Debra D Pittman, Charles Carrieri, Holly Soares, John McKay, Charles Y Tan, John Z Liang, Swapnil Rakhe, Jean-Claude Marshall, John E Murphy, Puneet Gaitonde, Jeremy Rupon
Background: Fidanacogene elaparvovec, an adeno-associated virus-based gene therapy vector expressing the high-activity factor IX (FIX) variant FIX-R338L, is in development for hemophilia B. One-stage clotting (OS) assays and chromogenic substrate (CS) assays are commonly used to measure FIX-R338L variant activity. Data from ongoing trials suggest FIX activity varies between different OS and CS assays.
Material and methods: To better understand FIX-R338L activity in clinical samples, an international multisite field study was conducted across a central laboratory and 18 local laboratories, using standard protocols, reagents, and instrumentation, with individual participant samples from a phase 1/2a study of fidanacogene elaparvovec.
Results: Unlike the wild-type FIX control, FIX-R338L activity was higher with the OS silica-based assay versus OS ellagic acid-based and CS assays. Variation in FIX activity was greater at the lowest activity levels. Activated FIX (FIXa) in plasma could result in higher OS assay activity or increased thrombin generation, which could overestimate FIX activity. However, FIXa was not detected in the participant samples, indicating that it was not contributing to the OS assay differences. Since individuals on gene therapy may receive exogenous replacement FIX products, replacement products were spiked into patient plasma samples to target a therapeutic concentration. Exogenous FIX was additive to endogenous FIX-R338L, with no interference from FIX-R338L.
Conclusion: These results demonstrate FIX-R338L activity can be measured with OS and CS assays in clinical laboratories and provide insight into assay variability when measuring FIX with endogenously produced FIX-R338L. The findings may help establish best practices for measuring FIX-R338L activity (Clinicaltrials.gov identifier: NCT02484092).
背景:Fidanacogene elaparvovec是一种表达高活性因子IX(FIX)变体FIX-R338L的基于腺相关病毒的基因治疗载体,目前正在开发用于治疗B型血友病。正在进行的试验数据表明,FIX活性在不同的OS和CS测定法中存在差异:为了更好地了解临床样本中FIX-R338L的活性,我们在一个中心实验室和18个地方实验室开展了一项国际多点实地研究,使用标准协议、试剂和仪器,对来自fidanacogene elaparvovec的1/2a期研究的个体参与者样本进行了检测:结果:与野生型 FIX 对照组不同,基于 OS 硅的检测方法与基于 OS 鞣酸的检测方法和 CS 检测方法相比,FIX-R338L 的活性更高。最低活性水平的 FIX 活性差异更大。血浆中的活化 FIX(FIXa)可能导致 OS 检测活性升高或凝血酶生成增加,从而高估 FIX 活性。不过,参与者样本中未检测到 FIXa,这表明它不会导致 OS 检测结果的差异。由于接受基因治疗的患者可能会接受外源性替代 FIX 产品,因此在患者血浆样本中添加了替代产品,以达到治疗浓度。外源性 FIX 与内源性 FIX-R338L 具有相加性,FIX-R338L 没有干扰:这些结果表明,在临床实验室中可以用 OS 和 CS 检测法测量 FIX-R338L 活性,并能深入了解用内源性 FIX-R338L 测量 FIX 时的检测变异性。这些发现可能有助于建立测量 FIX-R338L 活性的最佳实践(Clinicaltrials.gov 识别码:NCT02484092)。
{"title":"Field Study and Correlative Studies of Factor IX Variant FIX-R338L in Participants Treated with Fidanacogene Elaparvovec.","authors":"Debra D Pittman, Charles Carrieri, Holly Soares, John McKay, Charles Y Tan, John Z Liang, Swapnil Rakhe, Jean-Claude Marshall, John E Murphy, Puneet Gaitonde, Jeremy Rupon","doi":"10.1055/s-0044-1787734","DOIUrl":"https://doi.org/10.1055/s-0044-1787734","url":null,"abstract":"<p><strong>Background: </strong> Fidanacogene elaparvovec, an adeno-associated virus-based gene therapy vector expressing the high-activity factor IX (FIX) variant FIX-R338L, is in development for hemophilia B. One-stage clotting (OS) assays and chromogenic substrate (CS) assays are commonly used to measure FIX-R338L variant activity. Data from ongoing trials suggest FIX activity varies between different OS and CS assays.</p><p><strong>Material and methods: </strong> To better understand FIX-R338L activity in clinical samples, an international multisite field study was conducted across a central laboratory and 18 local laboratories, using standard protocols, reagents, and instrumentation, with individual participant samples from a phase 1/2a study of fidanacogene elaparvovec.</p><p><strong>Results: </strong> Unlike the wild-type FIX control, FIX-R338L activity was higher with the OS silica-based assay versus OS ellagic acid-based and CS assays. Variation in FIX activity was greater at the lowest activity levels. Activated FIX (FIXa) in plasma could result in higher OS assay activity or increased thrombin generation, which could overestimate FIX activity. However, FIXa was not detected in the participant samples, indicating that it was not contributing to the OS assay differences. Since individuals on gene therapy may receive exogenous replacement FIX products, replacement products were spiked into patient plasma samples to target a therapeutic concentration. Exogenous FIX was additive to endogenous FIX-R338L, with no interference from FIX-R338L.</p><p><strong>Conclusion: </strong> These results demonstrate FIX-R338L activity can be measured with OS and CS assays in clinical laboratories and provide insight into assay variability when measuring FIX with endogenously produced FIX-R338L. The findings may help establish best practices for measuring FIX-R338L activity (Clinicaltrials.gov identifier: NCT02484092).</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141306894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Benoît Guillet, Maxime Pawlowski, Pierre Boisseau, Yohann Répessé, Philippe Beurrier, Sophie Bayart, Xavier Delavenne, Marc Trossaërt, Peter J Lenting
Background: Desmopressin (DDAVP) is used in patients with moderate/mild hemophilia A (PWMHs) to increase their factor VIII (FVIII) level and, if possible, normalize it. However, its effectiveness varies between individuals. The GIDEMHA study aims to investigate the influence of F8 gene variants.
Material and methods: The study collected the trajectory of FVIII levels from therapeutic intravenous DDAVP tests in four French hemophilia treatment centers. A pharmacological analysis was performed associated with efficacy scores according to F8 variants: absolute and relative responses, as well as new scores: absolute duration (based on duration with FVIII ≥ 0.50 IU.mL-1) and relative duration (based on half-life).
Results: From enrolled 439 PWMHs, 327 had a hot-spot F8 variant (with ≥5 PWMHs). For these, the median (min-max) basal and peak FVIII were 0.20 (0.02-0.040) and 0.74 (0.14-2.18) IU.mL-1 respectively, with FVIII recovery being 3.80 IU.ml-1 (1.15-14.75). The median FVIII half-life was 3.9 hours (0.7-15.9 hours). FVIII was normalized (≥0.50 IU.mL-1) in 224/327 PWMHs (69%) and the median time with normalized FVIII was 3.9 hours (0.0-54.1 hours). Following the response profiles to DDAVP defined by the four efficacy scores, four groups of F8 variants were isolated, and then compared using survival curves with normalized FVIII (p < 0.0001): "long-lastingly effective" [p.(Glu739Lys), p.(Ser2030Asn), p.(Arg2178His), p.(Gln2208Glu), and T-stretch deletion in intron 13]; "moderately effective" [p.(Ser112Phe), p.(Ala219Thr), p.(Thr2105Ile), p.Phe2146Ser), and p.(Asp2150Asn)]; "moderately ineffective" [p.Ala81Asp), p.(Gln324Pro), p.(Tyr492His), p.(Arg612Cys), p.(Met701Val), p.(Val2035Asn), and p.(Arg2178Cys)]; and "frequently ineffective" [c.-219C > T, p.(Cys2040Tyr), p.(Tyr2169His), p.(Pro2319Leu), and p.(Arg2326Gln)].
Conclusion: In view of our data, we propose indications for DDAVP use in PWMH based on F8 variants for minor and major invasive procedures.
{"title":"Genotype-Dependent Response to Desmopressin in Hemophilia A and Proposal of a Predictive Response Score.","authors":"Benoît Guillet, Maxime Pawlowski, Pierre Boisseau, Yohann Répessé, Philippe Beurrier, Sophie Bayart, Xavier Delavenne, Marc Trossaërt, Peter J Lenting","doi":"10.1055/a-2329-3375","DOIUrl":"10.1055/a-2329-3375","url":null,"abstract":"<p><strong>Background: </strong> Desmopressin (DDAVP) is used in patients with moderate/mild hemophilia A (PWMHs) to increase their factor VIII (FVIII) level and, if possible, normalize it. However, its effectiveness varies between individuals. The GIDEMHA study aims to investigate the influence of <i>F8</i> gene variants.</p><p><strong>Material and methods: </strong> The study collected the trajectory of FVIII levels from therapeutic intravenous DDAVP tests in four French hemophilia treatment centers. A pharmacological analysis was performed associated with efficacy scores according to <i>F8</i> variants: absolute and relative responses, as well as new scores: absolute duration (based on duration with FVIII ≥ 0.50 IU.mL<sup>-1</sup>) and relative duration (based on half-life).</p><p><strong>Results: </strong> From enrolled 439 PWMHs, 327 had a hot-spot <i>F8</i> variant (with ≥5 PWMHs). For these, the median (min-max) basal and peak FVIII were 0.20 (0.02-0.040) and 0.74 (0.14-2.18) IU.mL<sup>-1</sup> respectively, with FVIII recovery being 3.80 IU.ml<sup>-1</sup> (1.15-14.75). The median FVIII half-life was 3.9 hours (0.7-15.9 hours). FVIII was normalized (≥0.50 IU.mL<sup>-1</sup>) in 224/327 PWMHs (69%) and the median time with normalized FVIII was 3.9 hours (0.0-54.1 hours). Following the response profiles to DDAVP defined by the four efficacy scores, four groups of <i>F8</i> variants were isolated, and then compared using survival curves with normalized FVIII (<i>p</i> < 0.0001): \"long-lastingly effective\" [p.(Glu739Lys), p.(Ser2030Asn), p.(Arg2178His), p.(Gln2208Glu), and T-stretch deletion in intron 13]; \"moderately effective\" [p.(Ser112Phe), p.(Ala219Thr), p.(Thr2105Ile), p.Phe2146Ser), and p.(Asp2150Asn)]; \"moderately ineffective\" [p.Ala81Asp), p.(Gln324Pro), p.(Tyr492His), p.(Arg612Cys), p.(Met701Val), p.(Val2035Asn), and p.(Arg2178Cys)]; and \"frequently ineffective\" [c.-219C > T, p.(Cys2040Tyr), p.(Tyr2169His), p.(Pro2319Leu), and p.(Arg2326Gln)].</p><p><strong>Conclusion: </strong> In view of our data, we propose indications for DDAVP use in PWMH based on <i>F8</i> variants for minor and major invasive procedures.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140959589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Commentary: \"No Genetic Causality between Tobacco Smoking and Venous Thromboembolism: A Two-Sample Mendelian Randomization Study\".","authors":"Jinhua Liu, Youqian Zhang, Bo Zeng","doi":"10.1055/s-0044-1787653","DOIUrl":"https://doi.org/10.1055/s-0044-1787653","url":null,"abstract":"","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141284849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2023-12-11DOI: 10.1055/a-2225-5513
Francisco Ujueta
{"title":"Low Dietary Manganese and the Incidence of Venous Thromboembolism: Evidence for Minerals and Vitamins and the Other Comorbidities Linked to Venous Thromboembolism.","authors":"Francisco Ujueta","doi":"10.1055/a-2225-5513","DOIUrl":"10.1055/a-2225-5513","url":null,"abstract":"","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138800524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2023-12-11DOI: 10.1055/a-2225-5173
Timm Zahn, Nancy Schanze, Dawid L Staudacher, Tobias Wengenmayer, Sven Maier, Christoph Benk, Nadine Gauchel, Daniel Duerschmied, Alexander Supady
Background: Post-cardiac arrest syndrome (PCAS) is a frequent complication following successful cardiopulmonary resuscitation and correlates with poor outcome. PCAS is characterized by an excessive inflammatory response to whole-body ischemia and reperfusion. Cytokine adsorption was suggested as an adjunctive treatment option for the removal of cytokines from the patients' blood to restore the physiological equilibrium of pro- and anti-inflammatory activity and thus mitigate hemodynamic instability and end-organ complications.
Material and methods: To better understand the cellular effects of cytokine adsorption in patients receiving extracorporeal cardiopulmonary resuscitation (ECPR) after in- and out-of-hospital cardiac arrest, we compared the activation status of neutrophils, monocytes, and platelets as well as the formation of platelet-leukocyte complexes in intravenous whole blood samples from an exploratory subgroup (n = 24) from the randomized CYTER study.
Result: At 48 hours after initiation of ECPR, flow cytometry analyses did neither reveal significant differences in neutrophil (CD11b, CD66b, L-selectin, and PSGL-1) and monocyte (CD11b, L-selectin, and PSGL-1) surface molecule expression nor in circulating platelet-monocyte complexes between patients receiving cytokine adsorption and those without.
Conclusion: Data did not show a relevant effect of cytokine adsorption on neutrophil and monocyte activation during the first 48 hours after initiation of ECPR.
{"title":"The Effect of Cytokine Adsorption on Leukocyte and Platelet Activation after Extracorporeal Cardiopulmonary Resuscitation.","authors":"Timm Zahn, Nancy Schanze, Dawid L Staudacher, Tobias Wengenmayer, Sven Maier, Christoph Benk, Nadine Gauchel, Daniel Duerschmied, Alexander Supady","doi":"10.1055/a-2225-5173","DOIUrl":"10.1055/a-2225-5173","url":null,"abstract":"<p><strong>Background: </strong> Post-cardiac arrest syndrome (PCAS) is a frequent complication following successful cardiopulmonary resuscitation and correlates with poor outcome. PCAS is characterized by an excessive inflammatory response to whole-body ischemia and reperfusion. Cytokine adsorption was suggested as an adjunctive treatment option for the removal of cytokines from the patients' blood to restore the physiological equilibrium of pro- and anti-inflammatory activity and thus mitigate hemodynamic instability and end-organ complications.</p><p><strong>Material and methods: </strong> To better understand the cellular effects of cytokine adsorption in patients receiving extracorporeal cardiopulmonary resuscitation (ECPR) after in- and out-of-hospital cardiac arrest, we compared the activation status of neutrophils, monocytes, and platelets as well as the formation of platelet-leukocyte complexes in intravenous whole blood samples from an exploratory subgroup (<i>n</i> = 24) from the randomized CYTER study.</p><p><strong>Result: </strong> At 48 hours after initiation of ECPR, flow cytometry analyses did neither reveal significant differences in neutrophil (CD11b, CD66b, L-selectin, and PSGL-1) and monocyte (CD11b, L-selectin, and PSGL-1) surface molecule expression nor in circulating platelet-monocyte complexes between patients receiving cytokine adsorption and those without.</p><p><strong>Conclusion: </strong> Data did not show a relevant effect of cytokine adsorption on neutrophil and monocyte activation during the first 48 hours after initiation of ECPR.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138801136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Are the Direct Oral Anticoagulants Better for Patients with Low Time in the Therapeutic Range on Vitamin K Antagonist Therapy?","authors":"Jordan K Schaefer, Geoffrey D Barnes","doi":"10.1055/s-0044-1787299","DOIUrl":"https://doi.org/10.1055/s-0044-1787299","url":null,"abstract":"","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141186990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2023-11-20DOI: 10.1055/a-2213-9230
Cindy M M de Jong, Wilbert B van den Hout, Christel E van Dijk, Noor Heim, Lisette F van Dam, Charlotte E A Dronkers, Gargi Gautam, Waleed Ghanima, Jostein Gleditsch, Anders von Heijne, Herman M A Hofstee, Marcel M C Hovens, Menno V Huisman, Stan Kolman, Albert T A Mairuhu, Thijs E van Mens, Mathilde Nijkeuter, Marcel A van de Ree, Cornelis J van Rooden, Robin E Westerbeek, Jan Westerink, Eli Westerlund, Lucia J M Kroft, Frederikus A Klok
Background: The diagnosis of recurrent ipsilateral deep vein thrombosis (DVT) with compression ultrasonography (CUS) may be hindered by residual intravascular obstruction after previous DVT. A reference CUS, an additional ultrasound performed at anticoagulant discontinuation, may improve the diagnostic work-up of suspected recurrent ipsilateral DVT by providing baseline images for future comparison.
Objectives: To evaluate the cost-effectiveness of routinely performing reference CUS in DVT patients.
Methods: Patient-level data (n = 96) from a prospective management study (Theia study; NCT02262052) and claims data were used in a decision analytic model to compare 12 scenarios for diagnostic management of suspected recurrent ipsilateral DVT. Estimated health care costs and mortality due to misdiagnosis, recurrent venous thromboembolism, and bleeding during the first year of follow-up after presentation with suspected recurrence were compared.
Results: All six scenarios including reference CUS had higher estimated 1-year costs (€1,763-€1,913) than the six without reference CUS (€1,192-€1,474). Costs were higher because reference CUS results often remained unused, as 20% of patients (according to claims data) would return with suspected recurrent DVT. Estimated mortality was comparable in scenarios with (14.8-17.9 per 10,000 patients) and without reference CUS (14.0-18.5 per 10,000). None of the four potentially most desirable scenarios included reference CUS.
Conclusion: One-year health care costs of diagnostic strategies for suspected recurrent ipsilateral DVT including reference CUS are higher compared to strategies without reference CUS, without mortality benefit. These results can inform policy-makers regarding use of health care resources during follow-up after DVT. From a cost-effectiveness perspective, the findings do not support the routine application of reference CUS.
{"title":"Cost-Effectiveness of Performing Reference Ultrasonography in Patients with Deep Vein Thrombosis.","authors":"Cindy M M de Jong, Wilbert B van den Hout, Christel E van Dijk, Noor Heim, Lisette F van Dam, Charlotte E A Dronkers, Gargi Gautam, Waleed Ghanima, Jostein Gleditsch, Anders von Heijne, Herman M A Hofstee, Marcel M C Hovens, Menno V Huisman, Stan Kolman, Albert T A Mairuhu, Thijs E van Mens, Mathilde Nijkeuter, Marcel A van de Ree, Cornelis J van Rooden, Robin E Westerbeek, Jan Westerink, Eli Westerlund, Lucia J M Kroft, Frederikus A Klok","doi":"10.1055/a-2213-9230","DOIUrl":"10.1055/a-2213-9230","url":null,"abstract":"<p><strong>Background: </strong> The diagnosis of recurrent ipsilateral deep vein thrombosis (DVT) with compression ultrasonography (CUS) may be hindered by residual intravascular obstruction after previous DVT. A reference CUS, an additional ultrasound performed at anticoagulant discontinuation, may improve the diagnostic work-up of suspected recurrent ipsilateral DVT by providing baseline images for future comparison.</p><p><strong>Objectives: </strong> To evaluate the cost-effectiveness of routinely performing reference CUS in DVT patients.</p><p><strong>Methods: </strong> Patient-level data (<i>n</i> = 96) from a prospective management study (Theia study; NCT02262052) and claims data were used in a decision analytic model to compare 12 scenarios for diagnostic management of suspected recurrent ipsilateral DVT. Estimated health care costs and mortality due to misdiagnosis, recurrent venous thromboembolism, and bleeding during the first year of follow-up after presentation with suspected recurrence were compared.</p><p><strong>Results: </strong> All six scenarios including reference CUS had higher estimated 1-year costs (€1,763-€1,913) than the six without reference CUS (€1,192-€1,474). Costs were higher because reference CUS results often remained unused, as 20% of patients (according to claims data) would return with suspected recurrent DVT. Estimated mortality was comparable in scenarios with (14.8-17.9 per 10,000 patients) and without reference CUS (14.0-18.5 per 10,000). None of the four potentially most desirable scenarios included reference CUS.</p><p><strong>Conclusion: </strong> One-year health care costs of diagnostic strategies for suspected recurrent ipsilateral DVT including reference CUS are higher compared to strategies without reference CUS, without mortality benefit. These results can inform policy-makers regarding use of health care resources during follow-up after DVT. From a cost-effectiveness perspective, the findings do not support the routine application of reference CUS.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138177347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2023-08-18DOI: 10.1055/a-2156-7872
Yasushi Ueki, Jonas D Häner, Sylvain Losdat, Giuseppe Gargiulo, Hiroki Shibutani, Sarah Bär, Tatsuhiko Otsuka, Raminta Kavaliauskaite, Vera R Mitter, Fabrice Temperli, David Spirk, Stefan Stortecky, George C M Siontis, Marco Valgimigli, Stephan Windecker, Clemens Gutmann, Konstantinos C Koskinas, Manuel Mayr, Lorenz Räber
Objective: The effect of the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor alirocumab on platelet aggregation among patients with acute myocardial infarction (AMI) remains unknown. We aimed to explore the effect of alirocumab added to high-intensity statin therapy on P2Y12 reaction unit (PRU) among AMI patients receiving dual antiplatelet therapy (DAPT) with a potent P2Y12 inhibitor (ticagrelor or prasugrel). In addition, we assessed circulating platelet-derived noncoding RNAs (microRNAs and YRNAs).
Methods: This was a prespecified, powered, pharmacodynamic substudy of the PACMAN trial, a randomized, double-blind trial comparing biweekly alirocumab (150 mg) versus placebo in AMI patients undergoing percutaneous coronary intervention. Patients recruited at Bern University Hospital, receiving DAPT with a potent P2Y12 inhibitor, and adherent to the study drug (alirocumab or placebo) were analyzed for the current study. The primary endpoint was PRU at 4 weeks after study drug initiation as assessed by VerifyNow P2Y12 point-of-care assays.
Results: Among 139 randomized patients, the majority of patients received ticagrelor DAPT at 4 weeks (57 [86.4%] in the alirocumab group vs. 69 [94.5%] in the placebo group, p = 0.14). There were no significant differences in the primary endpoint PRU at 4 weeks between groups (12.5 [interquartile range, IQR: 27.0] vs. 19.0 [IQR: 30.0], p = 0.26). Consistent results were observed in 126 patients treated with ticagrelor (13.0 [IQR: 20.0] vs. 18.0 [IQR: 27.0], p = 0.28). Similarly, platelet-derived noncoding RNAs did not significantly differ between groups.
Conclusion: Among AMI patients receiving DAPT with a potent P2Y12 inhibitor, alirocumab had no significant effect on platelet reactivity as assessed by PRU and platelet-derived noncoding RNAs.
{"title":"Effect of Alirocumab Added to High-Intensity Statin on Platelet Reactivity and Noncoding RNAs in Patients with AMI: A Substudy of the PACMAN-AMI Trial.","authors":"Yasushi Ueki, Jonas D Häner, Sylvain Losdat, Giuseppe Gargiulo, Hiroki Shibutani, Sarah Bär, Tatsuhiko Otsuka, Raminta Kavaliauskaite, Vera R Mitter, Fabrice Temperli, David Spirk, Stefan Stortecky, George C M Siontis, Marco Valgimigli, Stephan Windecker, Clemens Gutmann, Konstantinos C Koskinas, Manuel Mayr, Lorenz Räber","doi":"10.1055/a-2156-7872","DOIUrl":"10.1055/a-2156-7872","url":null,"abstract":"<p><strong>Objective: </strong> The effect of the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor alirocumab on platelet aggregation among patients with acute myocardial infarction (AMI) remains unknown. We aimed to explore the effect of alirocumab added to high-intensity statin therapy on P2Y12 reaction unit (PRU) among AMI patients receiving dual antiplatelet therapy (DAPT) with a potent P2Y12 inhibitor (ticagrelor or prasugrel). In addition, we assessed circulating platelet-derived noncoding RNAs (microRNAs and YRNAs).</p><p><strong>Methods: </strong> This was a prespecified, powered, pharmacodynamic substudy of the PACMAN trial, a randomized, double-blind trial comparing biweekly alirocumab (150 mg) versus placebo in AMI patients undergoing percutaneous coronary intervention. Patients recruited at Bern University Hospital, receiving DAPT with a potent P2Y12 inhibitor, and adherent to the study drug (alirocumab or placebo) were analyzed for the current study. The primary endpoint was PRU at 4 weeks after study drug initiation as assessed by VerifyNow P2Y12 point-of-care assays.</p><p><strong>Results: </strong> Among 139 randomized patients, the majority of patients received ticagrelor DAPT at 4 weeks (57 [86.4%] in the alirocumab group vs. 69 [94.5%] in the placebo group, <i>p</i> = 0.14). There were no significant differences in the primary endpoint PRU at 4 weeks between groups (12.5 [interquartile range, IQR: 27.0] vs. 19.0 [IQR: 30.0], <i>p</i> = 0.26). Consistent results were observed in 126 patients treated with ticagrelor (13.0 [IQR: 20.0] vs. 18.0 [IQR: 27.0], <i>p</i> = 0.28). Similarly, platelet-derived noncoding RNAs did not significantly differ between groups.</p><p><strong>Conclusion: </strong> Among AMI patients receiving DAPT with a potent P2Y12 inhibitor, alirocumab had no significant effect on platelet reactivity as assessed by PRU and platelet-derived noncoding RNAs.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10209013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2023-11-20DOI: 10.1055/a-2213-8939
Yu Huang, Yanjun Zhang, Sisi Yang, Hao Xiang, Chun Zhou, Ziliang Ye, Mengyi Liu, Panpan He, Yuanyuan Zhang, Xiaoqin Gan, Xianhui Qin
Background: The association between dietary manganese (Mn) intake and the risk of venous thromboembolism (VTE) remains unknown. We aimed to investigate the associations of dietary Mn intake with incident VTE, and the underlying mediating roles of obesity markers (body mass index [BMI] and waist circumference), hemorheological parameters (red cell distribution width [RDW], platelet count [PLT], and mean platelet volume [MPV]), and inflammatory biomarkers (C-reactive protein [CRP] and white blood cell count [WBC]) in this association.
Methods: A total of 202,507 adults from the UK Biobank with complete dietary data and without VTE at baseline were included. Dietary information was collected by the online 24-hour diet recall questionnaires (Oxford WebQ). The primary outcome was incident VTE, a composite of incident deep vein thrombosis (DVT) and pulmonary embolism (PE).
Results: During a median follow-up of 11.6 years, 4,750 participants developed incident VTE. Overall, there were significantly inverse relationships of dietary Mn intake with incident VTE (per 1 mg/day increment; adjusted hazard ratio [HR]: 0.92; 95% confidence interval [CI]: 0.90-0.95), incident DVT (per 1 mg/day increment; adjusted HR: 0.93; 95% CI: 0. 90-0.96), and incident PE (per 1 mg/day increment; adjusted HR: 0.91; 95% CI: 0.88-0.95). BMI, waist circumference, RDW, CRP, and WBC significantly mediated the association between dietary Mn intake and incident VTE, with the mediated proportions of 36.0, 36.5, 4.2, 4.3, and 1.6%, respectively. However, MPV and PLT did not significantly mediate the association.
Conclusion: Our study shows that dietary Mn intake was inversely associated with incident VTE. The inverse association was mainly mediated by obesity, followed by inflammatory biomarkers and RDW. Our findings are just hypothesis-generating, and further confirmation of our findings in more studies is essential.
{"title":"Association and Pathways between Dietary Manganese Intake and Incident Venous Thromboembolism.","authors":"Yu Huang, Yanjun Zhang, Sisi Yang, Hao Xiang, Chun Zhou, Ziliang Ye, Mengyi Liu, Panpan He, Yuanyuan Zhang, Xiaoqin Gan, Xianhui Qin","doi":"10.1055/a-2213-8939","DOIUrl":"10.1055/a-2213-8939","url":null,"abstract":"<p><strong>Background: </strong> The association between dietary manganese (Mn) intake and the risk of venous thromboembolism (VTE) remains unknown. We aimed to investigate the associations of dietary Mn intake with incident VTE, and the underlying mediating roles of obesity markers (body mass index [BMI] and waist circumference), hemorheological parameters (red cell distribution width [RDW], platelet count [PLT], and mean platelet volume [MPV]), and inflammatory biomarkers (C-reactive protein [CRP] and white blood cell count [WBC]) in this association.</p><p><strong>Methods: </strong> A total of 202,507 adults from the UK Biobank with complete dietary data and without VTE at baseline were included. Dietary information was collected by the online 24-hour diet recall questionnaires (Oxford WebQ). The primary outcome was incident VTE, a composite of incident deep vein thrombosis (DVT) and pulmonary embolism (PE).</p><p><strong>Results: </strong> During a median follow-up of 11.6 years, 4,750 participants developed incident VTE. Overall, there were significantly inverse relationships of dietary Mn intake with incident VTE (per 1 mg/day increment; adjusted hazard ratio [HR]: 0.92; 95% confidence interval [CI]: 0.90-0.95), incident DVT (per 1 mg/day increment; adjusted HR: 0.93; 95% CI: 0. 90-0.96), and incident PE (per 1 mg/day increment; adjusted HR: 0.91; 95% CI: 0.88-0.95). BMI, waist circumference, RDW, CRP, and WBC significantly mediated the association between dietary Mn intake and incident VTE, with the mediated proportions of 36.0, 36.5, 4.2, 4.3, and 1.6%, respectively. However, MPV and PLT did not significantly mediate the association.</p><p><strong>Conclusion: </strong> Our study shows that dietary Mn intake was inversely associated with incident VTE. The inverse association was mainly mediated by obesity, followed by inflammatory biomarkers and RDW. Our findings are just hypothesis-generating, and further confirmation of our findings in more studies is essential.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138177346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Elena Campello, Paolo Bucciarelli, Filippo Catalani, Nicoletta Erba, Alessandro Squizzato, Daniela Poli
The management of anticoagulant therapy in pregnant women with mechanical heart valves (MHVs) is difficult and often challenging even for clinicians experienced in the field. These pregnancies, indeed, are burdened with higher rates of complications for both the mother and the fetus, compared to those in women without MHVs. The maternal need for an optimal anticoagulation as provided by vitamin K antagonists is counterbalanced by their teratogen effect on the embryo and fetus. On the other hand, several concerns have been raised about the efficacy of heparins in pregnant women with MHVs, considering the high risk of thrombotic complications in these patients. Therefore, numerous clinical issues about the management of pregnant women with MHVs remain unanswered, such as the selection of the best anticoagulant agent, the optimal anticoagulation levels to be achieved and maintained, and the evaluation of long-term effects for both the mother and the fetus. Based on a comprehensive review of the current literature, the Italian Federation of the Centers for the Diagnosis and the Surveillance of the Antithrombotic Therapies (FCSA) proposes experience-based suggestions and expert opinions. Particularly, this consensus document aims at providing practical guidance for clinicians dealing with pregnant women with MHVs, to optimize maternal and fetal outcomes while guaranteeing adequate anticoagulation. Finally, FCSA highlights the need for the creation of multidisciplinary teams experienced in the management of pregnant women with MHVs during pregnancy, delivery, and postpartum, in order to better deal with such complex clinical issues and provide a comprehensive counseling to these patients.
对患有机械性心脏瓣膜(MHV)的孕妇进行抗凝治疗非常困难,即使是对该领域经验丰富的临床医生来说也往往具有挑战性。事实上,与没有机械心脏瓣膜的孕妇相比,这些孕妇的母亲和胎儿的并发症发生率都更高。维生素 K 拮抗剂(VKAs)可提供最佳的抗凝作用,但其对受孕产物的致畸作用却抵消了母体对这种抗凝作用的需求。另一方面,考虑到肝素类药物对妊娠高血压患者的血栓并发症风险较高,肝素类药物对妊娠高血压患者的疗效也引起了一些担忧。因此,关于妊娠合并甲型肝炎病毒(MHVs)孕妇的治疗,仍有许多临床问题尚未解决,如最佳抗凝剂的选择、达到和维持的最佳抗凝水平以及对母亲和胎儿长期影响的评估等。意大利抗血栓治疗诊断与监测中心联合会(FCSA)在对现有文献进行全面回顾的基础上,提出了基于经验的建议和专家意见。尤其是,这份共识文件旨在为临床医生处理妊娠合并高血压的孕妇提供实用指导,在保证充分抗凝的同时,优化母体和胎儿的预后。最后,FCSA 强调有必要建立多学科团队,对妊娠、分娩和产后期间的 MHVs 孕妇管理提供经验,以便更好地处理此类复杂的临床问题,并为这些患者提供全面的咨询服务。
{"title":"Anticoagulant Therapy in Pregnant Women with Mechanical Heart Valves: Italian Federation of Centers for Diagnosis and Surveillance of the Antithrombotic Therapies (FCSA) Position Paper.","authors":"Elena Campello, Paolo Bucciarelli, Filippo Catalani, Nicoletta Erba, Alessandro Squizzato, Daniela Poli","doi":"10.1055/a-2325-5658","DOIUrl":"10.1055/a-2325-5658","url":null,"abstract":"<p><p>The management of anticoagulant therapy in pregnant women with mechanical heart valves (MHVs) is difficult and often challenging even for clinicians experienced in the field. These pregnancies, indeed, are burdened with higher rates of complications for both the mother and the fetus, compared to those in women without MHVs. The maternal need for an optimal anticoagulation as provided by vitamin K antagonists is counterbalanced by their teratogen effect on the embryo and fetus. On the other hand, several concerns have been raised about the efficacy of heparins in pregnant women with MHVs, considering the high risk of thrombotic complications in these patients. Therefore, numerous clinical issues about the management of pregnant women with MHVs remain unanswered, such as the selection of the best anticoagulant agent, the optimal anticoagulation levels to be achieved and maintained, and the evaluation of long-term effects for both the mother and the fetus. Based on a comprehensive review of the current literature, the Italian Federation of the Centers for the Diagnosis and the Surveillance of the Antithrombotic Therapies (FCSA) proposes experience-based suggestions and expert opinions. Particularly, this consensus document aims at providing practical guidance for clinicians dealing with pregnant women with MHVs, to optimize maternal and fetal outcomes while guaranteeing adequate anticoagulation. Finally, FCSA highlights the need for the creation of multidisciplinary teams experienced in the management of pregnant women with MHVs during pregnancy, delivery, and <i>postpartum</i>, in order to better deal with such complex clinical issues and provide a comprehensive counseling to these patients.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140923252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}