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

287 results found

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, 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

Crossette-Thambiah C, Pericleous C, Asmar N, Bomsztyk J, Ranger A, Shlebak A, Ramji S, Banerjee S, Laffan M, Jayakody Arachchillage Det al., 2021, Clinical and biological features of cerebral venous sinus thrombosis following ChAdOx1 nCov-19 vaccination, Journal of Neurology, Neurosurgery and Psychiatry, 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

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, Pages: 1-6, 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, ISSN: 1351-8216

Journal article

Mobayen G, Dhutia A, Clarke C, Prendecki M, McAdoo S, Keniyopoullos R, Malik T, Laffan M, Willicombe M, McKinnon Tet al., 2021, Severe COVID-19 is associated with endothelial activation and abnormal glycosylation of von Willebrand factor in patients undergoing hemodialysis., Res Pract Thromb Haemost, Vol: 5

Background: A major clinical feature of severe coronavirus diease 2019 (COVID-19) is microvascular thrombosis linked to endothelial cell activation. Consistent with this, a number of studies have shown that patients with severe COVID-19 have highly elevated plasma levels of von Willebrand Factor (VWF) that may contribute to the prothrombotic phenotype. In the current study, we investigated the extent of endothelial activation in patients receiving hemodialysis who had either mild or severe COVID-19. Methods: Plasma VWF, ADAMTS-13, angiopoietin-2 (Ang2), and syndecan-1 levels were determined by ELISA. The sialic acid content of VWF was investigated using a modified ELISA to measure elderberry bark lectin, specific for sialic acid residues, binding to VWF. Results: Patients receiving hemodialysis with severe COVID-19 had significantly higher plasma levels of VWF and lower ADAMTS-13. VWF levels peaked and were sustained during the first 10 days after positive confirmation of infection. While Ang2 trended toward being higher in severely ill patients, this did not reach significance; however, severely ill patients had significantly higher soluble syndecan-1 levels, with high levels related to risk of death. Finally, higher VWF levels in severely ill patients were correlated with lower VWF sialic acid content. Conclusions: Severe COVID-19 in patients undergoing hemodialysis is associated with both acute and sustained activation of the endothelium, leading to alteration of the VWF/ADAMTS-13 axis. Lower VWF sialic acid content represents altered VWF processing and further confirms the disturbance caused to the endothelium in COVID-19.

Journal article

Smadja DM, Mentzer SJ, Fontenay M, Laffan MA, Ackermann M, Helms J, Jonigk D, Chocron R, Pier GB, Gendron N, Pons S, Diehl J-L, Margadant C, Guerin C, Huijbers EJM, Philippe A, Chapuis N, Nowak-Sliwinska P, Karagiannidis C, Sanchez O, Kuempers P, Skurnik D, Randi AM, Griffioen AWet al., 2021, COVID-19 is a systemic vascular hemopathy: insight for mechanistic and clinical aspects, ANGIOGENESIS, ISSN: 0969-6970

Journal article

Crossette-Thambiah C, Nicolson P, Rajakaruna I, Langridge A, Sayar Z, Perelta MR, Essex S, Oakes R, Mounter P, Lewis S, Dutt T, Scott I, Aung N, Shapiro S, Laffan M, Arachchillage DRJet al., 2021, The clinical course of COVID-19 in pregnant versus non-pregnant women requiring hospitalisation: results from the multicentre UK CA-COVID-19 study, BRITISH JOURNAL OF HAEMATOLOGY, ISSN: 0007-1048

Journal article

Ashton C, Laffan M, Hutchinson PJ, Lecky F, Ralhan S, Smith JE, Coles JP, Stanworth S, Curry Net al., 2021, Survey evaluating clinical equipoise around platelet transfusion after head injury and traumatic intracranial haemorrhage (ICH) in patients on antiplatelet medications., Emerg Med J

INTRODUCTION: Patients aged 60 or over account for over half of the severely injured trauma patients and a traumatic brain injury is the most common injury sustained. Many of these patients are taking antiplatelet medications but there is clinical equipoise about the role of platelet transfusion in patients with traumatic intracranial haemorrhage (ICH) taking prior antiplatelet medications. METHOD: A prepiloted survey was designed to explore a range of clinical issues in managing patients taking antiplatelet medications admitted with a traumatic brain injury. This was sent via email to consultants and specialty registrar members of a variety of relevant UK societies and working groups in the fields of emergency medicine, critical care, neurosurgery and haematology. RESULTS: 193 responses were received, mostly from colleagues in emergency medicine, neurosurgery, anaesthesia and haematology. Respondents indicated that there is a lack of evidence to support the use of platelet transfusion in this patient population but also lack of evidence of harm. Results also demonstrate uncertainties as to whether platelets should be given to all or some patients and doubt regarding the value of viscoelastic testing. DISCUSSION: Our survey demonstrates equipoise in current practice with regards to platelet transfusion in patients with a traumatic ICH who are taking antiplatelet medication. There is support for additional trials to investigate the effect of platelet transfusion in this rising population of older, high-risk patients, in order to provide a better evidence-base for guideline development.

Journal article

Chan MV, Hayman MA, Sivapalaratnam S, Crescente M, Allan HE, Edin ML, Zeldin DC, Milne GL, Stephens J, Greene D, Hanif M, O'Donnell VB, Dong L, Malkowski MG, Lentaigne C, Wedderburn K, Stubbs M, Downes K, Ouwehand WH, Turro E, NIHR BioResource, Hart DP, Freson K, Laffan MA, Warner TDet al., 2021, Identification of a homozygous recessive variant in PTGS1 resulting in a congenital aspirin-like defect in platelet function, Haematologica: the hematology journal, Vol: 106, Pages: 1423-1432, ISSN: 0390-6078

We have identified a rare missense variant on chromosome 9, position 125145990 (GRCh37), in exon 8 in PTGS1 (the gene encoding cyclo-oxygenase 1, COX-1, the target of anti-thrombotic aspirin therapy). We report that in the homozygous state within a large consanguineous family this variant is associated with a bleeding phenotype and alterations in platelet reactivity and eicosanoid production. Western blotting and confocal imaging demonstrated that COX-1 was absent in the platelets of three family members homozygous for the PTGS1 variant but present in their leukocytes. Platelet reactivity, as assessed by aggregometry, lumi-aggregometry and flow cytometry, was impaired in homozygous family members, as were platelet adhesion and spreading. The productions of COX-derived eicosanoids by stimulated platelets were greatly reduced but there were no changes in the levels of urinary metabolites of COX-derived eicosanoids. The proband exhibited additional defects in platelet aggregation and spreading which may explain why her bleeding phenotype was slightly more severe than those of other homozygous affected relatives. This is the first demonstration in humans of the specific loss of platelet COX-1 activity and provides insight into its consequences for platelet function and eicosanoid metabolism. Notably despite the absence of thromboxane A2 (TXA2) formation by platelets, urinary TXA2 metabolites were in the normal range indicating these cannot be assumed as markers of in vivo platelet function. Results from this study are important benchmarks for the effects of aspirin upon platelet COX-1, platelet function and eicosanoid production as they define selective platelet COX-1 ablation within humans.

Journal article

Yuan S, Burgess S, Laffan M, Mason AM, Dichgans M, Gill D, Larsson SCet al., 2021, Genetically Proxied Inhibition of Coagulation Factors and Risk of Cardiovascular Disease: A Mendelian Randomization Study, JOURNAL OF THE AMERICAN HEART ASSOCIATION, Vol: 10, ISSN: 2047-9980

Journal article

Mehta P, Haskard DO, Laffan MA, Chambers RC, Hunt BJet al., 2021, Thromboses and COVID-19: reducing inflammation in addition to thromboprophylaxis, LANCET RHEUMATOLOGY, Vol: 3, Pages: E171-E172, ISSN: 2665-9913

Journal article

Ranger A, Gaspar M, Elkhatteb A, Jackson T, Fox S, Aw TC, Vipond L, Cotterill J, Ghori A, Laffan M, Arachchillage DRJet al., 2021, The heparin-von Willebrand factor interaction and conventional tests of haemostasis - the challenges in predicting bleeding in cardiopulmonary bypass, British Journal of Haematology, Vol: 192, Pages: 1073-1081, ISSN: 0007-1048

Bleeding is a significant complication of cardiopulmonary bypass (CPB), despite routine anticoagulation monitoring. This is likely to be multifactorial. In this prospective, single‐centre cohort study of 30 patients undergoing CPB surgery, our aim was to characterise the changes in von Willebrand factor (VWF) function, platelet interaction and the global coagulation changes during and after CPB surgery and to determine whether bleeding can be predicted. Samples were taken at six time points before, during and after CPB surgery. We observed a significant rise in VWF antigen (VWF:Ag) throughout surgery, which continued postoperatively. The absolute VWF collagen‐binding assays (VWF:CB) and VWF ristocetin cofactor (VWF:RCo) rose significantly but the VWF:CB/VWF:Ag and VWF:Ag/VWF:RCo fell significantly (P = 0·0015 and P = 0·0143), suggesting loss of large multimers. We detected a non‐significant trend to loss of VWF:RCo after heparinisation and a significant recovery after protamine reversal which could reflect a direct heparin effect. There was a significant increase in the R and K times with a fall in alpha angle and maximum amplitude after heparin administration, using heparinase‐thromboelastography (TEG). The parameters both significantly improved following protamine (P = 0·007 and P = 0·0054). The activated clotting time (ACT) and heparin anti‐Xa level correlated poorly; neither predicted clinically significant bleeding. None of these parameters had a relationship with intraoperative blood loss or requirement for blood product replacement.

Journal article

Turecek PL, Peck RC, Rangarajan S, Reilly-Stitt C, Laffan MA, Kazmi R, James I, Dushianthan A, Schrenk G, Gritsch H, Ewenstein BM, Mellgard B, Erdlenbruch W, Jain N, Binder NB, Mumford ADet al., 2021, Recombinant ADAMTS13 reduces abnormally up-regulated von Willebrand factor in plasma from patients with severe COVID-19, Thrombosis Research: vascular obstruction, hemorrhage and hemostasis, Vol: 201, Pages: 100-112, ISSN: 0049-3848

Thrombosis affecting the pulmonary and systemic vasculature is common during severe COVID-19 and causes adverse outcomes. Although thrombosis likely results from inflammatory activation of vascular cells, the mediators of thrombosis remain unconfirmed. In a cross-sectional cohort of 36 severe COVID-19 patients, we show that markedly increased plasma von Willebrand factor (VWF) levels were accompanied by a partial reduction in the VWF regulatory protease ADAMTS13. In all patients we find this VWF/ADAMTS13 imbalance to be associated with persistence of ultra-high-molecular-weight (UHMW) VWF multimers that are highly thrombogenic in some disease settings. Incubation of plasma samples from patients with severe COVID-19 with recombinant ADAMTS13 (rADAMTS13) substantially reduced the abnormally high VWF activity, reduced overall multimer size and depleted UHMW VWF multimers in a time and concentration dependent manner. Our data implicate disruption of normal VWF/ADAMTS13 homeostasis in the pathogenesis of severe COVID-19 and indicate that this can be reversed ex vivo by correction of low plasma ADAMTS13 levels. These findings suggest a potential therapeutic role for rADAMTS13 in helping restore haemostatic balance in COVID-19 patients.

Journal article

Burke T, Santana IR, Chowdary P, Curtis R, Khair K, Laffan M, Mclaughlin P, Noone D, O'Mahony B, Pasi J, Skinner M, O'Hara Jet al., 2021, EXAMINATION AND VALIDATION OF A PATIENT-CENTRIC JOINT METRIC: "PROBLEM JOINT"; EMPIRICAL EVIDENCE FROM THE CHESS II DATASET, Publisher: WILEY, Pages: 75-75, ISSN: 1351-8216

Conference paper

Chang KW, Owen S, Gaspar M, Laffan M, Arachchillage DRJet al., 2021, Outcome of major hemorrhage at a major cardiothoracic center in patients with activated major hemorrhage protocol versus nonactivated protocol., Seminars in Thrombosis and Hemostasis, Vol: 47, Pages: 74-83, ISSN: 0094-6176

This study aimed to determine the impact of major hemorrhage (MH) protocol (MHP) activation on blood administration and patient outcome at a UK major cardiothoracic center. MH was defined in patients (> 16 years) as those who received > 5 units of red blood cells (RBCs) in < 4 hours, or > 10 units in 24 hours. Data were collected retrospectively from patient electronic records and hospital transfusion databases recording issue of blood products from January 2016 to December 2018. Of 134 patients with MH, 24 had activated MHP and 110 did not have activated MHP. Groups were similar for age, sex, baseline hemoglobin, platelet count, coagulation screen, and renal function with no difference in the baseline clinical characteristics. The total number of red cell units (median and [IQR]) transfused was no different in the patients with activated (7.5 [5-11.75]) versus nonactivated (9 [6-12]) MHP (p = 0.35). Patients in the nonactivated MHP group received significantly higher number of platelet units (median: 3 vs. 2, p = 0.014), plasma (median: 4.5 vs. 1.5, p = 0.0007), and cryoprecipitate (median: 2 vs. 1, p = 0.008). However, activation of MHP was associated with higher mortality at 24 hours compared with patients with nonactivation of MHP (33.3 vs. 10.9%, p = 0.005) and 30 days (58.3 vs. 30.9%, p = 0.01). The total RBC and platelet (but not fresh frozen plasma [FFP]) units received were higher in deceased patients than in survivors. Increased mortality was associated with a higher RBC:FFP ratio. Only 26% of patients received tranexamic acid and these patients had higher mortality at 30 days but not at 24 hours. Deceased patients at 30 days had higher levels of fibrinogen than those who survived (median: 2.4 vs. 1.8, p = 0.01). Patients with activated MHP had significantly higher mortality at b

Journal article

O'Brien HER, Zhang XF, Sanz-Hernandez M, Chion A, Shapiro S, Mobayen G, Xu Y, De Simone A, Laffan MA, McKinnon TAJet al., 2021, Blocking von Willebrand factor free thiols inhibits binding to collagen under high and pathological shear stress, Journal of Thrombosis and Haemostasis, Vol: 19, Pages: 358-369, ISSN: 1538-7836

BackgroundVon Willebrand factor (VWF) contains a number of free thiols, the majority of which are located in its C‐domains, and these have been shown to alter VWF function, However, the impact of free thiols on function following acute exposure of VWF to collagen under high and pathological shear stress has not been determined.MethodsVWF free thiols were blocked with N‐ethylmaleimide and flow assays performed under high and pathological shear rates to determine the impact on platelet capture and collagen binding function. Atomic force microscopy (AFM) was used to probe the interaction of VWF with collagen and molecular simulations conducted to determine the effect of free thiols on the flexibility of the VWF‐C4 domain.ResultsBlockade of VWF free thiols reduced VWF‐mediated platelet capture to collagen in a shear‐dependent manner, with platelet capture virtually abolished above 5000 s−1 and in regions of stenosis in microfluidic channels. Direct visualization of VWF fibers formed under extreme pathological shear rates and analysis of collagen‐bound VWF attributed the effect to altered binding of VWF to collagen. AFM measurements showed that thiol‐blockade reduced the lifetime and strength of the VWF‐collagen bond. Pulling simulations of the VWF‐C4 domain demonstrated that with one or two reduced disulphide bonds the C4 domain has increased flexibility and the propensity to undergo free‐thiol exchange.ConclusionsWe conclude that free thiols in the C‐domains of VWF enhance the flexibility of the molecule and enable it to withstand high shear forces following collagen binding, demonstrating a previously unrecognized role for VWF free thiols.

Journal article

Connell NT, James PD, Brignardello-Petersen R, Abdul-Kadir R, Ameer B, Arapshian A, Couper S, Di Paola J, Eikenboom J, Giraud N, Grow JM, Haberichter S, Jacobs-Pratt V, Konkle BA, Kouides P, Laffan M, Lavin M, Leebeek FWG, McLintock C, McRae S, Montgomery R, O'Brien SH, O'Donnell JS, Ozelo MC, Scappe N, Sidonio R, Tosetto A, Weyand AC, Kalot MA, Husainat N, Mustafa RA, Flood VHet al., 2021, von Willebrand disease: proposing definitions for future research, BLOOD ADVANCES, Vol: 5, Pages: 565-569, ISSN: 2473-9529

Journal article

Arachchillage DRJ, Shi C, Saliu D, Kozman P, Mi E, Buti N, Kashef E, Copley SJ, Gomez C, Leonard R, Aziz R, Shlebak AA, Laffan Met al., 2021, Efficacy safety and of D-dimer, weight, and renal function-adjusted thromboprophylaxis in patients with coronavirus disease 2019 (COVID-19)., Seminars in Thrombosis and Hemostasis, Vol: 47, Pages: 436-441, ISSN: 0094-6176

Journal article

Connell NT, Flood VH, Brignardello-Petersen R, Abdul-Kadir R, Arapshian A, Couper S, Grow JM, Kouides P, Laffan M, Lavin M, Leebeek FWG, O'Brien SH, Ozelo MC, Tosetto A, Weyand AC, James PD, Kalot MA, Husainat N, Mustafa RAet al., 2021, ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease, BLOOD ADVANCES, Vol: 5, Pages: 301-325, ISSN: 2473-9529

Journal article

Maners J, Gill D, Pankratz N, Laffan MA, Wolberg AS, de Maat MPM, Ligthart S, Tang W, Ward-Caviness CK, Fomage M, Debette S, Dichgans M, McKnight B, Boerwinkle E, Smith NL, Morrison AC, Dehghan A, de Vries PSet al., 2020, A Mendelian randomization of γ′ and total fibrinogen levels in relation to venous thromboembolism and ischemic stroke, Blood, Vol: 136, Pages: 3062-3069, ISSN: 0006-4971

Fibrinogen is a key component of the coagulation cascade, and variation in its circulating levels may contribute to thrombotic diseases, such as venous thromboembolism (VTE) and ischemic stroke. Gamma prime (γ′) fibrinogen is an isoform of fibrinogen that has anticoagulant properties. We applied 2-sample Mendelian randomization (MR) to estimate the causal effect of total circulating fibrinogen and its isoform, γ′ fibrinogen, on risk of VTE and ischemic stroke subtypes using summary statistics from genome-wide association studies. Genetic instruments for γ′ fibrinogen and total fibrinogen were selected, and the inverse-variance weighted MR approach was used to estimate causal effects in the main analysis, complemented by sensitivity analyses that are more robust to the inclusion of pleiotropic variants, including MR-Egger, weighted median MR, and weighted mode MR. The main inverse-variance weighted MR estimates based on a combination of 16 genetic instruments for γ′ fibrinogen and 75 genetic instruments for total fibrinogen indicated a protective effect of higher γ′ fibrinogen and higher total fibrinogen on VTE risk. There was also a protective effect of higher γ′ fibrinogen levels on cardioembolic and large artery stroke risk. Effect estimates were consistent across sensitivity analyses. Our results provide evidence to support effects of genetically determined γ′ fibrinogen on VTE and ischemic stroke risk. Further research is needed to explore mechanisms underlying these effects and their clinical applications.

Journal article

Morrow GB, Beavis J, Harper S, Bignell P, Laffan MA, Curry Net al., 2020, Characterisation of a novel thrombomodulin c.1487delC,p.(Pro496Argfs*10) variant and evaluation of therapeutic strategies to manage the rare bleeding phenotype., Thrombosis Research: vascular obstruction, hemorrhage and hemostasis, Vol: 197, Pages: 100-108, ISSN: 0049-3848

INTRODUCTION: A novel variant in the thrombomodulin (TM) gene, c.1487delC,p.(Pro496Argfs*10), referred to as Pro496Argfs*10, was identified in a family with an unexplained bleeding disorder. The Pro496Argfs*10 variant results in loss of the transmembrane and intracellular segments of TM and is associated with an increase in soluble TM (sTM) in the plasma. The aim of this study was to characterise the effect of elevated sTM on thrombin generation (TG) and fibrinolysis, and to evaluate therapeutic strategies to manage the patients. METHODS: Plasma samples were obtained from two patients carrying the variant. TG was triggered using 5 pM tissue factor and measured using the Calibrated Automated Thrombogram. A turbidity clot lysis assay was used to monitor fibrinolysis. TM antigen was quantified by ELISA. RESULTS: Patients with the Pro496Argfs*10 variant had significantly elevated plasma sTM compared to controls (372.6 vs. 6.0 ng/ml). TG potential was significantly lower in patients but was restored by inhibition of activated protein C (APC) or addition of activated Factor VII (FVIIa) or platelet concentrates. In vitro experiments suggested that activated prothrombin complex concentrates (APCC) posed a risk of thrombosis. The time to 50% lysis was significantly prolonged in patients compared to controls, 69.7 vs. 42.3 min. Clot lysis time was shortened by inhibition of activated thrombin activatable fibrinolysis inhibitor (TAFIa). CONCLUSIONS: Our data demonstrate that increased sTM enhances APC generation and reduces TG. Simultaneously, the rate of fibrinolysis is delayed due to increased TAFI activation by sTM. Treatment with platelet or FVIIa concentrates may be beneficial to manage this rare bleeding disorder.

Journal article

Khan D, Mitchell J, Rana R, Kriek N, Unsworth A, Sage T, Laffan M, Shapiro S, Thakurta A, Ramasamy K, Gibbins Jet al., 2020, Prospective Study Reveals Increased Platelet Function Associated with Multiple Myeloma and Its Treatment, Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971

Conference paper

Burke T, Santana IR, Chowdary P, Curtis R, Khair K, Laffan M, McLaughlin P, Noone D, O'Mahony B, Pasi J, Skinner MW, O'Hara Jet al., 2020, Examination and Validation of a Patient-Centric Joint Metric: "Problem Joint"; Empirical Evidence from the CHESS US Dataset, Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971

Conference paper

Baker P, Platton S, Gibson C, Gray E, Jennings I, Murphy P, Laffan Met al., 2020, Guidelines on the laboratory aspects of assays used in haemostasis and thrombosis, BRITISH JOURNAL OF HAEMATOLOGY, Vol: 191, Pages: 347-362, ISSN: 0007-1048

Journal article

Arachchillage DRJ, Owen S, Anievas M, Gaspar M, Laffan Met al., 2020, Red cell alloimmunisation in patients receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO), Intensive Care Medicine, Vol: 46, Pages: 1932-1933, ISSN: 0342-4642

Journal article

Angus DC, Derde L, Al-Beidh F, Annane D, Arabi Y, Beane A, van Bentum-Puijk W, Berry L, Bhimani Z, Bonten M, Bradbury C, Brunkhorst F, Buxton M, Buzgau A, Cheng AC, de Jong M, Detry M, Estcourt L, Fitzgerald M, Goossens H, Green C, Haniffa R, Higgins AM, Horvat C, Hullegie SJ, Kruger P, Lamontagne F, Lawler PR, Linstrum K, Litton E, Lorenzi E, Marshall J, McAuley D, McGlothin A, McGuinness S, McVerry B, Montgomery S, Mouncey P, Murthy S, Nichol A, Parke R, Parker J, Rowan K, Sanil A, Santos M, Saunders C, Seymour C, Turner A, van de Veerdonk F, Venkatesh B, Zarychanski R, Berry S, Lewis RJ, McArthur C, Webb SA, Gordon ACet al., 2020, Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19, JAMA, Vol: 324, Pages: 1317-1329, ISSN: 0098-7484

Importance Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited.Objective To determine whether hydrocortisone improves outcome for patients with severe COVID-19.Design, Setting, and Participants An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020.Interventions The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108).Main Outcomes and Measures The primary end point was organ support–free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned –1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%).Results After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137)

Journal article

Arachchillage DJ, Remmington C, Rosenberg A, Xu T, Passariello M, Hall D, Laffan M, Patel BVet al., 2020, Anticoagulation with argatroban in patients with acute antithrombin deficiency in severe COVID‐19, British Journal of Haematology, Vol: 190, Pages: e286-e288, ISSN: 0007-1048

Journal article

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