Imperial College London

ProfessorMikeLaffan

Faculty of MedicineDepartment of Immunology and Inflammation

Professor of Haemostasis & Thrombosis
 
 
 
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Contact

 

+44 (0)20 3313 2178m.laffan

 
 
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Assistant

 

Mrs Lisa Pape +44 (0)20 3313 1320

 
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Location

 

5S5bHammersmith HospitalHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

316 results found

Robbins AJ, Che Bakri NA, Toke-Bjolgerud E, Edwards A, Vikraman A, Michalsky C, Fossler M, Lemm N-M, Medhipour S, Budd W, Gravani A, Hurley L, Kapil V, Jackson A, Lonsdale D, Latham V, Laffan M, Chapman N, Cooper N, Szydlo R, Boyle J, Pollock KM, Owen Det al., 2022, The effect of TRV027 on coagulation in COVID 19: A pilot randomized, placebo-controlled controlled trial, British Journal of Clinical Pharmacology, ISSN: 0306-5251

COVID-19 causes significant thrombosis and coagulopathy, with elevated D-dimer a predictor of adverse outcome. The precise mechanism of this coagulopathy remains unclear, one hypothesis is that loss of Angiotensin Converting Enzyme 2 activity during viral endocytosis leads to pro-inflammatory angiotensin II accumulation, loss of angiotensin-1-7 and subsequent vascular endothelial activation. We undertook a double blind randomised, placebo controlled experimental medicine study to assess the effect of TRV027, a synthetic angiotensin-1-7 analogue on D-dimer in 30 patients admitted to hospital with COVID-19 (REC ref. 20/HRA/3414), Clinical Trial No. NCT04419610.The study showed a similar rate of adverse events in TRV027 and control groups. There was a numerical decrease in D-dimer in the TRV027 group and increase in D-dimer in the placebo group, however, this did not reach statistical significance (p=0.15). A Bayesian analysis demonstrated there was a 92% probability that this change represented a true drug effect.

Journal article

Arachchillage DJ, Crossette-Thambiah C, Asmar N, Ramji S, Laffan Met al., 2022, Cerebral vein thrombosis after ChAdOx1 nCov-19 vaccination: Long-term outcome of four patients, RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS, Vol: 6

Journal article

Noble H, Crossette-Thambiah C, Odho Z, Karawitage N, Logan K, Pericleous C, Laffan M, Arachchillage DJet al., 2022, Frequency and Clinical Significance Anti-PS/PT Antibodies in Patients with Antiphospholipid Syndrome - Single Centre Observational Study in the United Kingdom, SEMINARS IN THROMBOSIS AND HEMOSTASIS, ISSN: 0094-6176

Journal article

Morrow GB, Feller T, McQuilten Z, Wake E, Ariens RAS, Winearls J, Mutch NJ, Laffan MA, Curry Net al., 2022, Cryoprecipitate transfusion in trauma patients attenuates hyperfibrinolysis and restores normal clot structure and stability: Results from a laboratory sub-study of the FEISTY trial, CRITICAL CARE, Vol: 26, ISSN: 1364-8535

Journal article

Bekono-Nessah I, Rosenburg A, Bowles CT, Riesgo-Gil F, Stock U, Szydlo RR, Laffan M, Arachchillage DJet al., 2022, Bleeding and thrombotic complications and their impact on mortality in patients supported with left ventricular assist device for cardiogenic shock, PERFUSION-UK, ISSN: 0267-6591

Journal article

Laffan MA, Rees S, Yadavalli M, Ferstenberg LB, Shankar NK, Medin J, Foskett N, Arnold M, da Silva HG, Bhuyan P, Nord Met al., 2022, Thrombosis with thrombocytopenia after AZD1222 (ChAdOx1 nCov-19) vaccination: Case characteristics and associations, VACCINE, Vol: 40, Pages: 5585-5593, ISSN: 0264-410X

Journal article

Morgan G, Brighton S, Laffan M, Goudemand J, Franks B, Finnegan Aet al., 2022, The Cost of Von Willebrand Disease in Europe: The CVESS Study, CLINICAL AND APPLIED THROMBOSIS-HEMOSTASIS, Vol: 28, ISSN: 1076-0296

Journal article

Arachchillage DJ, Crossette-Thambiah C, Laffan M, 2022, Lupus Anticoagulant and Cardiopulmonary Bypass, SEMINARS IN THROMBOSIS AND HEMOSTASIS, Vol: 48, Pages: 628-630, ISSN: 0094-6176

Journal article

Arachchillage DJ, Mackillop L, Chandratheva A, Motawani J, MacCallum P, Laffan Met al., 2022, Guidelines for thrombophilia testing: A British Society for Haematology guideline, BRITISH JOURNAL OF HAEMATOLOGY, Vol: 198, Pages: 443-458, ISSN: 0007-1048

Journal article

Boyce S, James I, Rangarajan S, Curry N, Bagot C, Austin S, Laffan M, Mangles S, Chandrakumaran K, Mundy Cet al., 2022, Seroprevalence to adeno-associated virus type 6 in people with hemophilia B from a UK adult cohort, RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS, Vol: 6

Journal article

El Alayli A, Petersen RB, Husainat NM, Kalot MA, Aljabiri Y, Turkmani H, Britt A, El-Khechen H, Shahid S, Roller J, Motaghi S, Mansour R, Tosetto A, Abdul-Kadir R, Laffan M, Weyand A, Leebeek FWG, Arapshian A, Kouides P, James P, Connell NT, Flood VH, Mustafa RAet al., 2022, Outcomes of long-term von Willebrand factor prophylaxis use in von Willebrand disease: A systematic literature review, Haemophilia, Vol: 28, Pages: 373-387, ISSN: 1351-8216

BackgroundVon Willebrand Disease (VWD) is a common inherited bleeding disorder. Patients with VWD suffering from severe bleeding may benefit from the use of secondary long-term prophylaxis.AimSystematically summarize the evidence on the clinical outcomes of secondary long-term prophylaxis in patients with VWD and severe recurrent bleedings.MethodsWe searched Medline and EMBASE through October 2019 for relevant randomized clinical trials (RCTs) and comparative observational studies (OS) assessing the effects of secondary long-term prophylaxis in patients with VWD. We used Cochrane Risk of Bias (RoB) tool and the RoB for Non-Randomized Studies of interventions (ROBINS-I) tool to assess the quality of the included studies. We conducted random-effects meta-analyses and assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.ResultsWe included 12 studies. Evidence from one placebo controlled RCT suggested that VWD prophylaxis as compared to no prophylaxis reduced the rate of bleeding episodes (Rate ratio [RR], .24; 95% confidence interval [CI], .17–.35; low certainty evidence), and of epistaxis (RR, .38; 95%CI, .21–.67; moderate certainty evidence), and may increase serious adverse events RR 2.73 (95%CI .12–59.57; low certainty). Evidence from four before-and-after studies in which researchers reported comparative data suggested that VWD prophylaxis reduced the rate of bleeding (RR .34; 95%CI, .25–.46; very low certainty evidence).ConclusionVWD prophylaxis treatment seems to reduce the risk of spontaneous bleeding, epistaxis, and hospitalizations. More RCTs should be conducted to increase the certainty in these benefits.

Journal article

Little C, Odho Z, Szydlo R, Aw T-C, Laffan M, Arachchillage DRJet al., 2022, Impact of aspirin on bleeding and blood product usage in off-pump and on-pump coronary artery bypass graft surgery., EJHaem, Vol: 3, Pages: 317-325

Major bleeding is linked to poorer outcomes following cardiac surgery. Current guidelines recommend continuation of aspirin prior to coronary artery by-pass graft (CABG) but the effect of continuing aspirin in patients with prior indication for aspirin, in particular during off-pump CABG (OPCABG), has not been systematically assessed. In this study, we analysed the effect of continuing aspirin prior to OPCABG and on-pump CABG with respect to bleeding and blood product usage. We compared propensity-matched cohorts of patients who continued aspirin until the day of OPCABG or CABG to controls (no antiplatelet) and to patients discontinuing aspirin 5-7 days prior. Length of hospital stay, 30-day mortality and thromboembolism rates were similar for both OPCABG and CABG. During OPCABG, aspirin-continued patients received more intraoperative red cell units compared to controls without difference in bleeding. Aspirin-continued patients received more blood products perioperatively and bled more than aspirin-discontinued patients undergoing OPCABG. The only difference during CABG was a small increase in the volume of cells salvaged among aspirin-continued patients compared to controls. Current guidelines on the continuation of aspirin prior to CABG and OPCABG are safe. Continuation of aspirin prior to OPCABG may result in more bleeding and blood product usage.

Journal article

Jayakody Arachchillage D, 2022, Autoimmune disease and COVID-19- a multicentre observational study in the United Kingdom, Rheumatology, ISSN: 1462-0324

ObjectiveTo establish the demographic characteristics, laboratory findings and clinical outcomes in patients with autoimmune disease (AD) in comparison to a propensity matched cohort of patients without AD admitted with COVID-19 to hospitals in the UK.MethodsThis is a multicentre observational study across 26 NHS Trusts. Data were collected both retrospectively and prospectively using a pre-designed standardised case record form. Adult patients (≥18 years) admitted between 1st of April 2020 and 31 July 2020 were included.ResultsOverall, 6288 patients were included to the study. Of these, 394 patients had AD prior to admission with COVID-19. Of 394 patients, 80 patients with systemic lupus erythematosus, rheumatoid arthritis or antiphospholipid syndrome were classified as severe rheumatologic AD. A higher proportion of those with AD had anaemia: 240(60.91%) vs 206(52.28%), p= 0.015, raised LDH 150(38.08%) vs 43(10.92%), p< 0.001 and raised creatinine 122(30.96%) vs 86(21.83%), p= 0.01 respectively. A significantly higher proportion of patients with severe rheumatologic AD had raised CRP : 77(96.25%) vs 70(87.5%), p= 0.044 and LDH 20(25%) vs 6(7.5%), p= 0.021. Patients with severe rheumatologic AD had significantly higher mortality [32/80(40%)] compared with propensity matched cohort of patients without AD [20/80(25%)], p= 0.043. However, there was no difference in 180-day mortality between propensity matched cohorts of patients with or without AD in general, p= 0.47.ConclusionsPatients with severe rheumatologic AD had significantly higher mortality. Anaemia, renal impairment and raised LDH were more frequent in patients with any AD whilst raised CRP and LDH were more frequent in patients with severe rheumatologic AD both of which have been shown to associate with increased mortality in patients with COVID-19.

Journal article

Crossette-Thambiah C, Laffan M, Arachchillage D, 2022, Lupus Anticoagulant and Cardiopulmonary Bypass, Publisher: WILEY, Pages: 43-43, ISSN: 0007-1048

Conference paper

Simini G, Akor F, Laffan M, 2022, Subcutaneous unfractionated heparin in patients with end-stage kidney disease requiring anticoagulation, Publisher: WILEY, Pages: 211-212, ISSN: 0007-1048

Conference paper

Ozelo MC, Mahlangu J, Pasi KJ, Giermasz A, Leavitt AD, Laffan M, Symington E, Quon DV, Wang J-D, Peerlinck K, Pipe SW, Madan B, Key NS, Pierce GF, O'Mahony B, Kaczmarek R, Henshaw J, Lawal A, Jayaram K, Huang M, Yang X, Wong WY, Kim B, GENEr8-1 Trial Groupet al., 2022, Valoctocogene roxaparvovec gene therapy for hemophilia A., The New England journal of medicine, Vol: 386, Pages: 1013-1025, ISSN: 0028-4793

BACKGROUND: Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) is an adeno-associated virus 5 (AAV5)-based gene-therapy vector containing a coagulation factor VIII complementary DNA driven by a liver-selective promoter. The efficacy and safety of the therapy were previously evaluated in men with severe hemophilia A in a phase 1-2 dose-escalation study. METHODS: We conducted an open-label, single-group, multicenter, phase 3 study to evaluate the efficacy and safety of valoctocogene roxaparvovec in men with severe hemophilia A, defined as a factor VIII level of 1 IU per deciliter or lower. Participants who were at least 18 years of age and did not have preexisting anti-AAV5 antibodies or a history of development of factor VIII inhibitors and who had been receiving prophylaxis with factor VIII concentrate received a single infusion of 6×1013 vector genomes of valoctocogene roxaparvovec per kilogram of body weight. The primary end point was the change from baseline in factor VIII activity (measured with a chromogenic substrate assay) during weeks 49 through 52 after infusion. Secondary end points included the change in annualized factor VIII concentrate use and bleeding rates. Safety was assessed as adverse events and laboratory test results. RESULTS: Overall, 134 participants received an infusion and completed more than 51 weeks of follow-up. Among the 132 human immunodeficiency virus-negative participants, the mean factor VIII activity level at weeks 49 through 52 had increased by 41.9 IU per deciliter (95% confidence interval [CI], 34.1 to 49.7; P<0.001; median change, 22.9 IU per deciliter; interquartile range, 10.9 to 61.3). Among the 112 participants enrolled from a prospective noninterventional study, the mean annualized rates of factor VIII concentrate use and treated bleeding after week 4 had decreased after infusion by 98.6% and 83.8%, respectively (P<0.001 for both comparisons). All the participants had at least one adverse event; 22 of 134 (16.4%) repor

Journal article

Crossette-Thambiah C, Pericleous C, Asmar N, Bomsztyk J, Ranger A, Shlebak A, Ramji S, Banerjee S, Laffan M, Jayakody Arachchillage Det al., 2022, Clinical and biological features of cerebral venous sinus thrombosis following ChAdOx1 nCov-19 vaccination, Journal of Neurology, Neurosurgery and Psychiatry, Vol: 93, Pages: 445-448, ISSN: 0022-3050

Vaccines for COVID-19were developed with unprecedented speedand since January 2021, the AstraZeneca/Oxford University ChAdOx1 nCoV-19 vaccine has been administered to over 400 million people globally1. In April 2021, the Medicines and Healthcare products Regulatory Agency (MHRA) and the European Medicines Agency (EMA)reported a possible association between ChAdOx1 nCoV-19 and a rare syndrome of unusual site thrombosis combined with thrombocytopenia, termed vaccine-induced immune thrombotic thrombocytopenia (VITT).Frequency of VITT varies across age groups. Overall 411 cases of VITT have been reported to Medicine & Healthcare prodcuts Regulatory Agency (MHRA) by 21st of July 2021 with fatality rate of 17.76% (73/411)2.

Journal article

Musgrave KM, Power K, Laffan M, O'Donnell JS, Thachil J, Maraveyas Aet al., 2022, Practical treatment guidance for cancer-associated thrombosis-Managing the challenging patient: A consensus statement, CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY, Vol: 171, ISSN: 1040-8428

Cancer-associated thrombosis (CAT) is a leading cause of death amongst people with cancer. Treatment decisions have become increasingly complex with the introduction of direct oral anticoagulants and existing guidelines are limited to evidence from patients meeting stringent trial-entry criteria.To assist decision making for healthcare professionals managing CAT in challenging ‘real-world’ situations, an expert working group of clinicians from oncology, haematology and pharmacology convened over a series of virtual meetings between September 2020 and January 2021 to catalogue the most challenging clinical problems and define consensus recommendations. Clinical problems were divided amongst the group members according to their areas of expertise, with each reviewing the literature and writing their recommendations. Using a web-based file-sharing platform, each contribution was reviewed until consensus was reached.Each clinical problem is discussed; these include managing gastrointestinal impairment, renal impairment, liver impairment, increased risk of bleeding, extremes of body weight, drug interactions, anticoagulation beyond the initial six months and managing recurrent thrombosis.A user-friendly, practical, colour-coded algorithm was produced to help guide clinical decision-making in CAT. Red highlights decision steps where shared decision making, such as with the multi-disciplinary team, is recommended. Amber steps reflect uncertainty of existing evidence. Multiple amber steps per patient warrant increased caution.Making anticoagulation decisions in people with cancer is challenging; it is important that healthcare providers can discuss where there is a lack of evidence and ensure that patient preference is given priority. This algorithm and consensus recommendations are a useful tool to guide these complex discussions.

Journal article

Ashton C, Laffan M, Hutchinson PJ, Lecky F, Ralhan S, Smith JE, Coles JP, Stanworth S, Curry N, Ashton C, Laffan M, Hutchinson PJ, Lecky F, Ralhan S, Smith JE, Coles JP, Stanworth S, Curry Net al., 2022, Survey evaluating clinical equipoise around platelet transfusion after head injury and traumatic intracranial haemorrhage (ICH) in patients on antiplatelet medications, EMERGENCY MEDICINE JOURNAL, Vol: 39, Pages: 220-223, ISSN: 1472-0205

Journal article

Kefalogianni R, Kamani F, Gaspar M, Aw TC, Donovan J, Laffan M, Pickering MC, Arachchillage DJet al., 2022, Complement activation during cardiopulmonary bypass and association with clinical outcomes., EJHaem, Vol: 3, Pages: 86-96

In this prospective, single-centre observational study of 30 patients undergoing cardiopulmonary bypass (CPB), the effect of unfractionated heparin (UFH), CPB surgery and protamine sulphate on complement and on post-operative blood loss were assessed. Although C3 and C4 levels decreased significantly immediately following the administration of UFH, C3a, C5a, Bb fragment and SC5b-9 remained unchanged. During CPB, C3 and C4 continued to fall whilst both alternative and classical pathways activation markers, Bb, C3a, C5a and SC5b-9 increased significantly. Protamine sulphate had no effect on classical pathway components or activation markers but decreased alternative pathway activation marker Bb. Over the 12-24 h post-surgery, both classical and alternative pathway activation markers returned to baseline, whilst C3 and C4 levels increased significantly but not to baseline values. Total drain volume 24 h after the surgery showed a moderate inverse correlation with post-protamine C3 (r = -0.46, p = 0.01) and C4 (r = -0.57, p = 0.0009) levels, whilst a moderate positive correlation was observed with post-protamine C3a (r = 0.46, p = 0.009), C5a (r = 0.37, p = 0.04) and SC5b-9 (r = 0.56, p = 0.001) levels but not with Bb fragment (r = 0.25, p = 0.17). Thus, inhibition of complement activation may be a therapeutic intervention to reduce post-operative blood in patients undergoing CPB.

Journal article

Tan J, Chow YP, Abidin NZ, Chang KM, Selvaratnam V, Tumian NR, Poh YM, Veerakumarasivam A, Laffan MA, Wong CLet al., 2022, Analysis of genetic variants in myeloproliferative neoplasms using a 22-gene next-generation sequencing panel, BMC MEDICAL GENOMICS, Vol: 15

Journal article

Brignardello-Petersen R, El Alayli A, Husainat N, Kalot M, Shahid S, Aljabirii Y, Britt A, Alturkmani H, El-Khechen H, Motaghi S, Roller J, Dimassi A, Abughanimeh O, Madoukh B, Arapshian A, Grow JM, Kouides P, Laffan M, Leebeek FWG, O'Brien SH, Tosetto A, James PD, Connell NT, Flood V, Mustafa RAet al., 2022, Surgical management of patients with von Willebrand disease: summary of 2 systematic reviews of the literature, Blood Advances, Vol: 6, Pages: 121-128, ISSN: 2473-9529

von Willebrand disease (VWD) is the most common inherited bleeding disorder. The management of patients with VWD who are undergoing surgeries is crucial to prevent bleeding complications. We systematically summarized the evidence on the management of patients with VWD who are undergoing major and minor surgeries to support the development of practice guidelines. We searched Medline and EMBASE from inception through October 2019 for randomized clinical trials (RCTs), comparative observational studies, and case series that compared maintaining factor VIII (FVIII) levels or von Willebrand factor (VWF) levels at >0.50 IU/mL for at least 3 days in patients undergoing major surgery, and those with options for perioperative management of patients undergoing minor surgery. Two authors screened and abstracted data and assessed the risk of bias. We conducted meta-analyses when possible. We evaluated the certainty of the evidence using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. We included 7 case series for major surgeries and 2 RCTs and 12 case series for minor surgeries. Very-low-certainty evidence showed that maintaining FVIII levels or VWF levels of >0.50 IU/mL for at least 3 consecutive days showed excellent hemostatic efficacy (as labeled by the researchers) after 74% to 100% of major surgeries. Low- to very-low-certainty evidence showed that prescribing tranexamic acid and increasing VWF levels to 0.50 IU/mL resulted in fewer bleeding complications after minor procedures compared with increasing VWF levels to 0.50 IU/mL alone. Given the low-quality evidence for guiding management decisions, a shared-decision model leading to individualized therapy plans will be important in patients with VWD who are undergoing surgical and invasive procedures.

Journal article

Pipe SW, Ozelo MC, Kenet G, Reding MT, Mason J, Leavitt AD, Madan B, Laffan M, Quon DV, Drygalski A, Chou S-C, Shapiro S, Dunn AL, Wang M, Key NS, Kaczmarek R, Symington E, Lawal A, Mahajan R, Chavele K-M, Reddy DB, Yu H, Wong WY, Robinson TM, Kim Bet al., 2021, Relationship between Endogenous, Transgene FVIII Expression and Bleeding Events Following Valoctocogene Roxaparvovec Gene Transfer for Severe Hemophilia A: A Post-Hoc Analysis of the GENEr8-1 Phase 3 Trial, Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971

Conference paper

Arachchillage DJ, Rajakaruna I, Scott I, Gaspar M, Odho Z, Banya W, Vlachou A, Isgro G, Cagova L, Wade J, Fleming L, Laffan M, Szydlo R, Ledot S, Jooste R, Vuylsteke A, Yusuff Het al., 2021, Impact of major bleeding and thrombosis on 180-day survival in patients with severe COVID-19 supported with veno-venous extracorporeal membrane oxygenation in the United Kingdom: a multicentre observational study, BRITISH JOURNAL OF HAEMATOLOGY, Vol: 196, Pages: 566-576, ISSN: 0007-1048

Journal article

Nair M, Chhabra S, Choudhury SS, Deka D, Deka G, Kakoty SD, Kumar P, Mahanta P, Medhi R, Rani A, Rao S, Roy I, Solomi C, Talukdar RK, Zahir F, Kansal N, Arora A, Opondo C, Armitage J, Laffan M, Stanworth S, Quigley M, Baigent C, Knight M, Kurinczuk JJet al., 2021, Relationship between anaemia, coagulation parameters during pregnancy and postpartum haemorrhage at childbirth: a prospective cohort study, BMJ OPEN, Vol: 11, ISSN: 2044-6055

Journal article

Arachchillage DJ, Rajakaruna I, Odho Z, Crossette-Thambiah C, Nicolson PLR, Roberts LN, Allan C, Lewis S, Riat R, Mounter P, Lynch C, Langridge A, Oakes R, Aung N, Drebes A, Dutt T, Raheja P, Delaney A, Essex S, Lowe G, Sutton D, Lentaigne C, Sayar Z, Kilner M, Everington T, Shapiro S, Alikhan R, Szydlo R, Makris M, Laffan Met al., 2021, Clinical outcomes and the impact of prior oral anticoagulant use in patients with coronavirus disease 2019 admitted to hospitals in the UK - a multicentre observational study, BRITISH JOURNAL OF HAEMATOLOGY, Vol: 196, Pages: 79-94, ISSN: 0007-1048

Journal article

The REMAP-CAP, ACTIV-4a, and ATTACC Investigators, 2021, Therapeutic anticoagulation with heparin in critically Ill patients with Covid-19, New England Journal of Medicine, Vol: 385, Pages: 777-789, ISSN: 0028-4793

BACKGROUNDThrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19.METHODSIn an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. The primary outcome was organ support–free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of −1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge.RESULTSThe trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support–free days was 1 (interquartile range, −1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, −1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio <1.2], 99.9%). The percentage of patients who survived to hospital discharge was similar in the two groups (62.7% and 64.5%, respectively; adjusted odds ratio, 0.84; 95% credible interval, 0.64 to 1.11). Major bleeding occurred in 3.8% of the patients assigned to therapeutic-dose anticoagulation and in 2.3% of those assigned to usual-care pharmacologic thromboprophylaxis.CONCLUSIONSIn critically ill patients with Covid-19, an initial strategy of therapeu

Journal article

The ATTACC, ACTIV-4a, and REMAP-CAP Investigators, 2021, Therapeutic anticoagulation with heparin in noncritically Ill patients with Covid-19, New England Journal of Medicine, Vol: 385, Pages: 790-802, ISSN: 0028-4793

BACKGROUNDThrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19.METHODSIn this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care–level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support–free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of −1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level.RESULTSThe trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support–free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic

Journal article

Weatherill A, Laffan M, Gasper M, Bianchi P, Passariello M, Singh S, Doyle J, Patel B, Ledot S, Garfield B, Arachchillage DJet al., 2021, Impact of thrombosis and bleeding in patients with severe COVID-19 versus other viral pneumonias in the context of extracorporeal membrane oxygenation, Seminars in Thrombosis and Hemostasis, Vol: 48, Pages: 118-123, ISSN: 0094-6176

Journal article

Pasi KJ, Laffan M, Rangarajan S, Robinson TM, Mitchell N, Lester W, Symington E, Madan B, Yang X, Kim B, Pierce GF, Wong WYet al., 2021, Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A, Haemophilia, Vol: 27, Pages: 947-956, ISSN: 1351-8216

IntroductionValoctocogene roxaparvovec is an investigational AAV5-based factor VIII (FVIII) gene therapy that has demonstrated sustained clinical benefit in people with severe haemophilia A.AimTo report safety, tolerability, efficacy, and quality of life (QOL) among participants who received valoctocogene roxaparvovec in a phase 1/2 clinical study (NCT02576795).MethodsMen ≥18 years of age with severe haemophilia A (FVIII ≤1 IU/dl) without history of FVIII inhibitors or anti-AAV5 antibodies received a single infusion of valoctocogene roxaparvovec and were followed for 5 years (6 × 1013 vg/kg dose, n = 7) and 4 years (4 × 1013 vg/kg dose, n = 6).ResultsOver the past 2 years, few adverse events and no FVIII inhibitors were reported. Per chromogenic substrate (CSA) assay at years 5 and 4, four of seven and three of six participants in the 6 × 1013 and 4 × 1013 vg/kg cohorts, respectively, maintained median FVIII levels >5 IU/dl, corresponding to mild haemophilia. By regression analysis, rate of change in FVIII activity was -0.14 (95% confidence interval [CI]: -.32 to .03) IU/dl/wk in the 6 × 1013 vg/kg cohort in year 5 and -.06 (95% CI: -.14 to .01) IU/dl/wk in the 4 × 1013 vg/kg cohort in year 4. No participants resumed FVIII prophylaxis, and eight of 13 participants reported zero bleeds in the past 2 years. Improved QOL from baseline persisted in the 6 × 1013 vg/kg cohort; all six Haemo-QOL-A domain scores increased. For the 4 × 1013 vg/kg cohort, high baseline Haemo-QOL-A scores persisted.ConclusionThese results demonstrate transgene expression and haemostatic response for up to 5 years in individuals with haemophilia A.

Journal article

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