Research and Practice in Thrombosis and Haemostasis最新文献_第5页

Risk factors for neurologic sequelae in children and adolescents with hemophilia after intracranial hemorrhage 颅内出血后儿童和青少年血友病神经系统后遗症的危险因素

IF 3.4 3区医学 Q2 HEMATOLOGY

Research and Practice in Thrombosis and Haemostasis

Pub Date : 2024-11-01 DOI: 10.1016/j.rpth.2024.102607

Melike Sezgin Evim , Ayşegül Ünüvar , Canan Albayrak , Emine Zengin , Ebru Yılmaz , Zühre Kaya , Nihal Karadaş , Mehtap Ertekin , Hülya Üzel , Gül Nihal Özdemir , Davut Albayrak , Funda Tayfun Küpesiz , Ayşenur Bahadır , Hüseyin Tokgöz , Kamuran Karaman , Barış Yılmaz , Sinan Akbayram , Burçak Tatlı Güneş , Burcu Belen Apak , Can Acıpayam , Hale Ören

Background

Intracranial hemorrhage (ICH) is reportedly rare but has high morbidity and mortality risk in persons with hemophilia. Although the risk factors that facilitate bleeding are known, the factors affecting the sequelae are not well known.

Objectives

We planned to investigate the risk factors for neurologic sequelae in children and adolescents with hemophilia suffering from ICH.

Methods

An invitation was sent to pediatric hematology centers via email. Clinical and laboratory findings, neurologic sequelae, and recurrence of bleeding in persons with hemophilia who developed ICH were questioned.

Results

Eighty-six patients from 21 centers were evaluated. All patients were less than 18 years of age at the time of ICH. Thirteen patients had ICH in the neonatal period, while 40 patients had a known diagnosis of hemophilia before ICH, and 33 patients were undiagnosed before ICH. Five patients died, 2 of whom died in the neonatal period. The rate of neurologic sequelae was 25 of 81 (30%). The most common neurologic sequela was epilepsy (n = 11/25), followed by hemiparesis (n = 5/25). Cerebral shift (odds ratio, 3.48) and development of ICH in the neonatal period (odds ratio, 4.67) were significant for the development of neurologic sequelae in multivariate analysis. On follow-up, recurrence of ICH occurred in 8 of 81 (10%).

Conclusion

ICH in the neonatal period and cerebral shift were the two main risk factors for the development of neurologic sequelae. Neonatal departments must be alert to the signs of bleeding. It is important for healthcare professionals to overcome the barriers to primary prophylaxis and to take trauma-related precautions.

背景：据报道，颅内出血（ICH）在血友病患者中很少见，但有很高的发病率和死亡率。虽然已知促进出血的危险因素，但影响后遗症的因素尚不清楚。目的探讨儿童和青少年血友病脑出血患者神经系统后遗症的危险因素。方法通过电子邮件向儿童血液学中心发送邀请函。对发展为脑出血的血友病患者的临床和实验室结果、神经系统后遗症和出血复发进行了质疑。结果共对21个中心的86例患者进行了评估。所有患者发生脑出血时年龄均小于18岁。13例患者在新生儿期发生脑出血，40例患者在脑出血前已确诊为血友病，33例患者在脑出血前未确诊。5例死亡，其中2例死于新生儿期。神经系统后遗症发生率为25 / 81（30%）。最常见的神经系统后遗症是癫痫（n = 11/25），其次是偏瘫（n = 5/25）。多因素分析显示，新生儿期脑移（优势比为3.48）和脑出血的发生（优势比为4.67）对神经系统后遗症的发生有显著影响。在随访中，81例脑出血患者中有8例（10%）复发。结论新生儿期脑出血和脑移位是神经系统后遗症发生的两个主要危险因素。新生儿科必须警惕出血的迹象。对于医疗保健专业人员来说，克服初级预防的障碍并采取与创伤有关的预防措施是很重要的。

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引用次数: 0

Complex immunogenicity assessment in caplacizumab-treated patients with immune-mediated thrombotic thrombocytopenic purpura who have received plasma exchange 接受血浆置换的卡哌珠单抗治疗的免疫介导的血栓性血小板减少性紫癜患者的复杂免疫原性评估

IF 3.4 3区医学 Q2 HEMATOLOGY

Research and Practice in Thrombosis and Haemostasis

Pub Date : 2024-11-01 DOI: 10.1016/j.rpth.2024.102620

Brendy Van Butsel , Maria Laura Sargentini-Maier , Ana Paula Marques , Yana Vandenbossche , Gabriela Marcheva , Sriya Gunawardena , Samuel Pine

Background

International Society on Thrombosis and Haemostasis guidelines for immune-mediated thrombotic thrombocytopenic purpura (iTTP) treatment recommend concurrent therapeutic plasma exchange (TPE), immunosuppressive therapy (IST), and caplacizumab. TPE can complicate antidrug antibody (ADA) measurements by transferring pre-existing antibodies (pre-Abs) into patients via donor plasma and/or diluting treatment-emergent (TE) ADAs.

Objectives

To assess the presence of ADAs in patients with iTTP who received caplacizumab.

Methods

Immunogenicity data from patients with iTTP receiving caplacizumab once daily plus TPE/immunosuppressive therapy in 4 clinical trials (TITAN, HERCULES, Post-HERCULES, and a trial conducted in Japanese patients) in the clinical development program were analyzed. ADA and modified ADA assays differentiated pre-Abs from TE ADAs. A functional neutralizing antibody (NAb) assay and a neutralizing epitope characterization assay (NECA) assessed the presence of ADAs with neutralizing potential. The impact of ADAs on efficacy, pharmacokinetics/pharmacodynamics, and safety was evaluated.

Results

Among 228 patients in 4 studies, prevalence of pre-Abs ranged from 17.1% (TITAN) to 56.7% (HERCULES), while TE ADA prevalence ranged from 3.1% (HERCULES) to 14.3% (Japanese study). The TE NAb-positive rate ranged from 0% (Japanese study) to 12% (Post-HERCULES) using the functional NAb assay and from 2.7% (Post- HERCULES) to 14.3% (Japanese study) using the NECA. The presence of these antibodies did not impact treatment efficacy or safety.

Conclusion

A complex immunogenicity assay strategy was required to define the pre-Ab/TE ADA status of patients with iTTP treated with caplacizumab in a clinical trial setting. In addition to the wide range of pre-Abs observed, few patients had detectable TE ADAs or NAbs, neither of which affected efficacy/safety.

国际血栓形成和止血学会免疫介导的血栓性血小板减少性紫癜（iTTP）治疗指南推荐同步治疗血浆置换（TPE）、免疫抑制治疗（IST）和卡帕单抗。TPE通过供体血浆将预先存在的抗体（pre-Abs）转移到患者体内和/或稀释治疗产生的（TE） ADAs，从而使抗药抗体（ADA）的测量复杂化。目的评估接受卡普拉珠单抗治疗的iTTP患者中ADAs的存在。方法分析iTTP患者在4项临床试验（TITAN、HERCULES、Post-HERCULES和一项日本患者试验）中接受每日1次卡帕珠单抗加TPE/免疫抑制治疗的免疫原性数据。ADA和改良的ADA检测将pre-Abs与TE - ADA区分开来。功能性中和抗体（NAb）测定和中和表位表征测定（NECA）评估具有中和电位的ADAs的存在。评估ADAs对疗效、药代动力学/药效学和安全性的影响。结果在4项研究的228例患者中，预抗体的患病率从17.1% （TITAN）到56.7% （HERCULES）不等，而TE ADA的患病率从3.1% （HERCULES）到14.3%（日本研究）不等。使用功能性NAb检测，TE NAb阳性率从0%（日本研究）到12% （HERCULES后），使用NECA检测，TE NAb阳性率从2.7% （HERCULES后）到14.3%（日本研究）。这些抗体的存在不影响治疗的有效性和安全性。结论：在临床试验中，需要一种复杂的免疫原性检测策略来确定使用卡普拉珠单抗治疗的iTTP患者的ab /TE前ADA状态。除了观察到广泛的预抗体外，很少有患者检测到TE ADAs或nab，这两者都不影响疗效/安全性。

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引用次数: 0

The influence of severity of hemophilia on bone mineral density and fracture risk 血友病严重程度对骨密度及骨折风险的影响

IF 3.4 3区医学 Q2 HEMATOLOGY

Research and Practice in Thrombosis and Haemostasis

Pub Date : 2024-11-01 DOI: 10.1016/j.rpth.2024.102624

Pia Ransmann , Jamil Hmida , Marius Brühl , Frank Alexander Schildberg , Georg Goldmann , Johannes Oldenburg , Max Jaenisch , Fabian Tomschi , Thomas Hilberg , Andreas Christian Strauss

Background

Evidence states that persons with hemophilia are frequently affected by low bone mineral density (BMD). Data assessing the relationship between severity of hemophilia and occurrence of osteoporosis are lacking.

Objectives

This prospective cohort study aimed to assess the impact of hemophilia severity on BMD and to investigate trabecular bone score (TBS) and fracture risk (FRAX).

Methods

This prospective cohort study evaluated the BMD, TBS, and FRAX in 255 persons with hemophilia using dual x-ray absorptiometry. The International Society for Clinical Densitometry guidelines were used for classification: osteoporosis (T-score <−2.5), osteopenia (T-score <−1.0), normal (T-score >−1.0). Patients younger than 50 years of age with a Z-score of <−2.0 were considered below the expected range for age.

Results

Of 255 persons with hemophilia (mild: n = 52, moderate: n = 53, severe: n = 150) aged 43 ± 15 years (mean ± SD), 63.1% showed reduced BMD. Even 11.9% of persons with hemophilia aged <50 years were classified as below the expected range for age. Neck BMD decreased linearly with severity (mild: 0.907 ± 0.229, moderate: 0.867 ± 0.131, severe: 0.799 ± 0.143; P = .01). TBS was classified as “normal” in n = 178 (81.3%) with a mean value of 1.403 ± 0.136, and there were no differences between severity levels (P = .54). The FRAX was 4.4% ± 3.0%. After adjustment of TBS, it was 2.8% ± 3.7%.

Conclusion

The present study shows that BMD is decreased in 63.1% of persons with hemophilia also depending on the severity of hemophilia. However, the largely normal TBS implies that the microarchitecture of the bone does not seem to be affected. It is recommended to include osteoporosis screening, including TBS analysis, in the comprehensive diagnostic work-up of persons with hemophilia, especially as they age.

背景：有证据表明血友病患者经常受到低骨密度（BMD）的影响。评估血友病严重程度与骨质疏松症发生之间关系的数据缺乏。目的：本前瞻性队列研究旨在评估血友病严重程度对骨密度的影响，并调查骨小梁评分（TBS）和骨折风险（FRAX）。方法采用双x线吸收仪对255例血友病患者的骨密度、TBS和FRAX进行了前瞻性队列研究。采用国际临床密度测定学会指南进行分类：骨质疏松症（T-score < - 2.5）、骨质减少症（T-score < - 1.0）、正常（T-score > - 1.0）。年龄小于50岁且z评分为<；−2.0的患者被认为低于年龄的预期范围。结果255例血友病患者（轻度52例，中度53例，重度150例），年龄43±15岁（平均±SD），骨密度降低63.1%。甚至11.9%的50岁血友病患者被归类为低于预期年龄范围。颈部骨密度随严重程度呈线性下降(轻度：0.907±0.229，中度：0.867±0.131，重度：0.799±0.143；P = 0.01)。n = 178（81.3%）例TBS归为“正常”，平均值为1.403±0.136，严重程度之间无差异（P = 0.54）。FRAX为4.4%±3.0%。TBS调整后为2.8%±3.7%。结论血友病患者骨密度降低的比例为63.1%，且与血友病严重程度有关。然而，大体正常的TBS意味着骨骼的微结构似乎没有受到影响。建议将骨质疏松筛查，包括TBS分析，纳入血友病患者的综合诊断工作中，特别是随着年龄的增长。

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引用次数: 0

Dependence of clot structure and fibrinolysis on apixaban and clotting activator 阿哌沙班和凝血活化剂对血块结构和纤溶的影响

IF 3.4 3区医学 Q2 HEMATOLOGY

Research and Practice in Thrombosis and Haemostasis

Pub Date : 2024-11-01 DOI: 10.1016/j.rpth.2024.102614

Rebecca A. Risman , Mitali Shroff , Julie Goswami , Valerie Tutwiler

Background

Anticoagulants prevent the formation of potentially fatal blood clots. Apixaban is a direct oral anticoagulant that inhibits factor (F)Xa, thereby impeding the conversion of prothrombin into thrombin and the formation of blood clots. Blood clots are held together by fibrin networks that must be broken down (fibrinolysis) to restore blood flow. Fibrinolysis is initiated when tissue plasminogen activator (tPA) converts plasminogen to plasmin, which binds to and degrades a fibrin fiber. The effects of apixaban on clot structure and lysis have been incompletely studied.

Objectives

We aimed to study apixaban effects on clot structure, kinetics, and fibrinolysis using thrombin (low or high concentration) or tissue factor (TF) to activate clot formation.

Methods

We used a combination of confocal and scanning electron microscopy and turbidity to analyze the structure, formation kinetics, and susceptibility to lysis when plasma was activated with low concentrations of thrombin, high concentrations of thrombin, or TF in the presence or absence of apixaban.

Results

We found that the clotting activator and apixaban differentially modulated clot structure and lytic potential. Low thrombin clots with apixaban lysed quickly due to a loose network and FXa cleavage product’s cofactor with tPA; high thrombin clots lysed faster due to FXa cleavage product’s cofactor with tPA; TF generated loose clots with restricted lysis due to their activation of thrombin activatable fibrinolytic inhibitor.

Conclusion

Our study elucidates the role of apixaban in fibrinolytic pathways with different clotting activators and can be used for the development of therapeutic strategies using apixaban as a cofactor in fibrinolytic pathways.

背景：抗凝剂可以防止潜在的致命血块的形成。阿哌沙班是一种直接口服抗凝剂，可抑制因子(F)Xa，从而阻碍凝血酶原转化为凝血酶和血栓的形成。血凝块是由纤维蛋白网络连接在一起的，纤维蛋白网络必须被分解（纤维蛋白溶解）才能恢复血液流动。当组织纤溶酶原激活剂（tPA）将纤溶酶原转化为纤溶酶时，纤溶酶溶解开始，纤溶酶原结合并降解纤维蛋白纤维。阿哌沙班对血块结构和溶解的影响尚未完全研究。目的研究阿哌沙班对凝血酶（低或高浓度）或组织因子（TF）激活凝血形成的凝血结构、动力学和纤溶的影响。方法采用共聚焦、扫描电镜和浊度相结合的方法分析血浆在阿哌沙班存在或不存在的情况下，低浓度凝血酶、高浓度凝血酶或TF激活时的结构、形成动力学和溶解敏感性。结果发现凝血活化剂和阿哌沙班对凝血结构和溶血电位有不同的调节作用。阿哌沙班的低凝血酶凝块由于其松散的网络和FXa裂解产物与tPA的辅因子而快速溶解；由于FXa裂解产物与tPA的辅因子，高凝血酶凝块溶解更快；由于凝血酶可激活的纤溶酶抑制剂的激活，TF产生的松散凝块裂解受限。结论本研究阐明了阿哌沙班在不同凝血激活剂的纤溶途径中的作用，可用于开发阿哌沙班作为纤溶途径辅助因子的治疗策略。

{"title":"Dependence of clot structure and fibrinolysis on apixaban and clotting activator","authors":"Rebecca A. Risman , Mitali Shroff , Julie Goswami , Valerie Tutwiler","doi":"10.1016/j.rpth.2024.102614","DOIUrl":"10.1016/j.rpth.2024.102614","url":null,"abstract":"<div><h3>Background</h3><div>Anticoagulants prevent the formation of potentially fatal blood clots. Apixaban is a direct oral anticoagulant that inhibits factor (F)Xa, thereby impeding the conversion of prothrombin into thrombin and the formation of blood clots. Blood clots are held together by fibrin networks that must be broken down (fibrinolysis) to restore blood flow. Fibrinolysis is initiated when tissue plasminogen activator (tPA) converts plasminogen to plasmin, which binds to and degrades a fibrin fiber. The effects of apixaban on clot structure and lysis have been incompletely studied.</div></div><div><h3>Objectives</h3><div>We aimed to study apixaban effects on clot structure, kinetics, and fibrinolysis using thrombin (low or high concentration) or tissue factor (TF) to activate clot formation.</div></div><div><h3>Methods</h3><div>We used a combination of confocal and scanning electron microscopy and turbidity to analyze the structure, formation kinetics, and susceptibility to lysis when plasma was activated with low concentrations of thrombin, high concentrations of thrombin, or TF in the presence or absence of apixaban.</div></div><div><h3>Results</h3><div>We found that the clotting activator and apixaban differentially modulated clot structure and lytic potential. Low thrombin clots with apixaban lysed quickly due to a loose network and FXa cleavage product’s cofactor with tPA; high thrombin clots lysed faster due to FXa cleavage product’s cofactor with tPA; TF generated loose clots with restricted lysis due to their activation of thrombin activatable fibrinolytic inhibitor.</div></div><div><h3>Conclusion</h3><div>Our study elucidates the role of apixaban in fibrinolytic pathways with different clotting activators and can be used for the development of therapeutic strategies using apixaban as a cofactor in fibrinolytic pathways.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"8 8","pages":"Article 102614"},"PeriodicalIF":3.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142748650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Development and internal validation of a simple clinical score for the estimation of the probability of deep vein thrombosis in outpatient emergency department patients. 开发和内部验证的一个简单的临床评分估计的概率深静脉血栓的门诊急诊科患者。

IF 3.4 3区医学 Q2 HEMATOLOGY

Research and Practice in Thrombosis and Haemostasis

Pub Date : 2024-10-29 eCollection Date: 2024-11-01 DOI: 10.1016/j.rpth.2024.102608

Thor-David Halstensen, Camilla Hardeland, Waleed Ghanima, Vigdis Abrahamsen Grøndahl, Aliaksandr Hubin, Mazdak Tavoly

Background: Wells score comprises subjective elements, making physicians reluctant to use Wells score or cause them to use it incorrectly.

Objectives: To develop and internally validate a prediction score that is objective and simple for evaluating suspected deep vein thrombosis (DVT), with a safety comparable with that of Wells score.

Methods: We performed a post hoc analysis using data from the Ri-Schedule study (NCT02486445) involving suspected DVT patients at Østfold Hospital's Emergency Department, Norway (2015-2018). Candidate variables were identified through bootstrapping technique, with a confirmed DVT diagnosis as the outcome variable. Sensitivity, specificity, negative predictive value (NPV), and positive predictive values (PPV) were estimated and compared with the 2-tier Wells score.

Results: Among 1312 patients (median age, 64 years [IQR, 52-73]; 55% women), 19.9% were diagnosed with DVT. Exploration of 30 variables identified tenderness along deep veins and previous venous thromboembolism as significant predictors (selection frequency >60% in 1000 bootstrapping samples). The derived score categorized 450 patients with 0 items as unlikely to have DVT, of whom 8.0% were diagnosed with DVT, compared with 8.2% in DVT unlikely category according to Wells score. Compared with Wells score, the derived score demonstrated sensitivity of 86.2 (95% CI, 81.4-90.2) vs 80.1 (95% CI, 74.7-84.8), specificity of 39.4 (95% CI, 36.4-42.4) vs 55.3 (95% CI, 52.2-58.3), NPV of 92.0 (95% CI, 89.4-94.0) vs 91.8 (95% CI, 89.7-93.5), and PPV of 26.1 (95% CI, 24.8-27.5) vs 30.8 (95% CI, 28.9-32.8). When incorporating D-dimer cutoff of <0.5 µg/mL, the derived score had sensitivity of 99.6 (95% CI, 97.9-99.9), specificity of 16.1 (95% CI, 13.1-18.4), NPV of 99.4 (95% CI, 96.0-99.9), and PPV of 22.8 (95% CI, 22.3-23.3).

Conclusion: The derived DVT score, with 2 objective variables, had a comparable safety with that of the Wells score. However, an external validation is mandated prior to clinical use.

背景：Wells评分包含主观因素，使医生不愿意使用Wells评分或导致其使用错误。目的：开发并内部验证一种客观、简单的评估疑似深静脉血栓形成（DVT）的预测评分，其安全性与Wells评分相当。方法：我们使用Ri-Schedule研究（NCT02486445）的数据进行了事后分析，该研究涉及挪威Østfold医院急诊科（2015-2018）的疑似DVT患者。候选变量通过自举技术确定，以确诊的DVT诊断作为结果变量。评估敏感性、特异性、阴性预测值（NPV）和阳性预测值（PPV），并与2层Wells评分进行比较。结果：1312例患者中位年龄64岁[IQR， 52-73]；55%为女性)，19.9%诊断为深静脉血栓。对30个变量的探索发现，深静脉的压痛和以前的静脉血栓栓塞是重要的预测因素（在1000个自举样本中选择频率为60%）。得出的评分将450名患者分为0项不太可能发生DVT，其中8.0%被诊断为DVT，而根据Wells评分，不太可能发生DVT的患者为8.2%。与Wells评分相比，衍生评分的敏感性为86.2 (95% CI, 81.4-90.2) vs 80.1 (95% CI, 74.7-84.8)，特异性为39.4 (95% CI, 36.4-42.4) vs 55.3 (95% CI, 52.2-58.3)， NPV为92.0 (95% CI, 89.4-94.0) vs 91.8 (95% CI, 89.7-93.5)， PPV为26.1 (95% CI, 24.8-27.5) vs 30.8 （95% CI, 28.9-32.8）。结论：导出的DVT评分具有2个客观变量，其安全性与Wells评分相当。然而，在临床使用之前必须进行外部验证。

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引用次数: 0

Complement-mediated hemolytic uremic syndrome associated with postpartum hemorrhage: case series and systematic review of individual participant data. 补体介导的与产后出血相关的溶血性尿毒症综合征：病例系列和个体参与者数据的系统回顾

IF 3.4 3区医学 Q2 HEMATOLOGY

Research and Practice in Thrombosis and Haemostasis

Pub Date : 2024-10-03 eCollection Date: 2024-11-01 DOI: 10.1016/j.rpth.2024.102579

Anna Gurevich-Shapiro, Sharon Orbach-Zinger, Avi Leader, Galia Stemer, Arnon Wiznitzer, Pierre Singer, Miriam Davidovits, Michael Shapiro, Eva N Hamulyák, Pia Raanani, Galia Spectre

Background: Postpartum hemorrhage is considered a risk factor for pregnancy-associated complement-mediated hemolytic uremic syndrome (CM-HUS; previously known as atypical hemolytic uremic syndrome) but has not been systematically studied.

Objectives: To systematically examine the role of postpartum hemorrhage in precipitating CM-HUS and to describe the characteristics of postpartum hemorrhage-associated CM-HUS, its prognosis and recommended management.

Methods: A systematic review of individual participant data from case series and reports in addition to a case series from our institution. Search terms were "thrombotic microangiopathy," "atypical hemolytic uremic syndrome," and "complement mediated" combined with "pregnancy," "postpartum," and/or "postpartum hemorrhage". Cases of thrombotic microangiopathy other than CM-HUS were excluded. Outcomes were clinical and laboratory characteristics of postpartum hemorrhage-associated CM-HUS, treatment, and outcomes.

Results: Thirty-three studies comprising 48 women with postpartum hemorrhage-associated CM-HUS and 3 patients from our institution were included in the study. Most women presented at term (28/45; 62%), delivered by cesarean section (21/41; 51%), and had pregnancy complications, mainly preeclampsia (16/51; 31%) or fetal demise (9/51; 18%). Hematological and renal abnormalities usually appeared within the first 24 hours postdelivery. The median platelet count was 46 × 10⁹/L (IQR, 26-72), and the median maximal lactate dehydrogenase was 2638 U/L (IQR, 1620-3588). Renal function normalized in 20/23 (87%) women treated with C5 inhibitors with or without plasma exchange; in 7/11 (63%) women treated with plasma exchange alone, but only in 3/17 (18%) patients treated with supportive care. Patients treated with C5 inhibitors and/or plasma exchange achieved significantly better renal outcomes compared with supportive care alone (P < .001).

Conclusion: CM-HUS is a rare complication following postpartum hemorrhage and occurs mainly in women with preeclampsia and/or following cesarean section. Patients treated with C5 inhibitors and/or plasma exchange had a better renal prognosis compared with patients who received supportive treatment alone.

背景：产后出血被认为是妊娠相关补体介导的溶血性尿毒症综合征(CM-HUS；以前称为非典型溶血性尿毒症综合征)，但尚未系统研究。目的：系统探讨产后出血在CM-HUS发病中的作用，探讨产后出血相关CM-HUS的特点、预后及建议的治疗方法。方法：系统回顾来自病例系列和报告的个体参与者数据，以及我们机构的病例系列。搜索词是“血栓性微血管病”、“非典型溶血性尿毒症综合征”和“补体介导”合并“妊娠”、“产后”和/或“产后出血”。排除CM-HUS以外的血栓性微血管病变病例。结果是产后出血相关cm -溶血性尿毒综合征的临床和实验室特征、治疗和结果。结果：共纳入33项研究，包括48名产后出血相关CM-HUS患者和我院3名患者。大多数妇女在足月出现(28/45；62%)，剖宫产分娩(21/41；51%)，并有妊娠并发症，主要为子痫前期(16/51；31%)或胎儿死亡(9/51；18%)。血液学和肾脏异常通常在产后24小时内出现。血小板计数中位数为46 × 109/L (IQR, 26-72)，乳酸脱氢酶中位数最大值为2638 U/L （IQR, 1620-3588）。有20/23（87%）的女性接受C5抑制剂治疗伴或不伴血浆置换后肾功能恢复正常；7/11（63%）的女性单独接受血浆置换治疗，而只有3/17（18%）的患者接受支持性治疗。与单纯支持治疗相比，接受C5抑制剂和/或血浆置换治疗的患者获得了明显更好的肾脏预后（P < 0.001）。结论：CM-HUS是一种罕见的产后出血并发症，主要发生在子痫前期和/或剖宫产术后。与单独接受支持治疗的患者相比，接受C5抑制剂和/或血浆置换治疗的患者具有更好的肾脏预后。

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引用次数: 0

Efficacy and safety of hetrombopag in the treatment of recombinant human thrombopoietin–resistant thrombocytopenia after allogeneic hematopoietic stem cell transplantation 赫曲波帕治疗同种异体造血干细胞移植后重组人血小板生成素抵抗性血小板减少症的有效性和安全性

IF 3.4 3区医学 Q2 HEMATOLOGY

Research and Practice in Thrombosis and Haemostasis

Pub Date : 2024-10-01 DOI: 10.1016/j.rpth.2024.102578

Jing Ni , Jian Hong , Xinglin Liang , Jifei Dai , Zhangbiao Long , ChengXin Luan , Mingzhen Yang , Qingsheng Li

Background

Thrombocytopenia after allogeneic hematopoietic cell transplantation is a challenging clinical problem. Recombinant human thrombopoietin (rhTPO) and thrombopoietin receptor agonists are increasingly used in posttransplant thrombocytopenia. However, the use of hetrombopag in patients with posttransplant thrombocytopenia, especially in patients with resistance to rhTPO, has not yet been reported.

Objectives

The present study aimed to investigate the efficacy and safety of hetrombopag in patients with rhTPO-resistant posttransplant thrombocytopenia.

Methods

This retrospective study included 21 patients with rhTPO-resistant posttransplant thrombocytopenia who received hetrombopag from August 2021 to July 2022. The primary endpoint was the overall response rate, including partial response and complete response (CR). We also evaluated the predictors of hetrombopag efficacy and adverse events.

Results

The overall response rate to hetrombopag was 81%, and the CR rate was 62%. The median time from hetrombopag initiation to response and CR were 16 and 31 days, respectively. Decreased megakaryocytes in bone marrow negatively correlated with CR to hetrombopag (P = .03). All the patients tolerated hetrombopag well without any significant increase in adverse events. At the last follow-up, 71% of responders had discontinued hetrombopag and sustained their best response.

Conclusion

Our results suggested that hetrombopag is an effective treatment option to promote platelet recovery in patients with posttransplant thrombocytopenia, even in patients resistant to rhTPO.

背景异基因造血细胞移植后血小板减少是一个具有挑战性的临床问题。重组人血小板生成素（rhTPO）和血小板生成素受体激动剂越来越多地被用于治疗移植后血小板减少症。方法这项回顾性研究纳入了21例rhTPO耐药的移植后血小板减少症患者，他们在2021年8月至2022年7月期间接受了赫曲波帕治疗。主要终点是总反应率，包括部分反应和完全反应（CR）。我们还评估了赫曲波帕格疗效和不良事件的预测因素。结果赫曲波帕格的总体应答率为81%，CR率为62%。从开始使用赫曲博帕到出现应答和CR的中位时间分别为16天和31天。骨髓中巨核细胞的减少与赫曲波帕的 CR 负相关（P = 0.03）。所有患者都能很好地耐受赫曲波帕，不良反应没有明显增加。结论我们的研究结果表明，希曲波帕是促进移植后血小板减少症患者血小板恢复的有效治疗方案，即使是对 rhTPO 耐药的患者也不例外。

{"title":"Efficacy and safety of hetrombopag in the treatment of recombinant human thrombopoietin–resistant thrombocytopenia after allogeneic hematopoietic stem cell transplantation","authors":"Jing Ni , Jian Hong , Xinglin Liang , Jifei Dai , Zhangbiao Long , ChengXin Luan , Mingzhen Yang , Qingsheng Li","doi":"10.1016/j.rpth.2024.102578","DOIUrl":"10.1016/j.rpth.2024.102578","url":null,"abstract":"<div><h3>Background</h3><div>Thrombocytopenia after allogeneic hematopoietic cell transplantation is a challenging clinical problem. Recombinant human thrombopoietin (rhTPO) and thrombopoietin receptor agonists are increasingly used in posttransplant thrombocytopenia. However, the use of hetrombopag in patients with posttransplant thrombocytopenia, especially in patients with resistance to rhTPO, has not yet been reported.</div></div><div><h3>Objectives</h3><div>The present study aimed to investigate the efficacy and safety of hetrombopag in patients with rhTPO-resistant posttransplant thrombocytopenia.</div></div><div><h3>Methods</h3><div>This retrospective study included 21 patients with rhTPO-resistant posttransplant thrombocytopenia who received hetrombopag from August 2021 to July 2022. The primary endpoint was the overall response rate, including partial response and complete response (CR). We also evaluated the predictors of hetrombopag efficacy and adverse events.</div></div><div><h3>Results</h3><div>The overall response rate to hetrombopag was 81%, and the CR rate was 62%. The median time from hetrombopag initiation to response and CR were 16 and 31 days, respectively. Decreased megakaryocytes in bone marrow negatively correlated with CR to hetrombopag (<em>P</em> = .03). All the patients tolerated hetrombopag well without any significant increase in adverse events. At the last follow-up, 71% of responders had discontinued hetrombopag and sustained their best response.</div></div><div><h3>Conclusion</h3><div>Our results suggested that hetrombopag is an effective treatment option to promote platelet recovery in patients with posttransplant thrombocytopenia, even in patients resistant to rhTPO.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"8 7","pages":"Article 102578"},"PeriodicalIF":3.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142653653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Extracellular vesicle tissue factor and tissue factor pathway inhibitor are independent discriminators of sepsis-induced coagulopathy 细胞外囊泡组织因子和组织因子通路抑制因子是脓毒症诱发凝血病的独立判别指标

IF 3.4 3区医学 Q2 HEMATOLOGY

Research and Practice in Thrombosis and Haemostasis

Pub Date : 2024-10-01 DOI: 10.1016/j.rpth.2024.102596

Anna K. Tobiasch , Georg F. Lehner , Clemens Feistritzer , Andreas Peer , Birgit Zassler , Viktoria M. Neumair , Sebastian J. Klein , Michael Joannidis

Background

Sepsis-induced disseminated intravascular coagulopathy (DIC) remains a challenging clinical entity associated with significant morbidity and mortality. Endothelial injury or activation and extracellular vesicles (EV) are postulated as important determinants of DIC.

Objectives

The aim of this study was to test the discriminatory ability of E-selectin, EV, tissue factor (TF) and TF pathway inhibitor (TFPI) in sepsis-induced coagulopathy.

Methods

In this prospective, single-center study, we collected plasma samples within 24 hours after sepsis diagnosis and followed these patients for 5 consecutive days. Overt DIC was determined by the International Society on Thrombosis and Haemostasis (ISTH) DIC score. Eighty-seven sepsis patients were recruited (35 with overt DIC) who presented with increased levels of EV, EV-associated TF procoagulant activity (TF-PCA), E-selectin, TF, and TFPI at admission compared with healthy subjects.

Results

Only TFPI levels and TF-PCA discriminated between sepsis patients with or without DIC (area under the curve = 0.76; P = .0002). Increased TF-PCA was not sensitive in detecting sepsis-associated DIC; however, levels above 1.38 pg/mL showed high specificity in this cohort (sensitivity 27%, specificity 95%). The hazard ratio to progress to DIC over 5 days was 1.14 (95% CI, 0.64-2.07) for TF-PCA levels of 0.5 pg/mL or higher and 3.18 (95% CI, 1.74-5.79) for TFPI levels of 22.28 ng/mL or higher at admission.

Conclusion

These findings highlight the pivotal roles of TF-PCA and TFPI in an early phase of sepsis-induced DIC. Only EV-associated and functionally active TF and not TF antigen levels showed a predictive potential regarding DIC. These novel results might support the improvement of diagnostic or even therapeutic strategies to mitigate the devastating consequences of DIC in septic patients.

背景溶血诱发的弥散性血管内凝血病（DIC）仍是一种具有挑战性的临床实体，与严重的发病率和死亡率有关。本研究的目的是测试 E-选择素、EV、组织因子（TF）和 TF 通路抑制剂（TFPI）在败血症诱发的凝血病中的鉴别能力。方法在这项前瞻性单中心研究中，我们在败血症确诊后 24 小时内采集血浆样本，并对这些患者进行了连续 5 天的随访。根据国际血栓与止血学会（ISTH）的 DIC 评分确定是否存在明显的 DIC。结果只有TFPI水平和TF-PCA能区分有无DIC的败血症患者（曲线下面积=0.76；P=0.0002）。TF-PCA 的增加对检测脓毒症相关 DIC 不敏感；但在该队列中，TF-PCA 水平超过 1.38 pg/mL 则显示出很高的特异性（敏感性 27%，特异性 95%）。入院时 TF-PCA 水平为 0.5 pg/mL 或更高时，5 天内进展为 DIC 的危险比为 1.14（95% CI，0.64-2.07）；TFPI 水平为 22.28 ng/mL 或更高时，5 天内进展为 DIC 的危险比为 3.18（95% CI，1.74-5.79）。只有 EV 相关和功能活跃的 TF 而非 TF 抗原水平才具有预测 DIC 的潜力。这些新结果可能有助于改进诊断甚至治疗策略，以减轻脓毒症患者 DIC 的破坏性后果。

{"title":"Extracellular vesicle tissue factor and tissue factor pathway inhibitor are independent discriminators of sepsis-induced coagulopathy","authors":"Anna K. Tobiasch , Georg F. Lehner , Clemens Feistritzer , Andreas Peer , Birgit Zassler , Viktoria M. Neumair , Sebastian J. Klein , Michael Joannidis","doi":"10.1016/j.rpth.2024.102596","DOIUrl":"10.1016/j.rpth.2024.102596","url":null,"abstract":"<div><h3>Background</h3><div>Sepsis-induced disseminated intravascular coagulopathy (DIC) remains a challenging clinical entity associated with significant morbidity and mortality. Endothelial injury or activation and extracellular vesicles (EV) are postulated as important determinants of DIC.</div></div><div><h3>Objectives</h3><div>The aim of this study was to test the discriminatory ability of E-selectin, EV, tissue factor (TF) and TF pathway inhibitor (TFPI) in sepsis-induced coagulopathy.</div></div><div><h3>Methods</h3><div>In this prospective, single-center study, we collected plasma samples within 24 hours after sepsis diagnosis and followed these patients for 5 consecutive days. Overt DIC was determined by the International Society on Thrombosis and Haemostasis (ISTH) DIC score. Eighty-seven sepsis patients were recruited (35 with overt DIC) who presented with increased levels of EV, EV-associated TF procoagulant activity (TF-PCA), E-selectin, TF, and TFPI at admission compared with healthy subjects.</div></div><div><h3>Results</h3><div>Only TFPI levels and TF-PCA discriminated between sepsis patients with or without DIC (area under the curve = 0.76; <em>P</em> = .0002). Increased TF-PCA was not sensitive in detecting sepsis-associated DIC; however, levels above 1.38 pg/mL showed high specificity in this cohort (sensitivity 27%, specificity 95%). The hazard ratio to progress to DIC over 5 days was 1.14 (95% CI, 0.64-2.07) for TF-PCA levels of 0.5 pg/mL or higher and 3.18 (95% CI, 1.74-5.79) for TFPI levels of 22.28 ng/mL or higher at admission.</div></div><div><h3>Conclusion</h3><div>These findings highlight the pivotal roles of TF-PCA and TFPI in an early phase of sepsis-induced DIC. Only EV-associated and functionally active TF and not TF antigen levels showed a predictive potential regarding DIC. These novel results might support the improvement of diagnostic or even therapeutic strategies to mitigate the devastating consequences of DIC in septic patients.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"8 7","pages":"Article 102596"},"PeriodicalIF":3.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142654133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Enhanced thrombin and plasmin generation profiles in alpha-2-antiplasmin–deficient patients: Data from the Rare Bleeding disorders in the Netherlands study α-2-抗凝血酶缺乏症患者凝血酶和凝血酶生成谱增强：荷兰罕见出血性疾病研究数据

IF 3.4 3区医学 Q2 HEMATOLOGY

Research and Practice in Thrombosis and Haemostasis

Pub Date : 2024-10-01 DOI: 10.1016/j.rpth.2024.102604

Bauke Haisma , Sanna R. Rijpma , Marjon H. Cnossen , Paul L. den Exter , Ilmar C. Kruis , Karina Meijer , Laurens Nieuwenhuizen , Nick van Es , Roger E.G. Schutgens , Nicole M.A. Blijlevens , Waander L. van Heerde , Saskia E.M. Schols

Background

α2-Antiplasmin (A2AP) deficiency is a rare and often unidentified disorder characterized by increased fibrinolysis and subsequent bleeding. Global hemostasis assays may increase insight into the altered coagulation and fibrinolysis in these patients.

Objectives

To explore thrombin and plasmin generation profiles in A2AP-deficient patients, corresponding A2AP activity levels and associated bleeding phenotypes.

Methods

The Nijmegen hemostasis assay was used to assess thrombin and plasmin generation in 23 A2AP-deficient patients (median age, 50 years; 70% women) from the cross-sectional Rare Bleeding disorders in the Netherlands study. Analyzed parameters included thrombin peak height, thrombin potential, fibrin lysis time, plasmin peak height, plasmin velocity index, and plasmin potential. These parameters were expressed as percentages of a reference obtained from 37 healthy controls (median age, 46 years; 57% women). The Nijmegen hemostasis assay data were correlated with A2AP activity levels and International Society on Thrombosis and Hemostasis Bleeding Assessment Tool scores using Pearson correlation coefficients.

Results

Patients’ A2AP activity levels ranged from 23% to 83% (reference range, 89%-122%). Plasmin generation increased, as evidenced by significantly shorter fibrin lysis times (73%; P < .001) and higher plasmin peak heights (203%; P < .001), plasmin velocity indices (302%; P < .001) and plasmin potentials (154%; P < .001) in A2AP-deficient patients than those in healthy controls. Moreover, significantly higher thrombin potentials (146%; P < .001) and thrombin peak heights (132%; P < .001) were observed. Enhanced plasmin generation parameters showed statistically significant correlations with lower A2AP activity levels and higher International Society on Thrombosis and Hemostasis Bleeding Assessment Tool scores.

Conclusion

A2AP-deficient patients exhibited augmented plasmin generation profiles that correlated with A2AP activity level and bleeding phenotype. Interestingly, increased thrombin generation profiles were also found in these patients.

背景α2-抗凝血酶（A2AP）缺乏症是一种罕见的、通常无法确定的疾病，其特点是纤维蛋白溶解增加和随后的出血。方法采用奈梅亨止血测定法评估荷兰罕见出血疾病横断面研究中 23 名 A2AP 缺乏症患者（中位年龄 50 岁，70% 为女性）的凝血酶和凝血酶生成情况。分析的参数包括凝血酶峰高、凝血酶潜能、纤维蛋白溶解时间、凝血酶峰高、凝血酶速度指数和凝血酶潜能。这些参数表示为从 37 名健康对照者（中位年龄 46 岁；57% 为女性）中获得的参考值的百分比。使用皮尔逊相关系数将奈梅亨止血检测数据与 A2AP 活性水平和国际血栓与止血学会出血评估工具评分相关联。与健康对照组相比，A2AP 缺乏患者的纤维蛋白溶解时间明显缩短（73%；P <；.001），凝血酶峰高（203%；P <；.001）、凝血酶速度指数（302%；P <；.001）和凝血酶潜能值（154%；P <；.001）也更高。此外，还观察到凝血酶电位（146%；P <；.001）和凝血酶峰高（132%；P <；.001）明显升高。增强的凝血酶生成参数与较低的 A2AP 活性水平和较高的国际血栓与止血学会出血评估工具评分有统计学意义的相关性。有趣的是，在这些患者中还发现了凝血酶生成增加的特征。

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引用次数: 0

Bleeding and quality of life in people with Glanzmann thrombasthenia—insights from the Glanzmann’s 360 study 格兰兹曼血栓形成症患者的出血与生活质量--格兰兹曼 360 研究的启示

IF 3.4 3区医学 Q2 HEMATOLOGY

Research and Practice in Thrombosis and Haemostasis

Pub Date : 2024-10-01 DOI: 10.1016/j.rpth.2024.102586

Kate Khair, Simon Fletcher, Matthew Boyton, Michael Holland

Background

Glanzmann thrombasthenia (GT) is a rare platelet function disorder that results in severe bleeding. We assessed clinical symptoms and psychological parameters to identify the unmet needs associated with GT.

Objectives

Glanzmann’s 360 is a mixed-methods study designed to give a contemporary snapshot of the impact of living with GT.

Methods

The study comprised a self-completion online survey complemented by interviews conducted with affected individuals and carers recruited via social media and hemophilia treatment centers.

Results

The survey was completed by 88 people with GT and 29 carers of children/young people with GT aged <16 years. The population ranged in age from <2 years to >70 years; 56% were female. Although 47% had been diagnosed with GT under the age of 2 years, 12% were diagnosed after 20 years of age. For 82%, a bleeding phenotype was apparent by the age of 5 years. Most respondents (88%) had experienced at least one bleed in the past week. Bleeding disproportionally affected women. Bleeds resulted in frequent hospital contact and considerable psychological distress: 26% of the population had scores suggestive of low self-esteem, while 30% met criteria suggestive of symptomatic depression. Exploratory analyses suggest that bleed experiences are associated with impaired health-related quality of life.

Conclusion

The Glanzmann’s 360 study reveals the significant physical, psychosocial, and quality-of-life impairments that are likely to be linked to the frequent bleeds experienced by those with GT. Clinicians treating people with GT should promote access to multidisciplinary comprehensive care, including psychosocial support.

背景格兰兹曼血栓形成症（GT）是一种罕见的血小板功能失调症，可导致严重出血。我们对临床症状和心理参数进行了评估，以确定与 GT 相关的未满足的需求。Glanzmann's 360 是一项混合方法研究，旨在提供有关 GT 患者生活影响的当代快照。调查对象的年龄从 2 岁到 70 岁不等；56% 为女性。47%的患者在2岁以下被诊断出患有GT，12%的患者在20岁以后才被诊断出患有GT。82%的受访者在 5 岁前就已出现出血表型。大多数受访者（88%）在过去一周内至少经历过一次出血。出血对女性的影响尤为严重。出血导致她们经常去医院就诊，并承受着巨大的心理压力：26%的人有自卑感，30%的人符合症状性抑郁的标准。探索性分析表明，出血经历与健康相关的生活质量受损有关。结论格兰兹曼 360 研究揭示了 GT 患者频繁出血可能带来的严重身体、心理和生活质量损害。治疗 GT 患者的临床医生应促进患者获得多学科综合治疗，包括心理支持。

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引用次数: 0