Christof Geisen, Erika Fleck, Stephan Martin Gastón Schäfer, Carmen Walter, Susanne Braeuninger, Jens Søndergaard Jensen, Douglas Sheridan, Kiran Patki, Róisín Armstrong, Bjørn Skogen, Frank Behrens, Erhard Seifried, Jens Kjeldsen-Kragh, Mette Kjær, Michaela Köhm
Background: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a rare bleeding disorder of the fetus/newborn caused by development of maternal alloantibodies against fetal human platelet antigens (HPAs), predominantly HPA-1a. Currently there are no treatments available to prevent maternal alloimmunization to HPAs or FNAIT.
Methods: This proof-of-concept study (EudraCT Number: 2021-005380-49) was designed to assess the ability of subcutaneous (SC) RLYB212, a monoclonal anti-HPA-1a antibody, to eliminate HPA-1a-positive platelets in an antigen challenge model of a 30 mL fetal-maternal hemorrhage. Subjects were randomized to receive a single SC dose of RLYB212 or placebo on day 1 in a single-blinded manner, followed by transfusion of 10 × 109 HPA-1a-positive platelets on day 8.
Results: Four subjects received 0.09 mg SC RLYB212, five received 0.29 mg SC RLYB212, and two received placebo. RLYB212 achieved rapid elimination of HPA-1a-positive platelets in a concentration-dependent manner, with concentrations as low as 3.57 ng/mL meeting the prespecified proof-of-concept criterion of ≥90% reduction in platelet elimination half-life versus placebo. Following HPA-1a-positive platelet transfusion, a rapid decline was observed in the concentration of RLYB212 over a period of 2 to 24 hours, corresponding to the time needed for RLYB212 to bind to ∼10% of HPA-1a on cell surfaces. RLYB212 was well tolerated with no reports of drug-related adverse events.
Conclusion: The data from this study are consistent with preclinical efficacy data and support the potential use of RLYB212 as a prophylactic treatment for FNAIT that prevents maternal HPA-1a alloimmunization during at-risk pregnancies.
{"title":"A Phase 1b PK/PD Study to Demonstrate Antigen Elimination with RLYB212, a Monoclonal Anti-HPA-1a Antibody for FNAIT Prevention.","authors":"Christof Geisen, Erika Fleck, Stephan Martin Gastón Schäfer, Carmen Walter, Susanne Braeuninger, Jens Søndergaard Jensen, Douglas Sheridan, Kiran Patki, Róisín Armstrong, Bjørn Skogen, Frank Behrens, Erhard Seifried, Jens Kjeldsen-Kragh, Mette Kjær, Michaela Köhm","doi":"10.1055/a-2398-9344","DOIUrl":"10.1055/a-2398-9344","url":null,"abstract":"<p><strong>Background: </strong> Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a rare bleeding disorder of the fetus/newborn caused by development of maternal alloantibodies against fetal human platelet antigens (HPAs), predominantly HPA-1a. Currently there are no treatments available to prevent maternal alloimmunization to HPAs or FNAIT.</p><p><strong>Methods: </strong> This proof-of-concept study (EudraCT Number: 2021-005380-49) was designed to assess the ability of subcutaneous (SC) RLYB212, a monoclonal anti-HPA-1a antibody, to eliminate HPA-1a-positive platelets in an antigen challenge model of a 30 mL fetal-maternal hemorrhage. Subjects were randomized to receive a single SC dose of RLYB212 or placebo on day 1 in a single-blinded manner, followed by transfusion of 10 × 10<sup>9</sup> HPA-1a-positive platelets on day 8.</p><p><strong>Results: </strong> Four subjects received 0.09 mg SC RLYB212, five received 0.29 mg SC RLYB212, and two received placebo. RLYB212 achieved rapid elimination of HPA-1a-positive platelets in a concentration-dependent manner, with concentrations as low as 3.57 ng/mL meeting the prespecified proof-of-concept criterion of ≥90% reduction in platelet elimination half-life versus placebo. Following HPA-1a-positive platelet transfusion, a rapid decline was observed in the concentration of RLYB212 over a period of 2 to 24 hours, corresponding to the time needed for RLYB212 to bind to ∼10% of HPA-1a on cell surfaces. RLYB212 was well tolerated with no reports of drug-related adverse events.</p><p><strong>Conclusion: </strong> The data from this study are consistent with preclinical efficacy data and support the potential use of RLYB212 as a prophylactic treatment for FNAIT that prevents maternal HPA-1a alloimmunization during at-risk pregnancies.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142018700","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}
Background: Primary analysis of the phase III AGEHA study suggested a favorable benefit-risk profile for emicizumab prophylaxis in patients with acquired hemophilia A (PwAHA); however, only patients undergoing immunosuppressive therapy (IST; Cohort 1) were included.
Objectives: To present final analysis results of AGEHA, including data on IST-ineligible patients (Cohort 2) and on long-term prophylaxis with emicizumab.
Methods: For patients in both Cohorts 1 and 2, emicizumab was administered subcutaneously at 6 mg/kg on Day 1, 3 mg/kg on Day 2, and 1.5 mg/kg once weekly from Day 8 onward.
Results: Twelve patients (Cohort 1) and two patients (Cohort 2) were enrolled. Duration of emicizumab treatment was 8 to 639 days (median: 44.5 days) in Cohort 1 and 64 and 450 days in Cohort 2. In both cohorts, no major bleeds were observed after initial emicizumab administration. Six patients started their first rehabilitation sessions during emicizumab treatment and no rehabilitation-related bleeds occurred. Twenty-three surgeries were performed under emicizumab prophylaxis and there were no bleeds related to surgeries. Although asymptomatic deep vein thrombosis was reported in one patient in the primary analysis, no other thrombotic events occurred thereafter. Two patients developed anti-emicizumab antibodies, one of whom showed accelerated emicizumab clearance. Tailored IST approaches (delayed initiation, no use, or reduced dose) were successfully executed in three patients undergoing emicizumab prophylaxis.
Conclusion: These results suggest that emicizumab prophylaxis has a favorable benefit-risk profile in PwAHA regardless of eligibility for IST.
{"title":"Final Analysis Results from the AGEHA Study: Emicizumab Prophylaxis for Acquired Hemophilia A with or without Immunosuppressive Therapy.","authors":"Midori Shima, Nobuaki Suzuki, Hidekazu Nishikii, Kagehiro Amano, Yoshiyuki Ogawa, Ryota Kobayashi, Ryoto Ozaki, Koichiro Yoneyama, Narumi Mizuno, Emiko Sakaida, Makoto Saito, Takashi Okamura, Toshihiro Ito, Norimichi Hattori, Satoshi Higasa, Yoshinobu Seki, Keiji Nogami","doi":"10.1055/a-2384-3585","DOIUrl":"10.1055/a-2384-3585","url":null,"abstract":"<p><strong>Background: </strong> Primary analysis of the phase III AGEHA study suggested a favorable benefit-risk profile for emicizumab prophylaxis in patients with acquired hemophilia A (PwAHA); however, only patients undergoing immunosuppressive therapy (IST; Cohort 1) were included.</p><p><strong>Objectives: </strong> To present final analysis results of AGEHA, including data on IST-ineligible patients (Cohort 2) and on long-term prophylaxis with emicizumab.</p><p><strong>Methods: </strong> For patients in both Cohorts 1 and 2, emicizumab was administered subcutaneously at 6 mg/kg on Day 1, 3 mg/kg on Day 2, and 1.5 mg/kg once weekly from Day 8 onward.</p><p><strong>Results: </strong> Twelve patients (Cohort 1) and two patients (Cohort 2) were enrolled. Duration of emicizumab treatment was 8 to 639 days (median: 44.5 days) in Cohort 1 and 64 and 450 days in Cohort 2. In both cohorts, no major bleeds were observed after initial emicizumab administration. Six patients started their first rehabilitation sessions during emicizumab treatment and no rehabilitation-related bleeds occurred. Twenty-three surgeries were performed under emicizumab prophylaxis and there were no bleeds related to surgeries. Although asymptomatic deep vein thrombosis was reported in one patient in the primary analysis, no other thrombotic events occurred thereafter. Two patients developed anti-emicizumab antibodies, one of whom showed accelerated emicizumab clearance. Tailored IST approaches (delayed initiation, no use, or reduced dose) were successfully executed in three patients undergoing emicizumab prophylaxis.</p><p><strong>Conclusion: </strong> These results suggest that emicizumab prophylaxis has a favorable benefit-risk profile in PwAHA regardless of eligibility for IST.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141971911","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}
Katarina Glise Sandblad, Carl Johan Svensson, Kristina Svennerholm, Jacob Philipson, Aldina Pivodic, Sam Schulman, Mazdak Tavoly
Background: Recent data on temporal trends in excess mortality for patients with pulmonary embolism (PE) and deep vein thrombosis (DVT) compared with the general population are scarce.
Methods: A nationwide Swedish register study conducted from 2006 to 2018 including 68,960 PE and 70,949 DVT cases matched with population controls. Poisson regression determined relative risk (RR) for 30-day and 1-year mortality trends while Cox regression determined adjusted hazard ratios (aHRs). A significance level of 0.001 was applied.
Results: In PE cases, both 30-day mortality (12.5% in 2006 to 7.8% in 2018, RR: 0.95 [95% CI: 0.95-0.96], p < 0.0001) and 1-year mortality (26.5 to 22.1%, RR: 0.98 [0.97-0.98], p < 0.0001) decreased during the study period. Compared with controls, no significant change was seen in 30-day (aHR: 33.08 [95% CI: 25.12-43.55] to 24.64 [95% CI: 18.81-32.27], p = 0.0015 for interaction with calendar year) or 1-year (aHR: 5.85 [95% CI: 5.31-6.45] to 7.07 [95% CI: 6.43-7.78], p = 0.038) excess mortality. The 30-day excess mortality decreased significantly (aHR: 39.93 [95% CI: 28.47-56.00) to 24.63 [95% CI: 17.94-33.83], p = 0.0009) in patients with PE without known cancer before baseline, while the excess 1-year mortality increased (aHR: 3.55 [95% CI: 3.16-3.99] to 5.38 [95% CI: 4.85-5.98], p < 0.0001) in PE cases surviving to fill a prescription of anticoagulation. In DVT cases, 30-day and 1-year mortality declined, while excess mortality compared with controls remained stable.
Conclusion: In general, the improved mortality following PE and DVT paralleled population trends. However, PE cases without cancer had decreasing excess 30-day mortality, whereas those surviving to fill a prescription for anticoagulant medication showed increasing excess 1-year mortality.
背景：关于肺栓塞（PE）和深静脉血栓形成（DVT）患者与普通人群相比死亡率过高的时间趋势的最新数据很少：有关肺栓塞（PE）和深静脉血栓形成（DVT）患者死亡率高于普通人群的时间趋势的最新数据很少：2006-2018年瑞典全国范围内的登记研究，包括68960例PE和70949例DVT病例，并与人群对照匹配。泊松回归确定了 30 天和一年死亡率趋势的相对风险 (RR)，而 Cox 回归确定了调整后的危险比 (aHR)。显著性水平为 0.001：在 PE 病例中，30 天死亡率（2006 年为 12.5%，2018 年为 7.8%，RR 0.95 95% CI 0.95-0.96，pConclusion：总体而言，PE和深静脉血栓后死亡率的改善与人口趋势一致。然而，未患癌症的 PE 病例 30 天内的超额死亡率有所下降，而因开具抗凝药物处方而存活的患者一年内的超额死亡率有所上升。
{"title":"Time Trends and Excess Mortality Compared to Population Controls after a First-Time Pulmonary Embolism or Deep Vein Thrombosis.","authors":"Katarina Glise Sandblad, Carl Johan Svensson, Kristina Svennerholm, Jacob Philipson, Aldina Pivodic, Sam Schulman, Mazdak Tavoly","doi":"10.1055/a-2402-6192","DOIUrl":"10.1055/a-2402-6192","url":null,"abstract":"<p><strong>Background: </strong> Recent data on temporal trends in excess mortality for patients with pulmonary embolism (PE) and deep vein thrombosis (DVT) compared with the general population are scarce.</p><p><strong>Methods: </strong> A nationwide Swedish register study conducted from 2006 to 2018 including 68,960 PE and 70,949 DVT cases matched with population controls. Poisson regression determined relative risk (RR) for 30-day and 1-year mortality trends while Cox regression determined adjusted hazard ratios (aHRs). A significance level of 0.001 was applied.</p><p><strong>Results: </strong> In PE cases, both 30-day mortality (12.5% in 2006 to 7.8% in 2018, RR: 0.95 [95% CI: 0.95-0.96], <i>p</i> < 0.0001) and 1-year mortality (26.5 to 22.1%, RR: 0.98 [0.97-0.98], <i>p</i> < 0.0001) decreased during the study period. Compared with controls, no significant change was seen in 30-day (aHR: 33.08 [95% CI: 25.12-43.55] to 24.64 [95% CI: 18.81-32.27], <i>p</i> = 0.0015 for interaction with calendar year) or 1-year (aHR: 5.85 [95% CI: 5.31-6.45] to 7.07 [95% CI: 6.43-7.78], <i>p</i> = 0.038) excess mortality. The 30-day excess mortality decreased significantly (aHR: 39.93 [95% CI: 28.47-56.00) to 24.63 [95% CI: 17.94-33.83], <i>p</i> = 0.0009) in patients with PE without known cancer before baseline, while the excess 1-year mortality increased (aHR: 3.55 [95% CI: 3.16-3.99] to 5.38 [95% CI: 4.85-5.98], <i>p</i> < 0.0001) in PE cases surviving to fill a prescription of anticoagulation. In DVT cases, 30-day and 1-year mortality declined, while excess mortality compared with controls remained stable.</p><p><strong>Conclusion: </strong> In general, the improved mortality following PE and DVT paralleled population trends. However, PE cases without cancer had decreasing excess 30-day mortality, whereas those surviving to fill a prescription for anticoagulant medication showed increasing excess 1-year mortality.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142047247","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}
Background Increased clot permeability and susceptibility to lysis have been reported in women with heavy menstrual bleeding. We hypothesized that similarly altered fibrin clot properties in women with postpartum hemorrhage (PPH) of unknown cause. Objective To determine fibrin clot properties and their determinants in women after PPH of unknown cause. Methods We studied 52 consecutive women, aged 35 years (27-40), after at least 3 months since PPH of unknown cause and 52 matched controls for age, weight, and fibrinogen. Coagulation factors (F), antithrombin, thrombin generation, along with a comprehensive plasma fibrin clot analysis including fibrin polymerization, clot permeability (Ks), and fibrinolysis efficiency were determined. Results Women with PPH showed reduced activity of FII (-10.3%), FV (-6.6%), FIX (-6.5%), FX (-7.2%), and FXI (-5.7%) compared to the controls, though all values were within ranges (all p<0.05). There were no intergroup differences in fibrinogen, FVIII, FXIII, and thrombin generation. The PPH group formed with a delay looser plasma fibrin network (Ks; +16.3%, p=0.008) with lower maximum absorbance and shorter clot lysis time (CLT; -13.5%, p=0.001) compared to the controls. On multivariable logistic regression, PPH was independently associated with higher C-reactive protein (per 1 mg/L, OR=1.70, 95% CI 1.09-2.68), lower FII (per 1%, OR=0.93, 95% CI 0.89-0.98), lower FV (per 1%, OR=0.93, 95% CI 0.89-0.97), and shorter CLT (per 1 min, OR=0.94, 95% CI 0.90-0.98). Conclusion Prohemorrhagic fibrin clot properties, with lower, though normal coagulation factors characterize women with PPH of unknown cause, which suggests novel mechanisms contributing to this type of bleeding.
背景 据报道，大量月经出血的妇女血凝块的通透性和易裂解性增加。我们假设原因不明的产后出血（PPH）妇女的纤维蛋白凝块特性也会发生类似的改变。目的 确定原因不明的 PPH 女性的纤维蛋白凝块特性及其决定因素。方法 我们连续研究了 52 名年龄在 35 岁（27-40 岁）、原因不明的 PPH 后至少 3 个月的妇女，以及 52 名年龄、体重和纤维蛋白原相匹配的对照组。我们测定了凝血因子（F）、抗凝血酶、凝血酶生成量以及血浆纤维蛋白凝块综合分析，包括纤维蛋白聚合度、凝块渗透性（Ks）和纤维蛋白溶解效率。结果 PPH 女性患者的 FII（-10.3%）、FV（-6.6%）、FIX（-6.5%）、FX（-7.2%）和 FXI（-5.7%）的活性均低于对照组，但所有数值均在范围之内（均 p<0.05）。在纤维蛋白原、FVIII、FXIII 和凝血酶生成方面，组间没有差异。与对照组相比，PPH 组形成的血浆纤维蛋白网络延迟松散（Ks；+16.3%，P=0.008），最大吸光度较低，凝块溶解时间（CLT；-13.5%，P=0.001）较短。在多变量逻辑回归中，PPH 与较高的 C 反应蛋白（每 1 mg/L，OR=1.70，95% CI 1.09-2.68）、较低的 FII（每 1%，OR=0.93，95% CI 0.89-0.98）、较低的 FV（每 1%，OR=0.93，95% CI 0.89-0.97）和较短的 CLT（每 1 分钟，OR=0.94，95% CI 0.90-0.98）独立相关。结论 原因不明的 PPH 女性具有出血性纤维蛋白凝块特性，凝血因子较低但正常，这表明导致此类出血的新机制。
{"title":"Unfavorably altered fibrin clot phenotype in women following postpartum hemorrhage of unknown cause: effect of lower coagulation factors.","authors":"Magdalena Piróg,Michał Ząbczyk,Joanna Natorska,Elżbieta Broniatowska,Robert Jach,Anetta Undas","doi":"10.1055/a-2413-2966","DOIUrl":"https://doi.org/10.1055/a-2413-2966","url":null,"abstract":"Background Increased clot permeability and susceptibility to lysis have been reported in women with heavy menstrual bleeding. We hypothesized that similarly altered fibrin clot properties in women with postpartum hemorrhage (PPH) of unknown cause. Objective To determine fibrin clot properties and their determinants in women after PPH of unknown cause. Methods We studied 52 consecutive women, aged 35 years (27-40), after at least 3 months since PPH of unknown cause and 52 matched controls for age, weight, and fibrinogen. Coagulation factors (F), antithrombin, thrombin generation, along with a comprehensive plasma fibrin clot analysis including fibrin polymerization, clot permeability (Ks), and fibrinolysis efficiency were determined. Results Women with PPH showed reduced activity of FII (-10.3%), FV (-6.6%), FIX (-6.5%), FX (-7.2%), and FXI (-5.7%) compared to the controls, though all values were within ranges (all p<0.05). There were no intergroup differences in fibrinogen, FVIII, FXIII, and thrombin generation. The PPH group formed with a delay looser plasma fibrin network (Ks; +16.3%, p=0.008) with lower maximum absorbance and shorter clot lysis time (CLT; -13.5%, p=0.001) compared to the controls. On multivariable logistic regression, PPH was independently associated with higher C-reactive protein (per 1 mg/L, OR=1.70, 95% CI 1.09-2.68), lower FII (per 1%, OR=0.93, 95% CI 0.89-0.98), lower FV (per 1%, OR=0.93, 95% CI 0.89-0.97), and shorter CLT (per 1 min, OR=0.94, 95% CI 0.90-0.98). Conclusion Prohemorrhagic fibrin clot properties, with lower, though normal coagulation factors characterize women with PPH of unknown cause, which suggests novel mechanisms contributing to this type of bleeding.","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":"7 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222653","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}
Mikkel Lundbech,Andreas Engel Krag,Lene Hjerrild Iversen,Birgitte Brandsborg,Nina Madsen,Anne-Mette Hvas
INTRODUCTION Surgical treatment of colorectal cancer carries a risk for venous thromboembolism (VTE). We investigated changes in coagulation and fibrinolysis and the VTE incidence within 30 days in patients undergoing open cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS+HIPEC) for peritoneal metastases from colorectal cancer and minimally invasive surgery (MIS) for localized rectal cancer. METHODS This cohort study included 45 CRS+HIPEC and 45 MIS patients. Blood samples were obtained preoperatively, at the end of surgery, and postoperative day (POD) 1, 3-4, and 5-7. Systematic ultrasonographic screening for VTE was performed between POD 3-7. Computed tomography scan was performed if complications were suspected. The primary endpoint was the difference in mean change ( with [95% confidence intervals] from preoperative to end of surgery in prothrombin fragment 1+2 (F1+2) levels. Secondary endpoints were the difference in mean change in biomarkers of coagulation and fibrinolysis from preoperative to POD 5-7, and the VTE incidence. RESULTS F1+2 levels increased from preoperative to the end of surgery in both groups. The mean increase from preoperative to end of surgery in F1+2 levels was significantly greater in CRS+HIPEC patients than MIS patients: 1322 [1040:1604] pmol/l, P = 0.001. The VTE incidence was significantly higher after CRS+HIPEC than MIS (24% vs. 5%, P = 0.012). CONCLUSION F1+2 levels were increased after both procedures, but to a far greater extent following CRS+HIPEC. The VTE incidence within 30 days was significantly higher in patients treated with CRS+HIPEC than in MIS patients.
{"title":"Elevated thrombin generation and VTE incidence in patients undergoing cytoreductive surgery with HIPEC compared with minimally invasive rectal surgery.","authors":"Mikkel Lundbech,Andreas Engel Krag,Lene Hjerrild Iversen,Birgitte Brandsborg,Nina Madsen,Anne-Mette Hvas","doi":"10.1055/a-2413-4989","DOIUrl":"https://doi.org/10.1055/a-2413-4989","url":null,"abstract":"INTRODUCTION Surgical treatment of colorectal cancer carries a risk for venous thromboembolism (VTE). We investigated changes in coagulation and fibrinolysis and the VTE incidence within 30 days in patients undergoing open cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS+HIPEC) for peritoneal metastases from colorectal cancer and minimally invasive surgery (MIS) for localized rectal cancer. METHODS This cohort study included 45 CRS+HIPEC and 45 MIS patients. Blood samples were obtained preoperatively, at the end of surgery, and postoperative day (POD) 1, 3-4, and 5-7. Systematic ultrasonographic screening for VTE was performed between POD 3-7. Computed tomography scan was performed if complications were suspected. The primary endpoint was the difference in mean change ( with [95% confidence intervals] from preoperative to end of surgery in prothrombin fragment 1+2 (F1+2) levels. Secondary endpoints were the difference in mean change in biomarkers of coagulation and fibrinolysis from preoperative to POD 5-7, and the VTE incidence. RESULTS F1+2 levels increased from preoperative to the end of surgery in both groups. The mean increase from preoperative to end of surgery in F1+2 levels was significantly greater in CRS+HIPEC patients than MIS patients: 1322 [1040:1604] pmol/l, P = 0.001. The VTE incidence was significantly higher after CRS+HIPEC than MIS (24% vs. 5%, P = 0.012). CONCLUSION F1+2 levels were increased after both procedures, but to a far greater extent following CRS+HIPEC. The VTE incidence within 30 days was significantly higher in patients treated with CRS+HIPEC than in MIS patients.","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":"99 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222664","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}
Mehdi Khourssaji,Marion Bareille,Lorenzo Alberio,Delphine Borgel,Marc Fouassier,Marie Christine Bene,Thomas Lecompte,François Mullier
Accurate assessment of platelet secretion is essential for the diagnosis of inherited or acquired platelet function disorders (PFDs) and more specifically in identifying δ-storage pool disease. Mepacrine, a fluorescent dye, specifically accumulates in platelet δ-granules. The mepacrine flow cytometry (FCM) assay has been used for more than half a century in the clinical laboratory as a diagnostic tool for platelet δ-granule disorders. The assay requires a small volume of blood, can be performed in thrombocytopenic patients, provides rapid assessment of δ-granule content and secretion and, thus, enables differentiation between storage and release defects. FCM has been shown to have added value compared to light transmission aggregometry. There is however a broad heterogeneity in methods, reagents, and equipment used. Lack of standardization and limited data on analytical and clinical performances have led the 2022 ISTH SSC Subcommittee on Platelet Physiology expert consensus to rate this assay as simple but of uncertain value. Yet, the data used by experts to formulate the recommendations were not discussed and even not mentioned. Guidance for laboratory studies of platelet secretion assay would be very helpful for clinical laboratories and health authorities especially considering the implications of the new In Vitro Diagnostic Regulation (IVDR) in Europe. The purpose of the present work was to systematically review the reported methodologies for the mepacrine FCM assay and to offer an example of detailed protocol. This would help standardization and pave the way for more rigorous comparative studies.
{"title":"Mepacrine flow cytometry assay for the diagnosis of platelet δ-granule defects : literature review on methods - towards a shared detailed protocol.","authors":"Mehdi Khourssaji,Marion Bareille,Lorenzo Alberio,Delphine Borgel,Marc Fouassier,Marie Christine Bene,Thomas Lecompte,François Mullier","doi":"10.1055/a-2413-2870","DOIUrl":"https://doi.org/10.1055/a-2413-2870","url":null,"abstract":"Accurate assessment of platelet secretion is essential for the diagnosis of inherited or acquired platelet function disorders (PFDs) and more specifically in identifying δ-storage pool disease. Mepacrine, a fluorescent dye, specifically accumulates in platelet δ-granules. The mepacrine flow cytometry (FCM) assay has been used for more than half a century in the clinical laboratory as a diagnostic tool for platelet δ-granule disorders. The assay requires a small volume of blood, can be performed in thrombocytopenic patients, provides rapid assessment of δ-granule content and secretion and, thus, enables differentiation between storage and release defects. FCM has been shown to have added value compared to light transmission aggregometry. There is however a broad heterogeneity in methods, reagents, and equipment used. Lack of standardization and limited data on analytical and clinical performances have led the 2022 ISTH SSC Subcommittee on Platelet Physiology expert consensus to rate this assay as simple but of uncertain value. Yet, the data used by experts to formulate the recommendations were not discussed and even not mentioned. Guidance for laboratory studies of platelet secretion assay would be very helpful for clinical laboratories and health authorities especially considering the implications of the new In Vitro Diagnostic Regulation (IVDR) in Europe. The purpose of the present work was to systematically review the reported methodologies for the mepacrine FCM assay and to offer an example of detailed protocol. This would help standardization and pave the way for more rigorous comparative studies.","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":"21 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222651","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":"The effect of increasing factor X levels on emicizumab-driven coagulation potential.","authors":"Ecaterina Scarlatescu","doi":"10.1055/a-2413-4453","DOIUrl":"https://doi.org/10.1055/a-2413-4453","url":null,"abstract":"No Abstract.","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":"97 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222652","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}
Gene therapy is a therapeutic approach for treating life-threatening disorders. Despite the clinical improvements observed with gene therapy, immune responses either innate or adaptive against the vector used for gene delivery can affect treatment efficacy and lead to adverse reactions. Thrombotic microangiopathy (TMA) is a thrombosis with thrombocytopenia syndrome (TTS) characterized by microangiopathic hemolytic anemia, thrombocytopenia, and small vessel occlusion known to be elicited by several drugs that has been reported as an adverse event of adeno-associated virus (AAV)-gene therapy. TMA encompasses a heterogenous group of disorders, its classification and underlining mechanisms are still uncertain, and lacks validated biomarkers. The identification of predictors of TMA, such as vector dose and patient characteristics, is a pressing need to recognize patients at risk before and after AAV-based gene therapy administration. This review aims to explore the literature on TMA associated with AAV-based gene therapy in the context of TMA (i.e., hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura and other drug-related TMAs). Considering the wide attention recently gained by another TTS associated with a non-gene therapy viral platform (adenovirus, AV COVID-19 vaccine), namely vaccine-induced immune thrombocytopenia and thrombosis (VITT), AAV gene therapy-related TMA mechanisms will be discussed and differentiated from those of VITT to avoid recency bias and favor a correct positioning of these two recently emerged syndromes within the heterogenous group of drug-related TTS. The review will discuss strategies for enhancing the safety and optimize the management of AAV-based gene therapy, emerging as an efficacious therapeutic option for disparate, severe, and often orphan condition.
{"title":"Emerging thrombotic disorders associated with virus-based innovative therapies: from VITT to AAV-gene therapy-related thrombotic microangiopathy.","authors":"Silvia Benemei,Francesca Gatto,Rossella Marcucci,Paolo Gresele","doi":"10.1055/a-2413-4345","DOIUrl":"https://doi.org/10.1055/a-2413-4345","url":null,"abstract":"Gene therapy is a therapeutic approach for treating life-threatening disorders. Despite the clinical improvements observed with gene therapy, immune responses either innate or adaptive against the vector used for gene delivery can affect treatment efficacy and lead to adverse reactions. Thrombotic microangiopathy (TMA) is a thrombosis with thrombocytopenia syndrome (TTS) characterized by microangiopathic hemolytic anemia, thrombocytopenia, and small vessel occlusion known to be elicited by several drugs that has been reported as an adverse event of adeno-associated virus (AAV)-gene therapy. TMA encompasses a heterogenous group of disorders, its classification and underlining mechanisms are still uncertain, and lacks validated biomarkers. The identification of predictors of TMA, such as vector dose and patient characteristics, is a pressing need to recognize patients at risk before and after AAV-based gene therapy administration. This review aims to explore the literature on TMA associated with AAV-based gene therapy in the context of TMA (i.e., hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura and other drug-related TMAs). Considering the wide attention recently gained by another TTS associated with a non-gene therapy viral platform (adenovirus, AV COVID-19 vaccine), namely vaccine-induced immune thrombocytopenia and thrombosis (VITT), AAV gene therapy-related TMA mechanisms will be discussed and differentiated from those of VITT to avoid recency bias and favor a correct positioning of these two recently emerged syndromes within the heterogenous group of drug-related TTS. The review will discuss strategies for enhancing the safety and optimize the management of AAV-based gene therapy, emerging as an efficacious therapeutic option for disparate, severe, and often orphan condition.","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":"60 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222649","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}
Stephan Nopp,Oliver Königsbrügge,Sabine Schmaldienst,Marcus Säemann,Ingrid Pabinger,Anne Yaël Nossent,Cihan Ay
BACKGROUNDPatients with end-stage kidney disease (ESKD) are at very high risk for thromboembolism and bleeding. This study aimed to identify small non-coding RNAs (sncRNAs), specifically microRNAs and transfer-RNA (tRNA)-derived fragments (tRFs), as potential novel biomarkers for predicting thromboembolism and bleeding in this high-risk population.METHODSIn this sncRNA discovery research, we leveraged the VIVALDI cohort, consisting of 625 ESKD patients on hemodialysis, to conduct two nested case-control studies, each comprising 18 participants. The primary outcomes were ischemic stroke in the first study and major bleeding in the second. Plasma samples were processed using the miND pipeline for RNA-seq analysis to investigate differential expression of microRNAs and tRNA/tRFs between cases and their respective matched controls, with results stringently adjusted for false discovery rate (FDR).RESULTSNo significant differential expression of microRNAs for either ischemic stroke or major bleeding outcomes was observed in the two nested case-control studies. However, we identified four tRNAs significantly differentially expressed in ischemic stroke cases and seven in major bleeding cases, compared to controls (FDR<0.1). Coverage plots indicated that specific tRNA fragments (tRFs), rather than full-length tRNAs, were detected, however. Alternative mapping approaches revealed challenges and technical limitations that precluded in-depth differential expression analyses on these specific tRFs. Yet, they also underscored the potential of tRNAs and tRFs as markers for thromboembolism and bleeding.CONCLUSIONWhile microRNAs did not show significant differential expression, our study identifies specific tRNAs/tRFs as potential novel biomarkers for ischemic stroke and major bleeding in ESKD patients. .
{"title":"Transfer RNAs are linked to ischemic stroke and major bleeding in patients with end-stage kidney disease.","authors":"Stephan Nopp,Oliver Königsbrügge,Sabine Schmaldienst,Marcus Säemann,Ingrid Pabinger,Anne Yaël Nossent,Cihan Ay","doi":"10.1055/a-2413-2792","DOIUrl":"https://doi.org/10.1055/a-2413-2792","url":null,"abstract":"BACKGROUNDPatients with end-stage kidney disease (ESKD) are at very high risk for thromboembolism and bleeding. This study aimed to identify small non-coding RNAs (sncRNAs), specifically microRNAs and transfer-RNA (tRNA)-derived fragments (tRFs), as potential novel biomarkers for predicting thromboembolism and bleeding in this high-risk population.METHODSIn this sncRNA discovery research, we leveraged the VIVALDI cohort, consisting of 625 ESKD patients on hemodialysis, to conduct two nested case-control studies, each comprising 18 participants. The primary outcomes were ischemic stroke in the first study and major bleeding in the second. Plasma samples were processed using the miND pipeline for RNA-seq analysis to investigate differential expression of microRNAs and tRNA/tRFs between cases and their respective matched controls, with results stringently adjusted for false discovery rate (FDR).RESULTSNo significant differential expression of microRNAs for either ischemic stroke or major bleeding outcomes was observed in the two nested case-control studies. However, we identified four tRNAs significantly differentially expressed in ischemic stroke cases and seven in major bleeding cases, compared to controls (FDR<0.1). Coverage plots indicated that specific tRNA fragments (tRFs), rather than full-length tRNAs, were detected, however. Alternative mapping approaches revealed challenges and technical limitations that precluded in-depth differential expression analyses on these specific tRFs. Yet, they also underscored the potential of tRNAs and tRFs as markers for thromboembolism and bleeding.CONCLUSIONWhile microRNAs did not show significant differential expression, our study identifies specific tRNAs/tRFs as potential novel biomarkers for ischemic stroke and major bleeding in ESKD patients. .","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":"60 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222650","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 : 2024-09-01Epub Date: 2024-02-15DOI: 10.1055/a-2269-1123
Dong-Seon Kang, Pil-Sung Yang, Daehoon Kim, Eunsun Jang, Hee Tae Yu, Tae-Hoon Kim, Jung Hoon Sung, Hui-Nam Pak, Moon-Hyoung Lee, Gregory Y H Lip, Boyoung Joung
Background: This study aimed to evaluate racial differences in bleeding incidence by conducting an ecological epidemiological study using data from Korea and the United Kingdom.
Methods: We included healthy participants from the Korean National Health Insurance Service-Health Screening and the UK Biobank who underwent health examinations between 2006 and 2010 and had no comorbidities or history of medication use. Finally, 112,750 East Asians (50.7% men, mean age 52.6 years) and 210,995 Caucasians (44.7% men, mean age 55.0 years) were analyzed. The primary outcome was composed of intracranial hemorrhage (ICH) and bleeding from the gastrointestinal, respiratory, and genitourinary systems.
Results: During the follow-up, primary outcome events occurred in 2,110 East Asians and in 6,515 Caucasians. East Asians had a 38% lower 5-year incidence rate compared with Caucasians (3.88 vs. 6.29 per 1,000 person-years; incidence rate ratio [IRR]: 0.62, 95% confidence interval [CI]: 0.59-0.65). East Asians showed a lower incidence of major bleeding (IRR: 0.86, 95% CI: 0.81-0.91), bleeding from the gastrointestinal (IRR: 0.53, 95% CI: 0.49-0.56), and genitourinary systems (IRR: 0.49, 95% CI: 0.44-0.53) compared with Caucasians. The incidence rates of ICH (IRR: 3.20, 95% CI: 2.67-3.84) and bleeding from the respiratory system (IRR: 1.28, 95% CI: 1.11-1.47) were higher in East Asians. Notably, East Asians consuming alcohol ≥3 times/week showed a higher incidence of the primary outcome than Caucasians (IRR: 1.12, 95% CI: 1.01-1.25).
Conclusion: This ecological study revealed significant racial differences in bleeding incidence, influenced by anatomical sites and lifestyle habits, underscoring the need for tailored approaches in bleeding management based on race.
背景：本研究旨在利用韩国和英国的数据开展生态流行病学研究，评估出血发生率的种族差异：本研究旨在利用韩国和英国的数据开展生态流行病学研究，评估出血发生率的种族差异：我们纳入了韩国国民健康保险服务-健康筛查和英国生物库中在 2006 年至 2010 年间接受健康检查、无合并症或用药史的健康参与者。最后，对 112,750 名东亚人（50.7% 为男性，平均年龄 52.6 岁）和 210,995 名白种人（44.7% 为男性，平均年龄 55.0 岁）进行了分析。主要结果包括颅内出血（ICH）以及消化系统、呼吸系统和泌尿生殖系统出血：结果：在随访期间，2110 名东亚人和 6515 名白种人发生了主要结果事件。东亚人的五年发病率比白种人低 38%（每 1000 人年 3.88 例 vs. 6.29 例；发病率比 [IRR] 0.62，95% 置信区间 [CI] 0.59-0.65）。与白种人相比，东亚人大出血（IRR 0.86，95% CI 0.81-0.91）、胃肠道出血（IRR 0.53，95% CI 0.49-0.56）和泌尿生殖系统出血（IRR 0.49，95% CI 0.44-0.53）的发生率较低。东亚人的 ICH（IRR 3.20，95% CI 2.67-3.84）和呼吸系统出血（IRR 1.28，95% CI 1.11-1.47）发病率较高。每周饮酒≥3次的东亚人的主要结果发生率高于白种人（IRR为1.12，95% CI为1.01-1.25）：这项生态学研究显示，受解剖部位和生活习惯的影响，出血发生率存在明显的种族差异，这表明在出血管理中需要采取针对不同种族的综合方法。
{"title":"Racial Differences in Bleeding Risk: An Ecological Epidemiological Study Comparing Korea and United Kingdom Subjects.","authors":"Dong-Seon Kang, Pil-Sung Yang, Daehoon Kim, Eunsun Jang, Hee Tae Yu, Tae-Hoon Kim, Jung Hoon Sung, Hui-Nam Pak, Moon-Hyoung Lee, Gregory Y H Lip, Boyoung Joung","doi":"10.1055/a-2269-1123","DOIUrl":"10.1055/a-2269-1123","url":null,"abstract":"<p><strong>Background: </strong> This study aimed to evaluate racial differences in bleeding incidence by conducting an ecological epidemiological study using data from Korea and the United Kingdom.</p><p><strong>Methods: </strong> We included healthy participants from the Korean National Health Insurance Service-Health Screening and the UK Biobank who underwent health examinations between 2006 and 2010 and had no comorbidities or history of medication use. Finally, 112,750 East Asians (50.7% men, mean age 52.6 years) and 210,995 Caucasians (44.7% men, mean age 55.0 years) were analyzed. The primary outcome was composed of intracranial hemorrhage (ICH) and bleeding from the gastrointestinal, respiratory, and genitourinary systems.</p><p><strong>Results: </strong> During the follow-up, primary outcome events occurred in 2,110 East Asians and in 6,515 Caucasians. East Asians had a 38% lower 5-year incidence rate compared with Caucasians (3.88 vs. 6.29 per 1,000 person-years; incidence rate ratio [IRR]: 0.62, 95% confidence interval [CI]: 0.59-0.65). East Asians showed a lower incidence of major bleeding (IRR: 0.86, 95% CI: 0.81-0.91), bleeding from the gastrointestinal (IRR: 0.53, 95% CI: 0.49-0.56), and genitourinary systems (IRR: 0.49, 95% CI: 0.44-0.53) compared with Caucasians. The incidence rates of ICH (IRR: 3.20, 95% CI: 2.67-3.84) and bleeding from the respiratory system (IRR: 1.28, 95% CI: 1.11-1.47) were higher in East Asians. Notably, East Asians consuming alcohol ≥3 times/week showed a higher incidence of the primary outcome than Caucasians (IRR: 1.12, 95% CI: 1.01-1.25).</p><p><strong>Conclusion: </strong> This ecological study revealed significant racial differences in bleeding incidence, influenced by anatomical sites and lifestyle habits, underscoring the need for tailored approaches in bleeding management based on race.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":"842-851"},"PeriodicalIF":5.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11349425/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139742093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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