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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-
Tang N, Bai H, Chen X, et al., 2020, Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy., J Thromb Haemost, Vol: 18, Pages: 1094-1099
BACKGROUND: A relatively high mortality of severe coronavirus disease 2019 (COVID-19) is worrying, and the application of heparin in COVID-19 has been recommended by some expert consensus because of the risk of disseminated intravascular coagulation and venous thromboembolism. However, its efficacy remains to be validated. METHODS: Coagulation results, medications, and outcomes of consecutive patients being classified as having severe COVID-19 in Tongji hospital were retrospectively analyzed. The 28-day mortality between heparin users and nonusers were compared, as was a different risk of coagulopathy, which was stratified by the sepsis-induced coagulopathy (SIC) score or D-dimer result. RESULTS: There were 449 patients with severe COVID-19 enrolled into the study, 99 of them received heparin (mainly with low molecular weight heparin) for 7 days or longer. D-dimer, prothrombin time, and age were positively, and platelet count was negatively, correlated with 28-day mortality in multivariate analysis. No difference in 28-day mortality was found between heparin users and nonusers (30.3% vs 29.7%, P = .910). But the 28-day mortality of heparin users was lower than nonusers in patients with SIC score ≥4 (40.0% vs 64.2%, P = .029), or D-dimer >6-fold of upper limit of normal (32.8% vs 52.4%, P = .017). CONCLUSIONS: Anticoagulant therapy mainly with low molecular weight heparin appears to be associated with better prognosis in severe COVID-19 patients meeting SIC criteria or with markedly elevated D-dimer.
Ranger A, Gaspar M, Elkhatteb A, et al., 2020, Haemostatic markers in cardiopulmonary bypass surgery (MIC-B Study), 60th Annual Scientific Meeting of the British-Society-for-Haematology (BSH), Publisher: WILEY, Pages: 261-262, ISSN: 0007-1048
Arachchillage DRJ, Laffan M, 2020, What is the appropriate anticoagulation strategy for thrombotic antiphospholipid syndrome?, British Journal of Haematology, Vol: 189, Pages: 216-227, ISSN: 0007-1048
Antiphospholipid syndrome (APS) is an autoimmune prothrombotic disorder mediated by a heterogeneous group of autoantibodies collectively known as antiphospholipid antibodies (aPL). They include lupus anticoagulant (LA), IgG and IgM anticardiolipin antibodies (aCL) and anti‐β2‐glycoprotein I (anti‐β2GPI) antibodies. It has been shown that those patients with all three aPL (triple positive) are at highest risk of both a first thrombotic event and of a recurrence, despite anticoagulation. In response to publication of a meta‐analysis and a randomised controlled trial assessing the safety and efficacy of rivaroxaban versus warfarin in triple‐positive APS with venous and/or arterial thrombosis, the Medicines and Healthcare Products Regulatory Agency (MHRA) and European Medicines Agency (EMA) issued recommendations that direct‐acting oral anticoagulant (DOACs) should not be used for secondary prevention of thrombosis in all APS patients (although they did draw specific attention to the high risk of triple‐positive patients). As there is less evidence for patients with single‐ or dual‐positive patients with APS, this may be an over‐interpretation of the data. In this review, we explore the available evidence on safety and efficacy of DOACs in thrombotic APS, the problem of detecting LA while on DOAC, and provide some practical guidance for managing this problem.
Arachchillage DRJ, Gomez K, Alikhan R, et al., 2020, British Society for Haematology Guidelines on Investigation and Management of Antiphospholipid syndrome (vol 157, pg 47, 2012), BRITISH JOURNAL OF HAEMATOLOGY, Vol: 189, Pages: 212-215, ISSN: 0007-1048
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Arachchillage DJ, Gaspar M, Ahnstroem J, et al., 2020, Prospective cohort study of haemostatic activation markers and correlation with bleeding and thrombotic complications in patients receiving Veno-Venous Extra-Corporeal Membrane Oxygenation (VV-ECMO) -HAE study, 60th Annual Scientific Meeting of the British-Society-for-Haematology (BSH), Publisher: WILEY, Pages: 154-155, ISSN: 0007-1048
Mathias M, Collins P, Curry N, et al., 2020, UK EHL OUTCOMES REGISTRY: REASON FOR SWITCHING TO EXTENDED HALF-LIFE PRODUCT, Publisher: WILEY, Pages: 113-114, ISSN: 1351-8216
Pasi KJ, Rangarajan S, Mitchell N, et al., 2020, Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for Hemophilia A, New England Journal of Medicine, Vol: 382, Pages: 29-40, ISSN: 0028-4793
BACKGROUND: Adeno-associated virus (AAV)-mediated gene therapy is under investigation as a therapeutic option for persons with hemophilia A. Efficacy and safety data include 3 years of follow-up after a single administration of AAV5-hFVIII-SQ. METHODS: We report durable efficacy, long-term safety, and clinical and biologic results in 15 adults with severe hemophilia A (factor VIII level, ≤1 IU per deciliter) who had received a single infusion of AAV5-hFVIII-SQ at various dose levels. We evaluated the factor VIII level, annualized rate of bleeding events, use of factor VIII, safety, expression kinetics, and biologic markers of AAV transduction for up to 3 years. RESULTS: Three years after infusion, two participants (one who had received 6×1012 vector genomes [vg] per kilogram of body weight and one who had received 2×1013 vg per kilogram) had factor VIII expression of less than 1 IU per deciliter, as assessed on chromogenic assay. Seven participants (who had received 6×1013 vg per kilogram) had a median factor VIII expression of 20 IU per deciliter; the median number of annualized treated bleeding events was 0, and the median use of exogenous factor VIII was reduced from 138.5 infusions to 0 infusions per year. Bleeding in all target joints (major joints with ≥3 bleeding events within 6 months) in this cohort resolved (≤2 bleeding events within 12 months). Two years after infusion, six participants (who had received 4×1013 vg per kilogram) had a median factor VIII expression of 13 IU per deciliter; the median annualized rate of bleeding events was 0, and the median use of factor VIII was reduced from 155.5 infusions to 0.5 infusions per year. Bleeding in target joints resolved in five of six participants. The factor VIII pharmacodynamic profiles reflected cellular turnover in the blood and molecular events leading to episomal DNA stabilization for persistent expression, findings that are consistent with previous observations in two mo
Ahnström J, Gierula M, Temenu J, et al., 2020, Partial rescue of naturally occurring active site factor X variants through decreased inhibition by tissue factor pathway inhibitor and antithrombin., Journal of Thrombosis and Haemostasis, Vol: 18, Pages: 136-150, ISSN: 1538-7836
BACKGROUND: Activated coagulation factor X (FXa) is the serine protease component of prothrombinase, the physiological activator of prothrombin. FX Nottingham (A404T) and Taunton (R405G) are two naturally occurring mutations, identified in families with a bleeding phenotype. OBJECTIVE: To functionally characterise these FX variants. METHODS: The activity and inhibition of recombinant FX variants was quantified in plasma based and pure component assays. RESULTS: The prothrombin times in FX-depleted plasma supplemented with FX Nottingham and Taunton were greatly increased compared to wild-type (WT) FX. Kinetic investigations of activated variants in the prothrombinase complex showed kcat /Km , reduced ~50-fold and ~5-fold, respectively, explaining the prolonged PT times. The substituted residues are located in the protease domain Na+ -binding loop, important for the activity of FXa, as well as its inhibition. Both FXa Nottingham and Taunton showed reduced affinity for Na+ . Plasma-based thrombin generation assays triggered with 1pM tissue factor (TF) demonstrated only small differences in activities compared to WT FX, but large reductions at 10pM TF. Severely reduced inhibition of both FXa Nottingham and Taunton by tissue factor pathway inhibitor (TFPI) and antithrombin (AT), was shown in pure-component FXa inhibition assays. FXa Nottingham and Taunton produced higher amounts of thrombin than WT FXa in pure-component prothrombinase assays in the presence of TFPI and AT, explaining the results from the plasma-based assay. CONCLUSIONS: FX Nottingham and Taunton both display decreased proteolytic activity. However, their reduced activity in plasma triggered by low TF can be rescued by decreased inhibition by the natural FXa inhibitors, TFPI and AT.
Lentaigne C, Greene D, Sivapalaratnam S, et al., 2019, Germline mutations in the transcription factor IKZF5 cause thrombocytopenia, Blood, Vol: 134, Pages: 2070-2081, ISSN: 1528-0020
To identify novel causes of hereditary thrombocytopenia, we performed a genetic association analysis of whole-genome sequencing (WGS) data from 13,037 individuals enrolled in the NIHR BioResource, including 233 cases with isolated thrombocytopenia. We found an association between rare variants in the transcription factor (TF)-encoding gene IKZF5 and thrombocytopenia. We report five causal missense variants in or near IKZF5 zinc fingers (Znfs), of which two occurred de novo and three co-segregated in three pedigrees. A canonical DNA-Znf binding model predicts that three of the variants alter DNA recognition. Expression studies showed that chromatin binding was disrupted in mutant compared to wild-type (WT) IKZF5 and electron microscopy (EM) revealed a reduced quantity of alpha granules in normally sized platelets. Proplatelet formation (PPF) was reduced in megakaryocytes (MKs) from seven cases relative to six controls. Comparison of RNA-seq data from platelets, monocytes, neutrophils and CD4+ T-cells from three cases and 14 healthy controls showed 1,194 differentially expressed genes (DEGs) in platelets but only four DEGs in each of the other blood cell types. In conclusion, IKZF5 is a novel transcriptional regulator of megakaryopoiesis and the eighth transcription factor associated with dominant thrombocytopenia in humans.
Downes K, Megy K, Duarte D, et al., 2019, Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders, Blood, Vol: 134, Pages: 2082-2091, ISSN: 1528-0020
A targeted high-throughput sequencing (HTS) panel test for clinical diagnostics requires careful consideration of the inclusion of appropriate diagnostic-grade genes, the ability to detect multiple types of genomic variation with high levels of analytic sensitivity and reproducibility, and variant interpretation by a multi-disciplinary team (MDT) in the context of the clinical phenotype. We have sequenced 2,396 index patients using the ThromboGenomics HTS panel test of diagnostic-grade genes known to harbour variants associated with rare bleeding, thrombotic or platelet disorders (BTPD). The molecular diagnostic rate was determined by the clinical phenotype, with an overall rate of 49.2% for all thrombotic, coagulation, platelet count and function disorder patients and a rate of 3.2% for patients with unexplained bleeding disorders characterized by normal hemostasis test results. The MDT classified 745 unique variants, including copy number and intronic variants, as Pathogenic, Likely Pathogenic or Variants of Uncertain Significance. Half (50.9%) of these variants are novel and 41 unique variants were identified in 7 genes recently found to be implicated in BTPD. Inspection of canonical hemostasis pathways identified 29 patients with evidence of oligogenic inheritance. A molecular diagnosis has been reported for 894 index patients providing evidence that introducing an HTS genetic test is a valuable addition to laboratory diagnostics in patients with a high likelihood of having an inherited BTPD.
Jayakody Arachchillage DR, Gaspar M, Makhecha S, et al., 2019, Use of Antithrombin concentrate for acquired antithrombin deficiency in acutely unwell children receiving unfractionated heparin, Seminars in Thrombosis and Hemostasis, Vol: 45, Pages: 859-863, ISSN: 0094-6176
Arachchillage DR, Laffan M, 2019, Pathogenesis and management of thrombotic disease in myeloproliferative neoplasms, Seminars in Thrombosis and Hemostasis, Vol: 45, Pages: 604-611, ISSN: 0094-6176
Chronic myeloproliferative neoplasms (MPN) are characterized by clonal expansion of an abnormal hematopoietic stem/progenitor cell and include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Venous thrombosis, often at unusual sites, including splanchnic vein thrombosis and arterial thrombosis, as well as a hemorrhagic tendency and a propensity to transform into myelofibrosis or acute leukemia are common complications in patients with MPNs. The pathogenesis of thrombosis in MPN patients is complex and multifactorial. Disease related factors, such as an increase in blood cell counts (i.e., leukocytosis, erythrocytosis, and thrombocytosis), and more importantly presence of JAK2 mutation can interact with non-disease patient related factors such as age, previous history of thrombotic events, obesity, hypertension, hyperlipidemia, and presence of thrombophilic defects. The overall rate of recurrent thrombosis after venous thromboembolism (VTE) is 6.0 to 6.5 per 100 patient-years in patients with MPN compared to 2.7 to 3.7 per 100 patient-years in patients without MPN, and antithrombotic therapy with vitamin K antagonists (VKAs) is associated with a clear benefit, reducing the incidence of recurrence by 48 to 69%. Life-long oral anticoagulation with VKAs is the cornerstone of the antithrombotic treatment for splanchnic vein thrombosis (SVT). Patients with MPN-related cerebral venous thrombosis (CVT) should also be treated with long-term anticoagulation with VKAs. The role of direct acting oral anticoagulants in patients with thrombosis and MPN is not established and the use of these anticoagulants should be considered on an individual basis according to the risk of recurrent of VTE and bleeding.
Arachchillage DRJ, Vipond L, Laffan M, 2019, Limitations on point care APTT for monitoring of unfractionated heparin in intensive care patients, Thrombosis Research: vascular obstruction, hemorrhage and hemostasis, Vol: 181, Pages: 124-126, ISSN: 0049-3848
Tham C, Lee K, Laffan M, 2019, Utility of fibrinogen in the coagulation screen, 58th Annual Scientific Meeting of the British-Society-for-Haematology, Publisher: WILEY, Pages: E137-E139, ISSN: 0007-1048
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Lester W, Gomez K, Shapiro S, et al., 2019, NICE NG89 recommendations for extended pharmacological thromboprophylaxis - is it justified and is it cost effective: a rebuttal from the British Society for Haematology., Br J Haematol
Shapiro S, Stephensen D, Camp C, et al., 2019, The top 10 research priorities in bleeding disorders: a James Lind Alliance Priority Setting Partnership, British Journal of Haematology, Vol: 186, Pages: E98-E100, ISSN: 0007-1048
Gill D, Benyamin B, Moore LSP, et al., 2019, Associations of genetically determined iron status across the phenome: a mendelian randomization study, PLoS Medicine, Vol: 16, ISSN: 1549-1277
BackgroundIron is integral to many physiological processes and variations in its levels, even within the normal range, can have implications for health. The objective of this study was to explore the broad clinical effects of varying iron status.Methods and FindingsGenome-wide association study summary data obtained from 48,972 European individuals (55% female) across 19 cohorts in the Genetics of Iron Status Consortium were used to identify three genetic variants (rs1800562 and rs1799945 in the hemochromatosis gene, and rs855791 in the transmembrane protease serine 6 gene) that associate with increased serum iron, ferritin and transferrin saturation, and decreased transferrin levels, thus serving as instruments for systemic iron status. Phenome-wide association study (PheWAS) of these instruments was performed on 415,482 European individuals (54% female) in the UK Biobank that were aged 40-69 years when recruited from 2006 to 2010, with their genetic data linked to Hospital Episode Statistics from April 1995 to March 2016. Two-sample summary data Mendelian randomization (MR) analysis was performed to investigate the effect of varying iron status on outcomes across the human phenome. MR-PheWAS analysis for the three iron status genetic instruments was performed separately and then pooled by meta-analysis. Correction was made for testing of multiple correlated phenotypes using a 5% false discovery rate threshold. Heterogeneity between MR estimates for different instruments was used to indicate possible bias due to effects of the genetic variants through pathways unrelated to iron status. There were 904 distinct phenotypes included in the MR-PheWAS analyses. After correcting for multiple testing, the three genetic instruments for systemic iron status demonstrated consistent evidence of a causal effect of higher iron status on decreasing risk of traits related to anemia (iron deficiency anemia: odds ratio [OR] scaled to a standard deviation increase in genetically dete
Ishihara J, Ishihara A, Starke RD, et al., 2019, The heparin binding domain of von Willebrand factor binds to growth factors and promotes angiogenesis in wound healing, Blood, Vol: 133, Pages: 2559-2569, ISSN: 0006-4971
During wound healing, the distribution, availability, and signaling of growth factors (GFs) are orchestrated by their binding to extracellular matrix components in the wound microenvironment. Extracellular matrix proteins have been shown to modulate angiogenesis and promote wound healing through GF binding. The hemostatic protein von Willebrand factor (VWF) released by endothelial cells (ECs) in plasma and in the subendothelial matrix has been shown to regulate angiogenesis; this function is relevant to patients in whom VWF deficiency or dysfunction is associated with vascular malformations. Here, we show that VWF deficiency in mice causes delayed wound healing accompanied by decreased angiogenesis and decreased amounts of angiogenic GFs in the wound. We show that in vitro VWF binds to several GFs, including vascular endothelial growth factor-A (VEGF-A) isoforms and platelet-derived growth factor-BB (PDGF-BB), mainly through the heparin-binding domain (HBD) within the VWF A1 domain. VWF also binds to VEGF-A and fibroblast growth factor-2 (FGF-2) in human plasma and colocalizes with VEGF-A in ECs. Incorporation of the VWF A1 HBD into fibrin matrices enables sequestration and slow release of incorporated GFs. In vivo, VWF A1 HBD-functionalized fibrin matrices increased angiogenesis and GF retention in VWF-deficient mice. Treatment of chronic skin wounds in diabetic mice with VEGF-A165 and PDGF-BB incorporated within VWF A1 HBD-functionalized fibrin matrices accelerated wound healing, with increased angiogenesis and smooth muscle cell proliferation. Therefore, the VWF A1 HBD can function as a GF reservoir, leading to effective angiogenesis and tissue regeneration.
Wei W, Tuna S, Keogh MJ, et al., 2019, Germline selection shapes human mitochondrial DNA diversity, Science, Vol: 364, ISSN: 0036-8075
INTRODUCTIONOnly 2.4% of the 16.5-kb mitochondrial DNA (mtDNA) genome shows homoplasmic variation at >1% frequency in humans. Migration patterns have contributed to geographic differences in the frequency of common genetic variants, but population genetic evidence indicates that selection shapes the evolving mtDNA phylogeny. The mechanism and timing of this process are not clear.Unlike the nuclear genome, mtDNA is maternally transmitted and there are many copies in each cell. Initially, a new genetic variant affects only a proportion of the mtDNA (heteroplasmy). During female germ cell development, a reduction in the amount of mtDNA per cell causes a “genetic bottleneck,” which leads to rapid segregation of mtDNA molecules and different levels of heteroplasmy between siblings. Although heteroplasmy is primarily governed by random genetic drift, there is evidence of selection occurring during this process in animals. Yet it has been difficult to demonstrate this convincingly in humans.RATIONALETo determine whether there is selection for or against heteroplasmic mtDNA variants during transmission, we studied 12,975 whole-genome sequences, including 1526 mother–offspring pairs of which 45.1% had heteroplasmy affecting >1% of mtDNA molecules. Harnessing both the mtDNA and nuclear genome sequences, we then determined whether the nuclear genetic background influenced mtDNA heteroplasmy, validating our findings in another 40,325 individuals.RESULTSPreviously unknown mtDNA variants were less likely to be inherited than known variants, in which the level of heteroplasmy tended to increase on transmission. Variants in the ribosomal RNA genes were less likely to be transmitted, whereas variants in the noncoding displacement (D)–loop were more likely to be transmitted. MtDNA variants predicted to affect the protein sequence tended to have lower heteroplasmy levels than synonymous variants. In 12,975 individuals, we identified a correlation between
Newnham M, South K, Bleda M, et al., 2019, The ADAMTS13-VWF axis is dysregulated in chronic thromboembolic pulmonary hypertension, European Respiratory Journal, Vol: 53, ISSN: 0903-1936
Chronic thromboembolic pulmonary hypertension (CTEPH) is an important consequence of pulmonary embolism (PE) that is associated with abnormalities in haemostasis. We investigated the ADAMTS13-VWF axis in CTEPH, including its relationship to disease severity, inflammation, ABO groups and ADAMTS13 genetic variants.ADAMTS13 and VWF plasma antigen levels were measured in patients with CTEPH (n=208), chronic thromboembolic disease without pulmonary hypertension (CTED; n=35), resolved PE (n=28), idiopathic pulmonary arterial hypertension (n=30) and healthy controls (n=68). CTEPH genetic ABO associations and protein quantitative trait loci were investigated. ADAMTS-VWF axis abnormalities were assessed in CTEPH and healthy control subsets by measuring ADAMTS13 activity, D-dimers and VWF-multimeric size.CTEPH patients had decreased ADAMTS13 (adjusted β (95% CI)=−23.4 (−30.9– −15.1)%, p<0.001) and increased VWF levels (β=+75.5 (44.8–113)%, p<0.001) compared to healthy controls. ADAMTS13 levels remained low after reversal of pulmonary hypertension by pulmonary endarterectomy surgery and were equally reduced in CTED. We identify a genetic variant near the ADAMTS13 gene associated with ADAMTS13 protein that accounted for ∼8% of the variation in levels.The ADAMTS13-VWF axis is dysregulated in CTEPH. This is unrelated to pulmonary hypertension, disease severity or markers of systemic inflammation and implicates the ADAMTS13-VWF axis in CTEPH pathobiology.
Arachchillage DRJ, Alavian S, Griffin J, et al., 2019, Efficacy and safety of prothrombin complex concentrate in patients treated with rivaroxaban or apixaban compared to warfarin presenting with major bleeding, British Journal of Haematology, Vol: 184, Pages: 808-816, ISSN: 1365-2141
This retrospective study investigated the efficacy and safety of prothrombin complex concentrates (PCCs) for management of major bleeding events (MBE) in 344 patients receiving the anticoagulants rivaroxaban, apixaban or warfarin during the period January 2016 to April 2018. Median (range) PCC dose was 2000 units (1000-4500). Intracranial haemorrhage (ICH) was the most common indication (137/344, 39·8%) for PCC use followed by gastrointestinal bleeding (93/344, 27%). ICH patients more frequently received rivaroxaban (62·5%) or apixaban (52·5%) compared to warfarin (34·5%), P = 0·002; and visceral bleeding patients received warfarin more frequently (24·2%) than rivaroxaban (5%) or apixaban (10%), P = 0·003. Median rivaroxaban and apixaban levels were 230 ng/ml (47-759) and 159 ng/ml (45-255). Median International Normalised Ratio pre- and post-PCC in patients on warfarin were 3·4 (1·9-15·4) and 1·2 (1·0-1·9). Blood products use was the same between groups. Thirty-day mortality and re-bleeding rates in patients with ICH were 35% (P = 0·50) and 18% (P = 0·90) with no differences between the groups. Thrombosis occurred in 4·1% patients within 30 days with no difference between groups. Two of 91 (2·2%) patients with ICH only (both on warfarin) had ischaemic strokes within 30 days post-PCC. In conclusion, there was no difference in the safety (thrombosis) or efficacy (30-day mortality, re-bleeding) in use of PCC for MBE in patients on warfarin, rivaroxaban or apixaban.
Rhodes CJ, Batai K, Bleda M, et al., 2019, Genetic determinants of risk in pulmonary arterial hypertension: international case-control studies and meta-analysis, Lancet Respiratory Medicine, Vol: 7, Pages: 227-238, ISSN: 2213-2600
BackgroundRare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes.MethodsWe did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses.FindingsA locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13 × 10–15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42–1·71], p=7·65 × 10–20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25–1·48], p=1·69 × 10–12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-media
Arachchillage DJ, Gaspar M, Owen S, et al., 2019, Use of antithrombin concentrate in acquired antithrombin deficiency in acutely unwell children receiving unfractionated heparin - a single centre experience, 59th Annual Scientific Meeting of the British-Society-for-Hematology, Publisher: WILEY, Pages: 133-133, ISSN: 0007-1048
Arachchillage DJ, Khanna S, Passariello M, et al., 2019, Incidences of thrombosis, major bleeding and 30-day mortality in patients receiving veno-venous extracorporeal membrane oxygenation and value of laboratory parameters at presentation in predicting outcomes, 59th Annual Scientific Meeting of the British-Society-for-Hematology, Publisher: WILEY, Pages: 133-134, ISSN: 0007-1048
Shapiro S, Stephenson D, Camp C, et al., 2019, The top 10 research priorities in bleeding disorders: a James Lind Alliance Priority Setting Partnership, 59th Annual Scientific Meeting of the British-Society-for-Hematology, Publisher: WILEY, Pages: 131-131, ISSN: 0007-1048
O'Hara J, Khair K, McLaughlin P, et al., 2019, "Problem Joint" a more patient relevant definition for joint morbidity in haemophilia, Publisher: WILEY, Pages: 111-112, ISSN: 1351-8216
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O'Hara J, Burke T, Chowdary P, et al., 2019, Key findings from an expert validation workshop to establish an appropriate modelling framework in severe haemophilia A, Publisher: WILEY, Pages: 182-183, ISSN: 1351-8216
Willock R, Laffan M, Goudemand J, et al., 2019, An introduction to CVESS: The cost of von Willebrand disease in Europe-a socioeconomic study, Publisher: WILEY, Pages: 163-163, ISSN: 1351-8216
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Riddell A, Vinayagam S, Gomez K, et al., 2019, Evaluation of von Willebrand factor concentrates by platelet adhesion to collagen using an in vitro flow assay, RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS, Vol: 3, Pages: 126-135, ISSN: 2475-0379
BackgroundVon Willebrand disease (VWD) results from quantitative or qualitative deficiency of von Willebrand factor (VWF) and is treated using VWF‐containing concentrates. Several studies have compared the function of various VWF containing concentrates however this has not been performed using shear based assays.ObjectivesTo compare the platelet‐capture potential of 10 commercially available, plasma‐derived VWF concentrates under shear conditions.MethodsVWF containing concentrates were assessed for VWF:Ag, VWF:CB, VWF:RCo, factor VIII:C ADAMTS13 content, VWF multimeric profile and glycan content using lectin binding assays. Free‐thiol content of each concentrate was investigated using MPB binding assays. An in vitro flow assay was used to determine the ability of each concentrate to mediate platelet capture to collagen.ResultsVWF multimeric analysis revealed reduction of high molecular weight (HMW) forms in four of the concentrates (Alphante, Octanate and Haemoctin, and 8Y). The high MW multimer distribution of the remaining six concentrates (Optivate, Wilate, Fandhi, Wilfactin, Haemate P, and Voncento) was similar to the plasma control. Lectin analysis demonstrated that 8Y had increased amount of T‐antigen. Although platelet capture after 5 minutes perfusion was similar for all concentrates; Alphante, Octanate, and Haemoctin, demonstrated the lowest levels of platelet capture after 60 seconds of perfusion. Free‐thiol content and ADAMTS13 levels varied widely between the concentrates but was not correlated with function.ConclusionAlphanate, Octanate, and Haemoctin, lacked HMW multimers and had the lowest initial platelet capture levels suggesting that the presence of VWF HMW multimers are required for initial platelet deposition.
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