Pub Date : 2025-07-17DOI: 10.1016/j.tmrv.2025.150909
Ayesha Butt, Anish Sharda, Alfred Ian Lee, Jason S Knight
Antiphospholipid syndrome (APS) is an autoimmune prothrombotic disorder defined by the presence of one or more antiphospholipid antibodies (aPL) in conjunction with clinical manifestations such as thrombosis and/or obstetrical complications. One of the notable recent developments in APS research is the identification of a contributory role for neutrophil extracellular traps (NETs) in its pathogenesis, establishing a mechanistic link between thrombosis, inflammation, and complement activation. NETs, composed of decondensed chromatin and neutrophil-derived granule proteins, are released in response to various infectious and sterile triggers. In individuals with APS, elevated NET levels and the presence of anti-NET antibodies have been observed, aligning with thrombotic events and enhanced complement system activation. Studies support an emerging model that neutrophils are primed in APS to form NETs as a central mechanism in the development of thrombosis. This review explores multiple mechanisms linking NETs and thrombosis in APS including: contribution of aPL to enhanced leukocyte adhesion and the induction of NETosis via P-selectin glycoprotein ligand-1 (PSGL-1) and the transcription factor KLF2; cyclic AMP and the adenosine A2A receptor on the neutrophil surface as negative regulators of NETosis and thrombus formation in APS; and NET-mediated resistance to activated protein C leading to hypercoagulability, amongst others. Intervening in NET-related pathways represents a promising therapeutic strategy to mitigate thrombotic risk in APS, underscoring the need for ongoing investigation into neutrophil-mediated mechanisms in this autoimmune disorder.
{"title":"Analytical Review: Neutrophil Extracellular Traps and Antiphospholipid syndrome.","authors":"Ayesha Butt, Anish Sharda, Alfred Ian Lee, Jason S Knight","doi":"10.1016/j.tmrv.2025.150909","DOIUrl":"https://doi.org/10.1016/j.tmrv.2025.150909","url":null,"abstract":"<p><p>Antiphospholipid syndrome (APS) is an autoimmune prothrombotic disorder defined by the presence of one or more antiphospholipid antibodies (aPL) in conjunction with clinical manifestations such as thrombosis and/or obstetrical complications. One of the notable recent developments in APS research is the identification of a contributory role for neutrophil extracellular traps (NETs) in its pathogenesis, establishing a mechanistic link between thrombosis, inflammation, and complement activation. NETs, composed of decondensed chromatin and neutrophil-derived granule proteins, are released in response to various infectious and sterile triggers. In individuals with APS, elevated NET levels and the presence of anti-NET antibodies have been observed, aligning with thrombotic events and enhanced complement system activation. Studies support an emerging model that neutrophils are primed in APS to form NETs as a central mechanism in the development of thrombosis. This review explores multiple mechanisms linking NETs and thrombosis in APS including: contribution of aPL to enhanced leukocyte adhesion and the induction of NETosis via P-selectin glycoprotein ligand-1 (PSGL-1) and the transcription factor KLF2; cyclic AMP and the adenosine A<sub>2A</sub> receptor on the neutrophil surface as negative regulators of NETosis and thrombus formation in APS; and NET-mediated resistance to activated protein C leading to hypercoagulability, amongst others. Intervening in NET-related pathways represents a promising therapeutic strategy to mitigate thrombotic risk in APS, underscoring the need for ongoing investigation into neutrophil-mediated mechanisms in this autoimmune disorder.</p>","PeriodicalId":56081,"journal":{"name":"Transfusion Medicine Reviews","volume":" ","pages":"150909"},"PeriodicalIF":2.5,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812713","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 : 2025-07-01DOI: 10.1016/j.tmrv.2025.150906
Florence Oyekan PGDip , Helinor McAleese MSc , Montasir Ahmed MPhil , Cath Booth MBBS , Louise Bowles MBBS , Michael F Murphy MD , Florian Tomini PhD , Laura Green MD , Josephine McCullagh DClinSci
ABO-incompatible (ABOi) red blood cell (RBC) transfusions can lead to severe clinical consequences, including patient death. Electronic systems, such as Bedside Electronic Transfusion Checks (BETC), have been developed to lower the risk of these serious incidents occurring due to errors in patient identification at the bedside; however, the benefits for patients have not yet been fully quantified. To address this gap, we aimed to quantify the harms (ie, morbidity and mortality) associated with ABOi RBC transfusions in the UK, enabling us to better understand the benefits of BETC in preventing these events for patients.
Twenty-seven years of published UK hemovigilance data from cases submitted to Serious Hazards of Transfusion (SHOT), including reports from 1996 to 2023 were reviewed using systematic review methodology by 2 independent reviewers. Data was collated into a Microsoft Excel database for further analysis. The data were analyzed to determine the number of reports of ABOi RBC transfusion and the rate of mortality/morbidity associated with these events. Morbidity was defined as hemolytic transfusion reaction (acute and delayed), any organ injury, extended length of hospital stays, the requirement for mechanical ventilation and ITU admission (including critical care units), and any other adverse events as reported in each case.
Over 27 years (1996-2023), 55.3 million RBC units were issued in the UK, with 368 ABO-incompatible (ABOi) transfusions, equating to 0.67 per 100,000 transfusions. Clinical errors accounted for 53.3% of the observed ABOi transfusions (0.36 per 100,000), primarily occurring during administration (0.16 per 100,000), blood collection (0.10 per 100,000), and sample collection (0.07 per 100,000). Laboratory errors made up for 13.6% of the observed ABOi transfusions (0.09 per 100,000), predominantly being a consequence of errors in pretransfusion testing (0.06 per 100,000). Mortality among the observed ABOi transfusions was 6.3% (0.04 per 100,000), with major morbidity at 23.9% (0.16 per 100,000), which includes ICU admissions (0.03 per 100,000) and hemolytic reactions (0.05 per 100,000).
While ABOi RBC transfusions have become rare in the UK, they are associated with significant short-term morbidity and mortality. Early SHOT reports lacked standardization and provide limited data on patient outcome. When patient outcome was reported, it was limited to short-term outcomes immediately post ABOi transfusions. No data was reported on longer -term patient outcomes limiting the ability to provide long-term outcome assessment. Enhancing hemovigilance practices is essential to reducing ABOi risks. National hemovigilance schemes worldwide need to harmonize/standardize the reporting of short-term and long-term outcome data collection for ABOi RBC transfusions so we can better understand the risk and burden of these events on patients.
{"title":"Quantifying Harms Associated With Red Cell ABO Incompatible Blood Transfusion: A Systematic Review of the UK SHOT Literature","authors":"Florence Oyekan PGDip , Helinor McAleese MSc , Montasir Ahmed MPhil , Cath Booth MBBS , Louise Bowles MBBS , Michael F Murphy MD , Florian Tomini PhD , Laura Green MD , Josephine McCullagh DClinSci","doi":"10.1016/j.tmrv.2025.150906","DOIUrl":"10.1016/j.tmrv.2025.150906","url":null,"abstract":"<div><div>ABO-incompatible (ABOi) red blood cell (RBC) transfusions can lead to severe clinical consequences, including patient death. Electronic systems, such as Bedside Electronic Transfusion Checks (BETC), have been developed to lower the risk of these serious incidents occurring due to errors in patient identification at the bedside; however, the benefits for patients have not yet been fully quantified. To address this gap, we aimed to quantify the harms (ie, morbidity and mortality) associated with ABOi RBC transfusions in the UK, enabling us to better understand the benefits of BETC in preventing these events for patients.</div><div>Twenty-seven years of published UK hemovigilance data from cases submitted to Serious Hazards of Transfusion (SHOT), including reports from 1996 to 2023 were reviewed using systematic review methodology by 2 independent reviewers. Data was collated into a Microsoft Excel database for further analysis. The data were analyzed to determine the number of reports of ABOi RBC transfusion and the rate of mortality/morbidity associated with these events. Morbidity was defined as hemolytic transfusion reaction (acute and delayed), any organ injury, extended length of hospital stays, the requirement for mechanical ventilation and ITU admission (including critical care units), and any other adverse events as reported in each case.</div><div>Over 27 years (1996-2023), 55.3 million RBC units were issued in the UK, with 368 ABO-incompatible (ABOi) transfusions, equating to 0.67 per 100,000 transfusions. Clinical errors accounted for 53.3% of the observed ABOi transfusions (0.36 per 100,000), primarily occurring during administration (0.16 per 100,000), blood collection (0.10 per 100,000), and sample collection (0.07 per 100,000). Laboratory errors made up for 13.6% of the observed ABOi transfusions (0.09 per 100,000), predominantly being a consequence of errors in pretransfusion testing (0.06 per 100,000). Mortality among the observed ABOi transfusions was 6.3% (0.04 per 100,000), with major morbidity at 23.9% (0.16 per 100,000), which includes ICU admissions (0.03 per 100,000) and hemolytic reactions (0.05 per 100,000).</div><div>While ABOi RBC transfusions have become rare in the UK, they are associated with significant short-term morbidity and mortality. Early SHOT reports lacked standardization and provide limited data on patient outcome. When patient outcome was reported, it was limited to short-term outcomes immediately post ABOi transfusions. No data was reported on longer -term patient outcomes limiting the ability to provide long-term outcome assessment. Enhancing hemovigilance practices is essential to reducing ABOi risks. National hemovigilance schemes worldwide need to harmonize/standardize the reporting of short-term and long-term outcome data collection for ABOi RBC transfusions so we can better understand the risk and burden of these events on patients.</div></div>","PeriodicalId":56081,"journal":{"name":"Transfusion Medicine Reviews","volume":"39 3","pages":"Article 150906"},"PeriodicalIF":2.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144569926","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 : 2025-07-01DOI: 10.1016/j.tmrv.2025.150907
Orlando Rubén Pérez-Nieto , Ignacio Rodríguez-Guevara , Rafael Alfonso Reyes-Monge , Marian Elizabeth Phinder-Puente
{"title":"Ultra-Restrictive Transfusion Thresholds in Critically Ill Adults: Perhaps Not for Everyone","authors":"Orlando Rubén Pérez-Nieto , Ignacio Rodríguez-Guevara , Rafael Alfonso Reyes-Monge , Marian Elizabeth Phinder-Puente","doi":"10.1016/j.tmrv.2025.150907","DOIUrl":"10.1016/j.tmrv.2025.150907","url":null,"abstract":"","PeriodicalId":56081,"journal":{"name":"Transfusion Medicine Reviews","volume":"39 3","pages":"Article 150907"},"PeriodicalIF":2.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144580156","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 : 2025-07-01DOI: 10.1016/j.tmrv.2025.150912
Lisa Richards , Jacob Pendergrast , Michael Angers , Grant Johnson , Christine Cserti-Gazdewich
<div><h3>Introduction</h3><div>IQMH standard VI.1 TM042 states there shall be a 2<sup>nd</sup> check of the ABO group (ABOConf) either by testing of a second sample or identifying supportive prior records, because verification is a pre-requisite for the provision of group-specific blood (GSB) for transfusion. The use of GSB in turn is valued in inventory management by decreasing the unnecessary use of group O red cells for non-O patients. However, Choosing Wisely advises against sampling more blood than is needed. As such, when lacking historical data, ABOConf demands additional venipuncture, though from the ensuing 7-10 ml specimen, only a few drops of blood are used. Our twin goal was to reduce ABOConf collections while decreasing turnaround times (TATs) by using existing samples. Avoiding new collections is patient-centred by eliminating repeat venipuncture discomfort and leveraging available alternative specimens, as iatrogenic blood loss is a known driver of anemia in healthcare. Furthermore, retroactive leveraging in a laboratory environment was recognized as uniquely free from the possibility of premeditated bedside "double-draw" fraud.</div></div><div><h3>Design and Methods</h3><div>When an order for red cell transfusion is received, the laboratory information system assists in determining if ABOConf is required. This flag recruits a technologist to determine if, among previously-collected CBCs, there is a sample meeting Transfusion Medicine (TM) labelling requirements (ie- an independent collection in the last 3 days). If present, the sample is retrieved and re-processed in an ABOConf order under the Confirmatory Blood Type Medical Directive. The original collection information (collector/date/time) is documented in the Clinical Information System (CIS). The ABOConf order process includes documentation of the specimen number used for testing, with verification that the sample was a collection distinct from the original Type and Screen. Only if an appropriate CBC is unavailable will a new blood draw occur.</div></div><div><h3>Results</h3><div>Six months (Jul-Dec 2024) were reviewed. Surgical order locations (Main Operating Room and Pre-operative Clinic) were assessed separately as a group exempt from the lab-ordered ABOConf process, owing to distinct expedient transfusion-readiness concerns. Of 567 non-surgical orders, 364 new collections (2,548 mL) were averted (64%), vs only 5 saved collections in 533 surgical samples (Z 22.2, p< .00001). A 10 day audit showed a TAT decrease as well in the use of previously-collected samples (average 12 minutes vs 77 for new collections).</div></div><div><h3>Conclusions</h3><div>The use of previously collected samples for ABOConf testing reduced sample collection significantly in the non-surgical population with significantly decreased TAT, while satisfying IQMH standards and Choosing Wisely recommendations. Future goals are to reduce specimen volume when ABOConf draws remain necessary, and to expand
{"title":"Clash of the Standards: An Institutional Approach to Fulfilling ABO Confirmation Mandates While Upholding Patient Blood Management Principles","authors":"Lisa Richards , Jacob Pendergrast , Michael Angers , Grant Johnson , Christine Cserti-Gazdewich","doi":"10.1016/j.tmrv.2025.150912","DOIUrl":"10.1016/j.tmrv.2025.150912","url":null,"abstract":"<div><h3>Introduction</h3><div>IQMH standard VI.1 TM042 states there shall be a 2<sup>nd</sup> check of the ABO group (ABOConf) either by testing of a second sample or identifying supportive prior records, because verification is a pre-requisite for the provision of group-specific blood (GSB) for transfusion. The use of GSB in turn is valued in inventory management by decreasing the unnecessary use of group O red cells for non-O patients. However, Choosing Wisely advises against sampling more blood than is needed. As such, when lacking historical data, ABOConf demands additional venipuncture, though from the ensuing 7-10 ml specimen, only a few drops of blood are used. Our twin goal was to reduce ABOConf collections while decreasing turnaround times (TATs) by using existing samples. Avoiding new collections is patient-centred by eliminating repeat venipuncture discomfort and leveraging available alternative specimens, as iatrogenic blood loss is a known driver of anemia in healthcare. Furthermore, retroactive leveraging in a laboratory environment was recognized as uniquely free from the possibility of premeditated bedside \"double-draw\" fraud.</div></div><div><h3>Design and Methods</h3><div>When an order for red cell transfusion is received, the laboratory information system assists in determining if ABOConf is required. This flag recruits a technologist to determine if, among previously-collected CBCs, there is a sample meeting Transfusion Medicine (TM) labelling requirements (ie- an independent collection in the last 3 days). If present, the sample is retrieved and re-processed in an ABOConf order under the Confirmatory Blood Type Medical Directive. The original collection information (collector/date/time) is documented in the Clinical Information System (CIS). The ABOConf order process includes documentation of the specimen number used for testing, with verification that the sample was a collection distinct from the original Type and Screen. Only if an appropriate CBC is unavailable will a new blood draw occur.</div></div><div><h3>Results</h3><div>Six months (Jul-Dec 2024) were reviewed. Surgical order locations (Main Operating Room and Pre-operative Clinic) were assessed separately as a group exempt from the lab-ordered ABOConf process, owing to distinct expedient transfusion-readiness concerns. Of 567 non-surgical orders, 364 new collections (2,548 mL) were averted (64%), vs only 5 saved collections in 533 surgical samples (Z 22.2, p< .00001). A 10 day audit showed a TAT decrease as well in the use of previously-collected samples (average 12 minutes vs 77 for new collections).</div></div><div><h3>Conclusions</h3><div>The use of previously collected samples for ABOConf testing reduced sample collection significantly in the non-surgical population with significantly decreased TAT, while satisfying IQMH standards and Choosing Wisely recommendations. Future goals are to reduce specimen volume when ABOConf draws remain necessary, and to expand","PeriodicalId":56081,"journal":{"name":"Transfusion Medicine Reviews","volume":"39 3","pages":"Article 150912"},"PeriodicalIF":2.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144723866","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 : 2025-07-01DOI: 10.1016/j.tmrv.2025.150908
Marco Amato , Manfred Astl , Lisa Seekircher , Lena Tschiderer , Peter Willeit , Harald Schennach , Anita Siller
Optimizing platelet yield in pooled buffy coat (BC)-derived platelet products by sorting them according to donor whole blood (WB) platelet counts is a promising approach to increase the production of double-dose platelet concentrates while reducing the variability among products. We aimed to assess the benefit of sorting according to an HTML-report generated by an in-house developed preselection algorithm. In this study, we compared two approaches of BC pooling to produce pathogen-inactivated double-dose platelet concentrates. The platelet count of donor WB was measured using a hematology analyzer prior to pooling. In one group, six BCs were randomly assigned to pools, while in the other group, six BCs were sorted by platelet counts of WB samples prior to pooling according to an in-house developed preselection algorithm, selecting six BCs for each pool in a way that yields for each product are similar. All BCs were included as no minimum or maximum platelet count entry criteria were used. Yield and divisibility rate of both approaches were compared using Wilcoxon Rank−Sum Test to assess the impact of sorting by platelet count. Sorting BCs according to our in-house developed algorithm resulted in significantly higher median platelet concentrations (×10³/µL), rising from 1247 (interquartile range [IQR] 1207-1349) when randomly assigned to 1307 (IQR 1237-1381) when sorted (P = .0434). In line, yields per platelet unit (×1011/unit) significantly increased from 4.6 (IQR 4.3-4.8) when randomly assigned to 4.8 (IQR 4.5-5.1) when sorted (P = .0191). The proportion of divisible pathogen-inactivated platelet units increased from 72.1% to 89.5%. For both approaches, all units were above the minimum threshold (>2.0 × 1011/unit) and no maximum threshold was defined. Assigning BCs to pools according to an in-house developed preselection algorithm enables the production of platelet concentrates with increased yields and leads to more standardized products.
{"title":"Optimizing Buffy Coat Pooling: Enhancing Platelet Yield Through Platelet Count-Based Sorting","authors":"Marco Amato , Manfred Astl , Lisa Seekircher , Lena Tschiderer , Peter Willeit , Harald Schennach , Anita Siller","doi":"10.1016/j.tmrv.2025.150908","DOIUrl":"10.1016/j.tmrv.2025.150908","url":null,"abstract":"<div><div>Optimizing platelet yield in pooled buffy coat (BC)-derived platelet products by sorting them according to donor whole blood (WB) platelet counts is a promising approach to increase the production of double-dose platelet concentrates while reducing the variability among products. We aimed to assess the benefit of sorting according to an HTML-report generated by an in-house developed preselection algorithm. In this study, we compared two approaches of BC pooling to produce pathogen-inactivated double-dose platelet concentrates. The platelet count of donor WB was measured using a hematology analyzer prior to pooling. In one group, six BCs were randomly assigned to pools, while in the other group, six BCs were sorted by platelet counts of WB samples prior to pooling according to an in-house developed preselection algorithm, selecting six BCs for each pool in a way that yields for each product are similar. All BCs were included as no minimum or maximum platelet count entry criteria were used. Yield and divisibility rate of both approaches were compared using Wilcoxon Rank−Sum Test to assess the impact of sorting by platelet count. Sorting BCs according to our in-house developed algorithm resulted in significantly higher median platelet concentrations (×10³/µL), rising from 1247 (interquartile range [IQR] 1207-1349) when randomly assigned to 1307 (IQR 1237-1381) when sorted (<em>P</em> = .0434). In line, yields per platelet unit (×10<sup>11</sup>/unit) significantly increased from 4.6 (IQR 4.3-4.8) when randomly assigned to 4.8 (IQR 4.5-5.1) when sorted (<em>P</em> = .0191). The proportion of divisible pathogen-inactivated platelet units increased from 72.1% to 89.5%. For both approaches, all units were above the minimum threshold (>2.0 × 10<sup>11</sup>/unit) and no maximum threshold was defined. Assigning BCs to pools according to an in-house developed preselection algorithm enables the production of platelet concentrates with increased yields and leads to more standardized products.</div></div>","PeriodicalId":56081,"journal":{"name":"Transfusion Medicine Reviews","volume":"39 3","pages":"Article 150908"},"PeriodicalIF":2.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144557572","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 : 2025-07-01DOI: 10.1016/j.tmrv.2025.150913
Keyvan Karkouti , Jeannie Callum , Cristina Solomon , Sigurd Knaub , Sylvia Werner , Kenichi Tanaka , Jerrold H. Levy
Introduction
Cardiac surgery with cardiopulmonary bypass (CPB) is often complicated by coagulopathic bleeding, leading to morbidity and mortality. Although guidelines recommend using either frozen plasma (FP) or four-factor prothrombin complex (PCC) for bleeding management, the mainstay of therapy in North America is FP. This randomized controlled non-inferiority trial compared the efficacy and safety of PCC with FP in cardiac surgery.
Design and Methods
FARES-II (LEX-211; NCT05523297) included patients aged ≥18 years undergoing cardiac surgery with CPB. After protamine administration, patients who developed coagulopathic bleeding with INR ≥1.5 were randomized 1:1 to receive PCC (1500 IU if ≤60 kg; 2000 IU if >60 kg) or FP (3 U if ≤60 kg; 4 U if >60 kg). The clinical team was blinded to group allocation until treatment initiation. The primary endpoint was hemostatic response (effective if no additional hemostatic interventions were administered from 60 min to 24 h after treatment initiation). Safety endpoints included 30-day treatment-emergent serious adverse events, thromboembolic events and death.
Results
Of 538 enrolled patients at 12 sites, 420 were randomized, treated, consented and included in the analysis (PCC=213; FP=207). Baseline characteristics were comparable between groups; median (range) age was 66 years (20–88) and 74% of patients were male. Effective hemostasis was achieved in 77.9% (n=166) of PCC patients vs. 60.4% (n=125) of FP patients (difference 17.6%; 95% CI 8.7, 26.4; p< 0.0001 for non-inferiority and superiority). Overall, the mean (95% CI) number of allogeneic blood product units transfused within 24 h post-CPB, including intervention FP, was 6.6 (5.9, 7.5) in PCC patients and 13.8 (12.3, 15.5) in FP patients (ratio 0.48; 95% CI 0.41, 0.57; p< 0.0001). Treatment-emergent thromboembolic events and mortality occurred in 8.5% (n=18) and 3.3% (n=7) of PCC patients and 7.2% (n=15) and 3.9% (n=8) of FP patients, respectively. Treatment-emergent serious adverse events (36.2% vs. 47.3%; relative risk 0.76; 95% CI 0.61, 0.96; p=0.02) and acute kidney injury (10.3% vs. 18.8%; relative risk 0.55; 95% CI 0.34, 0.89; p=0.02) were significantly less frequent in the PCC group compared with the FP group.
Conclusion
PCC has superior hemostatic efficacy and may have safety advantages over FP in patients requiring coagulation factor replacement for bleeding during cardiac surgery. These findings support the use of PCC over FP for bleeding management in cardiac surgery.
心脏手术合并体外循环（CPB）常并发凝血性出血，导致发病率和死亡率。尽管指南建议使用冷冻血浆（FP）或四因子凝血酶原复合物（PCC）进行出血管理，但北美的主要治疗方法是FP。这项随机对照非劣效性试验比较了PCC与FP在心脏手术中的疗效和安全性。设计与方法fares - ii (LEX-211；NCT05523297)纳入年龄≥18岁接受CPB心脏手术的患者。鱼精蛋白给药后，INR≥1.5发生凝血性出血的患者按1:1随机分组接受PCC治疗(≤60 kg为1500 IU；2000 IU（≤60 kg）或FP（≤60 kg）4u（60公斤）。临床小组在治疗开始前对分组分配不知情。主要终点是止血反应（如果在治疗开始后60分钟至24小时内没有额外的止血干预，则有效）。安全性终点包括30天治疗后出现的严重不良事件、血栓栓塞事件和死亡。结果在12个站点的538例入组患者中，420例被随机、治疗、同意并纳入分析(PCC=213；FP = 207)。各组间基线特征具有可比性；中位（范围）年龄为66岁（20-88岁），74%的患者为男性。PCC患者有效止血率为77.9% (n=166)， FP患者有效止血率为60.4% (n=125)(差异17.6%；95% ci 8.7, 26.4；术中;0.0001表示非劣效性和优越性)。总体而言，cpb后24小时内输注同种异体血液制品单位（包括干预FP）的平均（95% CI）数量在PCC患者中为6.6(5.9,7.5)，在FP患者中为13.8(12.3,15.5)(比值0.48；95% ci 0.41, 0.57；术中;0.0001)。治疗后出现的血栓栓塞事件和死亡率在PCC患者中分别为8.5% （n=18）和3.3% (n=7)，在FP患者中分别为7.2% （n=15）和3.9% （n=8）。治疗后出现的严重不良事件(36.2% vs 47.3%；相对危险度0.76；95% ci 0.61, 0.96；P =0.02)和急性肾损伤(10.3% vs. 18.8%；相对危险度0.55；95% ci 0.34, 0.89；p=0.02)与FP组相比，PCC组的发生率明显降低。结论pcc在心脏手术出血患者中具有较好的止血效果，且在安全性上优于FP。这些发现支持在心脏外科出血管理中使用PCC而不是FP。
{"title":"Four-Factor Prothrombin Complex Concentrate is Superior to Frozen Plasma for Coagulopathic Bleeding in Cardiac Surgery—The FARES-II (LEX-211) Phase 3, Multicentre, Randomized, Clinical Trial","authors":"Keyvan Karkouti , Jeannie Callum , Cristina Solomon , Sigurd Knaub , Sylvia Werner , Kenichi Tanaka , Jerrold H. Levy","doi":"10.1016/j.tmrv.2025.150913","DOIUrl":"10.1016/j.tmrv.2025.150913","url":null,"abstract":"<div><h3>Introduction</h3><div>Cardiac surgery with cardiopulmonary bypass (CPB) is often complicated by coagulopathic bleeding, leading to morbidity and mortality. Although guidelines recommend using either frozen plasma (FP) or four-factor prothrombin complex (PCC) for bleeding management, the mainstay of therapy in North America is FP. This randomized controlled non-inferiority trial compared the efficacy and safety of PCC with FP in cardiac surgery.</div></div><div><h3>Design and Methods</h3><div>FARES-II (LEX-211; NCT05523297) included patients aged ≥18 years undergoing cardiac surgery with CPB. After protamine administration, patients who developed coagulopathic bleeding with INR ≥1.5 were randomized 1:1 to receive PCC (1500 IU if ≤60 kg; 2000 IU if >60 kg) or FP (3 U if ≤60 kg; 4 U if >60 kg). The clinical team was blinded to group allocation until treatment initiation. The primary endpoint was hemostatic response (effective if no additional hemostatic interventions were administered from 60 min to 24 h after treatment initiation). Safety endpoints included 30-day treatment-emergent serious adverse events, thromboembolic events and death.</div></div><div><h3>Results</h3><div>Of 538 enrolled patients at 12 sites, 420 were randomized, treated, consented and included in the analysis (PCC=213; FP=207). Baseline characteristics were comparable between groups; median (range) age was 66 years (20–88) and 74% of patients were male. Effective hemostasis was achieved in 77.9% (n=166) of PCC patients vs. 60.4% (n=125) of FP patients (difference 17.6%; 95% CI 8.7, 26.4; p< 0.0001 for non-inferiority and superiority). Overall, the mean (95% CI) number of allogeneic blood product units transfused within 24 h post-CPB, including intervention FP, was 6.6 (5.9, 7.5) in PCC patients and 13.8 (12.3, 15.5) in FP patients (ratio 0.48; 95% CI 0.41, 0.57; p< 0.0001). Treatment-emergent thromboembolic events and mortality occurred in 8.5% (n=18) and 3.3% (n=7) of PCC patients and 7.2% (n=15) and 3.9% (n=8) of FP patients, respectively. Treatment-emergent serious adverse events (36.2% vs. 47.3%; relative risk 0.76; 95% CI 0.61, 0.96; p=0.02) and acute kidney injury (10.3% vs. 18.8%; relative risk 0.55; 95% CI 0.34, 0.89; p=0.02) were significantly less frequent in the PCC group compared with the FP group.</div></div><div><h3>Conclusion</h3><div>PCC has superior hemostatic efficacy and may have safety advantages over FP in patients requiring coagulation factor replacement for bleeding during cardiac surgery. These findings support the use of PCC over FP for bleeding management in cardiac surgery.</div></div>","PeriodicalId":56081,"journal":{"name":"Transfusion Medicine Reviews","volume":"39 3","pages":"Article 150913"},"PeriodicalIF":2.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144723846","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 : 2025-07-01DOI: 10.1016/j.tmrv.2025.150914
Alexandra Witt , Ed Pryzdial , Lihua Hao , Scott Meixner , William Sheffield
<div><h3>Introduction</h3><div>Heart attacks and strokes are the leading causes of death worldwide, most often caused by clots that block the flow of blood. The favoured clot-dissolving (i.e. thrombolytic) drug is a recombinant (r) version of tissue plasminogen activator (tPA). The high rtPA dose required for clot lysis causes clinical hemorrhage in up to 6% of patients, resulting in part from systemic, rather than clot-localized, enzyme activity. The Pryzdial lab has discovered a thrombolytic function for the plasma protein, clotting factor X (FX), which acts non-enzymatically to accelerate tPA. Here we present a recombinant variant of FX (rFXic) with two key characteristics: an inhibitory (i) mutation that blocks the intrinsic clotting function, and a cleavage-resistant (c) mutation for increased half-life of tPA-accelerating function in plasma. We hypothesize that <strong>rFXic is thrombolytic and has superior safety compared to rtPA.</strong></div></div><div><h3>Methods</h3><div>Wild type (rFXwt), single mutant (rFXi and rFXc), and double mutant (rFXic) FX were produced in HEK 293 cells and purified via conformational affinity chromatography. Their plasmin-cleavage profile and prothrombin clotting times functionally confirmed the successful insertion of mutations. Calcium-dependent binding to anionic phospholipid was tested to evaluate proper post-translational modification and clot-localizing function of the γ-carboxyglutamic acid (Gla)-domain, which is known to enable binding of FX to anionic phospholipid-containing membrane and fibrin. Acceleration of rtPA activity was evaluated using a plasmin-selective chromogenic substrate. In a mouse model of carotid artery occlusion, Doppler ultrasound recordings of blood flow were used to measure the ability of rFXic to affect clot dissolution.</div></div><div><h3>Results</h3><div>Compared to rFXwt, which was cleaved by plasmin into the predicted rFXβ and FXγ forms of FX, proteolysis of rFXic was limited to production of rFXβ. This is expected to stabilize thrombolytic activity in plasma. In contrast to rFXwt, rFXic had undetectable clotting activity in reconstituted FX-deficient plasma. Neither mutation impacted calcium-dependent binding to anionic phospholipid. <em>In vitro</em>, rtPA generated 10-fold more plasmin in the presence of rFXic than rFXwt, indicative of thrombolytic acceleration by the former. In mouse models of thrombosis, rFXic decreased the thrombolytic dose of rtPA by at least 50% as an adjunctive therapeutic but did not promote thrombolysis without rtPA.</div></div><div><h3>Conclusion</h3><div>These data support the hypothesis that rFXic has thrombolytic activity in combination with rtPA. By lowering the therapeutic dose of rtPA, rFXic could be used as an adjunctive therapeutic to reduce the bleeding risk of thrombolysis. Next, we will assess the quantitative efficacy of rFXic <em>in vivo</em> and therapeutic safety <em>ex vivo</em>, and anticipate advocating for rFXic as both an e
{"title":"Modulating recombinant clotting factor X to improve clot-dissolution","authors":"Alexandra Witt , Ed Pryzdial , Lihua Hao , Scott Meixner , William Sheffield","doi":"10.1016/j.tmrv.2025.150914","DOIUrl":"10.1016/j.tmrv.2025.150914","url":null,"abstract":"<div><h3>Introduction</h3><div>Heart attacks and strokes are the leading causes of death worldwide, most often caused by clots that block the flow of blood. The favoured clot-dissolving (i.e. thrombolytic) drug is a recombinant (r) version of tissue plasminogen activator (tPA). The high rtPA dose required for clot lysis causes clinical hemorrhage in up to 6% of patients, resulting in part from systemic, rather than clot-localized, enzyme activity. The Pryzdial lab has discovered a thrombolytic function for the plasma protein, clotting factor X (FX), which acts non-enzymatically to accelerate tPA. Here we present a recombinant variant of FX (rFXic) with two key characteristics: an inhibitory (i) mutation that blocks the intrinsic clotting function, and a cleavage-resistant (c) mutation for increased half-life of tPA-accelerating function in plasma. We hypothesize that <strong>rFXic is thrombolytic and has superior safety compared to rtPA.</strong></div></div><div><h3>Methods</h3><div>Wild type (rFXwt), single mutant (rFXi and rFXc), and double mutant (rFXic) FX were produced in HEK 293 cells and purified via conformational affinity chromatography. Their plasmin-cleavage profile and prothrombin clotting times functionally confirmed the successful insertion of mutations. Calcium-dependent binding to anionic phospholipid was tested to evaluate proper post-translational modification and clot-localizing function of the γ-carboxyglutamic acid (Gla)-domain, which is known to enable binding of FX to anionic phospholipid-containing membrane and fibrin. Acceleration of rtPA activity was evaluated using a plasmin-selective chromogenic substrate. In a mouse model of carotid artery occlusion, Doppler ultrasound recordings of blood flow were used to measure the ability of rFXic to affect clot dissolution.</div></div><div><h3>Results</h3><div>Compared to rFXwt, which was cleaved by plasmin into the predicted rFXβ and FXγ forms of FX, proteolysis of rFXic was limited to production of rFXβ. This is expected to stabilize thrombolytic activity in plasma. In contrast to rFXwt, rFXic had undetectable clotting activity in reconstituted FX-deficient plasma. Neither mutation impacted calcium-dependent binding to anionic phospholipid. <em>In vitro</em>, rtPA generated 10-fold more plasmin in the presence of rFXic than rFXwt, indicative of thrombolytic acceleration by the former. In mouse models of thrombosis, rFXic decreased the thrombolytic dose of rtPA by at least 50% as an adjunctive therapeutic but did not promote thrombolysis without rtPA.</div></div><div><h3>Conclusion</h3><div>These data support the hypothesis that rFXic has thrombolytic activity in combination with rtPA. By lowering the therapeutic dose of rtPA, rFXic could be used as an adjunctive therapeutic to reduce the bleeding risk of thrombolysis. Next, we will assess the quantitative efficacy of rFXic <em>in vivo</em> and therapeutic safety <em>ex vivo</em>, and anticipate advocating for rFXic as both an e","PeriodicalId":56081,"journal":{"name":"Transfusion Medicine Reviews","volume":"39 3","pages":"Article 150914"},"PeriodicalIF":2.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144723847","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 : 2025-07-01DOI: 10.1016/j.tmrv.2025.150911
Dimpy Modi, Nancy Heddle, Dongyoung Kim, Yang Liu, Donald Arnold
Introduction/Objective
Patients with hematological malignancies who are receiving chemotherapy have a heightened risk of bleeding because of the presence of both anemia and thrombocytopenia. The objective of this study was to determine the association between severe anemia, defined as hemoglobin (Hb) < 70 g/L in the three days before the first major bleeding event, and the risk of major bleeding in patients with hematological malignancy. A major bleed was defined as Grade 2 or higher on the World Health Organization (WHO) scale.
Design and Methods
We did a substudy of patients from the PREPAReS trial, a randomized trial comparing the efficacy of pathogen-inactivated platelets versus untreated platelet products in patients with hematological malignancy undergoing chemotherapy treatment. Daily hemoglobin levels, platelet counts, and WHO-graded bleeding assessments were collected during the trial. Cox regression analysis was used to assess the effect of anemia on risk of the first major bleed. Anemia was defined as a daily binary covariate of lowest Hb < 70 g/L or >/=70 g/L in the past three days. Cox regression models were adjusted for potential risk factors including sex, age, diagnosis (acute myeloid leukemia [AML] or non-AML), country, treatment stage, and study randomization arm. The substudy was approved by the research ethics board.
Results
565 patients were included from ten centres in three countries. 270 patients had AML (47.8%) and 182 patients were female (32.2%). In total, 321 patients (56.8%) developed a bleed of Grade 2 or higher. The first bleeding events were Grade 2 (n=309; 96.3%), Grade 3 (n=4; 1.2%) or Grade 4 (n= 8; 2.5%). A significant association between Hb < 70 and risk of bleeding was observed (Hazard ratio=1.71, p=0.009). Females had a higher risk of bleeding during the first seven days from randomization compared to males (HR=2.28, p< 0.001). Five (0.9%) females had vaginal-related bleeding. Difference in risk of major bleeding was observed between countries (p< 0.05).
Conclusions
Severe anemia was associated with major bleeding in patients with hematological malignancy undergoing chemotherapy. Maintaining a higher hemoglobin level for this patient group should be considered and evaluated in prospective trials.
{"title":"The Association Between Anemia and Bleeding in Thrombocytopenic Patients with a Hematological Malignancy","authors":"Dimpy Modi, Nancy Heddle, Dongyoung Kim, Yang Liu, Donald Arnold","doi":"10.1016/j.tmrv.2025.150911","DOIUrl":"10.1016/j.tmrv.2025.150911","url":null,"abstract":"<div><h3>Introduction/Objective</h3><div>Patients with hematological malignancies who are receiving chemotherapy have a heightened risk of bleeding because of the presence of both anemia and thrombocytopenia. The objective of this study was to determine the association between severe anemia, defined as hemoglobin (Hb) < 70 g/L in the three days before the first major bleeding event, and the risk of major bleeding in patients with hematological malignancy. A major bleed was defined as Grade 2 or higher on the World Health Organization (WHO) scale.</div></div><div><h3>Design and Methods</h3><div>We did a substudy of patients from the PREPAReS trial, a randomized trial comparing the efficacy of pathogen-inactivated platelets versus untreated platelet products in patients with hematological malignancy undergoing chemotherapy treatment. Daily hemoglobin levels, platelet counts, and WHO-graded bleeding assessments were collected during the trial. Cox regression analysis was used to assess the effect of anemia on risk of the first major bleed. Anemia was defined as a daily binary covariate of lowest Hb < 70 g/L or >/=70 g/L in the past three days. Cox regression models were adjusted for potential risk factors including sex, age, diagnosis (acute myeloid leukemia [AML] or non-AML), country, treatment stage, and study randomization arm. The substudy was approved by the research ethics board.</div></div><div><h3>Results</h3><div>565 patients were included from ten centres in three countries. 270 patients had AML (47.8%) and 182 patients were female (32.2%). In total, 321 patients (56.8%) developed a bleed of Grade 2 or higher. The first bleeding events were Grade 2 (n=309; 96.3%), Grade 3 (n=4; 1.2%) or Grade 4 (n= 8; 2.5%). A significant association between Hb < 70 and risk of bleeding was observed (Hazard ratio=1.71, p=0.009). Females had a higher risk of bleeding during the first seven days from randomization compared to males (HR=2.28, p< 0.001). Five (0.9%) females had vaginal-related bleeding. Difference in risk of major bleeding was observed between countries (p< 0.05).</div></div><div><h3>Conclusions</h3><div>Severe anemia was associated with major bleeding in patients with hematological malignancy undergoing chemotherapy. Maintaining a higher hemoglobin level for this patient group should be considered and evaluated in prospective trials.</div></div>","PeriodicalId":56081,"journal":{"name":"Transfusion Medicine Reviews","volume":"39 3","pages":"Article 150911"},"PeriodicalIF":2.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144723865","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 : 2025-06-04DOI: 10.1016/j.tmrv.2025.150905
Martin Bedan , Christian Lottrup
This systematic review aimed to assess and compare the effect of blood transfusion and intravenous iron therapy on the hemoglobin levels based on clinical trials. To do this, a search was conducted 25th of September 2024 by using PubMed, Cochrane, and Embase databases to identify studies comparing intravenous iron with blood transfusion in patients with iron deficiency anemia (<12 g/dL for women and <13 g/dL for men). The outcome selected was change in hemoglobin levels. The quality of the trials was assessed using Cochrane Risk of Bias Tool and Newcastle-Ottawa Quality Assessment Scale. We included 5 studies (three randomized controlled trials, 1 observational study and 1 retrospective study) comprising a total of 154,539 patients. Patient populations were heterogenous, encompassing surgical patients, patients undergoing hip fracture and pregnant women. Due to heterogeneity among the included studies, hemoglobin levels were reported at varying follow-up intervals. At 3 weeks follow-up or later after initial treatment, 3 studies reported significantly higher hemoglobin levels (ranging from 0.7 g/dL to 1.4 g/dL higher) in the intravenous iron group compared to the blood transfusion group. The remaining 2 studies found similar hemoglobin levels. Less than 3 weeks after initial treatment, 2 studies reported significantly higher hemoglobin levels in the blood transfusion group compared to the intravenous iron group. Our findings indicate that blood transfusion is more effective in achieving a rapid increase in hemoglobin levels shortly after therapy initiation, although this effect diminishes relatively swiftly. In contrast, intravenous iron seems to exert a more gradual increase in, but also longer lasting effect on, hemoglobin levels. However, our findings are limited by the small number of trials as well as questionable methodological quality of the included studies, resulting in a high risk of bias. Further investigation is warranted.
{"title":"Intravenous Iron Therapy Versus Blood Transfusion for Iron Deficiency Anemia: A Systematic Review","authors":"Martin Bedan , Christian Lottrup","doi":"10.1016/j.tmrv.2025.150905","DOIUrl":"10.1016/j.tmrv.2025.150905","url":null,"abstract":"<div><div>This systematic review aimed to assess and compare the effect of blood transfusion and intravenous iron therapy on the hemoglobin levels based on clinical trials. To do this, a search was conducted 25<sup>th</sup> of September 2024 by using PubMed, Cochrane, and Embase databases to identify studies comparing intravenous iron with blood transfusion in patients with iron deficiency anemia (<12 g/dL for women and <13 g/dL for men). The outcome selected was change in hemoglobin levels. The quality of the trials was assessed using Cochrane Risk of Bias Tool and Newcastle-Ottawa Quality Assessment Scale. We included 5 studies (three randomized controlled trials, 1 observational study and 1 retrospective study) comprising a total of 154,539 patients. Patient populations were heterogenous, encompassing surgical patients, patients undergoing hip fracture and pregnant women. Due to heterogeneity among the included studies, hemoglobin levels were reported at varying follow-up intervals. At 3 weeks follow-up or later after initial treatment, 3 studies reported significantly higher hemoglobin levels (ranging from 0.7 g/dL to 1.4 g/dL higher) in the intravenous iron group compared to the blood transfusion group. The remaining 2 studies found similar hemoglobin levels. Less than 3 weeks after initial treatment, 2 studies reported significantly higher hemoglobin levels in the blood transfusion group compared to the intravenous iron group. Our findings indicate that blood transfusion is more effective in achieving a rapid increase in hemoglobin levels shortly after therapy initiation, although this effect diminishes relatively swiftly. In contrast, intravenous iron seems to exert a more gradual increase in, but also longer lasting effect on, hemoglobin levels. However, our findings are limited by the small number of trials as well as questionable methodological quality of the included studies, resulting in a high risk of bias. Further investigation is warranted.</div></div>","PeriodicalId":56081,"journal":{"name":"Transfusion Medicine Reviews","volume":"39 3","pages":"Article 150905"},"PeriodicalIF":2.7,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144490312","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}
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