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
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300 results found

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

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, 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

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

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

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

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, ISSN: 2688-6146

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

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 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

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

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

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, Research and Practice in Thrombosis and Haemostasis, Vol: 5, ISSN: 2475-0379

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, Vol: 24, Pages: 755-788, 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, Vol: 195, Pages: 85-89, ISSN: 0007-1048

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, Pages: 1-20, ISSN: 2047-9980

BackgroundWe conducted Mendelian randomization analyses investigating the linear associations of genetically proxied inhibition of different coagulation factors with risk of common cardiovascular diseases.Methods and ResultsGenetic instruments proxying coagulation factor inhibition were identified from genome‐wide association studies for activated partial thromboplastin time and prothrombin time in BioBank Japan (up to 58 110 participants). Instruments were identified for 9 coagulation factors (fibrinogen alpha, beta, and gamma chain; and factors II, V, VII, X, XI, and XII). Age‐ and sex‐adjusted estimates for associations of the instruments with the outcomes were derived from UK Biobank and the FinnGen, CARDIoGRAMplusC4D (Coronary Artery Disease Genome‐wide Replication and Meta‐analysis), and MEGASTROKE consortia with numbers of incident and prevalent cases of 820 to 60 810. Genetically proxied inhibition of fibrinogen alpha, beta, and gamma chain, factor II, and factor XI were associated with reduced risk of venous thromboembolism (P<0.001). With the exception of fibrinogen beta and factor II, inhibition of these factors was also associated with reduced risk of any ischemic stroke and cardioembolic stroke (P≤0.002). Genetically proxied inhibition of fibrinogen beta and gamma were associated with reduced large‐artery stroke risk (P=0.001). There were suggestive protective associations of genetically proxied inhibition of factors V, VII, and X with ischemic stroke (P<0.05), and suggestive adverse associations of genetically proxied inhibition of factors II and XII with subarachnoid hemorrhage.ConclusionsThis study supports targeting fibrinogen and factor XI for reducing venous thromboembolism and ischemic stroke risk, and showed suggestive evidence that inhibition of factors V, VII, and X might reduce ischemic stroke risk.

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

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

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

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