Publications
347 results found
Turecek PL, Peck RC, Rangarajan S, et 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.
Burke T, Santana IR, Chowdary P, et 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
Chang KW, Owen S, Gaspar M, et 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
Gomez K, Laffan M, Bradbury C, 2021, Debate: Should the dose or duration of anticoagulants for the prevention of venous thrombosis be increased in patients with COVID-19 while we are awaiting the results of clinical trials?, British Journal of Haematology, Vol: 192, Pages: 459-466, ISSN: 0007-1048
O'Brien HER, Zhang XF, Sanz-Hernandez M, et 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.
Laffan M, Sathar J, Johnsen JM, 2021, von Willebrand disease: Diagnosis and treatment, treatment of women, and genomic approach to diagnosis, HAEMOPHILIA, Vol: 27, Pages: 66-74, ISSN: 1351-8216
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- Citations: 10
Connell NT, James PD, Brignardello-Petersen R, et al., 2021, von Willebrand disease: proposing definitions for future research, BLOOD ADVANCES, Vol: 5, Pages: 565-569, ISSN: 2473-9529
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- Citations: 19
Arachchillage DRJ, Shi C, Saliu D, et 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
Connell NT, Flood VH, Brignardello-Petersen R, et 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
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- Citations: 118
Pang KH, Laffan M, 2021, Haemostasis and Thrombosis, Basic Urological Sciences, Pages: 40-45, ISBN: 9780367250669
Pang KH, Laffan M, 2021, Blood Products and Antithrombotic Agents, Basic Urological Sciences, Pages: 282-288, ISBN: 9780367250669
Maners J, Gill D, Pankratz N, et 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.
Morrow GB, Beavis J, Harper S, et 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.
Burke T, Santana IR, Chowdary P, et 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
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- Citations: 1
Khan D, Mitchell J, Rana R, et al., 2020, Prospective Study Reveals Increased Platelet Function Associated with Multiple Myeloma and Its Treatment, Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Baker P, Platton S, Gibson C, et 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
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- Citations: 20
Arachchillage DRJ, Owen S, Anievas M, et 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
Angus DC, Derde L, Al-Beidh F, et 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)
Arachchillage DJ, Remmington C, Rosenberg A, et 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
Arachchillage DJ, Stacey A, Akor F, et al., 2020, Thrombolysis restores perfusion in COVID-19 hypoxia, British Journal of Haematology, Vol: 190, Pages: E270-E274, ISSN: 0007-1048
Nesr G, Laffan M, Claudiani S, et al., 2020, Platelet function in patients with chronic myeloid leukemia treated with asciminib, Leukemia & Lymphoma, Vol: 61, Pages: 3021-3023, ISSN: 1042-8194
Turro E, Astle WJ, Megy K, et al., 2020, Whole-genome sequencing of patients with rare diseases in a national health system, Nature, Vol: 583, Pages: 96-102, ISSN: 0028-0836
Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.
Little C, Szydlo R, Aw TC, et al., 2020, Effect of direct-acting oral anticoagulants (DOACs) on bleeding and blood product usage in cardiac surgery compared to warfarin and controls, British Journal of Haematology, Vol: 190, Pages: 284-293, ISSN: 0007-1048
In this retrospective, single-centre, observational study, we assessed (i) use of anticoagulant and antiplatelet (AP) therapy, (ii) the duration of direct-acting oral anticoagulant (DOAC) discontinuation, (iii) renal function and (iv) PT and APTT as predictors of bleeding and blood product usage; in adults (>18 years) undergoing major cardiac surgery from 01.01.2015 to 31.12.2018. Comparisons were made between each treatment group (warfarin, DOAC and DOAC + AP) and untreated controls, and between warfarin and DOAC. A total of 2928 patients were included for analysis. Median (range) of DOAC discontinuation prior to surgery was five days (1-22) for DOAC and five days (2-7) for DOAC + AP. There were no differences in bleeding between anticoagulant groups versus control, or DOAC versus warfarin. There were no differences in blood product use between DOAC and warfarin patients. The duration of DOAC discontinuation but not the creatinine clearance influenced bleeding and blood products use. Thrombosis occurred in 0·7% and 3·1% in controls and patients on warfarin respectively (P = 0·099) with none among patients on DOAC or DOAC + AP. The PT/APTT had no predictive value. Median five-day discontinuation of DOAC +/- AP irrespective of renal function prevents an increase in bleeding compared to patients on warfarin or controls with no increase in thrombosis.
Morrow GB, Beavis J, Harper S, et al., 2020, Coagulation status of critically ill patients with and without liver disease assessed using a novel thrombin generation analyzer, JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Vol: 18, Pages: 1576-1585, ISSN: 1538-7933
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- Citations: 8
Guy A, Danaee A, Paschalaki K, et al., 2020, Absence of JAK2V617F mutated endothelial colony-forming cells in patients with JAK2V617F myeloproliferative neoplasms and splanchnic vein thrombosis, HemaSphere, Vol: 4, Pages: 1-4, ISSN: 2572-9241
Philadelphia (Ph)-negative myeloproliferative neoplasms (MPN) are acquired hematologic diseases with increased production of mature blood cells. They include polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF). The most frequent molecular abnormality found in Ph negative MPN is JAK2V617F, an activating mutation of JAK2 which is responsible for constitutive signaling of various cytokine receptors. Arterial and venous thromboses are the main complications of these diseases and are responsible for high rates of morbidity and mortality. Of note there is a disproportionate incidence of thrombosis at unusual sites including splanchnic vein thrombosis.1 Splanchnic vein thromboses (SVT) involve one or more abdominal veins, the two most frequent are Portal Vein Thrombosis (PVT) and Budd Chiari Syndrome (BCS). Pathophysiology of thrombosis in MPN is complex and involves abnormalities in blood cells, plasma factors, and endothelial cells (ECs). Several groups, using different techniques, have shown JAK2V617F expression in endothelial cells (Supplemental Fig. 1, http://links.lww.com/HS/A79). Using laser capture microdissection, JAK2V617F was demonstrated in ECs from hepatic venules in 2 of 3 patients with PV and BCS.2JAK2V617F endothelial cells were demonstrated in microdissected splenic capillaries and in ECs cultured from splenic vein in patients with myelofibrosis but without SVT.3 Although these teams performed experiments to ensure that the DNA they obtained originated from ECs, it is difficult to completely rule out a possible contamination by blood cells. Analysis of endothelial progenitor cells, specifically endothelial colony forming cells (ECFCs), is an alternative way to look for JAK2V617F ECs. Indeed, ECFCs are reported to be the only “true” endothelial progenitor cells, as they are the only ones able to generate blood vessels in vivo: they display clonogenic potential, endothelial but not myeloid cell surface markers, and prono
Pavord S, Thachil J, Hunt BJ, et al., 2020, Practical guidance for the management of adults with immune thrombocytopenia during the COVID-19 pandemic, BRITISH JOURNAL OF HAEMATOLOGY, Vol: 189, Pages: 1038-1043, ISSN: 0007-1048
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- Citations: 72
Tang N, 2020, Response to 'Reply to Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy', JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Vol: 18, Pages: 1520-1521, ISSN: 1538-7933
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- Citations: 5
Davies A, Onida S, Shalhoub J, et al., 2020, Rapid Response to: Clinical features of covid-19, BMJ: British Medical Journal, ISSN: 0959-535X
Tang N, Bai H, Chen X, et al., 2020, Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy, JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Vol: 18, Pages: 1094-1099, ISSN: 1538-7933
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- Citations: 749
Jayakody Arachchillage DR, Laffan M, Khanna S, et al., 2020, Frequency of thrombocytopenia and heparin induced thrombocytopenia in patients receiving extracorporeal membrane oxygenation compared to cardiopulmonary bypass and the limited sensitivity of pre-test probability score, Critical Care Medicine, Vol: 48, Pages: e371-e379, ISSN: 0090-3493
Objectives:To ascertain:i)the frequency of thrombocytopeniaand heparininducedthrombocytopenia (HIT), ii)positive predictive value (PPV) of the pre-test probability score (PTPS) in identifying HIT iii)clinical outcome of HITin adult patients receiving veno-venous (VV)-extracorporeal membraneoxygenation(ECMO)or veno-arterial (VA)-ECMO, comparedto cardiopulmonary bypass (CPB). Design: A single-centre, retrospective, observational cohort study from January 2016 to April 2018Setting: Tertiary referral centre for cardiac and respiratory failure Patients:Patients who received ECMOfor>48hrs or had CPB during specified period Interventions: None.Measurements and Main Results:Clinical and laboratory data were collected retrospectively. PTPS and HIT testing results were collected prospectively. Mean age (standard deviation) of the EMCO and CPB cohorts were 45.4 (±15.6) and 64.9 (±13), p< 0.00001.Median duration of CPB was 4.6 [2-16.5]hrs compared to 170.4[70-1008] hrson ECMO.Moderateand severethrombocytopenia were more common in ECMO compared to CPB throughout (p<0.0001).Thrombocytopenia increased in CPB patients on day2 but was 4normal in 83% compared to 42.3 % ofECMOpatients at day 10. Patients on ECMO also followed a similar pattern of platelet recoveryfollowing cessation of ECMO. The incidences of HIT in ECMO and CPB were 6.4% (19/298) and 0.6% (18/2998) respectivelyp<0.0001). There was no difference in prevalence of HIT in patients on VV-ECMO (9/156, 5.7%) vs VA-ECMO (11/142, 7.7%), p=0.81. The PPV of the PTPS in identifying HIT in patients post-CPB and on ECMO were 56.25% (18/32) and 25% (15/60) respectively. Mortalitywas not different with (6/19, 31.6%) or without (89/279, 32.2%) HIT in patients on ECMO,p=0.79. Conclusions Thrombocytopenia is already common at ECMO initiation. HIT is more frequent in both VV-and VA-
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