344 results found
Mitchell JL, Khan D, Rana RH, et al., 2023, Multiple myeloma and its treatment contribute to increased platelet reactivity., Platelets, Vol: 34
Multiple myeloma (MM) and its precursor states, smoldering myeloma (SM) and monoclonal gammopathy of undetermined significance (MGUS) are associated with increased incidence of thrombosis, however the cause of this is unknown. Lenalidomide treatment of MM substantially improves patient survival, although significantly increases thrombotic risk by an unknown mechanism. This pilot study aimed to establish the impact of MM and its treatment with Lenalidomide on platelet function. We analyzed platelet function in MGUS, SM and MM compared to healthy controls. We report an increase in platelet reactivity in MGUS, SM, and MM where increases in fibrinogen binding, P-selectin exposure, altered receptor expression, elevated levels of aggregation and enhanced sensitivity to agonist stimulation were observed. We also demonstrate an increase in patient platelet reactivity post Lenalidomide treatment compared to pre-treatment. We show Lenalidomide treatment of platelets ex vivo increased reactivity that was associated with formation of larger thrombi at arterial shear rates but not venous shear rates. This study demonstrates a clear increase in platelet reactivity and prothrombotic potential in patients with MGUS, SM and MM which is elevated further upon treatment with Lenalidomide. Our observations suggest that more detailed studies are warranted to determine mechanisms of thrombotic complications to enable the development of new preventative strategies that specifically target platelets.
Arachchillage DJ, Weatherill A, Rajakaruna I, et al., 2023, Thrombosis, major bleeding, and survival in COVID-19 supported by VV- ECMO in the first vs second wave- multicentre observational study in the UK, Journal of Thrombosis and Haemostasis, Vol: 21, Pages: 2735-2746, ISSN: 1538-7836
BACKGROUND: Bleeding and thrombosis are major complications of veno-venous extracorporeal membrane (VV-ECMO). OBJECTIVES: To assess thrombosis, major bleeding (MB) and 180-day in patients supported by VV-ECMO between first (1st March-31st May 2020) and second (1st June 2020-30th June 2021) waves of the COVID-19 pandemic. PATIENTS/METHODS: Observational study of 309 consecutive patients (≥18years) with severe COVID-19 supported by VV-ECMO in four nationally commissioned ECMO centres, UK. RESULTS: Median age was 48 (19-75)years and 70.6% were male. Probabilities of survival, thrombosis, and MB at 180 days in the overall cohort were 62.5% (193/309), 39.8%(123/309) and 30%(93/309). In multivariate analysis, age >55 years (HR 2.29 [1.33-3.93],p=0.003) and elevated creatinine (HR 1.91 [1.19-3.08],p=0.008) were associated with increased mortality. Corrected for duration of VV-ECMO support, arterial thrombosis alone (HR 3.0 [95% CI1.5-5.9], P= 0.002) or circuit thrombosis alone (HR 3.9 [95% 2.4-6.3], P<0.001), but not venous thrombosis, increased mortality. MB during ECMO had 3-fold risk (95% CI 2.6-5.8, P<0.001) of mortality. The first wave cohort had more males (76.7% vs 64%, p=0.014), higher 180-day survival (71.1% vs 53.3% p=0.003), more venous thrombosis alone (46.4% vs 29.2%, p=0.02) and lower circuit thrombosis (9.2% vs 28.1%, p<0.001). The second wave cohort received more steroids (121/150 [80.6%] vs 86/159 [54.1%], p<0.0001) and Tocilizumab (20/150 [13.3%] vs 4/159 [2.5%] p=0.005). CONCLUSIONS: MB and thrombosis are frequent complications in patients on VV-ECMO and significantly increase mortality. Arterial thrombosis alone or circuit thrombosis alone increased mortality whilst venous thrombosis alone had no effect. MB during ECMO support increased mortality 3.9-fold.
Stefanucci L, Collins JH, Sims MC, et al., 2023, The effects of pathogenic variants for inherited hemostasis disorders in 140,214 UK Biobank participants., Blood
Rare genetic diseases affect millions, and identifying causal DNA variants is essential for patient care. Therefore, it is imperative to estimate the effect of each independent variant and improve their pathogenicity classification. Our study of 140,214 unrelated UK Biobank (UKB) participants found each carries a median of 7 variants previously reported as pathogenic or likely pathogenic. We focused on 967 diagnostic-grade genes (DGGs) variants for rare bleeding, thrombotic, and platelet disorders (BTPDs) observed in 12,367 UKB participants. By association analysis, for a subset of these variants, we estimated effect sizes for platelet count and volume, and odds ratios for bleeding and thrombosis. Variants causal of some autosomal recessive platelet disorders revealed phenotypic consequences in carriers. Loss-of-function variants in MPL, which cause chronic amegakaryocytic thrombocytopenia if biallelic, were unexpectedly associated with increased platelet counts in carriers. We also demonstrated that common variants identified by genome-wide association studies (GWAS) for platelet count or thrombosis risk may influence the penetrance of rare variants in BTPD DGGs on their associated hemostasis disorders. Network-propagation analysis applied to an interactome of 18,410 nodes and 571,917 edges showed that GWAS variants with large effect sizes are enriched in DGGs and their first-order interactors. Finally, we illustrate the modifying effect of polygenic scores for platelet count and thrombosis risk on disease severity in participants carrying rare variants in TUBB1, or PROC and PROS1, respectively. Our findings demonstrate the power of association analyses using large population datasets in improving pathogenicity classifications of rare variants.
Simini G, Akor F, Szydlo R, et al., 2023, Safety and Efficacy of Therapeutic Anticoagulation with Subcutaneous Unfractionated Heparin in Patients with Renal Failure, SEMINARS IN THROMBOSIS AND HEMOSTASIS, ISSN: 0094-6176
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, British Journal of Haematology, Vol: 202, Pages: 485-497, ISSN: 0007-1048
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, Journal of Thrombosis and Haemostasis, Vol: 21, Pages: 1802-1812, ISSN: 1538-7836
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.
Noble H, Crossette-Thambiah C, Odho Z, et al., 2023, 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, Vol: 49, Pages: 553-557, ISSN: 0094-6176
Bradbury CA, Lawler PR, McVerry BJ, et al., 2023, Continuation of therapeutic dose heparin for critically ill patients with COVID-19, INTENSIVE CARE MEDICINE, Vol: 49, Pages: 873-875, ISSN: 0342-4642
Simini G, Vinayagam S, Karawitage N, et al., 2023, Thrombocytosis and acquired bleeding disorders in patients with myeloproliferative neoplasms, 63rd Annual Scientific Meeting of the British-Society-for-Haematology, Publisher: WILEY, Pages: 53-54, ISSN: 0007-1048
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.
Arachchillage DJ, Rajakaruna I, Laffan M, et al., 2023, Outcomes in COVID-19 supported by ECMO in the first vs second wave -multicentre observational study, Publisher: WILEY, Pages: 25-25, ISSN: 0007-1048
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
Burke T, Rodriguez-Santana I, Chowdary P, et al., 2023, Humanistic burden of problem joints for children and adults with haemophilia, HAEMOPHILIA, Vol: 29, Pages: 608-618, 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, JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Vol: 21, Pages: 215-226, ISSN: 1538-7933
Laffan M, Dass N, Willock R, et al., 2023, RECOMBINANT VON WILLEBRAND FACTOR TREATMENT OUTCOMES IN ADULTS WITH VON WILLEBRAND DISEASE IN THE UK: AN INTERIM ANALYSIS, Publisher: WILEY, Pages: 147-148, ISSN: 1351-8216
Arachchillage DJ, Laffan M, Pericleous C, 2023, Hydroxychloroquine as an Immunomodulatory and Antithrombotic Treatment in Antiphospholipid Syndrome, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol: 24
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.
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
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
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
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
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
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, 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
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
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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