Thrombosis research最新文献_第6页

Investigating the Optimal Time of Administration of Heparin that will Improve Survival in a Murine Model of Sepsis 研究可提高小鼠败血症模型存活率的肝素最佳给药时间

IF 3.7 3区医学 Q1 HEMATOLOGY

Thrombosis research

Pub Date : 2024-10-01 DOI: 10.1016/j.thromres.2024.109162

Zarafshan Khan , Dhruva J. Dwivedi , Erblin Cani , Angela Bilic , Alessandra Giglia , Brenda Lin , Harman Bhogal , Maggie Chan , Seline May , Tyler Carson , Patricia C. Liaw

引用次数: 0

The role of anticoagulation on the long-term survival of patients with pulmonary arterial hypertension: A meta-analysis of 15 cohort studies 抗凝对肺动脉高压患者长期生存的影响：15项队列研究的荟萃分析。

IF 3.7 3区医学 Q1 HEMATOLOGY

Thrombosis research

Pub Date : 2024-09-29 DOI: 10.1016/j.thromres.2024.109173

Xinwang Chen , Zhenguo Zhai , Lan Lin , Dan Xue , Xiangqi Chen , Hong Zhang , Qiong Lin

Introduction

Anticoagulation was once recommended for patients with pulmonary arterial hypertension (PAH). However, its survival benefit still remained controversial. We performed a meta-analysis to evaluate the effect of anticoagulation on the long-term survival of PAH patients.

Methods

The PubMed, EMBASE, Web of Science, and WanFang electronic database were searched for eligible studies. Pooled hazard ratios (HRs) with 95 % confidence intervals (CIs) were calculated for effect estimate regarding anticoagulation on the survival of PAH patients.

Results

Fifteen cohort studies involving 4266 PAH patients were included. Approximately 45.8 % patients received anticoagulation. The mean follow-up period ranged from 2.1 to 14 years. Anticoagulation had a tendency to, however, did not significantly reduce mortality of PAH patients (HR: 0.86, 95 % CI: 0.73–1.02). In subgroup analysis, anticoagulation decreased the mortality risk as analyzed from retrospective studies (HR: 0.80, 95 % CI: 0.65–0.98), but not prospective studies (HR: 0.95, 95 % CI: 0.70–1.29). For both idiopathic PAH (IPAH) and connective tissue disease associated PAH (CTD-PAH), anticoagulation therapy did not significantly improve the long-term survival rate (HR: 0.83, 95 % CI: 0.65–1.07, and HR: 1.05, 95 % CI: 0.77–1.42, respectively), and this result remained unchanged when pooling data from either retrospective or prospective studies. Further analysis showed that anticoagulation had no advantage in reducing mortality in patients with systemic sclerosis associated PAH, systemic erythematosus lupus related PAH (free of antiphospholipid syndrome), or CTD-PAH of non-specified etiology.

Conclusion

Anticoagulation may not reduce the long-term mortality of PAH patients, including those with IPAH and CTD-PAH. In the management of PAH, anticoagulants should be prescribed with caution before comprehensive risk to benefit evaluation. Larger and more vigorously designed controlled trials are warranted.

导言：抗凝疗法曾一度被推荐用于肺动脉高压（PAH）患者。然而，其对患者生存的益处仍存在争议。我们进行了一项荟萃分析，以评估抗凝对 PAH 患者长期生存的影响：方法：我们在 PubMed、EMBASE、Web of Science 和 WanFang 电子数据库中检索了符合条件的研究。结果：有 15 项队列研究涉及 PAH 患者的长期生存期：共纳入 15 项队列研究，涉及 4266 名 PAH 患者。约 45.8% 的患者接受了抗凝治疗。平均随访时间从 2.1 年到 14 年不等。抗凝有降低 PAH 患者死亡率的趋势，但并不显著（HR：0.86，95% CI：0.73-1.02）。在亚组分析中，根据回顾性研究（HR：0.80，95% CI：0.65-0.98）和前瞻性研究（HR：0.95，95% CI：0.70-1.29）分析，抗凝治疗可降低死亡率风险。对于特发性 PAH（IPAH）和结缔组织病相关 PAH（CTD-PAH），抗凝治疗并不能显著提高长期存活率（HR：0.83，95 % CI：0.65-1.07；HR：1.05，95 % CI：0.77-1.42），当汇总回顾性或前瞻性研究的数据时，这一结果保持不变。进一步的分析表明，抗凝对降低系统性硬化相关性 PAH、系统性红斑狼疮相关性 PAH（无抗磷脂综合征）或病因不明的 CTD-PAH 患者的死亡率没有优势：抗凝治疗可能无法降低 PAH 患者（包括 IPAH 和 CTD-PAH 患者）的长期死亡率。在治疗 PAH 时，应在全面评估风险与获益之前慎用抗凝药物。有必要进行规模更大、设计更严谨的对照试验。

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引用次数: 0

Neutralizing protease Nexin-1 in hemophilia patients on emicizumab improves thrombin generation 使用埃米珠单抗的血友病患者中和蛋白酶 Nexin-1 可改善凝血酶的生成。

IF 3.7 3区医学 Q1 HEMATOLOGY

Thrombosis research

Pub Date : 2024-09-28 DOI: 10.1016/j.thromres.2024.109174

Véronique Arocas , Laurence Venisse , Yacine Boulaftali , Stéphane Loyau , Claire Flaujac , Emmanuelle de Raucourt , Marie-Christine Bouton

引用次数: 0

Hemophilia A: Economic burden, therapeutic advances, and future forecasts in the Middle East and North Africa region 血友病 A：中东和北非地区的经济负担、治疗进展和未来预测。

IF 3.7 3区医学 Q1 HEMATOLOGY

Thrombosis research

Pub Date : 2024-09-28 DOI: 10.1016/j.thromres.2024.109175

Radwa Ahmed Batran , Mohab Kamel , Ayman Bahr , Ahmed Khalil , Mohamed Elsokary

Hemophilia A, a severe hereditary hemorrhagic disorder characterized by a deficiency in blood clotting factors, imposes a significant economic burden on individuals, healthcare systems, and society, with inhibitors exacerbating the socioeconomic impact. The detrimental impact on the quality of life for patients and caregivers, including functional limitations, is particularly pronounced during bleeding episodes and in the presence of inhibitors. The increasing prevalence of Hemophilia A across the MENA region is evident, marked by the approval of various therapies and intensified research and development efforts focusing on treatment innovations. Despite commendable progress in Hemophilia management, challenges persist in providing care for Hemophilia patients in the region. This review aims to shed light on the current landscape, challenges, and market forecasts for Hemophilia A in the MENA region. Additionally, it strives to provide valuable insights for the future, emphasizing the need for clear approaches to ensure comprehensive care for individuals with Hemophilia.

血友病 A 是一种以凝血因子缺乏为特征的严重遗传性出血性疾病，给个人、医疗系统和社会造成了巨大的经济负担，而抑制剂则加剧了对社会经济的影响。对患者和护理人员生活质量的不利影响（包括功能限制）在出血发作期间和出现抑制剂时尤为明显。中东和北非地区的甲型血友病发病率明显上升，这主要得益于各种疗法的批准和以治疗创新为重点的研发工作的加强。尽管在血友病治疗方面取得了值得称道的进展，但该地区在为血友病患者提供治疗方面仍面临挑战。本综述旨在阐明中东和北非地区 A 型血友病的现状、挑战和市场预测。此外，它还致力于为未来提供有价值的见解，强调需要明确的方法来确保为血友病患者提供全面的护理。

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引用次数: 0

Limitations of a platelet count-based clinical decision support system to facilitate diagnosis of heparin-induced thrombocytopenia 基于血小板计数的临床决策支持系统在帮助诊断肝素诱导的血小板减少症方面的局限性

IF 3.7 3区医学 Q1 HEMATOLOGY

Thrombosis research

Pub Date : 2024-09-24 DOI: 10.1016/j.thromres.2024.109171

Brian C. Westbrook , Laura J. Taylor , Eric Wallace , Marisa B. Marques , Jori E. May

Heparin-induced thrombocytopenia (HIT) is a rare complication of heparin exposure with potential for significant morbidity and mortality. Early identification and treatment can prevent catastrophic thrombosis. Herein, we report the performance of a platelet count-based clinical decision support system (CDSS) where providers received a notification when a patient had a platelet count decline of ≥50 %. In the 90-day study period, the CDSS sent 302 notifications on 270 patients. Notifications were frequently inappropriate; 25 % had an expected platelet count decline (organ donation, stem cell transplant), an inaccurate count, or no heparin exposure. Patient testing for HIT prompted by the CDSS was not in accordance with best practice guidelines in most circumstances. For example, 36 % had a low probability 4Ts score, while 42 % with an intermediate or high probability 4Ts score were not tested. Due to concern for lack of efficacy, the CDSS was discontinued. Analysis of an 8-month period before and after discontinuation showed a significant decrease in the number of enzyme immunoassays ordered (547 vs. 386) without a change in the number of patients with HIT identified (13 vs. 13) or the rate of thrombosis in those with confirmed HIT (62 % vs. 62 %). In conclusion, a CDSS based on platelet count decline contributed to “alert fatigue” via inappropriate notification and did not improve evidence-based HIT testing. In addition, its removal did not decrease or delay HIT identification. Additional efforts are needed to better define how CDSS can support the rapid diagnosis and appropriate treatment of patients with HIT.

肝素诱导的血小板减少症（HIT）是一种罕见的肝素暴露并发症，可能导致严重的发病率和死亡率。早期识别和治疗可以预防灾难性血栓形成。在本文中，我们报告了基于血小板计数的临床决策支持系统（CDSS）的性能，当患者血小板计数下降≥50%时，医疗服务提供者会收到通知。在 90 天的研究期间，CDSS 向 270 名患者发送了 302 次通知。通知往往不恰当；25%的患者血小板计数下降在意料之中（器官捐献、干细胞移植）、计数不准确或未接触肝素。在大多数情况下，CDSS 提示患者进行 HIT 检测并不符合最佳实践指南。例如，有 36% 的患者的 4Ts 评分为低概率，而 42% 的患者的 4Ts 评分为中概率或高概率，却没有进行检测。由于担心缺乏疗效，CDSS 停止使用。对停用前后 8 个月的分析表明，订购酶免疫测定的数量显著减少（547 对 386），但确定的 HIT 患者人数（13 对 13）或确诊 HIT 患者的血栓形成率（62% 对 62%）均无变化。总之，基于血小板计数下降的 CDSS 通过不适当的通知造成了 "警报疲劳"，并没有改善循证 HIT 检测。此外，取消 CDSS 并没有减少或延迟 HIT 识别。还需要进一步努力，以更好地确定 CDSS 如何支持 HIT 患者的快速诊断和适当治疗。

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引用次数: 0

Prothrombin complex concentrate for direct factor Xa inhibitor-associated bleeding or before urgent surgery 凝血酶原复合物浓缩物用于治疗直接 Xa 因子抑制剂引起的出血或紧急手术前。

IF 3.7 3区医学 Q1 HEMATOLOGY

Thrombosis research

Pub Date : 2024-09-24 DOI: 10.1016/j.thromres.2024.109172

Joseph R. Shaw , Abdulrahman Abdulaziz Almujalli , Yan Xu , Jerrold H. Levy , Sam Schulman , Deborah Siegal , Dar Dowlatshahi , Melanie Tokessy , Hakan Buyukdere , Marc Carrier , Lana A. Castellucci

Introduction

Factor Xa inhibitor (FXaI)-associated bleeding events are common and associated with substantial morbidity. Systematic evaluation of widely available, effective, and affordable FXaI bleed management strategies is needed.

Materials and methods

We conducted a single-center retrospective cohort study of FXaI-treated patients presenting to a tertiary academic medical center from January 2018 to May 2019 who received 25–50 IU/kg 4F-PCC for either FXaI-associated major bleeding or urgent surgery. The primary outcome was hemostatic efficacy, and the safety outcome was the 30-day risk of thromboembolism.

Results

PCC was used to treat FXaI-associated bleeding in 83 cases (79.1 %) and was given before urgent surgery in 22 cases (20.9 %). Sixty-six patients were on apixaban, 38 were on rivaroxaban and one patient was on edoxaban. Intracranial hemorrhage (ICH) and gastrointestinal bleeding accounted for most bleeds (74.7 %). Median interval between last DOAC intake and presentation to triage was 9 h [IQR 5.3–14.8] and median PCC dosing was 40.0 IU/kg [IQR 28.5–46.6]. Forty-two patients (40.0 %) had pre-PCC FXaI levels drawn with median FXaI levels of 114.5 ng/mL [IQR 70.0–175.0]. Effective hemostasis occurred in 66.7 % [95%CI 55.4–76.3] of patients receiving PCC for bleeding and surgical hemostasis was rated as normal in 95.5 % (95%CI 76.5–100.0) for patients having urgent surgery. The 30-day risk of thromboembolism was 7.6 % [95%CI 3.7–14.5] and 22.9 % [95%CI 15.8–31.8] of patients died.

Conclusions

PCC for FXaI-associated bleeding was associated with hemostatic efficacy in two-thirds of patients and thromboembolic events were uncommon. PCC represents a promising treatment strategy for FXaI-associated bleeding.

导言：因子 Xa 抑制剂（FXaI）相关出血事件很常见，且发病率很高。需要对广泛可用、有效且负担得起的 FXaI 出血管理策略进行系统评估：我们开展了一项单中心回顾性队列研究，研究对象为 2018 年 1 月至 2019 年 5 月期间到一家三级学术医疗中心就诊的 FXaI 治疗患者，这些患者因 FXaI 相关大出血或紧急手术而接受了 25-50 IU/kg 4F-PCC 治疗。主要结果是止血效果，安全性结果是30天血栓栓塞风险：83例（79.1%）患者在治疗FXaI相关性出血时使用了PCC，22例（20.9%）患者在紧急手术前使用了PCC。66名患者使用阿哌沙班，38名患者使用利伐沙班，1名患者使用埃多沙班。颅内出血（ICH）和消化道出血占出血的大多数（74.7%）。最后一次服用 DOAC 与就诊到分诊之间的中位间隔为 9 h [IQR 5.3-14.8]，PCC 剂量中位数为 40.0 IU/kg [IQR 28.5-46.6]。42 名患者（40.0%）在 PCC 前提取了 FXaI 水平，中位 FXaI 水平为 114.5 ng/mL [IQR 70.0-175.0]。66.7%[95%CI 55.4-76.3]接受 PCC 治疗的出血患者止血有效，95.5%(95%CI 76.5-100.0)接受紧急手术的患者手术止血正常。30天血栓栓塞风险为7.6% [95%CI 3.7-14.5]，22.9% [95%CI 15.8-31.8]的患者死亡：结论：PCC治疗FXaI相关性出血对三分之二的患者具有止血效果，血栓栓塞事件并不常见。PCC是治疗FXaI相关性出血的一种很有前景的治疗策略。

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引用次数: 0

COVID-19 venous thromboembolism prophylaxis guidelines in pediatrics COVID-19 儿科静脉血栓栓塞预防指南。

IF 3.7 3区医学 Q1 HEMATOLOGY

Thrombosis research

Pub Date : 2024-09-22 DOI: 10.1016/j.thromres.2024.109169

Sara McElroy , Emily Cramer , Lauren Amos

Introduction

SARS-CoV-2 (COVID-19) infection and multisystem inflammatory syndrome in children (MIS-C) are risk factors for venous thromboembolism (VTE). Guidelines for VTE prophylaxis were established at our institution at the beginning of the pandemic. Patients who had any VTE risk factors in addition to COVID-19 met criteria for anticoagulation prophylaxis. Patients who were diagnosed with MIS-C met criteria regardless of additional risk factors.

Materials and methods

We conducted a retrospective review of patients admitted with COVID-19 or MIS-C to determine compliance with VTE prophylaxis guidelines and to evaluate the incidence of VTE and bleeding events in our population.

Results and conclusions

Among a total of 678 patients admitted with COVID-19 or MIS-C, 519 (76 %) patients met criteria for VTE prophylaxis and 348 (65.6 %) started prophylaxis. Logistic regression analysis identified a personal or family history of thrombosis or thrombophilia, diagnosis of MIS-C, admission to the intensive care unit, and presence of a central venous catheter as significantly associated with starting VTE prophylaxis. There were 18 patients who developed VTE. Minor bleeding events occurred in 19 patients (5 %), patient important bleeding, no intervention occurred in 8 patients (2 %), clinically relevant nonmajor bleeding in 8 patients (2 %), and major bleeding in 10 patients (3 %). The incidence of VTE in our patients with COVID-19 and MIS-C is similar to VTE rates at other institutions. We found that universally recognized VTE risk factors were appropriate to include as risk factors for thrombosis in hospitalized children with COVID-19 and MIS-C.

导言：SARS-CoV-2（COVID-19）感染和儿童多系统炎症综合征（MIS-C）是导致静脉血栓栓塞（VTE）的危险因素。我院在大流行之初就制定了 VTE 预防指南。除 COVID-19 外，具有任何 VTE 危险因素的患者都符合抗凝预防标准。确诊为 MIS-C 的患者无论是否存在其他风险因素均符合标准：我们对因COVID-19或MIS-C入院的患者进行了回顾性研究，以确定患者是否符合VTE预防指南，并评估我们人群中VTE和出血事件的发生率：在678名接受COVID-19或MIS-C治疗的患者中，519名（76%）患者符合VTE预防标准，348名（65.6%）患者开始接受预防治疗。逻辑回归分析表明，个人或家族血栓病史或血栓性疾病史、MIS-C 诊断、入住重症监护室和使用中心静脉导管与开始预防 VTE 有显著相关性。共有 18 名患者发生了 VTE。19名患者（5%）发生了轻微出血事件，8名患者（2%）发生了对患者有重要影响的出血，未采取任何干预措施，8名患者（2%）发生了与临床相关的非大出血，10名患者（3%）发生了大出血。我们的 COVID-19 和 MIS-C 患者的 VTE 发生率与其他机构的 VTE 发生率相似。我们发现，公认的 VTE 危险因素适合作为 COVID-19 和 MIS-C 住院患儿血栓形成的危险因素。

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引用次数: 0

Evolving patterns of intracranial hemorrhage in advanced therapies in patients with acute pulmonary embolism 急性肺栓塞患者颅内出血在先进疗法中的演变模式

IF 3.7 3区医学 Q1 HEMATOLOGY

Thrombosis research

Pub Date : 2024-09-21 DOI: 10.1016/j.thromres.2024.109168

Konstantinos C. Christodoulou , Katharina Mohr , Timo Uphaus , Max Jägersberg , Luca Valerio , Ioannis T. Farmakis , Thomas Münzel , Philipp Lurz , Stavros V. Konstantinides , Lukas Hobohm , Karsten Keller

Background

Dissecting trends and contributing risk factors for intracranial hemorrhage (ICH) in patients treated for acute pulmonary embolism (PE) may allow for a better patient selection for existing and emerging treatment options.

Methods

The German nationwide inpatient sample was screened for patients admitted due to PE 2005–2020. Hospitalizations were stratified for the occurrence of ICH; risk factors for ICH and temporal trends were investigated.

Results

Overall, 816,653 hospitalizations due to acute PE in the period 2005–2020 were analyzed in the study. ICH was reported in 2516 (0.3 %) hospitalizations, and time trend analysis revealed a fluctuating but overall, largely unchanged annual incidence. There was an increase of ICH with age. Patients with ICH had a higher comorbidity burden (Charlson-Comorbidity-Index [CCI], 5.0 [4.0–7.0] vs. 4.0 [2.0–5.0]; P < 0.001), and higher CCI was associated with an OR of 1.26 (95%CI 1.24–1.27) for ICH. Further independent risk factors for ICH were age ≥ 70 years (OR 1.23 [1.12–1.34]), severe (versus low-risk) PE (OR 3.09 [2.84–3.35]), surgery (OR 1.59 [1.47–1.72]), acute kidney injury (OR 3.60 [3.09–4.18]), and ischemic stroke (OR 14.64 [12.61–17.00]). The identified risk factors for ICH varied among different reperfusion treatment groups. As expected, ICH had a substantial impact on case-fatality of PE (OR 6.16 [5.64–6.72]; P < 0.001).

Conclusions

Incidence of ICH in patients hospitalized for acute PE in Germany was overall low and depended on the patients' comorbidity burden. Identifying patients at risk for ICH allows tailored patient selection for the different reperfusion treatments and might prevent ICH.

背景剖析急性肺栓塞（PE）患者颅内出血（ICH）的趋势和诱发风险因素，可以为现有和新出现的治疗方案提供更好的患者选择。研究对 2005-2020 年期间因急性 PE 住院的 816,653 例患者进行了分析。时间趋势分析显示，每年的发病率虽有波动，但总体上基本保持不变。随着年龄的增长，ICH的发病率也在增加。ICH 患者的合并症负担较重（Charlson-Comorbidity-Index [CCI]，5.0 [4.0-7.0] vs. 4.0 [2.0-5.0]；P < 0.001），较高的 CCI 与 ICH 的 OR 值 1.26（95%CI 1.24-1.27）相关。ICH 的其他独立危险因素包括年龄≥ 70 岁（OR 1.23 [1.12-1.34]）、重度（相对于低风险）PE（OR 3.09 [2.84-3.35]）、手术（OR 1.59 [1.47-1.72]）、急性肾损伤（OR 3.60 [3.09-4.18]）和缺血性卒中（OR 14.64 [12.61-17.00]）。在不同的再灌注治疗组中，已确定的 ICH 风险因素各不相同。正如预期的那样，ICH 对 PE 的病死率有很大影响（OR 6.16 [5.64-6.72]; P < 0.001）。识别有 ICH 风险的患者可为不同的再灌注治疗选择量身定制的患者，并可预防 ICH。

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引用次数: 0

The hemostatic system in chronic brain diseases: A new challenging frontier? 慢性脑部疾病中的止血系统：具有挑战性的新领域？

IF 3.7 3区医学 Q1 HEMATOLOGY

Thrombosis research

Pub Date : 2024-09-17 DOI: 10.1016/j.thromres.2024.109154

Mathias Chea , Sylvie Bouvier , Jean-Christophe Gris

Neurological diseases (ND), including neurodegenerative diseases (NDD) and psychiatric disorders (PD), present a significant public health challenge, ranking third in Europe for disability and premature death, following cardiovascular diseases and cancers. In 2017, approximately 540 million cases of ND were reported among Europe's 925 million people, with strokes, dementia, and headaches being most prevalent. Nowadays, more and more evidence highlight the hemostasis critical role in cerebral homeostasis and vascular events. Indeed, hemostasis, thrombosis, and brain abnormalities contributing to ND form a complex and poorly understood equilibrium. Alterations in vascular biology, particularly involving the blood-brain barrier, are implicated in ND, especially dementia, and PD. While the roles of key coagulation players such as thrombin and fibrinogen are established, the roles of other hemostasis components are less clear. Moreover, the involvement of these elements in psychiatric disease pathogenesis is virtually unstudied, except in specific pathological models such as antiphospholipid syndrome. Advanced imaging techniques, primarily functional magnetic resonance imaging and its derivatives like diffusion tensor imaging, have been developed to study brain areas affected by ND and to improve our understanding of the pathophysiology of these diseases. This literature review aims to clarify the current understanding of the connections between hemostasis, thrombosis, and neurological diseases, as well as explore potential future diagnostic and therapeutic strategies.

神经系统疾病（ND），包括神经退行性疾病（NDD）和精神障碍（PD），是一项重大的公共卫生挑战，其致残率和过早死亡率在欧洲排名第三，仅次于心血管疾病和癌症。2017 年，欧洲 9.25 亿人口中约有 5.4 亿例 ND 病例，其中中风、痴呆和头痛最为常见。如今，越来越多的证据凸显了止血在大脑稳态和血管事件中的关键作用。事实上，止血、血栓形成和导致 ND 的大脑异常形成了一种复杂而又鲜为人知的平衡。血管生物学的改变，尤其是涉及血脑屏障的改变，与 ND（尤其是痴呆症）和帕金森病有牵连。虽然凝血酶和纤维蛋白原等关键凝血成分的作用已经确定，但其他止血成分的作用却不太明确。此外，除了在抗磷脂综合征等特定病理模型中，这些因素在精神疾病发病机制中的参与几乎没有研究。先进的成像技术，主要是功能性磁共振成像及其衍生物（如弥散张量成像），已被用于研究受 ND 影响的大脑区域，并提高我们对这些疾病的病理生理学的认识。本文献综述旨在阐明目前对止血、血栓形成和神经系统疾病之间联系的理解，并探讨未来潜在的诊断和治疗策略。

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引用次数: 0

Regulation of macrophage fibrinolysis during venous thrombus resolution 静脉血栓溶解过程中巨噬细胞纤维蛋白溶解的调节作用

IF 3.7 3区医学 Q1 HEMATOLOGY

Thrombosis research

Pub Date : 2024-09-14 DOI: 10.1016/j.thromres.2024.109149

Tierra A. Johnson , Subhradip Mukhopadhyay , Marguerite S. Buzza , Jacob A. Brooks , Rajabrata Sarkar , Toni M. Antalis

Background

Venous thromboembolism (VTE), which includes pulmonary embolism (PE) and deep vein thrombosis (DVT), is a serious cardiovascular disease with significant mortality and morbidity. Clinically, patients with faster resolution of a venous thrombi have improved prognosis. Urokinase-plasminogen activator (uPA), produced by macrophages, is a key mediator of fibrinolysis required for resolving venous thrombi and restoring vascular integrity. The major macrophage protein, plasminogen activator inhibitor type-2 (PAI-2), was originally identified as an inhibitor of uPA and is implicated in the modulation of pathways affecting fibrinolytic uPA activity, however its direct role in blocking uPA-mediated clot lysis is not known.

Objective

To determine the contribution of macrophage PAI-2 in inhibiting uPA-mediated fibrinolysis during resolution of DVT.

Methods

Using a murine model of venous thrombosis and resolution, we determined histological changes and molecular features of fibrin degradation in venous thrombi from WT mice and mice genetically deficient in PAI-2 and PAI-1, and determined the fibrinolytic activities of macrophages from these genotypes ex vivo.

Results

Acceleration of venous thrombus resolution by PAI-2^−/− mice increases fibrin degradation in venous thrombi showing a pattern similar to genetic deficiency of PAI-1, the major attenuator of fibrinolysis. PAI-2 deficiency was not associated with increased macrophage infiltration into thrombi or changes in macrophage PAI-1 expression. uPA-initiated fibrinolysis by macrophages in vitro could be accelerated by PAI-1 deficiency, but not PAI-2 deficiency.

Conclusion

PAI-2 has an alternate anti-fibrinolytic activity that is macrophage uPA independent, where PAI-1 is the dominant uPA inhibitor during DVT resolution.

背景静脉血栓栓塞症（VTE）包括肺栓塞（PE）和深静脉血栓形成（DVT），是一种严重的心血管疾病，死亡率和发病率都很高。在临床上，静脉血栓消退较快的患者预后较好。由巨噬细胞产生的尿激酶-浆肌酶原激活剂（uPA）是溶解静脉血栓和恢复血管完整性所需的纤维蛋白溶解的关键介质。巨噬细胞的主要蛋白plasminogen activator inhibitor type-2 (PAI-2)最初被确认为uPA的抑制剂，并与影响纤溶uPA活性的途径的调节有关，但其在阻断uPA介导的血栓溶解中的直接作用尚不清楚。方法利用小鼠静脉血栓形成和溶解模型，测定 WT 小鼠和 PAI-2 和 PAI-1 基因缺陷小鼠静脉血栓中纤维蛋白降解的组织学变化和分子特征，并测定这些基因型小鼠体内外巨噬细胞的纤溶活性。结果PAI-2-/-小鼠静脉血栓溶解速度的加快增加了静脉血栓中纤维蛋白的降解，其模式类似于遗传性 PAI-1 缺乏，而 PAI-1 是纤维蛋白溶解的主要减弱因子。结论 PAI-2 具有独立于巨噬细胞 uPA 的另一种抗纤维蛋白溶解活性，而 PAI-1 是深静脉血栓溶解过程中主要的 uPA 抑制剂。

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引用次数: 0