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1. Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial

Author

Ian Roberts, Haleema Shakur-Still, Adefemi Afolabi, Adegboyega Akere, Monica Arribas, Amy Brenner, Rizwana Chaudhri, Ian Gilmore, Kenneth Halligan, Irshad Hussain, Vipul Jairath, Kiran Javaid, Aasia Kayani, Ton Lisman, Raoul Mansukhani, Muttiullah Mutti, Muhammad Arif Nadeem, Richard Pollok, Jonathan Simmons, Majid Soomro, Simon Stanworth, Andrew Veitch, Christopher Hawkey, Jack Cuzick, David Henry, Chris Metcalfe, Richard Gray, Alan Barkun, Suresh David, Philip Devereaux, Tony Brady, Timothy Coats, Phil Edwards, Katharine Ker, Daniela Manno, Emma Austin, Kiran Bal, Eni Balogun, Collette Barrow, Danielle Beaumont, Myriam Benyahia, Imogen Brooks, Madeleine Cargill, Laura Carrington, Lauren Frimley, Amber Geer, Daniel Gilbert, Catherine Gilliam, Julio Gil Onandia, Nayia Golfi, Daniel Hetherington, Courtenay Howe, Carolyn Hughes, David I'anson, Rob Jackson, Miland Joshi, Sneha Kansagra, Taemi Kawahara, Sergey Kostrov, Hakim Miah, Bernard Ndungu, Kelly Needham, Aroudra Outtandy, Daniel Pearson, Tracey Pepple, Danielle Prowse, Nigel Quashi, Anna Quinn, Maria Ramos, Laura Ranopa, Mia Reid, Chris Roukas, Chelci Squires, Jemma Tanner, Andrew Thayne, Ruhama Uddin, Bukola Fawole, Folasade Adenike Bello, Oladapo Olayemi, Olujide Okunade, Olusade Adetayo, Hussein Khamis, Mohammad Shukri Bin Jahit, Tamar Gogichaishvili, Radu Bogdan Mateescu, Ajay Adhikaree, Abdelmounem Eltayeib Abdo, Mohammad Zaher, Conor Deasy, Joaquin Alvarez Gregori, Bobby Wellsh, Luke Lawton, Raghavendra Kamath, Adrian Barry, Racquel Carpio, Kay Finney, Holly Maguire, Martin James, Frank Coffey, Chris Gough, Lisa Sawers, Aye-Aye Thi, Claire Burnett, Nicola Jacques, Victoria Murray, Heather Jarman, Christine Lambe, Sarah Rounding, Simon Tucker, Romaih Al-Idari, Samuel Guest, Emma Stoddard, David Yeo, Colin Bergin, Elaine Hardy, Joanne Thunder, Paul Jhalli, Edward Hartley, Catherine Jarvis, Carly Swann, Matthew Reed, Bernadette Gallagher, Julia Grahamslaw, Rachel O'Brien, Timothy Harris, Geoffrey Bellhouse, Olivia Boulton, Imogen Skene, Adrian Stanley, Janet Johnstone, Donogh Maguire, Susan Thornton, Matthew Banks, Georgia Bercades, Daniel Marks, Jung Ryu, Claire Dowty, Jason Pott, James East, Adam Bailey, Sally Beer, Sian Davies, Andrew Appelboam, Daisy Mackle, Jennifer Small, Christiane Vorwerk, Rachel Atkins, Isobel Bradbury, Catriona Bryceland, Lisa McClelland, Martin Thomas, Kate Clayton, Angiy Michael, Stephen Haig, Saif Al-Nahhas, Tim Godfrey, Philip Boger, Rachel Comer, Barbara Watkins, Ola Afolabi, Shazad Afzal, Amanda Cowton, Simon Everett, Ruth Fazakerley, Felicia Onoviran, Jonathon Snook, Jackie Berry, Diane Simpson, Jeff Keep, Hannah Cotton, Sinead Helyar, Matthew Rutter, Tracey Johnston, Laura O'Rourke, Louisa Chan, Joanna Tambellini, Dawn Trodd, James Shutt, Sarah Moreton, Abby Oglesby, Adrian Boyle, Nicola Haeger, Susie Hardwick, Jason Kendall, Beverley Faulkner, Ruth Worner, Sarah Hearnshaw, Mary Doona, Maria Price, Laura Hunter, Maggie Bell, Vania Loureiro, Anthony Kehoe, Alison Jefferey, Rosalyn Squire, David Hartin, Stephanie Bell, Alexandra Newman, James Gagg, Jayne Foot, Sue Wakeford, Gabrielle May, Thomas Bartram, Paul Cumpstay, Lucy Parker, Rita Das, Sheik Pahary, Gavin Wright, Georgina Butt, Natasha Christmas, Sarah Wilson, Mohammed Ashfaq, Louise Chandler, Carrie Demetriou, Philip Kaye, Simon Carley, Andrew Brown, Lucy Jones, Amanda Whileman, John Greenaway, Julie Tregonning, Avril Kuhrt, Steve Goodacre, John Jones, Charlotte Owen, Anu Mitra, Abby Harper-Payne, Nigel Trudgill, Anne Hayes, Faheem Butt, Gayle Clifford, Andrew Kinnon, Susan Fowler, Kris Pillay, Shweta Gidwani, Alistair McNair, Omer Omer, Tanya de Weymarn, Adnan Amin, Jane Martin, Nick Mathieu, Simon Barnes, James Turvill, Helen Sweeting, Morten Draegebo, Marion McNaught, Mandy Grocutt, Jordi Margalef, Julian Humphrey, Richard Jackson, Fionn Bellis, Jane Hunt, Alastair Stevenson, Nicholas Watson, Steven Barden, Stuart Paterson, Chris Macdonald, David Hobday, Olu Orugun, Andrew Allison, Tristan Dyer, Samuel McBride, Wojciech Sawicki, Ben Rayner, Lynsey Flowerdew, Jamie Barbour, Jason Klein, Stephen Hood, Nicola Palmer, Jacob de Wolff, Achuth Shenoy, Peter Swallow, Rajaventhan Srirajaskanthan, Hamza Arshad, Naeem Aslam, Anam Bangash, Muhammad Qamar, Haroon Zahoor, Saba Arshad, Quratul ain Ghalib, Tehseen Hameed, Tayyaba Saif, Wajahat Shafi, Abid Ali, Shehroze Khan, Muhammad Muaaz, Ahmad Taj, Aamir Ghafoor, Aamir Afridi, Mansoor Ahmad, Mujahid Aslam, Sandeep Kumar, Mohsin Ali, Ubedullah Bughio, Adil Chang, Sana Shaikh, Syed Ahmad, Zeeshan Ali, Marium Waqar, Aiman Mushir, Sadaf Sattar, Saifullah Goraya, Sharmeen Aslam, Nighat Fatima, Saadia Noreen, Sheraz Saleem, Fazal Rahman, Nadeem Iqbal, Mohammad Khalid, Umar Riaz, Muhammad Umar, Tayyab Akhter, Javaria Khan, Noureen Misbah, Muhammad Afzal, Mobeen Kayani, Syed Shah, Shahida Tarar, Sherbat Khan, Yasir Iqbal, Essa Khan, Maqbool Reki, Tanveer Hussain, Shafqat Iqbal, Muhammad Khurram, Muhammad Shafi, Abrar Shaikh, Aijaz Ahmed, Ameet Kumar, Pinkey Sachdev, Khalid Mahmood Nasir, Zafar Iqbal Chaudhry, Muhammad Zubair, Ghias Tayyab, Junaid Mushtaq, Muhammad Nasir, Amir Khan, Amjad Ali, Sajjad Ali, Wasim Uddin, Sohaib Ahmed, Tazaeen Kazmi, Saleh Channa, Adeeqa Aman, Mouzam Shaikh, Tahir Rizvi, Amjad Hussain, Haider Zaigham Baqai, Zakawat Rasheed, Abdus Khan, Adeela Irfan, Aamir Husain, Asifa Aslam, Khalid Yahya, Salman Azhar, Mansoor Ul Haq, Adeel Afzal, Muhammad Imran, Iram Saeed, Aasim Yusuf, Mariam Hassan, Mumtaz Marwat, Muhammad Ishfaq, Tahir Bashir, Santosh Kumar, Sajjad Yaqoob, Abdul Wahid, Tinuola Fakoya, Temitope Oke, Edries Tejan, Oluwole Olaomi, Olawale Badejo, Okafor Nnaemaka, Nancy Ukwu, Olukayode Arowolo, Adewale Aderounmu, Funmilola Wuraola, Rose Ugiagbe, Alexander Atiri, Enadeghe Eghaghe, Adeleke Adekoya, Adedayo Oluyomi Tade, Olatunji Shonoiki, Samuel Olatoke, Toafiq Raji, Christopher Ekwunife, Chigozirim Onyekpere, Adamu Ahmed, Daniyan Muhammad, Emuobor Odeghe, Olufunmilayo Lesi, Azeberoje Osueni, Adamu Samaila, Aminu Nahuche, Akande Ajayi, Andrew Dongo, Uchenna Ijoma, Ademola Tolulope Adebanjo, Rufina Igetei, Monday Yilkudi, Kehinde Osisanya, Edith Nonyelum Okeke, Oguamanam Okezie Enwere, Serag Esmat, Omar Ashoush, Mazen Naga, Fady Nagy, Mostafa Saiid, Ahmed Shaker, Ashraf Helmy, Saafan Saafan, Mohammed Abdel Monem, Jiffre Din, Khairul Azis, Muhyuddin Brukan, Sanjay Singh, Andee Zakaria, Shaik Farid, Nizam Hashim, Masykurin Mafauzy, Wan Najmi, Nil Amri, Xin Yi, Mohammad Hisyam, Elaine Ng, Zuhrirahimi Ramli, Shyang Yee Lim, Kelvin Voon, Sir Young Yam, Mohammad Jahit, Lee Joon, Besik Melikidze, Davit Kazaishvili, Nino Grubelashvili, Baadur Mosidze, Gia Tomadze, Avto Megreladze, Ruxandra Oprita, Dorina Pestroiu Calescu, Camelia Chioncel, Andrei Ragea, Bogdan Mateescu, Bogdan Busuioc, Andrei Voiosu, Adrian Cotirlet, Iulia Pintilie, Mariana Jinga, Daniel Balaban, Marcel Tanău, Lucian Negreanu, Simona Bataga, Khushboo Priya, Shankar Baral, Anuj K.C., Vijay Sah, Vijay Yadav, Abdelmounem Abdo, Dalia Ahmed, Marzouqah Al Anazi, Areej Al Balkhi, Joaquín Álvarez Gregori, Helio Fornieles Pérez, and Arben Beqiri

Subjects
Gastrointestinal bleeding, Lower gastrointestinal bleeding, business.industry, Maintenance dose, Placebo-controlled study, General Medicine, 030204 cardiovascular system & hematology, A300, medicine.disease, Placebo, Loading dose, 03 medical and health sciences, 0302 clinical medicine, Anesthesia, Medicine, 030212 general & internal medicine, business, Stroke, Tranexamic acid, medicine.drug
Abstract

Summary Background Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124. Findings Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98). Interpretation We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial. Funding UK National Institute for Health Research Health Technology Assessment Programme.

Published
2020
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2. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial

Author

Haleema Shakur, Ian Roberts, Bukola Fawole, Rizwana Chaudhri, Mohamed El-Sheikh, Adesina Akintan, Zahida Qureshi, Hussein Kidanto, Bellington Vwalika, Abdulfetah Abdulkadir, Saturday Etuk, Shehla Noor, Etienne Asonganyi, Zarko Alfirevic, Danielle Beaumont, Carine Ronsmans, Sabaratnam Arulkumaran, Adrian Grant, Kaosar Afsana, Metin Gülmezoglu, Beverley Hunt, Oladapo Olayemi, Iain Chalmers, Pisake Lumbiganon, Gilda Piaggio, Tony Brady, Diana Elbourne, Eni Balogun, Tracey Pepple, Danielle Prowse, Nigel Quashi, Lin Barneston, Collette Barrow, Lisa Cook, Lauren Frimley, Daniel Gilbert, Catherine Gilliam, Rob Jackson, Taemi Kawahara, Hakim Miah, Sergey Kostrov, Maria Ramos, Phil Edwards, Tom Godec, Sumaya Huque, Olujide Okunade, Olusade Adetayo, Aasia Kayani, Kiran Javaid, Chrstine Biryabarema, Robert Tchounzou, Mohan Regmi, Kastriot Dallaku, Mateus Sahani, Sayeba Akhter, Nicolas Meda, Anthony Kwame Dah, Olufemi Odekunle, Oluwabusola Monehin, Austin Ojo, Grace Akinbinu, Ifeoma Offiah, Ubong Akpan, Uduak Udofia, Useneno Okon, Ezukwa Omoronyia, Okpe James, Nike Bello, Blessed Adeyemi, Chris Aimakhu, Olufemi Akinsanya, Bamidele Adeleye, Oluwaseun Adeyemi, Kayode Oluwatosin, Abiodun Aboyeji, Abiodun Adeniran, Adebayo Adewale, Noah Olaomo, Lawrence Omo-Aghoja, Emmanuel Okpako, Lucky Oyeye, Francis Alu, John Ogudu, Ezekiel Ladan, Ibrahim Habib, Babasola Okusanya, Olatunde Onafowokan, David Isah, Abalaka Aye, Felix Okogbo, Egbaname Aigere, Mark Ogbiti, Temitope Onile, Olaide Salau, Yinka Amode, Kamil Shoretire, Adebola Owodunni, Kehinde Ologunde, Akintunde Ayinde, Moses Alao, Olalekan Awonuga, Babatunde Awolaja, Omololu Adegbola, Fatimah Habeebu-Adeyemi, Adeyemi Okunowo, Hadiza Idris, Ola Okike, Nneka Madueke, Josiah Mutihir, Nankat Joseph, Babatunde Adebudo, Adeniyi Fasanu, Olugbenga Akintunde, Olufemi Abidoye, Owigho Opreh, Sophia Udonwa, Gladys Dibia, Simeon Bazuaye, Arafat Ifemeje, Aniefiok Umoiyoho, Emmanuel Inyang-Etoh, Sununu Yusuf, Kayode Olayinka, Babalola Adeyemi, Olusegun Ajenifuja, Umar Ibrahim, Yusuf Baffah Adamu, Oluwarotimi Akinola, Grace Adekola-Oni, Paul Kua, Roseline Iheagwam, Audu Idrisa, Ado Geidam, Andrea Jogo, Joseph Agulebe, Joseph Ikechebelu, Onyebuchi Udegbunam, Jacob Awoleke, Oluseyi Adelekan, Hajaratu Sulayman, Nkeiruka Ameh, Nurudeen Onaolapo, Affiss Adelodun, William Golit, Dachollom Audu, Adetunji Adeniji, Folasade Oyelade, Lamaran Dattijo, Palmer Henry, Olabisi Loto, Odidika Umeora, Abraham Onwe, Emily Nzeribe, Bartthy Okorochukwu, Augustine Adeniyi, Emmanuel Gbejegbe, Akpojaro Ikpen, Ikemefuna Nwosu, Abdulrasaq Sambo, Olubunmi Ladipo, Sola Abubakar, Ola Nene Okike, Enyinnaya Chikwendu Nduka, Eziamaka Pauline Ezenkwele, Daniel Onwusulu, Theresa Azonima Irinyenikan, Swati Singh, Amaitari Bariweni, Hadiza Galadanci, Peter Achara, Osagie Osayande, Mohammed Gana, Kiran Jabeen, Ayesha Mobeen, Sadaf Mufti, Maliha Zafar, Basharat Ahmad, Maimoona Munawar, Jeharat Gul, Naseema Usman, Fehmida Shaheen, Mariam Tariq, Nadia Sadiq, Rabia Batool, Habiba Sharaf Ali, Manahil Jaffer, Asma Baloch, Noonari Mukhtiar, Tasneem Ashraf, Raheela Asmat, Salma Khudaidad, Ghazala Taj, Roshan Qazi, Saira Dars, Faryal Sardar, Sanobar Ashfaq, Saeeda Majeed, Sadaqat Jabeen, Rukhsana Karim, Farzana Burki, Syeda Rabia Bukhari, Fouzia Gul, Musarrat Jabeen, Akhtar Sherin, Qurratul Ain, Shahid Rao, Uzma Shaheen, Samina Manzoor, Shabween Masood, Shabana Rizvi, Anita Ali, Abida Sajid, Aisha Iftikhar, Shazia Batool, Lubna Dar, Shahenzad Sohail, Shazia Rasul, Shamsa Humayun, Rashida Sultana, Sofia Manzoor, Syeda Mazhar, Afshan Batool, Asia Nazir, Nasira Tasnim, Hajira Masood, Razia Khero, Neelam Surhio, Samana Aleem, Naila Israr, Saba Javed, Lubna Bashir, Samina Iqbal, Faiza Aleem, Rubina Sohail, Saima Iqbal, Samina Dojki, Alia Bano, Naseem Saba, Maimoona Hafeez, Nishat Akram, Riffat Shaheen, Haleema Hashmi, Sharmeen Arshad, Rubina Hussain, Sadia Khan, Nighat Shaheen, Safia Khalil, Pushpa Sachdev, Gulfareen Arain, Amtullah Zarreen, Sara Saeed, Shamayela Hanif, Nabia Tariq, Mahwish Jamil, Shama Chaudhry, Hina Rajani, Tayyiba Wasim, Summera Aslam, Nilofar Mustafa, Huma Quddusi, Sajila Karim, Shazia Sultana, Misbah Harim, Mohd Chohan, Nabila Salman, Fareesa Waqar, Shamsunnisa Sadia, Lubna Kahloon, Shehla Manzoor, Samar Amin, Umbreen Akram, Ambreen Ikram, Samina Kausar, Tahira Batool, Brigadier Naila, Tahir Kyani, Christine Biryabarema, Ruth Bulime, Regina Akello, Bernadette Nakawooya Lwasa, Joselyn Ayikoru, Christine Namulwasira, Patrick Komagum, Isabirye Rebecca, Nayiga Annet, Nakirigya Nuulu, Elizabeth Nionzima, Rose Bwotya, Margret Nankya, Sarah Babirye, Joseph Ngonzi, Cesar Sanchez, Nkonwa Innocent, Kusasira Anitah, Ayiko Jackson, Elizabeth Ndagire, Christine Nanyongo, Dominic Drametu, Grace Meregurwa, Francis Banya, Rita Atim, Emmanuel Byaruhanga, Lema Felix, Hussein Iman, Vincent Oyiengo, Peninah Waigi, Rose Wangui, Faiza Nassir, Musimbi Soita, Rophina Msengeti, Zeinab Zubier, Hillary Mabeya, Antony Wanjala, Henry Mwangi, Brian Liyayi, Evelyn Muthoka, Alfred Osoti, Amos Otara, Veronicah Ongwae, Victor Wanjohi, Bonface Musila, Kubasu Wekesa, Alex Nyakundi Bosire, Alice Ntem, Angeline Njoache, Alice Ashu, André Simo, Dorothy Keka, Kenfack Bruno, Amadou Ndouoya, Martin Saadio, Mesack Tchana, Odel Gwan, Pauline Assomo, Venantius Mutsu, Nji Eric, Pascal Foumane, Philemon Nsem, Jeanne Fouedjio, Ymele Fouelifack, Pierre Marie Tebeu, Georges Nko'ayissi, Eta Ngole Mbong, Wisal Nabag, Riham Desougi, Hadia Mustafa, Huida Eltaib, Taha Umbeli, Khalid Elfadl, Murwan Ibrahim, Abdalla Mohammed, Awadia Ali, Somia Abdelrahiem, Mohammed Musa, Khidir Awadalla, Samirra Ahmed, Mahdi Bushra, Omer Babiker, Hala Abdullahi, Mohamed Ahmed, Elhassan Safa, Huida Almardi, Duria Rayis, Saeed Abdelrahman Abdelgabar, Gillian Houghton, Andrew Sharpe, Jim Thornton, Nick Grace, Carys Smith, Kim Hinshaw, Dawn Edmundson, Paul Ayuk, Alison Bates, George Bugg, Joanne Wilkins, Clare Tower, Alysha Allibone, Eugene Oteng-Ntim, Ahmad Kazumari, Anna Danford, Matilda Ngarina, Muzdalifat Abeid, Khadija Mayumba, Magreth Zacharia, George Mtove, Leonard Madame, Anthony Massinde, Berno Mwambe, Rwakyendela Onesmo, Sebastian Kitengile Ganyaka, Shyam Gupta, Rabindra Bhatt, Ajay Agrawal, Pramila Pradhan, Nikita Dhakal, Punita Yadav, Gyanendra Karki, Bhola Ram Shrestha, Mwansa Lubeya, Jane Mumba, Willies Silwimba, Isaiah Hansingo, Noojiri Bopili, Ziche Makukula, Alexander Kawimbe, Mwansa Ketty Lubeya, Willard Mtambo, Mathew Ng'ambi, Saimir Cenameri, Ilir Tasha, Aferdita Kruja, Besnik Brahimaj, Armida Tola, Leon Kaza, Desire Tshombe, Elizabeth Buligho, Roger Paluku-Hamuli, Charles Kacha, Kato Faida, Badibanga Musau, Herman Kalyana, Phanny Simisi, Serge Mulyumba, Nzanzu Kikuhe Jason, Jean Robert Lubamba, Willis Missumba, Ferdousi Islam, Nazneen Begum, Ferdousi Chowdhury, Rokeya Begum, Farjana Basher, Nazlima Nargis, Abu Kholdun, Shahela Jesmin, Shrodha Paul, Hailemariam Segni, Getachew Ayana, William Haleke, Hassen Hussien, Fikre Geremew, Moussa Bambara, Adolphe Somé, Amadou Ly, Roamba Pabakba, Horace Fletcher, Leslie Samuels, Henry Opare-Addo, Roderick Larsen-Reindorf, Kwadwo Nyarko-Jectey, Glen Mola, Malts Wai, Magdy El Rahman, Wafaa Basta, Hussein Khamis, Maria Fernanda Escobar, Liliana Vallecilla, and Gabriel Essetchi Faye

Subjects
medicine.medical_specialty, Hysterectomy, business.industry, medicine.medical_treatment, Placebo-controlled study, General Medicine, 030204 cardiovascular system & hematology, Placebo, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Relative risk, Anesthesia, Clinical endpoint, medicine, Caesarean section, Maternal death, 030212 general & internal medicine, business, Tranexamic acid, medicine.drug
Abstract

Background\ud Post-partum haemorrhage is the leading cause of maternal death worldwide. Early administration of tranexamic acid reduces deaths due to bleeding in trauma patients. We aimed to assess the effects of early administration of tranexamic acid on death, hysterectomy, and other relevant outcomes in women with post-partum haemorrhage.\ud \ud Methods\ud In this randomised, double-blind, placebo-controlled trial, we recruited women aged 16 years and older with a clinical diagnosis of post-partum haemorrhage after a vaginal birth or caesarean section from 193 hospitals in 21 countries. We randomly assigned women to receive either 1 g intravenous tranexamic acid or matching placebo in addition to usual care. If bleeding continued after 30 min, or stopped and restarted within 24 h of the first dose, a second dose of 1 g of tranexamic acid or placebo could be given. Patients were assigned by selection of a numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Participants, care givers, and those assessing outcomes were masked to allocation. We originally planned to enrol 15 000 women with a composite primary endpoint of death from all-causes or hysterectomy within 42 days of giving birth. However, during the trial it became apparent that the decision to conduct a hysterectomy was often made at the same time as randomisation. Although tranexamic acid could influence the risk of death in these cases, it could not affect the risk of hysterectomy. We therefore increased the sample size from 15 000 to 20 000 women in order to estimate the effect of tranexamic acid on the risk of death from post-partum haemorrhage. All analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN76912190 (Dec 8, 2008); ClinicalTrials.gov, number NCT00872469; and PACTR201007000192283.\ud \ud Findings\ud Between March, 2010, and April, 2016, 20 060 women were enrolled and randomly assigned to receive tranexamic acid (n=10 051) or placebo (n=10 009), of whom 10 036 and 9985, respectively, were included in the analysis. Death due to bleeding was significantly reduced in women given tranexamic acid (155 [1·5%] of 10 036 patients vs 191 [1·9%] of 9985 in the placebo group, risk ratio [RR] 0·81, 95% CI 0·65–1·00; p=0·045), especially in women given treatment within 3 h of giving birth (89 [1·2%] in the tranexamic acid group vs 127 [1·7%] in the placebo group, RR 0·69, 95% CI 0·52–0·91; p=0·008). All other causes of death did not differ significantly by group. Hysterectomy was not reduced with tranexamic acid (358 [3·6%] patients in the tranexamic acid group vs 351 [3·5%] in the placebo group, RR 1·02, 95% CI 0·88–1·07; p=0·84). The composite primary endpoint of death from all causes or hysterectomy was not reduced with tranexamic acid (534 [5·3%] deaths or hysterectomies in the tranexamic acid group vs 546 [5·5%] in the placebo group, RR 0·97, 95% CI 0·87-1·09; p=0·65). Adverse events (including thromboembolic events) did not differ significantly in the tranexamic acid versus placebo group.\ud \ud Interpretation\ud Tranexamic acid reduces death due to bleeding in women with post-partum haemorrhage with no adverse effects. When used as a treatment for postpartum haemorrhage, tranexamic acid should be given as soon as possible after bleeding onset.\ud \ud Funding\ud London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation.

Published
2017
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3. Histone deacetylases play distinct roles in telomeric VSG expression site silencing in African trypanosomes

Author

David Horn, Taemi Kawahara, and Qiao-Ping Wang

Subjects
Regulation of gene expression, Genetics, 0303 health sciences, biology, biology.organism_classification, Microbiology, 3. Good health, Chromatin, 03 medical and health sciences, 0302 clinical medicine, Histone, parasitic diseases, Antigenic variation, biology.protein, Trypanosoma, Gene silencing, Histone deacetylase activity, Epigenetics, Molecular Biology, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

African trypanosomes evade the host immune response through antigenic variation, which is achieved by periodically expressing different variant surface glycoproteins (VSGs). VSG expression is monoallelic such that only one of approximately 15 telomeric VSG expression sites (ESs) is transcribed at a time. Epigenetic regulation is involved in VSG control but our understanding of the mechanisms involved remains incomplete. Histone deacetylases are potential drug targets for diseases caused by protozoan parasites. Here, using recombinant expression we show that the essential Trypanosoma brucei deacetylases, DAC1 (class I) and DAC3 (class II) display histone deacetylase activity. Both DAC1 and DAC3 are nuclear proteins in the bloodstream stage parasite, while only DAC3 remains concentrated in the nucleus in insect-stage cells. Consistent with developmentally regulated localization, DAC1 antagonizes SIR2rp1-dependent telomeric silencing only in the bloodstream form, indicating a conserved role in the control of silent chromatin domains. In contrast, DAC3 is specifically required for silencing at VSG ES promoters in both bloodstream and insect-stage cells. We conclude that DAC1 and DAC3 play distinct roles in subtelomeric gene silencing and that DAC3 represents the first readily druggable target linked to VSG ES control in the African trypanosome.

Published
2010
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4. Two essential MYST-family proteins display distinct roles in histone H4K10 acetylation and telomeric silencing in trypanosomes

Author

Alexandra K. Ingram, T. Nicolai Siegel, Sam Alsford, Taemi Kawahara, David Horn, and George A. M. Cross

Subjects
DNA repair, Molecular Sequence Data, Trypanosoma brucei brucei, Protozoan Proteins, Trypanosoma brucei, Microbiology, Histones, 03 medical and health sciences, Acetyltransferases, Transcription (biology), parasitic diseases, Transcriptional regulation, Animals, Amino Acid Sequence, Gene Silencing, Molecular Biology, Research Articles, Phylogeny, Histone Acetyltransferases, 030304 developmental biology, Genetics, 0303 health sciences, biology, 030302 biochemistry & molecular biology, DNA replication, Acetylation, Telomere, biology.organism_classification, 3. Good health, Histone, biology.protein, HAT1
Abstract

Chromatin modification is important for virtually all aspects of DNA metabolism but little is known about the consequences of such modification in trypanosomatids, early branching protozoa of significant medical and veterinary importance. MYST-family histone acetyltransferases in other species function in transcription regulation, DNA replication, recombination and repair. Trypanosoma brucei HAT3 was recently shown to acetylate histone H4K4 and we now report characterization of all three T. brucei MYST acetyltransferases (HAT1-3). First, GFP-tagged HAT1-3 all localize to the trypanosome nucleus. While HAT3 is dispensable, both HAT1 and HAT2 are essential for growth. Strains with HAT1 knock-down display mitosis without nuclear DNA replication and also specific de-repression of a telomeric reporter gene, a rare example of transcription control in an organism with widespread and constitutive polycistronic transcription. Finally, we show that HAT2 is responsible for H4K10 acetylation. By analogy to the situation in Saccharomyces cerevisiae, we discuss low-level redundancy of acetyltransferase function in T. brucei and suggest that two MYST-family acetyltransferases are essential due to the absence of a Gcn5 homologue. The results are also consistent with the idea that HAT1 contributes to establishing boundaries between transcriptionally active and repressed telomeric domains in T. brucei.

Published
2008
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5. Acetylation of histone H4K4 is cell cycle regulated and mediated by HAT3 in Trypanosoma brucei

Author

George A. M. Cross, Jeffrey A. DeGrasse, Taemi Kawahara, Christian J. Janzen, T. Nicolai Siegel, and David Horn

Subjects
0303 health sciences, biology, 030306 microbiology, Histone acetyltransferase, SAP30, Microbiology, Histone H4, 03 medical and health sciences, Biochemistry, Histone H1, Histone methyltransferase, Histone H2A, biology.protein, Histone code, Histone octamer, Molecular Biology, 030304 developmental biology
Abstract

Post-translational histone modifications have been studied intensively in several eukaryotes. It has been proposed that these modifications constitute a 'histone code' that specifies epigenetic information for transcription regulation. With a limited number of histone-modifying enzymes, implying less redundancy, Trypanosoma brucei represents an excellent system in which to investigate the function of individual histone modifications and histone-modifying enzymes. In this study, we characterized the acetylation of lysine 4 of histone H4 (H4K4), the most abundant acetylation site in T. brucei histones. Because of the large sequence divergence of T. brucei histones, we generated highly specific antibodies to acetylated and unmodified H4K4. Immunofluorescence microscopy and Western blots with sorted cells revealed a strong enrichment of unmodified H4K4 in S phase and suggested a G1/G0-specific masking of the site, owing to non-covalently binding factors. Finally, we showed that histone acetyltransferase 3 (HAT3) is responsible for H4K4 acetylation and that treatment of cells with the protein synthesis inhibitor cycloheximide led to an almost instantaneous loss of unmodified H4K4 sites. As HAT3 is located inside the nucleus, our findings suggest that newly synthesized histone H4 with an unmodified K4 is imported rapidly into the nucleus, where it is acetylated, possibly irreversibly.

Published
2007
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6. Tagging a T. brucei RRNA locus improves stable transfection efficiency and circumvents inducible expression position effects

Author

Lucy Glover, Taemi Kawahara, Sam Alsford, David Horn, London School of Hygiene and Tropical Medicine (LSHTM), and This work was funded by The Wellcome Trust (069909 and 064563).

Subjects
[SDV]Life Sciences [q-bio], Trypanosoma brucei brucei, MESH: RNA Interference, Biology, Transfection, Article, Viral Proteins, 03 medical and health sciences, RNA interference, Transcription (biology), MESH: Promoter Regions, Genetic, medicine, Animals, T7 RNA polymerase, MESH: Animals, Promoter Regions, Genetic, Molecular Biology, 030304 developmental biology, 0303 health sciences, 030306 microbiology, MESH: Transfection, MESH: Trypanosoma brucei brucei, DNA-Directed RNA Polymerases, Ribosomal RNA, MESH: Viral Proteins, Molecular biology, MESH: DNA-Directed RNA Polymerases, Cell biology, Position effect, RNA, Ribosomal, MESH: RNA, Ribosomal, RNA Interference, MESH: RNA, Protozoan, Parasitology, Homologous recombination, Functional genomics, RNA, Protozoan, medicine.drug
Abstract

International audience; In Trypanosoma brucei, RNA interference (RNAi) and recombinant protein expression are established as powerful approaches for functional genomics, particularly when combined with inducible expression. The favoured methods involve exploiting homologous recombination to target expression cassettes to a chromosome sub-set to establish stable cell lines. Unfortunately, bloodstream-form cells, those that cause disease in mammals, exhibit low efficiency stable transfection. Current expression systems can also exhibit other undesirable features, including variable position effects and leaky, inducible expression. We have developed systems in bloodstream-form cells that alleviate these problems. Using constructs for RNAi and expression of (GFP) tagged proteins, we target a (hyg) tagged ribosomal RNA (RRNA) locus which circumvents position effects and allows increased targeting efficiency. We also report a compatible double-inducible system for tight regulation of highly toxic products. This system exploits a new inducible RRNA promoter to drive T7 RNA polymerase (T7RNAP) transcription which then drives expression from inducible T7 promoters. The developments described should facilitate functional analysis and increased throughput.

Published
2005
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8. Acetylation of histone H4K4 is cell cycle regulated and mediated by HAT3 in Trypanosoma brucei

Author

T Nicolai, Siegel, Taemi, Kawahara, Jeffrey A, Degrasse, Christian J, Janzen, David, Horn, and George A M, Cross

Subjects
Histones, Cell Cycle, Trypanosoma brucei brucei, Protozoan Proteins, Animals, Acetylation, Interphase, Research Articles, Histone Acetyltransferases
Abstract

Post-translational histone modifications have been studied intensively in several eukaryotes. It has been proposed that these modifications constitute a ‘histone code’ that specifies epigenetic information for transcription regulation. With a limited number of histone-modifying enzymes, implying less redundancy, Trypanosoma brucei represents an excellent system in which to investigate the function of individual histone modifications and histone-modifying enzymes. In this study, we characterized the acetylation of lysine 4 of histone H4 (H4K4), the most abundant acetylation site in T. brucei histones. Because of the large sequence divergence of T. brucei histones, we generated highly specific antibodies to acetylated and unmodified H4K4. Immunofluorescence microscopy and Western blots with sorted cells revealed a strong enrichment of unmodified H4K4 in S phase and suggested a G1/G0-specific masking of the site, owing to non-covalently binding factors. Finally, we showed that histone acetyltransferase 3 (HAT3) is responsible for H4K4 acetylation and that treatment of cells with the protein synthesis inhibitor cycloheximide led to an almost instantaneous loss of unmodified H4K4 sites. As HAT3 is located inside the nucleus, our findings suggest that newly synthesized histone H4 with an unmodified K4 is imported rapidly into the nucleus, where it is acetylated, possibly irreversibly.

Published
2008

9. A sirtuin in the African trypanosome is involved in both DNA repair and telomeric gene silencing but is not required for antigenic variation

Author

Cyril Isamah, Sam Alsford, Taemi Kawahara, and David Horn

Subjects
Genetics, DNA Repair, biology, DNA repair, Molecular Sequence Data, Trypanosoma brucei brucei, Protozoan Proteins, Telomere, Trypanosoma brucei, biology.organism_classification, Subtelomere, Antigenic Variation, Microbiology, Chromatin, Sirtuin, biology.protein, Antigenic variation, Animals, Sirtuins, Gene silencing, Amino Acid Sequence, Gene Silencing, Molecular Biology, Gene, Phylogeny
Abstract

Silent information regulator 2 (Sir2)-related proteins or sirtuins function as NAD(+)-dependent deacetylases or ADP ribosylases that target a range of substrates, thereby influencing chromatin structure and a diverse range of other biological functions. Genes encoding three Sir2-related proteins (SIR2rp1-3) have been identified in the parasitic trypanosomatids, early branching protozoa with no previously reported transcriptional silencing machinery. Here we show that, in the mammalian-infective bloodstream-stage of the African trypanosome, Trypanosoma brucei, SIR2rp1 localizes to the nucleus while SIR2rp2 and SIR2rp3 are both mitochondrial proteins. The nuclear protein, SIR2rp1, controls DNA repair and repression of RNA polymerase I-mediated expression immediately adjacent to telomeres. Antigenic variation, however, which involves the silencing and Pol I-mediated transcriptional switching of subtelomeric variant surface glycoprotein genes, continues to operate independent of SIR2rp1.

Published
2007
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