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Arachchillage DJ, Rajakaruna I, Odho Z, et al., 2023, Impact of thromboprophylaxis on hospital acquired thrombosis following discharge in patients admitted with COVID-19: Multicentre observational study in the UK., Br J Haematol
Post-discharge thromboprophylaxis in patients admitted with COVID-19 remains controversial. We aimed to determine the impact of thromboprophylaxis on hospital acquired thrombosis (HAT) in patients (≥18 years) discharged following admission for COVID-19 in an observational study across 26 NHS Trusts in the UK (01.04.2020-31.12.2021). Overall, 8895 patients were included to the study: 971 patients were discharged with thromboprophylaxis and propensity score matched (PSM) with a desired ratio of 1:1, from patients discharged without thromboprophylaxis. Patients with heparin induced thrombocytopenia, major bleeding during admission and pregnant women were excluded. As expected from 1:1 PSM, no difference was observed in parameters between the two groups, including duration of hospital stay, except the thromboprophylaxis group had a significantly higher proportion who had received therapeutic dose anticoagulation during admission. There were no differences in the laboratory parameters especially D-dimers between the two groups at admission or discharge. Median duration of thromboprophylaxis following discharge from hospital was 4 weeks (1-8 weeks). No difference was found in HAT in patients discharged with TP versus no TP (1.3% vs. 0.92%, p = 0.52). Increasing age and smoking significantly increased the risk of HAT. Many patients in both cohorts had raised D-dimer at discharge but D-dimer was not associated with increased risk of HAT.
Mobayen G, Smith K, Ediriwickrema K, et al., 2023, von Willebrand factor binds to angiopoietin-2 within endothelial cells and after release from Weibel-Palade bodies., J Thromb Haemost
BACKGROUND: The von Willebrand factor (VWF) is a multimeric plasma glycoprotein essential for hemostasis, inflammation, and angiogenesis. The majority of VWF is synthesized by endothelial cells (ECs) and stored in Weibel-Palade bodies (WPB). Among the range of proteins shown to co-localize to WPB is angiopoietin-2 (Angpt-2), a ligand of the receptor tyrosine kinase Tie-2. We have previously shown that VWF itself regulates angiogenesis, raising the hypothesis that some of the angiogenic activity of VWF may be mediated by its interaction with Angpt-2. METHODS: Static-binding assays were used to probe the interaction between Angpt-2 and VWF. Binding in media from cultured human umbilical vein ECs s and in plasma was determined by immunoprecipitation experiments. Immunofluorescence was used to detect the presence of Angpt-2 on VWF strings, and flow assays were used to investigate the effect on VWF function. RESULTS: Static-binding assays revealed that Angpt-2 bound to VWF with high affinity (KD,app ∼3 nM) in a pH and calcium-dependent manner. The interaction was localized to the VWF A1 domain. Co-immunoprecipitation experiments demonstrated that the complex persisted following stimulated secretion from ECs and was present in plasma. Angpt-2 was also visible on VWF strings on stimulated ECs. The VWF-Angpt-2 complex did not inhibit the binding of Angpt-2 to Tie-2 and did not significantly interfere with VWF-platelet capture. CONCLUSIONS: Together, these data demonstrate a direct binding interaction between Angpt-2 and VWF that persists after secretion. VWF may act to localize Angpt-2; further work is required to establish the functional consequences of this interaction.
Robbins AJ, Che Bakri NA, Toke-Bjolgerud E, et al., 2023, The effect of TRV027 on coagulation in COVID 19: A pilot randomized, placebo-controlled controlled trial, British Journal of Clinical Pharmacology, Vol: 89, Pages: 1495-1501, 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.
Laffan M, Benson G, Farrelly C, et al., 2023, An expert consensus to define how higher standards of equitable care for von Willebrand disease can be achieved in the UK and Republic of Ireland, HAEMOPHILIA, ISSN: 1351-8216
Mahlangu J, Kaczmarek R, von Drygalski A, et al., 2023, Two-Year Outcomes of Valoctocogene Roxaparvovec Therapy for Hemophilia A., N Engl J Med, Vol: 388, Pages: 694-705
BACKGROUND: Valoctocogene roxaparvovec delivers a B-domain-deleted factor VIII coding sequence with an adeno-associated virus vector to prevent bleeding in persons with severe hemophilia A. The findings of a phase 3 study of the efficacy and safety of valoctocogene roxaparvovec therapy evaluated after 52 weeks in men with severe hemophilia A have been published previously. METHODS: We conducted an open-label, single-group, multicenter, phase 3 trial in which 134 men with severe hemophilia A who were receiving factor VIII prophylaxis 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 the annualized rate of treated bleeding events at week 104 after receipt of the infusion. The pharmacokinetics of valoctocogene roxaparvovec were modeled to estimate the bleeding risk relative to the activity of transgene-derived factor VIII. RESULTS: At week 104, a total of 132 participants, including 112 with data that were prospectively collected at baseline, remained in the study. The mean annualized treated bleeding rate decreased by 84.5% from baseline (P<0.001) among the participants. From week 76 onward, the trajectory of the transgene-derived factor VIII activity showed first-order elimination kinetics; the model-estimated typical half-life of the transgene-derived factor VIII production system was 123 weeks (95% confidence interval, 84 to 232). The risk of joint bleeding was estimated among the trial participants; at a transgene-derived factor VIII level of 5 IU per deciliter measured with chromogenic assay, we expected that participants would have 1.0 episode of joint bleeding per year. At 2 years postinfusion, no new safety signals had emerged and no new serious adverse events related to treatment had occurred. CONCLUSIONS: The study data show the durability of factor VIII activity and bleeding reduction and the safety profile of valoctocogene roxaparvove
Curry NS, Davenport R, Wong H, et al., 2023, Traumatic coagulopathy in the older patient: analysis of coagulation profiles from the Activation of Coagulation and Inflammation in Trauma-2 (ACIT-2) observational, multicenter study., J Thromb Haemost, Vol: 21, Pages: 215-226
BACKGROUND: Most studies describing traumatic coagulopathy have used data from patient cohorts with an average age of between 35 and 45 years. The last 10 years has seen a steep increase in the number of patients admitted with significant injury and bleeding who are older than the age of 65 years. Many coagulation protein levels alter significantly with normal aging, and it is possible that traumatic coagulopathy has a different signature with age. OBJECTIVES: The aim of this study was to report the coagulation profiles, including standard and extended laboratory, as well as viscoelastic hemostatic assays, stratified according to age to explore age-related differences in hemostatic capability. METHODS: In total, 1576 patients were analyzed from 6 European level 1 trauma centers. RESULTS: As age increased, there was evidence of higher fibrinogen, greater thrombin generation, greater clotting factor consumption, and greater activation of fibrinolysis. Despite this, shock and severe injury led to the same pattern of changes within age groups: lower procoagulant factors (including fibrinogen), increased fibrinolysis, and higher levels of activated protein C. Thromboelastography and rotational thromboelastometry tests detected traumatic coagulopathy with prolongation of R/clotting time and reductions in clot amplitudes in each age cohort. Advancing age strongly correlated with higher fibrinogen levels and greater fibrinolysis. CONCLUSION: Age-related coagulation changes are evident in injured patients. Broadly, similar patterns of coagulation abnormalities are seen across age groups following severe injury/shock, but thresholds for single clotting factors differ. Age-related differences may need to be considered when clinical treatments (eg, transfusion therapy) are indicated.
Arachchillage DJ, Laffan M, Pericleous C, 2023, Hydroxychloroquine as an Immunomodulatory and Antithrombotic Treatment in Antiphospholipid Syndrome, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol: 24
Burke T, Rodriguez-Santana I, Chowdary P, et al., 2022, Humanistic burden of problem joints for children and adults with haemophilia, HAEMOPHILIA, ISSN: 1351-8216
Arachchillage DJ, Crossette-Thambiah C, Asmar N, et 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
Jayakody Arachchillage D, Rajakaruna I, Pericleous C, et al., 2022, Autoimmune disease and COVID-19- a multicentre observational study in the United Kingdom, Rheumatology, Vol: 61, Pages: 4643-4655, 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.
Prince RE, Schaeper U, Aretz J, et al., 2022, SLN140 a Small Interfering RNA Targeting Protein S Improves Hemostasis Potency in Hemophilia, 64th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, Pages: 1670-1671, ISSN: 0006-4971
Hart ACJ, Cabrera AM, Vladescu C, et al., 2022, Do Children with Immune Thrombocytopenia Have Cerebral Microbleeds?, 64th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Crossette-Thambiah C, Rajakaruna I, Odho Z, et al., 2022, Anticoagulation Practice, Recurrent Thrombosis, and Major Bleeding in Antiphospholipid Syndrome- a Multicentre Observational Study in the United Kingdom, 64th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Eladnani RP, Schaeper U, Aretz J, et al., 2022, A GalNAc conjugated Small Interfering RNA Targeting Protein S Improves Hemostasis Potency in Hemophilia, Publisher: E M H SWISS MEDICAL PUBLISHERS LTD, Pages: 2S-2S, ISSN: 1424-7860
Noble H, Crossette-Thambiah C, Odho Z, et 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
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Morrow GB, Feller T, McQuilten Z, et 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
Bekono-Nessah I, Rosenburg A, Bowles CT, et 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
Laffan MA, Rees S, Yadavalli M, et al., 2022, Thrombosis with thrombocytopenia after AZD1222 (ChAdOx1 nCov-19) vaccination: Case characteristics and associations, VACCINE, Vol: 40, Pages: 5585-5593, ISSN: 0264-410X
Morgan G, Brighton S, Laffan M, et al., 2022, The Cost of Von Willebrand Disease in Europe: The CVESS Study, CLINICAL AND APPLIED THROMBOSIS-HEMOSTASIS, Vol: 28, ISSN: 1076-0296
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
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Arachchillage DJ, Mackillop L, Chandratheva A, et al., 2022, Guidelines for thrombophilia testing: A British Society for Haematology guideline, BRITISH JOURNAL OF HAEMATOLOGY, Vol: 198, Pages: 443-458, ISSN: 0007-1048
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Boyce S, James I, Rangarajan S, et 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
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El Alayli A, Petersen RB, Husainat NM, et 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.
Little C, Odho Z, Szydlo R, et 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.
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
Crossette-Thambiah C, Laffan M, Arachchillage D, 2022, Lupus Anticoagulant and Cardiopulmonary Bypass, 2nd Annual Scientific Meeting of the British-Society-for-Haematology, Publisher: WILEY, Pages: 43-43, ISSN: 0007-1048
Ozelo MC, Mahlangu J, Pasi KJ, et 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
Crossette-Thambiah C, Pericleous C, Asmar N, et 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.
Musgrave KM, Power K, Laffan M, et 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.
Ashton C, Laffan M, Hutchinson PJ, et 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
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