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1. PB2612: UNITED KINGDOM RETROSPECTIVE OBSERVATIONAL STUDY OF ROMIPLOSTIM AND OTHER TREATMENTS IN EARLY IMMUNE THROMBOCYTOPENIA

Author: Vickie Mcdonald, Charlotte Bradbury, Kate Talks, Gillian Lowe, Sue Pavord, Gillian Evans, Mano Andiappan, Darcie Sandschafer, Vitor Jose De Sousa Barbosa, Lorraine Stephens, and Nichola Cooper
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Published: 2023
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2. Whole-genome sequencing of patients with rare diseases in a national health system.

Author: Ernest Turro, William J. Astle, Karyn Megy, Stefan Gräf, Daniel Greene, Olga Shamardina, Hana Lango Allen, Alba Sanchis-Juan, Mattia Frontini, Chantal Thys, Jonathan Stephens, Rutendo Mapeta, Oliver S. Burren, Kate Downes, Matthias Haimel, Salih Tuna, Sri V. V. Deevi, Timothy J. Aitman, David L. H. Bennett, Paul Calleja, Keren Carss, Mark J. Caulfield, Patrick F. Chinnery, Peter H. Dixon, Daniel P. Gale, Roger James, Ania Koziell, Michael A. Laffan, Adam P. Levine, Eamonn R. Maher, Hugh S. Markus, Joannella Morales, Nicholas W. Morrell, Andrew D. Mumford, Elizabeth Ormondroyd, Stuart Rankin, Augusto Rendon, Sylvia Richardson, Irene Roberts, Noemi B. A. Roy, Moin A. Saleem, Kenneth G. C. Smith, Hannah Stark, Rhea Y. Y. Tan, Andreas C. Themistocleous, Adrian J. Thrasher, Hugh Watkins, Andrew R. Webster, Martin R. Wilkins, Catherine Williamson, James Whitworth, Sean Humphray, David R. Bentley, Stephen Abbs, Lara Abulhoul, Julian Adlard, Munaza Ahmed, Hana Alachkar, David J. Allsup, Jeff Almeida-King, Philip Ancliff, Richard Antrobus, Ruth Armstrong, Gavin Arno, Sofie Ashford, Anthony Attwood, Paul Aurora, Christian Babbs, Chiara Bacchelli, Tamam Bakchoul, Siddharth Banka, Tadbir Bariana, Julian Barwell, Joana Batista, Helen E. Baxendale, Phil L. Beales, Agnieszka Bierzynska, Tina Biss, Maria A. K. Bitner-Glindzicz, Graeme C. M. Black, Marta Bleda, Iulia Blesneac, Detlef Bockenhauer, Harm Bogaard, Christian J. Bourne, Sara Boyce, John R. Bradley, Eugene Bragin, Gerome Breen, Paul Brennan, Carole Brewer, Matthew Brown, Andrew C. Browning, Michael J. Browning, Rachel J. Buchan, Matthew S. Buckland, Teofila Bueser, Carmen Bugarin Diz, John Burn, Siobhan O. Burns, Nigel Burrows, Carolyn Campbell, Gerald Carr-White, Ruth Casey, Jenny Chambers, John Chambers, Melanie M. Y. Chan, Calvin Cheah, Floria Cheng, Manali Chitre, Martin T. Christian, Colin Church, Jill Clayton-Smith, Maureen Cleary, Naomi Clements Brod, Gerry Coghlan, Elizabeth Colby, Trevor R. P. Cole, Janine Collins, Peter W. Collins, Camilla Colombo, Cecilia J. Compton, Robin Condliffe, Stuart A. Cook, H. Terence Cook, Nichola Cooper, Paul A. Corris, Abigail Furnell, Fiona Cunningham, Nicola S. Curry, Antony J. Cutler, Matthew J. Daniels, Mehul Dattani, Louise C. Daugherty, John Davis, Anthony De Soyza, Timothy Dent, Charu Deshpande, Eleanor F. Dewhurst, Sofia Douzgou, Anna M. Drazyk, Elizabeth Drewe, Daniel Duarte, Tina Dutt, J. David M. Edgar, Karen Edwards, William Egner, Melanie N. Ekani, Perry Elliott, Wendy N. Erber, Marie Erwood, Maria C. Estiu, Dafydd Gareth Evans, Gillian Evans, Tamara Everington, Mélanie Eyries, Hiva Fassihi, Remi Favier, Jack Findhammer, Debra Fletcher, Frances A. Flinter, R. Andres Floto, Tom Fowler, James Fox, Amy J. Frary, Courtney E. French, Kathleen Freson, Henning Gall, Vijeya Ganesan, Michael Gattens, Claire Geoghegan, Terence S. A. Gerighty, Ali G. Gharavi, Stefano Ghio, Hossein-Ardeschir Ghofrani, J. Simon R. Gibbs, Kate Gibson, Kimberly C. Gilmour, Barbara Girerd, Nicholas S. Gleadall, Sarah Goddard, David B. Goldstein, Keith Gomez, Pavels Gordins, David Gosal, Jodie Graham, Luigi Grassi, Lynn Greenhalgh, Andreas Greinacher, Paolo Gresele, Philip Griffiths, Sofia Grigoriadou, Russell J. Grocock, Detelina Grozeva, Mark Gurnell, Scott Hackett, Charaka Hadinnapola, William M. Hague, Rosie Hague, Matthew Hall, Helen L. Hanson, Eshika Haque, Kirsty Harkness, Andrew R. Harper, Claire L. Harris, Daniel Hart, Ahamad Hassan, Grant Hayman, Alex Henderson, Archana Herwadkar, Jonathan Hoffman, Simon Holden, Rita Horvath, Henry Houlden, Arjan C. Houweling, Luke S. G. E. Howard, Fengyuan Hu, Gavin Hudson, Joseph Hughes, Aarnoud P. Huissoon, Marc Humbert, Sarah Hunter, Matthew E. Hurles, Melita Irving, Louise Izatt, Sally A. Johnson, Stephen Jolles, Jennifer Jolley, Dragana Josifova, Neringa Jurkute, Tim Karten, Johannes Karten, Mary A. Kasanicki, Hanadi Kazkaz, Rashid Kazmi, Peter Kelleher, Anne M. Kelly, Wilf Kelsall, Carly Kempster, David G. Kiely, Nathalie Kingston, Robert Klima, Nils Koelling, Myrto Kostadima, Gabor Kovacs, Roman Kreuzhuber, Taco W. Kuijpers, Ajith Kumar, Dinakantha Kumararatne, Manju A. Kurian, Fiona Lalloo, Michele Lambert, Allan Lawrie, D. Mark Layton, Nick Lench, Claire Lentaigne, Tracy Lester, Rachel Linger, Hilary Longhurst, Lorena E. Lorenzo, Eleni Louka, Paul A. Lyons, Rajiv D. Machado, Robert V. MacKenzie Ross, Bella Madan, Jesmeen Maimaris, Samantha Malka, Sarah Mangles, Kevin J. Marchbank, Stephen Marks, Hanns-Ulrich Marschall, Andrew G. Marshall, Jennifer Martin, Mary Mathias, Emma Matthews, Heather Maxwell, Paul McAlinden, Mark I. McCarthy, Harriet McKinney, Aoife McMahon, Stuart Meacham, Adam J. Mead, Ignacio Medina Castello, Sarju G. Mehta, Michel Michaelides, Carolyn Millar, Shehla N. Mohammed, Shahin Moledina, David Montani, Anthony T. Moore, Monika Mozere, Keith W. Muir, Andrea H. Nemeth, William G. Newman, Michael Newnham, Sadia Noorani, Paquita Nurden, Jennifer O'Sullivan, Samya Obaji, Chris Odhams, Steven Okoli, Andrea Olschewski, Horst Olschewski, Kai Ren Ong, S. Helen Oram, Willem H. Ouwehand, Claire Palles, Sofia Papadia, Soo-Mi Park, David Parry 0003, Smita Patel, Joan Paterson, Andrew Peacock, Simon H. Pearce, John Peden, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, Romina Petersen, Clarissa Pilkington, Kenneth E. S. Poole, Radhika Prathalingam, Bethan Psaila, Angela Pyle, Richard Quinton, Shamima Rahman, Anupama Rao, F. Lucy Raymond, Paula J. Rayner-Matthews, Christine Rees, Tara Renton, Christopher J. Rhodes, Andrew S. C. Rice, Alex Richter, Leema Robert, Anthony Rogers, Sarah J. Rose, Robert Ross-Russell, Catherine Roughley, Deborah M. Ruddy, Omid Sadeghi-Alavijeh, Nilesh J. Samani, Crina Samarghitean, Ravishankar B. Sargur, Robert N. Sarkany, Simon Satchell, Sinisa Savic, John A. Sayer, Genevieve Sayer, Laura Scelsi, Andrew M. Schaefer, Sol Schulman, Richard Scott, Marie Scully, Claire Searle, Werner Seeger, Arjune Sen, W. A. Carrock Sewell, Denis Seyres, Neil Shah, Susan E. Shapiro, Adam C. Shaw, Patrick J. Short, Keith Sibson, Lucy Side, Ilenia Simeoni, Michael A. Simpson, Matthew C. Sims, Suthesh Sivapalaratnam, Damian Smedley, Katherine R. Smith, Katie Snape, Nicole Soranzo, Florent Soubrier, Laura Southgate, Olivera Spasic-Boskovic, Simon Staines, Emily Staples, Charles A. Steward, Kathleen E. Stirrups, Alex Stuckey, Jay Suntharalingam, Emilia M. Swietlik, Petros Syrris, R. Campbell Tait, Kate Talks, Katie Tate, John M. Taylor, Jenny C. Taylor, James E. Thaventhiran, Ellen Thomas, David Thomas 0004, Moira J. Thomas, Patrick Thomas, Kate Thomson, Glen Threadgold, Tobias Tilly, Marc Tischkowitz, Catherine Titterton, John A. Todd, Cheng-Hock Toh, Bas Tolhuis, Ian P. Tomlinson, Mark Toshner, Matthew Traylor, Carmen Treacy, Paul Treadaway, Richard Trembath, Wojciech Turek, Philip Twiss, Tom Vale, Chris Van Geet, Natalie van Zuydam, Maarten Vandekuilen, Anthony M. Vandersteen, Marta Vazquez-Lopez, Julie von Ziegenweidt, Anton Vonk-Noordegraaf, Annette Wagner, Quinten Waisfisz, Suellen M. Walker, Neil Walker, Klaudia Walter, James S. Ware, Christopher Watt, Lucy Wedderburn, Wei Wei, Steven B. Welch, Julie Wessels, Sarah K. Westbury, John-Paul Westwood, John Wharton, Deborah Whitehorn, Andrew O. M. Wilkie, Brian T. Wilson, Edwin K. S. Wong, Nicholas W. Wood, Yvette Wood, Christopher Geoffrey Woods, Emma R. Woodward, Stephen J. Wort, Austen Worth, Michael Wright, Katherine Yates, Patrick F. K. Yong, Timothy Young, Ping Yu, Patrick Yu-Wai-Man, and Eliska Zlamalova
Published: 2020
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3. Retrospective, Observational, Multicenter Study Assessing the Thrombopoietin Receptor Agonist (TPO-RA) Romiplostim and Other Treatments for Patients with Newly Diagnosed or Persistent Primary Immune Thrombocytopenia (ITP) in Routine Clinical Practice in the United Kingdom (UK)

Author: Vickie McDonald, Charlotte Bradbury, Kate Talks, Gillian Lowe, Sue Pavord, Gillian Evans, Manoharan Andiappan, Darcie Sandschafer, Vitor Jose De Sousa Barbosa, Lorraine Stephens, and Nichola Cooper
Subjects: Immunology, Cell Biology, Hematology, Biochemistry
Published: 2022

4. Mycophenolate Mofetil for First-Line Treatment of Immune Thrombocytopenia

Author: Rosemary Greenwood, Katie Breheny, Ian Thomas, Nichola Cooper, Quentin Hill, Kate Talks, Rachel Rayment, Catherine Bagot, Charlotte A Bradbury, Jenny Ingram, Gillian Evans, Rebecca Kandiyali, and Julie Pell
Subjects: Adult, Male, Pediatrics, medicine.medical_specialty, Adolescent, animal diseases, MEDLINE, Hemorrhage, chemical and pharmacologic phenomena, Mycophenolate, law.invention, Young Adult, Pharmacotherapy, Randomized controlled trial, Quality of life, law, hemic and lymphatic diseases, medicine, Humans, HEB, Platelet, Young adult, Glucocorticoids, Fatigue, Aged, Purpura, Thrombocytopenic, Idiopathic, Platelet Count, business.industry, General Medicine, Middle Aged, Mycophenolic Acid, biochemical phenomena, metabolism, and nutrition, Purpura, Quality of Life, bacteria, Drug Therapy, Combination, Female, medicine.symptom, business, Immunosuppressive Agents
Abstract: BACKGROUND Immune thrombocytopenia (ITP) is a rare autoimmune thrombocytopenia with associated bleeding risk and fatigue. Recommended first line ITP treatment is with high dose glucocorticoids but side effects, heterogeneous responses and high relapse rates are significant problems. METHODS In this multicenter, UK based, open label, randomized controlled trial, we randomly assigned adult patients with ITP requiring first line treatment to glucocorticoid alone (standard care) versus combined glucocorticoid and mycophenolate (1:1 ratio). The primary efficacy outcome was time from randomization to treatment failure, defined as platelets 100x109/L vs 63.9%, p
Published: 2021

5. Immune tolerance induction in severe haemophilia A: A UKHCDO inhibitor and paediatric working party consensus update

Author: Jayanthi Alamelu, Tina T. Biss, Mary Mathias, Georgina W. Hall, Oliver Tunstall, Neha Bhatnagar, Elizabeth Chalmers, Charles R. M. Hay, Jeanette Payne, Daniel P. Hart, Ben Palmer, Michael Makris, Charles Percy, Kate Talks, Peter William Collins, Anne Riddell, Michael Richards, Ri Liesner, and Jayashree Motwani
Subjects: Emicizumab, medicine.medical_specialty, Factor VIII, business.industry, Low dose, Hemorrhage, Hematology, General Medicine, Guideline, Bleed, Hemophilia A, Haemophilia, medicine.disease, United Kingdom, Immune tolerance, Immune Tolerance, medicine, Humans, Severe haemophilia A, Child, Intensive care medicine, business, Genetics (clinical), Consensus guideline
Abstract: INTRODUCTION In good risk patients (historic inhibitor peak
Published: 2021

6. Guidelines on the use of prophylactic factor replacement for children and adults with Haemophilia A and B

Author: Oliver Tunstall, Katherine Forsyth, Kate Talks, Anne M. Kelly, Elizabeth Chalmers, Rachel Rayment, Susan Shapiro, Tina Biss, and Richard Gooding
Subjects: Adult, Male, Pediatrics, medicine.medical_specialty, Factor VIII, Factor replacement, business.industry, Haemophilia A, MEDLINE, Hematology, Hemophilia A, medicine.disease, Hemophilia B, Factor IX, Practice Guidelines as Topic, Humans, Medicine, Child, business
Published: 2020

7. Bayesian Inference Associates Rare KDR Variants with Specific Phenotypes in Pulmonary Arterial Hypertension

Author: Emilia M. Swietlik, Daniel Greene, Na Zhu, Karyn Megy, Marcella Cogliano, Smitha Rajaram, Divya Pandya, Tobias Tilly, Katie A. Lutz, Carrie C.L. Welch, Michael W. Pauciulo, Laura Southgate, Jennifer M. Martin, Carmen M. Treacy, Christopher J. Penkett, Jonathan C. Stephens, Harm J. Bogaard, Colin Church, Gerry Coghlan, Anna W. Coleman, Robin Condliffe, Christina A. Eichstaedt, Mélanie Eyries, Henning Gall, Stefano Ghio, Barbara Girerd, Ekkehard Grünig, Simon Holden, Luke Howard, Marc Humbert, David G. Kiely, Gabor Kovacs, Jim Lordan, Rajiv D. Machado, Robert V. MacKenzie Ross, Colm McCabe, Shahin Moledina, David Montani, Horst Olschewski, Joanna Pepke-Zaba, Laura Price, Christopher J. Rhodes, Werner Seeger, Florent Soubrier, Jay Suntharalingam, Mark R. Toshner, Anton Vonk Noordegraaf, John Wharton, James M. Wild, Stephen John Wort, Allan Lawrie, Martin R. Wilkins, Richard C. Trembath, Yufeng Shen, Wendy K. Chung, Andrew J. Swift, William C. Nichols, Nicholas W. Morrell, Stefan Gräf, Stephen Abbs, Lara Abulhoul, Julian Adlard, Munaza Ahmed, Timothy J. Aitman, Hana Alachkar, David J. Allsup, Philip Ancliff, Richard Antrobus, Ruth Armstrong, Gavin Arno, Sofie Ashford, William J. Astle, Anthony Attwood, Paul Aurora, Christian Babbs, Chiara Bacchelli, Tamam Bakchoul, Siddharth Banka, Tadbir Bariana, Julian Barwell, Joana Batista, Helen E. Baxendale, Phil L. Beales, David L. Bennett, Agnieszka Bierzynska, Tina Biss, Maria A.K. Bitner-Glindzicz, Graeme C. Black, Marta Bleda, Iulia Blesneac, Detlef Bockenhauer, Sara Boyce, John R. Bradley, Gerome Breen, Paul Brennan, Carole Brewer, Matthew Brown, Andrew C. Browning, Michael J. Browning, Rachel J. Buchan, Matthew S. Buckland, Teofila Bueser, Carmen Bugarin Diz, John Burn, Siobhan O. Burns, Oliver S. Burren, Nigel Burrows, Carolyn Campbell, Gerald Carr-White, Keren Carss, Ruth Casey, Mark J. Caulfield, Jenny Chambers, John Chambers, Melanie M.Y. Chan, Floria Cheng, Patrick F. Chinnery, Manali Chitre, Martin T. Christian, Jill Clayton-Smith, Maureen Cleary, Naomi Clements Brod, Elizabeth Colby, Trevor R.P. Cole, Janine Collins, Peter W. Collins, Cecilia J. Compton, H. Terence Cook, Stuart Cook, Nichola Cooper, Paul A. Corris, Nicola S. Curry, Matthew J. Daniels, Mehul Dattani, Louise C. Daugherty, John Davis, Anthony De Soyza, Sri V.V. Deevi, Timothy Dent, Charu Deshpande, Eleanor F. Dewhurst, Peter H. Dixon, Sofia Douzgou, Kate Downes, Anna M. Drazyk, Elizabeth Drewe, Daniel Duarte, Tina Dutt, J. David M. Edgar, Karen Edwards, William Egner, Melanie N. Ekani, Perry Elliott, Wendy N. Erber, Marie Erwood, Maria C. Estiu, Dafydd Gareth Evans, Gillian Evans, Tamara Everington, Hiva Fassihi, Remi Favier, Debra Fletcher, Frances A. Flinter, R. Andres Floto, Tom Fowler, James Fox, Amy J. Frary, Courtney E. French, Kathleen Freson, Mattia Frontini, Abigail Furnell, Daniel P. Gale, Vijeya Ganesan, Michael Gattens, Hossein-Ardeschir Ghofrani, J. Simon R. Gibbs, Kate Gibson, Kimberly C. Gilmour, Nicholas S. Gleadall, Sarah Goddard, Keith Gomez, Pavels Gordins, David Gosal, Jodie Graham, Luigi Grassi, Lynn Greenhalgh, Andreas Greinacher, Paolo Gresele, Philip Griffiths, Sofia Grigoriadou, Detelina Grozeva, Mark Gurnell, Scott Hackett, Charaka Hadinnapola, Rosie Hague, William M. Hague, Matthias Haimel, Matthew Hall, Helen L. Hanson, Eshika Haque, Kirsty Harkness, Andrew R. Harper, Claire L. Harris, Daniel Hart, Ahamad Hassan, Grant Hayman, Alex Henderson, Archana Herwadkar, Jonathan Hoffman, Rita Horvath, Henry Houlden, Arjan C. Houweling, Fengyuan Hu, Gavin Hudson, Aarnoud P. Huissoon, Matthew Hurles, Melita Irving, Louise Izatt, Roger James, Sally A. Johnson, Stephen Jolles, Jennifer Jolley, Dragana Josifova, Neringa Jurkute, Mary A. Kasanicki, Hanadi Kazkaz, Rashid Kazmi, Peter Kelleher, Anne M Kelly, Wilf Kelsall, Carly Kempster, Nathalie Kingston, Nils Koelling, Myrto Kostadima, Ania Koziell, Roman Kreuzhuber, Taco W. Kuijpers, Ajith Kumar, Dinakantha Kumararatne, Manju A. Kurian, Michael A. Laffan, Fiona Lalloo, Michele Lambert, Hana Lango Allen, D. Mark Layton, Claire Lentaigne, Tracy Lester, Adam P. Levine, Rachel Linger, Hilary Longhurst, Lorena E. Lorenzo, Eleni Louka, Paul A. Lyons, Bella Madan, Eamonn R. Maher, Jesmeen Maimaris, Samantha Malka, Sarah Mangles, Rutendo Mapeta, Kevin J. Marchbank, Stephen Marks, Hugh S. Markus, Hanns-Ulrich Marschall, Andrew Marshall, Mary Mathias, Emma Matthews, Heather Maxwell, Paul McAlinden, Mark I. McCarthy, Harriet McKinney, Stuart Meacham, Adam J. Mead, Sarju G. Mehta, Michel Michaelides, Carolyn Millar, Shehla N. Mohammed, Anthony T. Moore, Monika Mozere, Keith W. Muir, Andrew D. Mumford, Andrea H. Nemeth, William G. Newman, Michael Newnham, Sadia Noorani, Paquita Nurden, Jennifer O’Sullivan, Samya Obaji, Chris Odhams, Steven Okoli, Andrea Olschewski, Kai Ren Ong, S. Helen Oram, Elizabeth Ormondroyd, Willem H. Ouwehand, Claire Palles, Sofia Papadia, Soo-Mi Park, David Parry, Smita Patel, Joan Paterson, Andrew Peacock, Simon H. Pearce, Kathelijne Peerlinck, Romina Petersen, Clarissa Pilkington, Kenneth E.S. Poole, Bethan Psaila, Angela Pyle, Richard Quinton, Shamima Rahman, Anupama Rao, F. Lucy Raymond, Paula J. Rayner-Matthews, Augusto Rendon, Tara Renton, Andrew S.C. Rice, Alex Richter, Leema Robert, Irene Roberts, Sarah J. Rose, Robert Ross-Russell, Catherine Roughley, Noemi B.A. Roy, Deborah M. Ruddy, Omid Sadeghi-Alavijeh, Moin A. Saleem, Nilesh Samani, Crina Samarghitean, Alba Sanchis-Juan, Ravishankar B. Sargur, Robert N. Sarkany, Simon Satchell, Sinisa Savic, Genevieve Sayer, John A. Sayer, Laura Scelsi, Andrew M. Schaefer, Sol Schulman, Richard Scott, Marie Scully, Claire Searle, Arjune Sen, W.A. Carrock Sewell, Denis Seyres, Neil Shah, Olga Shamardina, Susan E. Shapiro, Adam C. Shaw, Keith Sibson, Lucy Side, Ilenia Simeoni, Michael A. Simpson, Matthew C. Sims, Suthesh Sivapalaratnam, Damian Smedley, Katherine R. Smith, Kenneth G.C. Smith, Katie Snape, Nicole Soranzo, Olivera Spasic-Boskovic, Simon Staines, Emily Staples, Hannah Stark, Kathleen E. Stirrups, Alex Stuckey, Petros Syrris, R. Campbell Tait, Kate Talks, Rhea Y.Y. Tan, Jenny C. Taylor, John M. Taylor, James E. Thaventhiran, Andreas C. Themistocleous, David Thomas, Ellen Thomas, Moira J. Thomas, Patrick Thomas, Kate Thomson, Adrian J. Thrasher, Chantal Thys, Marc Tischkowitz, Catherine Titterton, Cheng-Hock Toh, Ian P. Tomlinson, Matthew Traylor, Paul Treadaway, Salih Tuna, Ernest Turro, Philip Twiss, Tom Vale, Chris Van Geet, Natalie van Zuydam, Anthony M Vandersteen, Marta Vazquez-Lopez, Julie von Ziegenweidt, Annette Wagner, Quinten Waisfisz, Neil Walker, Suellen M. Walker, James S. Ware, Hugh Watkins, Christopher Watt, Andrew R. Webster, Lucy Wedderburn, Wei Wei, Steven B. Welch, Julie Wessels, Sarah K. Westbury, John-Paul Westwood, Deborah Whitehorn, James Whitworth, Andrew O.M. Wilkie, Catherine Williamson, Brian T. Wilson, Edwin K.S. Wong, Nicholas Wood, Yvette Wood, Christopher Geoffrey Woods, Emma R. Woodward, Austen Worth, Michael Wright, Katherine Yates, Patrick F.K. Yong, Timothy Young, Ping Yu, Patrick Yu-Wai-Man, Eliska Zlamalova, Russel Hirsch, R. James White, Marc Simon, David Badesch, Erika Rosenzweig, Charles Burger, Murali Chakinala, Thenappan Thenappan, Greg Elliott, Robert Simms, Harrison Farber, Robert Frantz, Jean Elwing, Nicholas Hill, Dunbar Ivy, James Klinger, Steven Nathan, Ronald Oudiz, Ivan Robbins, Robert Schilz, Terry Fortin, Jeffrey Wilt, Delphine Yung, Eric Austin, Ferhaan Ahmad, Nitin Bhatt, Tim Lahm, Adaani Frost, Zeenat Safdar, Zia Rehman, Robert Walter, Fernando Torres, Sahil Bakshi, Stephen Archer, Rahul Argula, Christopher Barnett, Raymond Benza, Ankit Desai, Veeranna Maddipati, University of Cambridge [UK] (CAM), Columbia University [New York], University of Sheffield [Sheffield], University of Cincinnati (UC), St George's, University of London, Vrije Universiteit Amsterdam [Amsterdam] (VU), Golden Jubilee National Hospital, Glasgow, Royal Free Hospital [London, UK], Heidelberg University Hospital [Heidelberg], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Technische Hochschule Mittelhessen - University of Applied Sciences [Giessen] (THM), Fondazione IRCCS Policlinico San Matteo, Hypertension pulmonaire : physiopathologie et innovation thérapeutique (HPPIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Universität Heidelberg [Heidelberg], Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Imperial College London, Royal Hallamshire Hospital, University of Graz, Freeman Hospital, Royal United Hospitals Bath (RUH), Great Ormond Street Hospital for Children [London] (GOSH), Royal Papworth Hospital, Cambridge Biomedical Campus, Cambridge, United Kingdom., King‘s College London, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Karl-Franzens-Universität [Graz, Autriche], Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Swietlik, Emilia [0000-0002-4095-8489], Megy, Karyn [0000-0002-2826-3879], Tilly, Tobias [0000-0002-6762-5342], Stephens, Jonathan [0000-0003-2020-9330], Toshner, Mark [0000-0002-3969-6143], Morrell, Nicholas [0000-0001-5700-9792], Graf, Stefan [0000-0002-1315-8873], Apollo - University of Cambridge Repository, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Karl-Franzens-Universität Graz, HAL-SU, Gestionnaire, British Heart Foundation, and The Academy of Medical Sciences
Subjects: 0301 basic medicine, Candidate gene, Cardiac & Cardiovascular Systems, genetic association studies, 030204 cardiovascular system & hematology, Biology, Bayesian inference, 03 medical and health sciences, 0302 clinical medicine, Missing heritability problem, pulmonary hypertension, medicine, Family history, Gene, Genetics & Heredity, Genetics, family history, Science & Technology, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Kinase insert domain receptor, computed tomography, General Medicine, Original Articles, medicine.disease, Pulmonary hypertension, Phenotype, 3. Good health, 030104 developmental biology, Cardiovascular System & Cardiology, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Life Sciences & Biomedicine, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, vascular endothelial growth factor receptor
Abstract: Supplemental Digital Content is available in the text., Background: Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH, we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics. Methods: We analyzed 13 037 participants enrolled in the NBR study (NIHR BioResource—Rare Diseases), of which 1148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension, we used the Bayesian rare variant association method BeviMed. Results: Heterozygous, high impact, likely loss-of-function variants in the kinase insert domain receptor (KDR) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (posterior probability=0.989) and older age at diagnosis (posterior probability=0.912). We also provide evidence for familial segregation of a rare nonsense KDR variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the 5 patients harboring these predicted deleterious variants in KDR. Four additional PAH cases with rare likely loss-of-function variants in KDR were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. Conclusions: The Bayesian inference approach allowed us to independently validate KDR, which encodes for the VEGFR2 (vascular endothelial growth factor receptor 2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for KDR being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.
Published: 2020

8. Treatment of bleeding episodes in haemophilia A complicated by a factor VIII inhibitor in patients receiving Emicizumab. Interim guidance from UKHCDO Inhibitor Working Party and Executive Committee

Author: Peter William Collins, Michael Makris, C. L. Percy, Charles R. M. Hay, Pratima Chowdary, Kate Talks, Elizabeth Chalmers, Daniel P. Hart, R. Liesner, Georgina W. Hall, and Anne Riddell
Subjects: congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Haemophilia A, Guidelines as Topic, Hemorrhage, 030204 cardiovascular system & hematology, Antibodies, Monoclonal, Humanized, Hemophilia A, Haemophilia, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, Interim, Antibodies, Bispecific, Humans, Medicine, Intensive care medicine, Adverse effect, Activated prothrombin complex concentrate, Genetics (clinical), Emicizumab, Bleeding episodes, Factor VIII, business.industry, Hematology, General Medicine, medicine.disease, Thrombosis, 030220 oncology & carcinogenesis, business
Abstract: Emicizumab is a bispecific antibody that activates FX to FXa in the absence of FVIII. It has been shown to reduce bleeding episodes in people with haemophilia A complicated by a FVIII inhibitor. Despite the protection against bleeds, some breakthrough bleeds are inevitable and these may require additional haemostatic treatment. Emicizumab has been associated with severe adverse events when co-administered with activated prothrombin complex concentrate. To minimize the risk of adverse events, the UK Haemophilia Centre Doctors' Organisation issues the following updated interim guidance to its Inhibitor Guidelines for managing patients receiving Emicizumab based on the limit published information available in February 2018.
Published: 2018

9. Factor IX Expression within the Normal Range Prevents Spontaneous Bleeds Requiring Treatment Following FLT180a Gene Therapy in Patients with Severe Hemophilia B: Long-Term Follow-up Study of the B-Amaze Program

Author: Ted Tuddenham, Kate Talks, G. Evans, Gerry Dolan, Michael Makris, Amit C. Nathwani, Mark Phillips, Susan Shapiro, Sara Boyce, Michelle Quaye, Maria Rita Peralta, Pratima Chowdary, Anne Riddell, Julie Krop, Alison Long, and Ulrike M. Reiss
Subjects: medicine.medical_specialty, business.industry, Long term follow up, Genetic enhancement, Immunology, Cell Biology, Hematology, Biochemistry, Gastroenterology, Internal medicine, Medicine, In patient, business, Normal range, Factor IX, medicine.drug
Abstract: Introduction: FLT180a (verbrinacogene setparvovec) is an investigational, liver-directed AAV gene therapy for the treatment of patients with hemophilia B (HB). FLT180a consists of a novel, potent, engineered capsid (AAVS3) containing an expression cassette encoding a Factor IX (FIX) gain-of-function protein variant ('Padua'; FIX-R338L). The B-AMAZE study was designed to identify a dose of FLT180a that maintains FIX activity within the normal range (50-150%) and thereby protect patients with severe HB from spontaneous and traumatic bleeds. Methods: B-AMAZE was a multicentre, open-label Phase 1/2 clinical trial (NCT03369444; sponsored by UCL) that evaluated FLT180a dose levels using an escalating/descending adaptive design in patients with severe (FIX activity Results: Ten HB patients received a single dose of FLT180a. Four FLT180a doses ranging from 3.84e11 vg/kg to 1.28e12 vg/kg were assessed. As of the data cut-off date, all patients have been followed for ≥16 months. FLT180a demonstrated a favorable safety profile, without evidence of inhibitors against FIX, infusion-related or allergic reactions. The most common treatment-related adverse event was transient elevation in alanine aminotransferase. An event of AV fistula thrombosis occurred in a 67-year-old patient who received the highest dose of 1.28e12 vg/kg (total dose of 1.15e14 vg) and had supranormal FIX levels; this patient was treated with anticoagulants. While these FIX levels demonstrate the potency of our proprietary AAVS3 capsid, this dose will not be used in future hemophilia studies. At Week 26 after FLT180a administration, a dose-response relationship was observed with mean FIX activity of 45.0%, 35.5%, 141.5%, and 175.5% for 3.84e11, 6.4e11, 8.32e11, and 1.28e12 vg/kg doses, respectively (Table); FIX activity levels ≥50% were achieved in 7 of 8 patients treated with the three highest doses. One patient (Patient 4) who received 6.4e11 vg/kg lost transgene expression early due to transaminitis and resumed routine factor prophylaxis. The 8.32e11 vg/kg cohort received an extended immune management regimen (9-18 weeks) with prophylactic tacrolimus in addition to prednisolone to prevent breakthrough vector-related transaminitis. However, after cessation of the immune management regimen, transaminitis with concomitant reductions in FIX activity was observed in all patients in the 8.32e11 vg/kg cohort. The combination of prophylactic tacrolimus and prednisolone appeared to have suppressed immune-mediated transaminitis while administered, but recurrence of transaminitis developed soon after cessation. This unique and previously unreported observation suggests that the longer-duration prophylactic immune management regimen may have prevented tolerization to the vector because this was not observed in earlier cohorts where a brief course of tacrolimus was given reactively for breakthrough transaminitis. All patients (including the 8.32e11 vg/kg cohort) have achieved steady state. Patients in the earliest cohort who received the lowest dose (3.84e11 vg/kg) have shown stable FIX activity for >3 years. There were no spontaneous bleeds that required FIX supplementation in patients who maintained FIX activity above 50%; Patient 4 in the 6.4e11 vg/kg cohort experienced two bleeds (cause unknown) after he lost transgene expression, which were treated with exogenous FIX. One patient received exogenous FIX for treatment of a traumatic bleed, but his FIX activity level was 57% at the time of the event. Additional efficacy and safety results with >3.5 years of follow-up will be presented. Conclusions: B-AMAZE is the first HB gene therapy study to achieve normal levels of FIX activity using relatively low vector doses. Results suggest that a dose of 7.7e11 vg/kg, coupled with a short course of prophylactic immune management, has the potential to achieve durable FIX activity in the normal range (50-150%) and thereby prevent spontaneous bleeds and normalize hemostasis in the event of traumatic bleeds. Figure 1 Figure 1. Disclosures Chowdary: Sanofi: Honoraria; Roche: Honoraria; CSL Behring: Honoraria, Research Funding; Freeline: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; SOBI: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria; Chugai: Honoraria; Spark: Honoraria; Bayer: Honoraria, Research Funding. Shapiro: Roche: Honoraria; CSL Bering: Honoraria; Takeda: Honoraria, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau. Makris: Freeline: Consultancy. Dolan: Takeda: Speakers Bureau; Roche-Chugai: Speakers Bureau; Spark Therapeutics: Speakers Bureau; Octapharma: Speakers Bureau; CSL: Speakers Bureau; Biomarin: Speakers Bureau; Bayer: Research Funding, Speakers Bureau; Novo Nordisk: Research Funding, Speakers Bureau; Pfizer: Research Funding. Tuddenham: Freeline: Consultancy, Current holder of individual stocks in a privately-held company. Long: Freeline: Current Employment. Krop: Freeline: Current Employment. Nathwani: Freeline: Current holder of individual stocks in a privately-held company, Other: Board of directors.
Published: 2021

10. Assessment of the efficacy of a novel tailored vitamin K dosing regimen in lowering the International Normalised Ratio in over-anticoagulated patients: a randomised clinical trial

Author: Kate Talks, Peter Avery, Tina Biss, Farhad Kamali, John Hanley, Hilary Wynne, and Emmanouela Kampouraki
Subjects: Adult, Male, Vitamin, medicine.medical_specialty, Vitamin K, Administration, Oral, Hemorrhage, 030204 cardiovascular system & hematology, Asymptomatic, Drug Administration Schedule, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Oral administration, Thromboembolism, Internal medicine, medicine, Humans, International Normalized Ratio, Dosing, Blood Coagulation, Aged, Aged, 80 and over, Body surface area, Dose-Response Relationship, Drug, business.industry, Warfarin, Anticoagulants, Hematology, Middle Aged, Antifibrinolytic Agents, Clinical trial, Regimen, Treatment Outcome, chemistry, 030220 oncology & carcinogenesis, Physical therapy, Female, medicine.symptom, business, medicine.drug
Abstract: Summary Current guidelines advocate using fixed-doses of oral vitamin K to reverse excessive anticoagulation in warfarinised patients who are either asymptomatic or have minor bleeds. Over-anticoagulated patients present with a wide range of International Normalised Ratio (INR) values and response to fixed doses of vitamin K varies. Consequently a significant proportion of patients remain outside their target INR after vitamin K administration, making them prone to either haemorrhage or thromboembolism. We compared the performance of a novel tailored vitamin K dosing regimen to that of a fixed-dose regimen with the primary measure being the proportion of over-anticoagulated patients returning to their target INR within 24 h. One hundred and eighty-one patients with an index INR > 6·0 (asymptomatic or with minor bleeding) were randomly allocated to receive oral administration of either a tailored dose (based upon index INR and body surface area) or a fixed-dose (1 or 2 mg) of vitamin K. A greater proportion of patients treated with the tailored dose returned to within target INR range compared to the fixed-dose regimen (68·9% vs. 52·8%; P = 0·026), whilst a smaller proportion of patients remained above target INR range (12·2% vs. 34·0%; P
Published: 2017

11. First-line immune tolerance induction for children with severe haemophilia A: A protocol from the UK Haemophilia Centre Doctors' Organisation Inhibitor and Paediatric Working Parties

Author: Oliver Tunstall, Elizabeth Chalmers, Jayanthi Alamelu, Kate Talks, C. R. M. Hay, Daniel P. Hart, Peter William Collins, Michael Williams, Savita Rangarajan, Michael Makris, M Richards, Jeanette Payne, Mary Mathias, and Raina Liesner
Subjects: medicine.medical_specialty, Pediatrics, First line, MEDLINE, 030204 cardiovascular system & hematology, Hemophilia A, Haemophilia, Immune tolerance, 03 medical and health sciences, 0302 clinical medicine, Immune Tolerance, medicine, Humans, Child, Genetics (clinical), Protocol (science), Factor VIII, Dose-Response Relationship, Drug, business.industry, Hematology, General Medicine, medicine.disease, United Kingdom, Physical therapy, Severe haemophilia A, business, 030215 immunology
Published: 2017

12. Biallelic Mutation of ARHGEF18, Involved in the Determination of Epithelial Apicobasal Polarity, Causes Adult-Onset Retinal Degeneration

Author: Gavin Arno, Keren J. Carss, Sarah Hull, Ceniz Zihni, Anthony G. Robson, Alessia Fiorentino, Alison J. Hardcastle, Graham E. Holder, Michael E. Cheetham, Vincent Plagnol, Anthony T. Moore, F. Lucy Raymond, Karl Matter, Maria S. Balda, Andrew R. Webster, Graeme Black, Georgina Hall, Stuart Ingram, Rachel Gillespie, Forbes Manson, Panagiotis Sergouniotis, Chris Inglehearn, Carmel Toomes, Manir Ali, Martin McKibbin, James Poulter, Kamron Khan, Emma Lord, Andrea Nemeth, Susan Downes, Stephanie Halford, Jing Yu, Stefano Lise, Nikos Ponitkos, Michel Michaelides, Veronica van Heyningen, Timothy Aitman, Hana Alachkar, Sonia Ali, Louise Allen, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Ruth Armstrong, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Maria Bitner-Glindzicz, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Natalie Canham, Jenny Carmichael, Keren Carss, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Manali Chitre, Colin Church, Emma Clement, Naomi Clements-Brod, Virginia Clowes, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Charu Deshpande, Lisa Devlin, Eleanor Dewhurst, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Marie Erwood, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, Frances Flinter, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Neeti Ghali, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Detelina Grozeva, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Simon Holden, Muriel Holder, Susan Holder, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Jane Hurst, Roger James, Stephen Jolles, Dragana Josifova, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Melissa Lees, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Karyn Megy, Sarju Mehta, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Elaine Murphy, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Willem H. Ouwehand, Sofia Papadia, Soo-Mi Park, Alasdair Parker, John Pasi, Chris Patch, Joan Paterson, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Julia Rankin, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Elisabeth Rosser, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Alba Sanchis-Juan, Richard Sandford, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Richard Scott, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Jonathan Stephens, Kathleen Stirrups, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Marc Tischkowitz, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie Vogt, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Emma Wakeling, Ivy Wanjiku, Timothy Q. Warner, Evangeline Wassmer, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Pediatric surgery, Molecular cell biology and Immunology, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, APH - Quality of Care, Amsterdam Reproduction & Development (AR&D), RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: DA CDL Algemeen (9), and Med Microbiol, Infect Dis & Infect Prev
Subjects: Male, 0301 basic medicine, Retinal degeneration, Biallelic Mutation, RHOA, PROTEIN, Eye, Medical and Health Sciences, ACTIVATION, chemistry.chemical_compound, 0302 clinical medicine, 2.1 Biological and endogenous factors, Missense mutation, Exome, Aetiology, Genetics (clinical), Genetics & Heredity, Genetics, biology, Retinal Degeneration, Cell Polarity, MOSAIC EYES, Biological Sciences, Middle Aged, Phenotype, inherited retinal dystrophy, Pedigree, UK Inherited Retinal Disease Consortium, Female, apicobasal polarity, Retinal Dystrophies, Adult, NIHR Bioresource - Rare Diseases Consortium, ARHGEF18, Genotype, Mutation, Missense, Nerve Tissue Proteins, Retina, 03 medical and health sciences, Rare Diseases, retinitis pigmentosa, Report, CRB1, Retinitis pigmentosa, medicine, Humans, Amino Acid Sequence, Eye Proteins, Eye Disease and Disorders of Vision, Alleles, Human Genome, Neurosciences, Genetic Variation, Membrane Proteins, Epithelial Cells, Retinal, CELL FEATURES, medicine.disease, NUCLEOTIDE EXCHANGE FACTOR, p114RhoGEF, 030104 developmental biology, INTEGRATIVE GENOMICS VIEWER, OKO-MEDUZY, chemistry, Mutation, MORPHOGENESIS, 030221 ophthalmology & optometry, biology.protein, Missense, rhoA GTP-Binding Protein, Rho Guanine Nucleotide Exchange Factors, Genome-Wide Association Study
Abstract: Mutations in more than 250 genes are implicated in inherited retinal dystrophy; the encoded proteins are involved in a broad spectrum of pathways. The presence of unsolved families after highly parallel sequencing strategies suggests that further genes remain to be identified. Whole-exome and -genome sequencing studies employed here in large cohorts of affected individuals revealed biallelic mutations in ARHGEF18 in three such individuals. ARHGEF18 encodes ARHGEF18, a guanine nucleotide exchange factor that activates RHOA, a small GTPase protein that is a key component of tight junctions and adherens junctions. This biological pathway is known to be important for retinal development and function, as mutation of CRB1, encoding another component, causes retinal dystrophy. The retinal structure in individuals with ARHGEF18 mutations resembled that seen in subjects with CRB1 mutations. Five mutations were found on six alleles in the three individuals: c.808A>G (p.Thr270Ala), c.1617+5G>A (p.Asp540Glyfs ∗ 63), c.1996C>T (p.Arg666 ∗ ), c.2632G>T (p.Glu878 ∗ ), and c.2738_2761del (p.Arg913_Glu920del). Functional tests suggest that each disease genotype might retain some ARHGEF18 activity, such that the phenotype described here is not the consequence of nullizygosity. In particular, the p.Thr270Ala missense variant affects a highly conserved residue in the DBL homology domain, which is required for the interaction and activation of RHOA. Previously, knock-out of Arhgef18 in the medaka fish has been shown to cause larval lethality which is preceded by retinal defects that resemble those seen in zebrafish Crumbs complex knock-outs. The findings described here emphasize the peculiar sensitivity of the retina to perturbations of this pathway, which is highlighted as a target for potential therapeutic strategies.
Published: 2017

13. Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Author: Keren J. Carss, Gavin Arno, Marie Erwood, Jonathan Stephens, Alba Sanchis-Juan, Sarah Hull, Karyn Megy, Detelina Grozeva, Eleanor Dewhurst, Samantha Malka, Vincent Plagnol, Christopher Penkett, Kathleen Stirrups, Roberta Rizzo, Genevieve Wright, Dragana Josifova, Maria Bitner-Glindzicz, Richard H. Scott, Emma Clement, Louise Allen, Ruth Armstrong, Angela F. Brady, Jenny Carmichael, Manali Chitre, Robert H.H. Henderson, Jane Hurst, Robert E. MacLaren, Elaine Murphy, Joan Paterson, Elisabeth Rosser, Dorothy A. Thompson, Emma Wakeling, Willem H. Ouwehand, Michel Michaelides, Anthony T. Moore, Andrew R. Webster, F. Lucy Raymond, Timothy Aitman, Hana Alachkar, Sonia Ali, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Natalie Canham, Keren Carss, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Colin Church, Naomi Clements-Brod, Virginia Clowes, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Charu Deshpande, Lisa Devlin, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, Frances Flinter, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Neeti Ghali, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Simon Holden, Muriel Holder, Susan Holder, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Roger James, Stephen Jolles, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Melissa Lees, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Sarju Mehta, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Sofia Papadia, Soo-Mi Park, Alasdair Parker, John Pasi, Chris Patch, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Julia Rankin, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Richard Sandford, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Richard Scott, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Marc Tischkowitz, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie Vogt, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Ivy Wanjiku, Timothy Q. Warner, Evangeline Wassmer, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Pediatric surgery, Molecular cell biology and Immunology, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, APH - Quality of Care, Amsterdam Reproduction & Development (AR&D), Rue-Albrecht, K, RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: DA CDL Algemeen (9), Med Microbiol, Infect Dis & Infect Prev, RS: CARIM - R1.03 - Cell biochemistry of thrombosis and haemostasis, Biochemie, Raymond, Lucy [0000-0003-2652-3355], Apollo - University of Cambridge Repository, Vascular Medicine, and Paediatric Infectious Diseases / Rheumatology / Immunology
Subjects: 0301 basic medicine, Male, DNA Mutational Analysis, EXOME, PROTEIN, Eye, whole-genome sequence, NIHR-BioResource Rare Diseases Consortium, Medical and Health Sciences, Choroideremia, ACTIVATION, 0302 clinical medicine, Ethnicity, 2.1 Biological and endogenous factors, Exome, rare sequence variant, Copy-number variation, Aetiology, MUTATION, Genetics (clinical), Exome sequencing, Genetics & Heredity, Genetics, Genome, Adaptor Proteins, Biological Sciences, DYSTROPHY, copy-number variants, Female, Human, Common disease-common variant, LEBER CONGENITAL AMAUROSIS, Ethnic Groups, Genes, Recessive, Biology, DIAGNOSIS, Article, 03 medical and health sciences, Rare Diseases, Retinal Diseases, STARGARDT DISEASE, Clinical Research, REVEALS, Journal Article, medicine, Recessive, Humans, retinal dystrophy, Eye Disease and Disorders of Vision, Alleles, Adaptor Proteins, Signal Transducing, Whole genome sequencing, Base Sequence, Genome, Human, Human Genome, Signal Transducing, Neurosciences, Genetic Variation, medicine.disease, GENE, Introns, Stargardt disease, Good Health and Well Being, 030104 developmental biology, Genes, Mutation, 030221 ophthalmology & optometry, Human genome
Abstract: Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.
Published: 2017

14. A United Kingdom Immune Thrombocytopenia (ITP) Forum review of practice: thrombopoietin receptor agonists

Author: Michael F. Murphy, Jecko Thachil, G. Evans, John D. Grainger, Marie Scully, Drew Provan, Quentin A. Hill, Gillian C. Lowe, Will Lester, Catherine Bagot, Charlotte Bradbury, Mamta Garg, Keith Sibson, Henry G. Watson, Kate Talks, Paula H B Bolton-Maggs, Shirley Watson, Adrian C. Newland, and Nichola Cooper
Subjects: Thrombopoietin Receptor Agonists, Eltrombopag, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Romiplostim, Fibrosis, Thrombopoietin receptor agonist, medicine, Humans, Practice Patterns, Physicians', Disease management (health), Receptor, Purpura, Thrombocytopenic, Idiopathic, Practice patterns, business.industry, Disease Management, Hematology, medicine.disease, United Kingdom, Immune thrombocytopenia, chemistry, Health Care Surveys, 030220 oncology & carcinogenesis, Immunology, business, Receptors, Thrombopoietin, 030215 immunology, medicine.drug
Abstract: No abstract
Published: 2016

15. Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia

Author: Kathleen M. Gorman, Esther Meyer, Detelina Grozeva, Egidio Spinelli, Amy McTague, Alba Sanchis-Juan, Keren J. Carss, Emily Bryant, Adi Reich, Amy L. Schneider, Ronit M. Pressler, Michael A. Simpson, Geoff D. Debelle, Evangeline Wassmer, Jenny Morton, Diana Sieciechowicz, Eric Jan-Kamsteeg, Alex R. Paciorkowski, Mary D. King, J. Helen Cross, Annapurna Poduri, Heather C. Mefford, Ingrid E. Scheffer, Tobias B. Haack, Gary McCullagh, John J. Millichap, Gemma L. Carvill, Jill Clayton-Smith, Eamonn R. Maher, F. Lucy Raymond, Manju A. Kurian, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Siddharth Banka, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Helen Cox, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V. K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J. Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I. Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Julie Vogt, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Saeed Al Turki, Carl Anderson, Richard Anney, Dinu Antony, Maria Soler Artigas, Muhammad Ayub, Senduran Balasubramaniam, Inês Barroso, Phil Beales, Jamie Bentham, Shoumo Bhattacharya, Ewan Birney, Douglas Blackwood, Martin Bobrow, Elena Bochukova, Patrick Bolton, Rebecca Bounds, Chris Boustred, Gerome Breen, Mattia Calissano, Keren Carss, Krishna Chatterjee, Lu Chen, Antonio Ciampi, Sebhattin Cirak, Peter Clapham, Gail Clement, Guy Coates, David Collier, Catherine Cosgrove, Tony Cox, Nick Craddock, Lucy Crooks, Sarah Curran, David Curtis, Allan Daly, Aaron Day-Williams, Ian N.M. Day, Thomas Down, Yuanping Du, Ian Dunham, Sarah Edkins, Peter Ellis, David Evans, Sadaf Faroogi, Ghazaleh Fatemifar, David R. Fitzpatrick, Paul Flicek, James Flyod, A. Reghan Foley, Christopher S. Franklin, Marta Futema, Louise Gallagher, Matthias Geihs, Daniel Geschwind, Heather Griffin, Xueqin Guo, Xiaosen Guo, Hugh Gurling, Deborah Hart, Audrey Hendricks, Peter Holmans, Bryan Howie, Liren Huang, Tim Hubbard, Steve E. Humphries, Pirro Hysi, David K. Jackson, Yalda Jamshidi, Tian Jing, Chris Joyce, Jane Kaye, Thomas Keane, Julia Keogh, John Kemp, Karen Kennedy, Anja Kolb-Kokocinski, Genevieve Lachance, Cordelia Langford, Daniel Lawson, Irene Lee, Monkol Lek, Jieqin Liang, Hong Lin, Rui Li, Yingrui Li, Ryan Liu, Jouko Lönnqvist, Margarida Lopes, Valentina Iotchkova, Daniel MacArthur, Jonathan Marchini, John Maslen, Mangino Massimo, Iain Mathieson, Gaëlle Marenne, Peter McGuffin, Andrew McIntosh, Andrew G. McKechanie, Andrew McQuillin, Sarah Metrustry, Hannah Mitchison, Alireza Moayyeri, James Morris, Francesco Muntoni, Kate Northstone, Michael O'Donnovan, Alexandros Onoufriadis, Stephen O'Rahilly, Karim Oualkacha, Michael J. Owen, Aarno Palotie, Kalliope Panoutsopoulou, Victoria Parker, Jeremy R. Parr, Lavinia Paternoster, Tiina Paunio, Felicity Payne, Olli Pietilainen, Vincent Plagnol, Lydia Quaye, Michael A. Quail, Karola Rehnström, Susan Ring, Graham R.S. Ritchie, Nicola Roberts, David B. Savage, Peter Scambler, Stephen Schiffels, Miriam Schmidts, Nadia Schoenmakers, Robert K. Semple, Eva Serra, Sally I. Sharp, So-Youn Shin, David Skuse, Kerrin Small, Lorraine Southam, Olivera Spasic-Boskovic, David St Clair, Jim Stalker, Elizabeth Stevens, Beate St Pourcian, Jianping Sun, Jaana Suvisaari, Ionna Tachmazidou, Martin D. Tobin, Ana Valdes, Margriet Van Kogelenberg, Peter M. Visscher, Louise V. Wain, James T.R. Walters, Guangbiao Wang, Jun Wang, Yu Wang, Kirsten Ward, Elanor Wheeler, Tamieka Whyte, Hywel Williams, Kathleen A. Williamson, Crispian Wilson, Kim Wong, ChangJiang Xu, Jian Yang, Fend Zhang, Pingbo Zhang, Timothy Aitman, Hana Alachkar, Sonia Ali, Louise Allen, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Gavin Arno, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Jenny Carmichael, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Manali Chitre, Colin Church, Emma Clement, Naomi Clements-Brod, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Lisa Devlin, Eleanor Dewhurst, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Marie Erwood, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Roger James, Stephen Jolles, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Karyn Megy, Michel Michaelides, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Elaine Murphy, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Willem H. Ouwehand, Sofia Papadia, Alasdair Parker, John Pasi, Chris Patch, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Jonathan Stephens, Kathleen Stirrups, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Ivy Wanjiku, Timothy Q. Warner, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, Pediatric surgery, APH - Aging & Later Life, Molecular cell biology and Immunology, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, and APH - Quality of Care
Subjects: 0301 basic medicine, Male, Adolescent, Loss of Heterozygosity, Context (language use), Postnatal microcephaly, Neurotransmission, medicine.disease_cause, Bioinformatics, Synaptic Transmission, Loss of heterozygosity, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Calcium Channels, N-Type, Report, Genetics, medicine, Humans, Child, Genetics (clinical), Mutation, Dyskinesias, business.industry, Infant, medicine.disease, Hypotonia, Pedigree, 030104 developmental biology, Dyskinesia, Child, Preschool, Calcium, Female, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: © 2019 American Society of Human Genetics The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.
Published: 2018

16. De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures

Author: Yoko Ito, Keren J. Carss, Sofia T. Duarte, Taila Hartley, Boris Keren, Manju A. Kurian, Isabelle Marey, Perinne Charles, Carla Mendonça, Caroline Nava, Rolph Pfundt, Alba Sanchis-Juan, Hans van Bokhoven, Anthony van Essen, Conny van Ravenswaaij-Arts, Kym M. Boycott, Kristin D. Kernohan, Sarah Dyack, F. Lucy Raymond, Timothy Aitman, David Bennett, Mark Caulfield, Patrick Chinnery, Daniel Gale, Ania Koziell, Taco W. Kuijpers, Michael A. Laffan, Eamonn Maher, Hugh S. Markus, Nicholas W. Morrell, Willem H. Ouwehand, David J. Perry, Irene Roberts, Kenneth G.C. Smith, Adrian Thrasher, Hugh Watkins, Catherine Williamson, Geoffrey Woods, Sofie Ashford, John R. Bradley, Debra Fletcher, Tracey Hammerton, Roger James, Nathalie Kingston, Christopher J. Penkett, Kathleen Stirrups, Marijke Veltman, Tim Young, Matthew Brown, Naomi Clements-Brod, John Davis, Eleanor Dewhurst, Helen Dolling, Marie Erwood, Amy Frary, Rachel Linger, Jennifer M. Martin, Sofia Papadia, Karola Rehnstrom, Hannah Stark, David Allsup, Steve Austin, Tamam Bakchoul, Tadbir K. Bariana, Paula Bolton-Maggs, Elizabeth Chalmers, Janine Collins, Peter Collins, Wendy N. Erber, Tamara Everington, Remi Favier, Kathleen Freson, Bruce Furie, Michael Gattens, Johanna Gebhart, Keith Gomez, Daniel Greene, Andreas Greinacher, Paolo Gresele, Daniel Hart, Johan W.M. Heemskerk, Yvonne Henskens, Rashid Kazmi, David Keeling, Anne M. Kelly, Michele P. Lambert, Claire Lentaigne, Ri Liesner, Mike Makris, Sarah Mangles, Mary Mathias, Carolyn M. Millar, Andrew Mumford, Paquita Nurden, Jeanette Payne, John Pasi, Kathelijne Peerlinck, Shoshana Revel-Vilk, Michael Richards, Matthew Rondina, Catherine Roughley, Sol Schulman, Harald Schulze, Marie Scully, Suthesh Sivapalaratnam, Matthew Stubbs, R. Campbell Tait, Kate Talks, Jecko Thachil, Cheng-Hock Toh, Ernest Turro, Chris Van Geet, Minka De Vries, Timothy Q. Warner, Henry Watson, Sarah Westbury, Abigail Furnell, Rutendo Mapeta, Paula Rayner-Matthews, Ilenia Simeoni, Simon Staines, Jonathan Stephens, Christopher Watt, Deborah Whitehorn, Antony Attwood, Louise Daugherty, Sri V.V. Deevi, Csaba Halmagyi, Fengyuan Hu, Vera Matser, Stuart Meacham, Karyn Megy, Olga Shamardina, Catherine Titterton, Salih Tuna, Ping Yu, Julie von Ziegenweldt, William Astle, Marta Bleda, Stefan Gräf, Matthias Haimel, Hana Lango-Allen, Sylvia Richardson, Paul Calleja, Stuart Rankin, Wojciech Turek, Julie Anderson, Christine Bryson, Jenny Carmichael, Coleen McJannet, Sophie Stock, Louise Allen, Gautum Ambegaonkar, Ruth Armstrong, Gavin Arno, Maria Bitner-Glindzicz, Angie Brady, Natalie Canham, Manali Chitre, Emma Clement, Virginia Clowes, Patrick Deegan, Charu Deshpande, Rainer Doffinger, Helen Firth, Frances Flinter, Courtney French, Alice Gardham, Neeti Ghali, Paul Gissen, Detelina Grozeva, Robert Henderson, Anke Hensiek, Simon Holden, Muriel Holder, Susan Holder, Jane Hurst, Dragana Josifova, Deepa Krishnakumar, Melissa Lees, Robert MacLaren, Anna Maw, Sarju Mehta, Michel Michaelides, Anthony Moore, Elaine Murphy, Soo-Mi Park, Alasdair Parker, Chris Patch, Joan Paterson, Julia Rankin, Evan Reid, Elisabeth Rosser, Richard Sandford, Saikat Santra, Richard Scott, Aman Sohal, Penelope Stein, Ellen Thomas, Dorothy Thompson, Marc Tischkowitz, Julie Vogt, Emma Wakeling, Evangeline Wassmer, Andrew Webster, Sonia Ali, Souad Ali, Harm J. Boggard, Colin Church, Gerry Coghlan, Victoria Cookson, Paul A. Corris, Amanda Creaser-Myers, Rosa DaCosta, Natalie Dormand, Mélanie Eyries, Henning Gall, Pavandeep K. Ghataorhe, Stefano Ghio, Ardi Ghofrani, J. Simon R. Gibbs, Barbara Girerd, Alan Greenhalgh, Charaka Hadinnapola, Arjan C. Houweling, Marc Humbert, Anna Huis in’t Veld, Fiona Kennedy, David G. Kiely, Gabor Kovacs, Allan Lawrie, Rob V. Mackenzie Ross, Rajiv Machado, Larahmie Masati, Sharon Meehan, Shahin Moledina, David Montani, Shokri Othman, Andrew J. Peacock, Joanna Pepke-Zaba, Val Pollock, Gary Polwarth, Lavanya Ranganathan, Christopher J. Rhodes, Kevin Rue-Albrecht, Gwen Schotte, Debbie Shipley, Florent Soubrier, Laura Southgate, Laura Scelsi, Jay Suntharalingam, Yvonne Tan, Mark Toshner, Carmen M. Treacy, Richard Trembath, Anton Vonk Noordegraaf, Sara Walker, Ivy Wanjiku, John Wharton, Martin Wilkins, Stephen J. Wort, Katherine Yates, Hana Alachkar, Richard Antrobus, Gururaj Arumugakani, Chiara Bacchelli, Helen Baxendale, Claire Bethune, Shahnaz Bibi, Claire Booth, Michael Browning, Siobhan Burns, Anita Chandra, Nichola Cooper, Sophie Davies, Lisa Devlin, Elizabeth Drewe, David Edgar, William Egner, Rohit Ghurye, Kimberley Gilmour, Sarah Goddard, Pavel Gordins, Sofia Grigoriadou, Scott Hackett, Rosie Hague, Lorraine Harper, Grant Hayman, Archana Herwadkar, Aarnoud Huissoon, Stephen Jolles, Peter Kelleher, Dinakantha Kumararatne, Sara Lear, Hilary Longhurst, Lorena Lorenzo, Jesmeen Maimaris, Ania Manson, Elizabeth McDermott, Sai Murng, Sergey Nejentsev, Sadia Noorani, Eric Oksenhendler, Mark Ponsford, Waseem Qasim, Isabella Quinti, Alex Richter, Crina Samarghitean, Ravishankar Sargur, Sinisa Savic, Suranjith Seneviratne, Carrock Sewell, Emily Staples, Hans Stauss, James Thaventhiran, Moira Thomas, Steve Welch, Lisa Willcocks, Nigel Yeatman, Patrick Yong, Phil Ancliff, Christian Babbs, Mark Layton, Eleni Louka, Simon McGowan, Adam Mead, Noémi Roy, Jenny Chambers, Peter Dixon, Cecelia Estiu, Bill Hague, Hanns-Ulrich Marschall, Michael Simpson, Sam Chong, Ingrid Emmerson, Lionel Ginsberg, David Gosal, Rob Hadden, Rita Horvath, Mohamed Mahdi-Rogers, Adnan Manzur, Andrew Marshall, Emma Matthews, Mark McCarthy, Mary Reilly, Tara Renton, Andrew Rice, Andreas Themistocleous, Tom Vale, Natalie Van Zuydam, Suellen Walker, Liz Ormondroyd, Gavin Hudson, Wei Wei, Patrick Yu Wai Man, James Whitworth, Maryam Afzal, Elizabeth Colby, Moin Saleem, Omid S. Alavijeh, H. Terry Cook, Sally Johnson, Adam P. Levine, Edwin K.S. Wong, Rhea Tan, Alex MacKenzie, Jacek Majewski, Michael Brudno, Dennis Bulman, David Dyment, Freson, Kathleen, Peerlinck, Kathelijne, Van Geet, Christel, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: DA CDL Algemeen (9), Med Microbiol, Infect Dis & Infect Prev, Medical Research Council (MRC), Clinical Cognitive Neuropsychiatry Research Program (CCNP), APH - Aging & Later Life, Pediatric surgery, Human genetics, ACS - Atherosclerosis & ischemic syndromes, CCA - Cancer biology and immunology, CCA - Cancer Treatment and quality of life, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, APH - Quality of Care, and Molecular cell biology and Immunology
Subjects: 0301 basic medicine, Male, Care4Rare Canada Consortium, WAVE FAMILY PROTEINS, actin cytoskeleton, PROTEIN, HDE NEU PED, medicine.disease_cause, Whole Exome Sequencing, 0302 clinical medicine, Neurodevelopmental disorder, SYNAPTIC PLASTICITY, Intellectual disability, WAVE1 complex, PLASTICITY, EXCHANGE, 11 Medical and Health Sciences, Exome sequencing, Genetics (clinical), seizures, Genetics & Heredity, Genetics, Mutation, WASF1, DENDRITIC SPINES, developmental delay, Female, DISEASE GENE-DISCOVERY, Adult, Heterozygote, GENES, DISORDERS, autism, Biology, ACTIN, 03 medical and health sciences, Young Adult, Seizures, Report, Intellectual Disability, Exome Sequencing, medicine, Humans, PROTRUSIONS, recurrent de novo truncating mutations, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], COMPLEX, lamellipodia, neurodevelopmental disorder, Actin remodeling, Heterozygote advantage, NIHR BioResource, 06 Biological Sciences, medicine.disease, Actin cytoskeleton, Wiskott-Aldrich Syndrome Protein Family, 030104 developmental biology, WAVE, RETARDATION, 030217 neurology & neurosurgery
Abstract: Next-generation sequencing has been invaluable in the elucidation of the genetic etiology of many subtypes of intellectual disability in recent years. Here, using exome sequencing and whole-genome sequencing, we identified three de novo truncating mutations in WAS protein family member 1 (WASF1) in five unrelated individuals with moderate to profound intellectual disability with autistic features and seizures. WASF1, also known as WAVE1, is part of the WAVE complex and acts as a mediator between Rac-GTPase and actin to induce actin polymerization. The three mutations connected by Matchmaker Exchange were c.1516C>T (p.Arg506Ter), which occurs in three unrelated individuals, c.1558C>T (p.Gln520Ter), and c.1482delinsGCCAGG (p.Ile494MetfsTer23). All three variants are predicted to partially or fully disrupt the C-terminal actin-binding WCA domain. Functional studies using fibroblast cells from two affected individuals with the c.1516C>T mutation showed a truncated WASF1 and a defect in actin remodeling. This study provides evidence that de novo heterozygous mutations in WASF1 cause a rare form of intellectual disability. ispartof: AMERICAN JOURNAL OF HUMAN GENETICS vol:103 issue:1 pages:144-153 ispartof: location:United States status: published
Published: 2018

17. The incidence of factor <scp>VIII</scp> inhibitors in severe haemophilia A following a major switch from full‐length to B‐domain‐deleted factor <scp>VIII</scp> : a prospective cohort comparison

Author: R. Liesner, Michael Williams, B. Palmer, Elizabeth Chalmers, Daniel P. Hart, Savita Rangarajan, Peter William Collins, Kate Talks, and Charles R. M. Hay
Subjects: Adult, Male, medicine.medical_specialty, Pediatrics, Adolescent, Haemophilia A, Hemophilia A, Rate ratio, Severity of Illness Index, Gastroenterology, Young Adult, Isoantibodies, Risk Factors, Internal medicine, medicine, Humans, Public Health Surveillance, In patient, Prospective Studies, Child, Prospective cohort study, Genetics (clinical), Factor VIII, Drug Substitution, business.industry, Incidence, Incidence (epidemiology), Hematology, General Medicine, Middle Aged, medicine.disease, Peptide Fragments, Recombinant Proteins, Titer, Treatment Outcome, Severe haemophilia A, business, Previously treated
Abstract: Summary Although it has been suggested that switching of factor VIII (FVIII) products may increase inhibitor formation this is disputed. Half of UK patients changed rFVIII brands because of national contracting in 2010, presenting an opportunity to compare inhibitor incidence of switchers with non-switchers. Centres were requested to test all the patients for inhibitors prior to the switching date and 6-monthly thereafter. Positive and negative inhibitor test data were also collected to analyse for testing bias. A total of 1198 patients with severe haemophilia A and treated with Advate, Kogenate/Helixate or Refacto AF preswitch were included in the analysis, of whom 516 switched to Refacto-AF and 682 did not switch products. Five new inhibitors were reported amongst previously treated patients (>50 exposure days) with a median titre at the time of detection of 1.25 BU mL−1 (IQR 0.7–23.05). One inhibitor occurred in a non-switcher using Kogenate, an incidence of 1.5 per 1000 treatment-years (95% CI 0.2–10.5). Four inhibitors arose in patients who had switched from Kogenate (two) or Advate (two) to ReFacto-AF, an incidence of 7.8 per 1000 treatment-years (95% CI 2.9–20.8). These incidence rates did not differ significantly from one another (incidence rate ratio 5.3 (95% CI 0.5–260.3) or from the historical rate of 6.05 inhibitors/1000 treatment-years (95% CI 5.18–7.06). Only one inhibitor (non-switcher) persisted. Non-switchers were significantly older (P = 0.03), and used significantly less FVIII per year (P = 0.005) prior to switching. Following switching, factor usage increased similarly (P = 0.53) in both groups. Switching from FLRFVIII to Refacto-AF (BDDRFVIII) was not associated with an increased inhibitor development.
Published: 2014

18. Diagnosis and treatment of factor VIII and IX inhibitors in congenital haemophilia: (4th edition)

Author: Kate Talks, Peter William Collins, Michael D. Williams, Elizabeth Chalmers, Daniel P. Hart, Ri Liesner, Savita Rangarajan, and Charles R. M. Hay
Subjects: medicine.medical_specialty, business.industry, education, Hematology, University hospital, Haemophilia, medicine.disease, Sick child, Surgery, Blood loss, Newcastle upon tyne, Family medicine, medicine, business, health care economics and organizations
Abstract: Peter W. Collins, Elizabeth Chalmers, Daniel P. Hart, Ri Liesner, Savita Rangarajan, Kate Talks, Mike Williams and Charles R. Hay School of Medicine, Cardiff University, University Hospital of Wales, Wales, Royal Hospital for Sick Children, Glasgow, The London School of Medicine and Dentistry, Royal London Hospital, Barts, Queen Mary University, London, Great Ormond Street NHS Trust, London, Hampshire Hospital NHS Foundation Trust, Basingstoke & North Hampshire Hospital, Basingstoke, Royal Victoria Infirmary, Newcastle upon Tyne, Birmingham Childrens’ Hospital NHS Foundation Trust, Birmingham and Central Manchester University Hospitals, Manchester, UK
Published: 2012

19. A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A

Author: Brigit Brand, Alessandro Gringeri, Paul Giangrande, James J. Goedert, Michael Recht, Olga Katsarou, Ana Rosa Cid-Haro, Patrick F. Fogarty, Steven M. Wolinsky, Evelien P. Mauser-Bunschoten, Judith Lin, Kate Talks, Javier Martinez-Picado, Amy D. Shapiro, Amalio Telenti, Christine L. Kempton, Lucy Dorrell, David Goldstein, Jérôme Lane, Jerry S. Powell, Sara Colombo, Judith Dalmau, Jeremy J. Martinson, Johannes Oldenburg, Shehnaz K. Hussain, Barton F. Haynes, Michael Makris, Dimitrios A. Tsakiris, Amanda Stemke, Anne T. Neff, Stephen Moore, Shinichi Oka, Philip Kuriakose, Rathi V. Iyer, Jonathan T. Wilde, Peter William Collins, Maria Teresa Alvarez-Roman, Andrew J. McMichael, Rafael Parra, Françoise Boehlen, Paul J. McLaren, Deborah L Brown, Marilyn J. Manco-Johnson, Thynn Thynn Yee, Kimo C. Stine, Bonaventura Clotet, Kimberly Pelak, Jay H. Bream, Kristiina Peter-Salonen, Paula H B Bolton-Maggs, Elaine Y. Chiang, Lisa P. Jacobson, Mary Carrington, Lara Oyesiku, Anne Angelillo-Scherrer, Jacques Fellay, Kevin V. Shianna, and NIAID Center for HIV/AIDS Vaccine Immunology (CHAVI)
Subjects: Male, HIV Infections/genetics, HIV Infections, Genome-wide association study, Loss of heterozygosity, 0302 clinical medicine, HIV Seropositivity/genetics, hemic and lymphatic diseases, HIV Seropositivity, Prospective Studies, 030212 general & internal medicine, Copy-number variation, Genetics (clinical), Disease Resistance, ddc:616, Factor VIII/therapeutic use, Genetics, 0303 health sciences, education.field_of_study, Association Studies Articles, Homozygote, General Medicine, Middle Aged, 3. Good health, Phenotype, Female, Hemophilia A/genetics, Adult, Heterozygote, Receptors, CCR5, DNA Copy Number Variations, Disease Resistance/genetics, Population, 610 Medicine & health, Single-nucleotide polymorphism, Biology, Hemophilia A, Polymorphism, Single Nucleotide, 03 medical and health sciences, Meta-Analysis as Topic, Humans, SNP, Genetic Predisposition to Disease, Receptors, CCR5/genetics/metabolism, education, Molecular Biology, 030304 developmental biology, Factor VIII, Epistasis, Genetic, Heritability, Logistic Models, Gene Deletion, Imputation (genetics), Genome-Wide Association Study
Abstract: Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979-1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this population.
Published: 2016

20. Bilateral upper limb compartment syndrome induced by strenuous exercise in a patient with haemophilia A and a low titre inhibitor

Author: M. A. Abdelhalim, John Hanley, David Hopper, Paul V Fearon, Z. Abu Al-Rub, Kate Talks, C. R. Shaw, and Tina Biss
Subjects: Male, medicine.medical_specialty, business.industry, Strenuous exercise, Haemophilia A, Hematology, General Medicine, medicine.disease, Hemophilia A, Compartment Syndromes, Surgery, Upper Extremity, medicine.anatomical_structure, Medicine, Upper limb, Humans, Female, business, Compartment (pharmacokinetics), Exercise, Genetics (clinical)
Published: 2015

21. Interventions for preventing thrombosis in solid organ transplant recipients

Author: Mari Kilner, John Hanley, Tina T Biss, Kate Talks, and Colin H Wilson
Subjects: Pharmacology (medical)
Published: 2015

22. Factor VIII brand and the incidence of factor VIII inhibitors in previously untreated UK children with severe hemophilia A, 2000-2011

Author: Kate Talks, Ri Liesner, Charles R. M. Hay, Elizabeth Chalmers, Daniel P. Hart, Michael Williams, B. Palmer, Savita Rangarajan, and Peter William Collins
Subjects: Male, Pediatrics, medicine.medical_specialty, Clinical Trials and Observations, Immunology, Haemophilia, Hemophilia A, Biochemistry, Severity of Illness Index, Cohort Studies, Interquartile range, Isoantibodies, Internal medicine, hemic and lymphatic diseases, Severity of illness, Medicine, Humans, Child, Factor VIII, business.industry, Incidence (epidemiology), Incidence, Hazard ratio, Infant, Newborn, Infant, Cell Biology, Hematology, medicine.disease, Confidence interval, United Kingdom, Titer, Child, Preschool, Antibody Formation, business, Cohort study
Abstract: The effect of recombinant factor VIII (rFVIII) brand on inhibitor development was investigated in all 407 severe hemophilia A previously untreated patients born in the United Kingdom (UK) between 1 January 2000 and 31 December 2011. Eighty-eight (22%) had been in the RODIN study. Information was extracted from the National Haemophilia Database. Because exposure days (EDs) were not known for some patients, time from first treatment was used as a surrogate for rFVIII exposure. An inhibitor developed in 118 (29%) patients, 60 high and 58 low titer, after a median (interquartile range) of 7.8 (3.3-13.5) months from first exposure and 16 (9-30) EDs. Of 128 patients treated with Kogenate Bayer/Helixate NexGen, 45 (35.2%, 95% confidence interval [CI] 27.4-43.8) developed an inhibitor compared with 42/172 (24.4%, 95% CI 18.6% to 31.4%) with Advate (P = .04). The adjusted hazard ratio (HR) (95% CI) for Kogenate Bayer/Helixate NexGen compared with Advate was 2.14 (1.12-4.10) (P = .02) for high titer and 1.75 (1.11-2.76) (P = .02) for all inhibitors. When excluding UK-RODIN patients, the adjusted HR (95% CI) for high-titer inhibitors was 2.00 (0.93-4.34) (P = .08). ReFacto AF was associated with a higher incidence of all, but not high-titer, inhibitors than Advate. These results will help inform debate around the relative immunogenicity and use of rFVIII brands.
Published: 2014

23. Congenital and acquired bleeding problems in elderly patients

Author: AL Nicolle, Kate Talks, and John Hanley
Subjects: medicine.medical_specialty, business.industry, Structural Problem, medicine.disease, Asymptomatic, Tissue factor, Coagulation cascade, Internal medicine, Coagulation testing, Coagulopathy, Cardiology, Coagulation (water treatment), Medicine, Geriatrics and Gerontology, medicine.symptom, Bleeding problems, business, Gerontology
Abstract: Bleeding in elderly patients is most commonly due to an underlying structural problem or an acquired coagulopathy. Occasionally, previously asymptomatic congenital bleeding disorders may present at an advanced age. When considering the possible causes of a clinical bleeding problem, the coagulation cascade is still a good starting-point. However, it is important to realize that the traditional model of the coagulation cascade has been superceded by the concept of a ‘coagulation network’. This updated model recognizes the importance of tissue factor in the initiation of coagulation. Despite the complexity of this model, the basic coagulation tests can still be interpreted in relation to the ‘intrinsic’, ‘extrinsic’ and ‘final common pathway’ components of the old-fashioned cascade (Figure 1).
Published: 2005

24. Massive post-partum haemorrhage and management of disseminated intravascular coagulation

Author: Kate Talks and Sheila Macphail
Subjects: Disseminated intravascular coagulation, medicine.medical_specialty, Blood transfusion, business.industry, medicine.medical_treatment, Obstetrics and Gynecology, Maternal morbidity, medicine.disease, medicine, Level of care, Intensive care medicine, Good practice, business, Post partum
Abstract: Death from haemorrhage fell in the last triennial report from 5.5 to 3.3 per million maternities in the UK. Although the Confidential Report into Maternal Deaths in the UK 1997–1999 continues to make recommendations in relation to the management of obstetric haemorrhage in an attempt to improve the overall level of care, it is disappointing that care was considered to be substandard in 11 of the 14 cases reviewed. While various risk factors can be identified for post-partum haemorrhage, further improvements in care can only occur with dissemination of good practice and adoption of local protocols designed to deliver the optimal care to women in their care. The general management of massive post-partum haemorrhage has been outlined previously in Current Obstetrics & Gynaecology. Disseminated intravascular coagulation plays a significant role in the deaths described in the most recent Confidential Report, and this article focuses on the recent developments in managing coagulation problems as a result of massive post-partum haemorrhage.
Published: 2004

25. A national survey of immunosuppression strategies for acquired haemophilia A

Author: Charles R. M. Hay, R. Liesner, Savita Rangarajan, Elizabeth Chalmers, Daniel P. Hart, Michael Williams, Peter William Collins, B. Palmer, P. Batty, and Kate Talks
Subjects: Immunosuppression Therapy, medicine.medical_specialty, Time Factors, business.industry, medicine.medical_treatment, Data Collection, Immunosuppression, General Medicine, Hematology, Hemophilia A, United Kingdom, Withholding Treatment, Acquired haemophilia, Medicine, Humans, business, Intensive care medicine, Genetics (clinical)
Published: 2014

26. Reversal of warfarin-induced over-anticoagulation with individualized dosing of oral vitamin K: a pilot study

Author: Ann K. Daly, John P. Hanley, Patrick Kesteven, Farhad Kamali, Kate Talks, Peter Avery, and Montserrat Briz
Subjects: Adult, Male, medicine.medical_specialty, Vitamin K, Individualized dosing, Administration, Oral, Pilot Projects, Asymptomatic, Gastroenterology, law.invention, Randomized controlled trial, law, Internal medicine, Humans, Medicine, International Normalized Ratio, Dosing, CYP2C9, Aged, Aged, 80 and over, business.industry, Warfarin, Anticoagulants, Hematology, Middle Aged, Surgery, Oral vitamin, Female, VKORC1, medicine.symptom, business, medicine.drug
Abstract: Evidence from randomized controlled trials supports the use of low-dose oral vitamin K for the reversal of International Normalized Ratio (INR) in asymptomatic patients [1–4]. However, there is no clear consensus about the optimal dose that should be given to patients. The majority of the reported studies have used fixed oral doses of vitamin K (ranging from 1.0 to 5.0 mg) based upon assigning a fixed vitamin K dose (according to a dichotomy of elevated INR values) to reverse excessive anticoagulation, with a high percentage of patients at 24 h after vitamin K dosing being either undercoagulated or over-anticoagulated, leaving them at risk of either thromboembolism or hemorrhage, respectively [5,6]. The anticoagulation response to warfarin is influenced by a number of clinical, environmental and genetic factors [7] that could influence the vitamin K dose requirement. This pilot study evaluated the effectiveness of a novel tailored oral vitamin K dosing regimen for the reversal of non-urgent overanticoagulation based on the individual patient sI NR. The influences of patient age, sex, body weight, height, target INR, warfarin daily dose and CYP2C9 and VKORC1 polymorphisms on the extent of INR reversal were also retrospectively determined. The tailored vitamin K dosing algorithm was developed on the basis of a best fit bivariate regression model containing data on venous INR values at presentation on day 0 and on day 1 for 84 patients after oral vitamin K administration (1 or 2 mg), according to current anticoagulation reversal guidelines in place in the Northern Region of England [8]. The regression model produced the following equation for estimation of vitamin K dose: Vitamin K dose (mg) ¼½ Change in INR þ 3:51
Published: 2010

27. Diagnosis and treatment of factor VIII and IX inhibitors in congenital haemophilia: (4th edition). UK Haemophilia Centre Doctors Organization

Author: Peter W, Collins, Elizabeth, Chalmers, Daniel P, Hart, Ri, Liesner, Savita, Rangarajan, Kate, Talks, Mike, Williams, and Charles R, Hay
Subjects: Male, Clinical Trials as Topic, Factor VIII, DNA Mutational Analysis, Blood Loss, Surgical, Dose-Response Relationship, Immunologic, Hemorrhage, Factor VIIa, Immunologic Tests, Hemophilia A, Hemophilia B, Blood Coagulation Factors, Recombinant Proteins, State Medicine, United Kingdom, Factor IX, Desensitization, Immunologic, Isoantibodies, Risk Factors, Immune Tolerance, Humans, Female, Immunosuppressive Agents
Published: 2012

28. Rozrolimupab, a mixture of 25 recombinant human monoclonal RhD antibodies, in the treatment of primary immune thrombocytopenia

Author: Emanuil Gheorghita, Kate Talks, Isidro Jarque, Mario von Depka Prondzinski, Gloria Pérez Rus, Jerzy Windyga, Prasad Sripada, Javier Loscertales, Mimi F Flensburg, Peter S. Andersen, Mihaela Lazaroiu, T. P. R. Bharadwaj, Dina Attias, Henrik Næsted, Jørgen Petersen, Andrei Cucuianu, Tadeusz Robak, Kateryna Vilchevska, Jacek Treliński, Kazimierz Kuliczkowski, Dusica Celeketic, Niels Jorgen Ostergaard Skartved, Andrzej Hellmann, Ofer Shpilberg, Ann Janssens, María Teresa Álvarez-Román, Kalinina Svetlana, Wiesław Wiktor Jędrzejczak, Chantal Doyen, Mukhyaprana Prabhu, Aristoteles Giagounidis, Nichola Cooper, Torben P. Frandsen, Elena Karyagina, and Lana M. Golubovic
Subjects: Adult, Male, medicine.medical_specialty, medicine.drug_class, Immunology, Monoclonal antibody, Biochemistry, Gastroenterology, Immunoglobulin G, Rozrolimupab, Internal medicine, medicine, Humans, Platelet, Adverse effect, Aged, Purpura, Thrombocytopenic, Idiopathic, Hematology, biology, Dose-Response Relationship, Drug, business.industry, Antibodies, Monoclonal, Cell Biology, Middle Aged, Recombinant Proteins, Monoclonal, biology.protein, Female, Antibody, business
Abstract: Rozrolimupab, a recombinant mixture of 25 fully human RhD-specific monoclonal antibodies, represents a new class of recombinant human antibody mixtures. In a phase 1 or 2 dose escalation study, RhD+ patients (61 subjects) with primary immune thrombocytopenia received a single intravenous dose of rozrolimupab ranging from 75 to 300 μg/kg. The primary outcome was the occurrence of adverse events. The principal secondary outcome was the effect on platelet levels 7 days after the treatment. The most common adverse events were headache and pyrexia, mostly mild, and reported in 20% and 13% of the patients, respectively, without dose relationship. Rozrolimupab caused an expected transient reduction of hemoglobin concentration in the majority of the patients. At the dose of 300 μg/kg platelet responses, defined as platelet count ≥ 30 × 109/L and an increase in platelet count by > 20 × 109/L from baseline were observed after 72 hours and persisted for at least 7 days in 8 of 13 patients (62%). Platelet responses were observed within 24 hours in 23% of patients and lasted for a median of 14 days. Rozrolimupab was well tolerated and elicited rapid platelet responses in patients with immune thrombocytopenia and may be a useful alternative to plasma-derived products. This trial is registered at www.clinicaltrials.gov as #NCT00718692.
Published: 2012

29. Control of variceal bleeding in a patient with severe haemophilia A and factor VIII inhibitors using a transjugular intrahepatic portosystemic shunt

Author: John Hanley, Erin Hurst, and Kate Talks
Subjects: Variceal bleeding, medicine.medical_specialty, business.industry, medicine.medical_treatment, Treatment outcome, MEDLINE, Hematology, General Medicine, Gastroenterology, Internal medicine, medicine, Severe haemophilia A, business, Transjugular intrahepatic portosystemic shunt, Genetics (clinical)
Published: 2010

30. Correlation of a Condensed Bleeding Score with New Diagnosis of a Congenital Bleeding Disorder in Patients Referred to a Tertiary Centre

Author: Deepa R. J. Arachchillage, Kate Talks, John Hanley, and Tina T. Biss
Subjects: Prothrombin time, Pediatrics, medicine.medical_specialty, medicine.diagnostic_test, business.industry, Abnormal bleeding, Immunology, Cell Biology, Hematology, medicine.disease, Biochemistry, Bleeding diathesis, Von Willebrand disease, medicine, Coagulation testing, business, Congenital Bleeding Disorder, Factor XI, Partial thromboplastin time
Abstract: Abstract 1226 The performance and utility of a condensed bleeding score (Bowman et al, J Thromb Haemost., 2008;6:2062) in relation to the diagnosis of a congenital bleeding disorder in new referrals to a regional haemostasis clinic over an 8 month period is presented. Between November 2010 and June 2011, 50 patients over the age of 16 (median age, 31 years; range, 16–79), including 32 females, were referred for investigation of a possible congenital bleeding disorder following detection of abnormal coagulation results and/or presentation with a bleeding history. A bleeding score was performed as part of their initial assessment. 12(24%) patients were from local referral and 38(76%) patients were referred from other hospitals in the region for further investigation of a suspected bleeding disorder. Basic coagulation tests (activated partial thromboplastin time (APTT), prothrombin time Clauss fibrinogen and platelet count) were normal in the referred patients from other centres. 50% (6/12) of the local referrals were for investigation of a prolonged APTT detected on routine coagulation screening prior to major surgery. The median bleeding score was 6 with a range of −1 to 14 (Table 1). The presence of a congenital bleeding disorder was confirmed in 31 of the 50 patients (62%), including 19/31 (61%) of the female patients and 12/31(39%) of the males. Correlation of an abnormal bleeding score (score ≥ 4) with diagnosis of a congenital bleeding disorder was only seen for diagnosis of type 1 Von Willebrand Disease (VWD) (Table 2). Analysis of the cases with low scores and abnormal results identified two groups of patients; firstly, those who had not yet had a significant haemostatic challenge, and secondly, those in whom the abnormal coagulation results were explained by a non-haemostatically significant reduction in a coagulation factor level (e.g. FVII, 15%; dysfibrinogenaemia; F XII deficiency). These clinically insignificant laboratory abnormalities explain the discrepancy between the number of patients with abnormal laboratory tests (35) and the number of patients diagnosed with a congenital bleeding disorder (31).Table 1Bleeding score (range)Number of patients with normal lab resultsNumber of patients with abnormal lab results−1 to +1382–44105–74128–102311–1422Total1535Table 2DiagnosisNumber of patientsMedian bleeding scoreAge rangeType 1 VWD116 (4–10)17–51Type 2 VWD48 (5–13)17–36Factor XI123 (1–8)17–76Platelet function defect46 (2–9)17–57 Compared to previous reports the range of scores found with this assessment tool was narrow and could not exclude patients from further laboratory assessment. However the condensed bleeding score has only been validated prospectively for the diagnosis of type 1 VWD and all patients in this cohort who were diagnosed with type 1 VWD had an abnormal bleeding score (≥ 4). This observation supports the role of this scoring system in the assessment of patients for type 1 VWD. The use of the condensed bleeding score in assessing patients with suspected factor XI deficiency is difficult due to the lack of a phenotypic relationship between residual factor XI activity and a bleeding tendency. Furthermore, although factor XI deficiency is a rare congenital bleeding disorder in our cohort of patients 12/31(39%) were diagnosed with factor XI deficiency. This may explain the overall lack of correlation between bleeding score and diagnosis of a congenital bleeding disorder. Patients who have an abnormal bleeding score but normal laboratory tests need consideration of further investigations before concluding they are normal. The possibility of an acquired bleeding disorder should be considered. A thorough drug history is also important as one of the patients with a bleeding score of 14 was taking a non-steroidal anti-inflammatory drug. The use of the condensed bleeding score in the detection of congenital bleeding disorders other than type 1 VWD requires further validation in a larger number of patients. Disclosures: No relevant conflicts of interest to declare.
Published: 2011

31. Intracranial Haemorrhage in Patients with An Inherited Bleeding Disorder: A Review of 10 Years Experience in a UK Haemophilia Comprehensive Centre

Author: Kate Talks, Siamak Arami, and Tina T. Biss
Subjects: congenital, hereditary, and neonatal diseases and abnormalities, Pediatrics, medicine.medical_specialty, Immunology, Population, macromolecular substances, Haemophilia, Biochemistry, hemic and lymphatic diseases, medicine, Von Willebrand disease, Haemophilia B, education, education.field_of_study, biology, business.industry, Cell Biology, Hematology, medicine.disease, Prothrombin complex concentrate, Bleeding diathesis, Congenital afibrinogenemia, Recombinant factor VIIa, biology.protein, business, medicine.drug
Abstract: 3489 Poster Board III-426 Introduction- Inherited bleeding disorders comprise a heterogeneous group of diseases that reflect abnormalities of coagulation proteins, platelets and blood vessels. Intracranial haemorrhage (ICH) is an unusual but life-threatening complication of such disorders. A 10-year retrospective study was conducted to investigate the episodes of ICH in patients with an inherited bleeding disorder who where followed by a regional haemophilia comprehensive care center in the UK. Methods- All cases of ICH occurring in patients with an inherited bleeding disorder which presented between 1999 and 2009 were retrospectively identified using the haemophilia centre database. Case notes were reviewed and aetiology, clinical features, radiological findings, management and outcome of ICH in this population were studied. Results- Of 640 patients registered with an inherited bleeding disorder in haemophilia centre database, a total of 10 ICHs in 9 patients were identified. Age of patients ranged from 5 months to 72 years with a higher number of males (M:F = 7:2). Diagnosis included: Severe haemophilia A (3 patients); Mild haemophilia A (1 patient); Severe haemophilia B (1 patient); Type 2A von Willebrand disease (VWD) (1 patient); Type 3 VWD (1 patient); Congenital afibrinogenemia (1 patient); Severe factor V deficiency (1 patient). Two of the patients with severe haemophilia A had inhibitors, one of whom was receiving immune tolerance therapy at the time of the ICH. 7 of ICHs were spontaneous and 3 were trauma-related. ICH was the first significant bleeding event in 2 patients- one with severe haemophilia A, aged 5 months, and one with severe haemophilia B, aged 6 months. Type of ICHs were 7 subdural, 1 subarachnoid and 2 subdural with intracerebral. All patients were symptomatic. Common presenting features were headache (6 patients), vomiting (5 patients), limb paralysis (3 patients), cranial nerve palsy (3 patients) and seizures (2 patients). None had systemic bleeding concurrent to the ICH. Initial diagnostic modality was CT scan without contrast for all patients. The two patients with severe haemophilia A and inhibitors were initially treated with recombinant factor VIIa. The remaining patients with haemophilia were treated with factor VIII/IX concentrate. The patient with severe haemophilia B required surgical evacuation. The patients with severe haemophilia A/B without inhibitors were commenced on long-term prophylaxis with factor replacement therapy following their ICH. The patient with congenital afibrinogenemia was initially treated with fibrinogen concentrate, repeated CT scan on day ten showed significant expansion of hematoma, surgical evacuation was done and he was commenced on long-term prophylaxis. The patient with factor V deficiency received prothrombin complex concentrate (octaplex). The two patients with VWD were treated with haemate P, the patient with type 2A VWD received prophylaxis for 4 weeks. The patient with type 3 VWD died within an hour of admission despite haemate P treatment. Six patients had long-term morbidity including limb weakness, seizure, ventriculoperitoneal shunt and developmental delay. These results are summarized in [Table 1][1]. Conclusions- ICH can occur in patients with a severe inherited bleeding disorder and can result in substantial morbidity and mortality. ICH can also occur in patients with a mild inherited bleeding disorder following trauma. There is no reliable predictor for intracranial bleeding which could aid decision-making in terms of prophylactic therapy to prevent ICH. CT scan is an appropriate initial diagnostic modality. It is important to educate patients and parents about symptoms to allow early diagnosis. Treatment should be administered rapidly to control bleeding in order to limit adverse outcomes. | Age | Sex | Diagnosis | Type of ICH | Spontaneous or traumatic | Long term morbidity/mortality | |:----:| --- | -------------------------- | --------------------- | ------------------------ | -------------------------------------- | | 5Mo | M | Severe Haemophilia A | SDH | Spontaneous | Developmental delay, VP shunt | | 3Y | M | Severe Haemophilia A | SAH | Spontaneous | Limb weakness | | 48Y | M | Severe Haemophilia A | SDH | Spontaneous | Seizure | | 20Y | M | Mild Haemophilia A | SDH and Intracerebral | Traumatic | Nil | | 6Mo | M | Severe Haemophilia B | SDH | Spontaneous | Developmental delay, Seizure, VP shunt | | 37Y | M | Congenital afibrinogenemia | SDH | Spontaneous | Limb weakness | | 72Y | M | Type 2A VWD | SDH and Intracerebral | Spontaneous | Nil | | 19Y | F | Type 3 VWD | SDH | Traumatic | Died | | 53 Y | F | Severe factor V deficiency | SDH | Traumatic | Limb weakness | Table 1 Disclosures: No relevant conflicts of interest to declare. [1]: #T1
Published: 2009

32. Serial D-Dimer Measurements Are Useful in Predicting the Recurrence of Venous Thromboembolism after Discontinuation of Anticoagulation

Author: Patrick Kesteven, John Hanley, Helen Marr, Montserrat Briz, and Kate Talks
Subjects: Pregnancy, medicine.medical_specialty, business.industry, medicine.medical_treatment, Deep vein, Immunology, Cell Biology, Hematology, medicine.disease, Malignancy, Biochemistry, Thrombosis, Pulmonary embolism, Discontinuation, Surgery, medicine.anatomical_structure, D-dimer, medicine, Hormone therapy, business
Abstract: The optimal duration of anticoagulation following a venous thromboembolism (VTE) is influenced by the site of the event and the presence of risk factors. After anticoagulation is discontinued, approximately 10% of patients will have a recurrent event. At present, there is no accurate method of identifying this group of patients, in whom the benefits of reanticoagulation may outweigh the bleeding risks. In 2006, Palaretti et al reported the use of a single qualitative d-dimer measurement, 4 weeks after stopping anticoagulation for a spontaneous VTE, to identify patients at increased risk of a recurrent VTE. Our observational study investigates whether serial quantitative d-dimer measurements, after the discontinuation of anticoagulation for VTE, are of use in identifying patients at higher risk of VTE recurrence. We followed an unselected group of patients attending a hospital based Thrombosis Clinic in whom anticoagulation for VTE was stopped. Over a 2 year period from July 2005 to July 2007, anticoagulation was discontinued in 216 patients (112 females, 104 males) after a median period of 6 months’ treatment (range 2–324 months). The patients ranged in age from 16–88 years, with a mean age of 54 years. Of the group, 146 had been anticoagulated for a deep vein thrombosis (DVT), 59 for pulmonary embolism (PE) +/− DVT, and 11 had been anticoagulated for VTE at other sites. Major risk factors for VTE (recent surgical procedure, malignancy, pregnancy) were present at diagnosis in 80 patients. Minor risk factors (minor trauma, prolonged travel or immobility, hormone therapy) were present in 61 patients, while no risk factors were identified in 69 patients. Presence of risk factors was unknown in the remaining 6 patients. After discontinuation of their anticoagulation, patients were followed up in the Thrombosis Clinic for a median of 14.5 months (range 0–41 months). D-dimer measurements were recorded at the point of stopping anticoagulation, 4 weeks later, and then on subsequent clinic visits. Quantitative d-dimer results were obtained using an automated latex immunoassay (Instrumentation Laboratories, d-dimers HS) on an ACL TOP CTS analyser. Recurrence of VTE occurred in 23 of the 216 (10.7%) patients. D-dimer results off anticoagulation were available in 207 patients. Forty six patients had repeatedly high d-dimer measurements (> 300ng/ml) off anticoagulation. D-dimers remained within the normal range in 112 patients. In 33 patients, d-dimers were initially normal, but subsequently became high, while the opposite was true in 16 patients, where initially high d-dimers later fell into the normal range. Of the recurrences, 8 occurred in the group who had repeatedly high d-dimers after anticoagulation was stopped (17.4%), whilst only 3 recurrences occurred in patients whose d-dimers were consistently normal (2.7%). In the group whose d-dimers were initially normal, but subsequently became high during follow up, there were 6 recurrences (18.2%). There was 1 recurrence in the group whose d-dimers were initially high, but then became normal. In the 9 patients in whom serial d-dimer results were not available, 5 recurrent VTE were observed: 4 of these occurred within 4 weeks of the patient stopping anticoagulation. After statistical analysis of the data, taking into account the nature of the original event, age, gender and d-dimer measurements, a high d-dimer off anticoagulation was the only significant independent variable predicting for recurrence of VTE (Chi-square 13.1 p
Published: 2008

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32 results on '"Kate Talks"'

1. PB2612: UNITED KINGDOM RETROSPECTIVE OBSERVATIONAL STUDY OF ROMIPLOSTIM AND OTHER TREATMENTS IN EARLY IMMUNE THROMBOCYTOPENIA

2. Whole-genome sequencing of patients with rare diseases in a national health system.

3. Retrospective, Observational, Multicenter Study Assessing the Thrombopoietin Receptor Agonist (TPO-RA) Romiplostim and Other Treatments for Patients with Newly Diagnosed or Persistent Primary Immune Thrombocytopenia (ITP) in Routine Clinical Practice in the United Kingdom (UK)

4. Mycophenolate Mofetil for First-Line Treatment of Immune Thrombocytopenia

5. Immune tolerance induction in severe haemophilia A: A UKHCDO inhibitor and paediatric working party consensus update

6. Guidelines on the use of prophylactic factor replacement for children and adults with Haemophilia A and B

7. Bayesian Inference Associates Rare KDR Variants with Specific Phenotypes in Pulmonary Arterial Hypertension

8. Treatment of bleeding episodes in haemophilia A complicated by a factor VIII inhibitor in patients receiving Emicizumab. Interim guidance from UKHCDO Inhibitor Working Party and Executive Committee

9. Factor IX Expression within the Normal Range Prevents Spontaneous Bleeds Requiring Treatment Following FLT180a Gene Therapy in Patients with Severe Hemophilia B: Long-Term Follow-up Study of the B-Amaze Program

10. Assessment of the efficacy of a novel tailored vitamin K dosing regimen in lowering the International Normalised Ratio in over-anticoagulated patients: a randomised clinical trial

11. First-line immune tolerance induction for children with severe haemophilia A: A protocol from the UK Haemophilia Centre Doctors' Organisation Inhibitor and Paediatric Working Parties

12. Biallelic Mutation of ARHGEF18, Involved in the Determination of Epithelial Apicobasal Polarity, Causes Adult-Onset Retinal Degeneration

13. Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

14. A United Kingdom Immune Thrombocytopenia (ITP) Forum review of practice: thrombopoietin receptor agonists

15. Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia

16. De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures

17. The incidence of factor <scp>VIII</scp> inhibitors in severe haemophilia A following a major switch from full‐length to B‐domain‐deleted factor <scp>VIII</scp> : a prospective cohort comparison

18. Diagnosis and treatment of factor VIII and IX inhibitors in congenital haemophilia: (4th edition)

19. A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A

20. Bilateral upper limb compartment syndrome induced by strenuous exercise in a patient with haemophilia A and a low titre inhibitor

21. Interventions for preventing thrombosis in solid organ transplant recipients

22. Factor VIII brand and the incidence of factor VIII inhibitors in previously untreated UK children with severe hemophilia A, 2000-2011

23. Congenital and acquired bleeding problems in elderly patients

24. Massive post-partum haemorrhage and management of disseminated intravascular coagulation

25. A national survey of immunosuppression strategies for acquired haemophilia A

26. Reversal of warfarin-induced over-anticoagulation with individualized dosing of oral vitamin K: a pilot study

27. Diagnosis and treatment of factor VIII and IX inhibitors in congenital haemophilia: (4th edition). UK Haemophilia Centre Doctors Organization

28. Rozrolimupab, a mixture of 25 recombinant human monoclonal RhD antibodies, in the treatment of primary immune thrombocytopenia

29. Control of variceal bleeding in a patient with severe haemophilia A and factor VIII inhibitors using a transjugular intrahepatic portosystemic shunt

30. Correlation of a Condensed Bleeding Score with New Diagnosis of a Congenital Bleeding Disorder in Patients Referred to a Tertiary Centre

31. Intracranial Haemorrhage in Patients with An Inherited Bleeding Disorder: A Review of 10 Years Experience in a UK Haemophilia Comprehensive Centre

32. Serial D-Dimer Measurements Are Useful in Predicting the Recurrence of Venous Thromboembolism after Discontinuation of Anticoagulation

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