
9 Reads

Surgical Management of Haemophilic Pseudotumors: Experience in a Developing Country.

J Invest Surg 2017 Nov 2:1-10. Epub 2017 Nov 2.

a Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College , Department of Orthopaedics , Beijing , China.

Aim: Hemophilic pseudotumors result from repeated episodes of bleeding into bone, subperiosteum, and soft tissue. Since clotting factors became available, uncontrolled perioperative bleeding is a less significant problem for surgeons in developed countries. However, they are more difficult to come by in China. Read More

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http://dx.doi.org/10.1080/08941939.2017.1386737DOI Listing
November 2017
11 Reads

Human Tregs Made Antigen Specific by Gene Modification: The Power to Treat Autoimmunity and Antidrug Antibodies with Precision.

Front Immunol 2017 21;8:1117. Epub 2017 Sep 21.

Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, United States.

Human regulatory CD4 T cells (Tregs) are potent immunosuppressive lymphocytes responsible for immune tolerance and homeostasis. Since the seminal reports identifying Tregs, vast research has been channeled into understanding their genesis, signature molecular markers, mechanisms of suppression, and role in disease. This research has opened the doors for Tregs as a potential therapeutic for diseases and disorders such as multiple sclerosis, type I diabetes, transplantation, and immune responses to protein therapeutics, like factor VIII. Read More

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http://dx.doi.org/10.3389/fimmu.2017.01117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5613123PMC
September 2017
89 Reads

Long-term correction of hemophilia A mice following lentiviral mediated delivery of an optimized canine factor VIII gene.

Gene Ther 2017 11 14;24(11):742-748. Epub 2017 Sep 14.

Stead Family Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.

Current therapies for hemophilia A include frequent prophylactic or on-demand intravenous factor treatments which are costly, inconvenient and may lead to inhibitor formation. Viral vector delivery of factor VIII (FVIII) cDNA has the potential to alleviate the debilitating clotting defects. Lentiviral-based vectors delivered to murine models of hemophilia A mediate phenotypic correction. Read More

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http://www.nature.com/doifinder/10.1038/gt.2017.67
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http://dx.doi.org/10.1038/gt.2017.67DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5937993PMC
November 2017
15 Reads

Advanced cell-based modeling of the royal disease: characterization of the mutated F9 mRNA.

J Thromb Haemost 2017 11 25;15(11):2188-2197. Epub 2017 Sep 25.

Gene and Cell Therapy Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.

Essentials The Royal disease (RD) is a form of hemophilia B predicted to be caused by a splicing mutation. We generated an iPSC-based model of the disease allowing mechanistic studies at the RNA level. F9 mRNA analysis in iPSC-derived hepatocyte-like cells showed the predicted abnormal splicing. Read More

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http://dx.doi.org/10.1111/jth.13808DOI Listing
November 2017
7 Reads

Prophylaxis use among males with haemophilia B in the United States.

Haemophilia 2017 Nov 6;23(6):910-917. Epub 2017 Aug 6.

Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, CDC, Atlanta, GA, USA.

Introduction: Prophylaxis is considered the optimal treatment for persons with moderate to severe haemophilia (factor activity between 1-5% of normal and <1% of normal respectively) in countries where safe factor concentrates are available and economically feasible. Historically, prophylactic treatment has not been well studied in the haemophilia B (HB) population due to difficulties in obtaining a sufficiently large sample.

Aim: This study examines the prevalence of prophylaxis use among a robust sample of persons with HB in the United States and its association with specific demographic and clinical characteristics. Read More

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http://dx.doi.org/10.1111/hae.13317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5724962PMC
November 2017
11 Reads

Revascularization strategies and in-hospital management in acute coronary syndromes complicated by hemophilia A or hemophilia B.

Blood Coagul Fibrinolysis 2017 Dec;28(8):650-657

aDepartment of Medicine, University of Pennsylvania Health SystembDepartment of Biostatistics, Epidemiology and informatics, University of PennsylvaniacCardiovascular Division, Penn Presbyterian Medical CenterdDivision of Hematology/Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, USA*Phyllis A. Gimotty and Patrick F. Fogarty contributed equally to this article.†Address where work was carried out. Present address: 500 Arcola Road, Collegeville, PA 19426, USA.

: Among adult patients with hemophilia A and hemophilia B the emergent management of acute coronary syndromes (ACSs) is challenging, and exposure to antithrombotic agents and/or revascularization procedures may confer an enhanced risk of bleeding. We sought to identify clinical characteristics and in-hospital outcomes among ACS patients with hemophilia A/hemophilia B, compared with matched noncoagulopathic ACS controls. Case discharges from the Nationwide Inpatient Sample, Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality (1998-2011) had International Classification of Diseases, 9th Revision codes for hemophilia A/hemophilia B and ACS. Read More

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http://dx.doi.org/10.1097/MBC.0000000000000655DOI Listing
December 2017
39 Reads

CRISPR/Cas9-mediated genome editing via postnatal administration of AAV vector cures haemophilia B mice.

Sci Rep 2017 06 23;7(1):4159. Epub 2017 Jun 23.

Division of Cell and Molecular Medicine, Center for Molecular Medicine, Jichi Medical University, Tochigi, 329-0498, Japan.

Haemophilia B, a congenital haemorrhagic disease caused by mutations in coagulation factor IX gene (F9), is considered an appropriate target for genome editing technology. Here, we describe treatment strategies for haemophilia B mice using the clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system. Administration of adeno-associated virus (AAV) 8 vector harbouring Staphylococcus aureus Cas9 (SaCas9) and single guide RNA (sgRNA) to wild-type adult mice induced a double-strand break (DSB) at the target site of F9 in hepatocytes, sufficiently developing haemophilia B. Read More

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http://dx.doi.org/10.1038/s41598-017-04625-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482879PMC
June 2017
19 Reads

Co-morbidities and bleeding in elderly patients with haemophilia-A survey of the German, Austrian and Swiss Society of Thrombosis and Haemostasis Research (GTH).

Haemophilia 2017 Sep 21;23(5):721-727. Epub 2017 Jun 21.

Division of Haematology and Haemostaseology, Department of Medicine I, Medical University, Vienna, Austria.

Background: Nowadays patients with haemophilia survive longer due to improvements in haemophilia care. It has been hypothesized that the bleeding type and frequency may vary with age and are influenced by co-morbidities and co-medication in elderly patients.

Objectives: To investigate a large group of patients older than 60 years of age with haemophilia concerning haemophilia treatment, bleeding pattern changes, co-morbidities, co-medication, bleeding sites and patient mortality. Read More

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http://doi.wiley.com/10.1111/hae.13296
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http://dx.doi.org/10.1111/hae.13296DOI Listing
September 2017
5 Reads

Identification of liver-specific enhancer-promoter activity in the 3' untranslated region of the wild-type AAV2 genome.

Nat Genet 2017 Aug 19;49(8):1267-1273. Epub 2017 Jun 19.

Gene Therapy Research Unit, Children's Medical Research Institute and Sydney Children's Hospitals Network, University of Sydney, Sydney, New South Wales, Australia.

Vectors based on adeno-associated virus type 2 (AAV2) are powerful tools for gene transfer and genome editing applications. The level of interest in this system has recently surged in response to reports of therapeutic efficacy in human clinical trials, most notably for those in patients with hemophilia B (ref. 3). Read More

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http://dx.doi.org/10.1038/ng.3893DOI Listing
August 2017
38 Reads