Pub Date : 2025-02-01DOI: 10.1016/j.bvth.2024.100039
Tong Li , Colleen Hadigan , Jaeil Ahn , Chinmayee Mehta , Makheni Jean Pierre , Danial Mahmood , Metin Ozdemirli , Cooper James , Princy Kumar , Marta Catalfamo
{"title":"Chronic endothelial inflammation in PWH leads to reduced circulating megakaryocyte progenitor cells","authors":"Tong Li , Colleen Hadigan , Jaeil Ahn , Chinmayee Mehta , Makheni Jean Pierre , Danial Mahmood , Metin Ozdemirli , Cooper James , Princy Kumar , Marta Catalfamo","doi":"10.1016/j.bvth.2024.100039","DOIUrl":"10.1016/j.bvth.2024.100039","url":null,"abstract":"","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"2 1","pages":"Article 100039"},"PeriodicalIF":0.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143093753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.bvth.2024.100037
Biao Xiang ∗ , Yaoming Wang ∗ , Ruslan Rust , Kassandra Kisler , William J. Mack , José A. Fernández , Berislav V. Zlokovic † , John H. Griffin †
Abstract
The protease activated protein C (APC) and its variants provide neuroprotection for murine ischemic stroke and mortality reduction for murine sepsis. For these actions, APC’s in vivo mechanism of action, similar to in vitro studies using cultured cells, involves protease activated receptor 1 (PAR1)–mediated biased signaling. APC/PAR1 signaling in vitro requires β-arrestin 2, an intracellular scaffold protein, and β-arrestin 2–initiated signaling can alter diverse intracellular signaling pathways. This study used a proximal transient middle cerebral artery occlusion model to study the neuroprotective actions of the signaling-selective APC variant, 3K3A-APC, in β-arrestin 2–deficient (Arrb2–/–) mice. Based on quantitation of brain injuries, 3K3A-APC significantly limited brain injury in control mice to relatively small, localized areas, whereas 3K3A-APC’s protection was lost in Arrb2–/– mice. Thus, the major in vitro mechanism of action that requires β-arrestin 2 for APC/PAR1 biased signaling is central to the in vivo mechanism of action for APC’s neuroprotection.
{"title":"In vivo neuroprotection in ischemic stroke by activated protein C requires β-arrestin 2","authors":"Biao Xiang ∗ , Yaoming Wang ∗ , Ruslan Rust , Kassandra Kisler , William J. Mack , José A. Fernández , Berislav V. Zlokovic † , John H. Griffin †","doi":"10.1016/j.bvth.2024.100037","DOIUrl":"10.1016/j.bvth.2024.100037","url":null,"abstract":"<div><h3>Abstract</h3><div>The protease activated protein C (APC) and its variants provide neuroprotection for murine ischemic stroke and mortality reduction for murine sepsis. For these actions, APC’s in vivo mechanism of action, similar to in vitro studies using cultured cells, involves protease activated receptor 1 (PAR1)–mediated biased signaling. APC/PAR1 signaling in vitro requires β-arrestin 2, an intracellular scaffold protein, and β-arrestin 2–initiated signaling can alter diverse intracellular signaling pathways. This study used a proximal transient middle cerebral artery occlusion model to study the neuroprotective actions of the signaling-selective APC variant, 3K3A-APC, in β-arrestin 2–deficient (<em>Arrb2</em><sup>–/–</sup>) mice. Based on quantitation of brain injuries, 3K3A-APC significantly limited brain injury in control mice to relatively small, localized areas, whereas 3K3A-APC’s protection was lost in <em>Arrb2</em><sup>–/–</sup> mice. Thus, the major in vitro mechanism of action that requires β-arrestin 2 for APC/PAR1 biased signaling is central to the in vivo mechanism of action for APC’s neuroprotection.</div></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"2 1","pages":"Article 100037"},"PeriodicalIF":0.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143093755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-08DOI: 10.1016/j.bvth.2024.100031
Anuranita Gupta , Barbara D. Lam , Sabrina Zerbey , Rachel P. Rosovsky , Leslie Lake , Laura Dodge , Alys Adamski , Nimia Reyes , Karon Abe , Ioannis Vlachos , Jeffrey I. Zwicker , Mara A. Schonberg , Rushad Patell
{"title":"Artificial intelligence meets venous thromboembolism: informaticians’ insights on diagnosis, prevention, and management","authors":"Anuranita Gupta , Barbara D. Lam , Sabrina Zerbey , Rachel P. Rosovsky , Leslie Lake , Laura Dodge , Alys Adamski , Nimia Reyes , Karon Abe , Ioannis Vlachos , Jeffrey I. Zwicker , Mara A. Schonberg , Rushad Patell","doi":"10.1016/j.bvth.2024.100031","DOIUrl":"10.1016/j.bvth.2024.100031","url":null,"abstract":"","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"1 4","pages":"Article 100031"},"PeriodicalIF":0.0,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142592772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Acquired hemophilia A (AHA) is a rare and potentially fatal bleeding disorder. Although bypassing agents effectively control active bleeding, their disadvantages, such as high cost and frequent administration, necessitate an agent that prevents recurrent bleeding events requiring bypassing agents. Emicizumab, a recombinant, humanized, bispecific monoclonal antibody with coagulation factor VIII (FVIII)–mimetic activity, was approved in Japan in 2022 for preventing bleeding in patients with AHA. However, owing to the rarity of the disease, real-world data on emicizumab use in AHA are scarce. Therefore, we aimed to assess the clinical characteristics and outcomes of 19 patients who were newly diagnosed with AHA before (non-emicizumab group [non-emi group], n = 12) and after (emicizumab group [emi group], n = 7) emicizumab approval in Japan. The median age, FVIII coagulation activity, and FVIII inhibitor titer were 81 vs 76 years, 1.0% vs 1.0%, and 43.75 vs 622 Bethesda units per mL in the non-emi and emi groups, respectively. Severe bleeding occurred in 14% of patients in the emi group, compared with 58% of patients in the non-emi group. Additionally, the doses of bypassing agents per patient were 43.4 vs 7, and the units of red blood cell transfusion per patient were 26.7 vs 4 in the non-emi and emi groups, respectively. Their hospital stays were median 73.5 days and 44 days, respectively. All patients treated with emicizumab maintained their activities of daily living (ADLs) and experienced no side effects. This study suggests that emicizumab effectively prevents bleeding in patients with AHA. Moreover, emicizumab may lead to shorter hospital stays, maintained ADLs, reduced costs, and improved prognosis in patients with AHA.
摘要 后天获得性血友病 A（AHA）是一种罕见且可能致命的出血性疾病。虽然旁路药物能有效控制活动性出血，但由于其成本高、用药频繁等缺点，需要一种药物来预防需要旁路药物的反复出血事件。Emicizumab 是一种具有凝血因子 VIII（FVIII）模拟活性的重组人源化双特异性单克隆抗体，于 2022 年在日本获批用于预防 AHA 患者出血。然而，由于这种疾病的罕见性，有关埃米珠单抗用于 AHA 的实际数据很少。因此，我们旨在评估日本批准埃米珠单抗之前（非埃米珠单抗组[non-emicizumab group]，n=12）和之后（埃米珠单抗组[emicizumab group]，n=7）19 名新诊断为 AHA 患者的临床特征和预后。非埃米组和埃米组的中位年龄、FVIII 凝血活性和 FVIII 抑制剂滴度分别为 81 岁对 76 岁、1.0% 对 1.0%、43.75 对 622 贝塞斯达单位/毫升。埃米组有 14% 的患者发生严重出血，而非埃米组有 58% 的患者发生严重出血。此外，非埃米组和埃米组每名患者使用旁路药物的剂量分别为 43.4 vs 7，输注红细胞的单位分别为 26.7 vs 4。他们的中位住院时间分别为 73.5 天和 44 天。所有接受埃米珠单抗治疗的患者都能保持日常生活能力（ADL），并且没有出现副作用。这项研究表明，埃米珠单抗能有效预防 AHA 患者出血。此外，埃米珠单抗还可缩短 AHA 患者的住院时间、维持日常生活能力、降低费用并改善预后。
{"title":"Clinical characteristics and outcomes of acquired hemophilia A before and after emicizumab approval in Japan","authors":"Daichi Kishi , Masashi Nishikubo , Yoshimitsu Shimomura , Takayuki Ishikawa , Tadakazu Kondo","doi":"10.1016/j.bvth.2024.100027","DOIUrl":"10.1016/j.bvth.2024.100027","url":null,"abstract":"<div><h3>Abstract</h3><div>Acquired hemophilia A (AHA) is a rare and potentially fatal bleeding disorder. Although bypassing agents effectively control active bleeding, their disadvantages, such as high cost and frequent administration, necessitate an agent that prevents recurrent bleeding events requiring bypassing agents. Emicizumab, a recombinant, humanized, bispecific monoclonal antibody with coagulation factor VIII (FVIII)–mimetic activity, was approved in Japan in 2022 for preventing bleeding in patients with AHA. However, owing to the rarity of the disease, real-world data on emicizumab use in AHA are scarce. Therefore, we aimed to assess the clinical characteristics and outcomes of 19 patients who were newly diagnosed with AHA before (non-emicizumab group [non-emi group], n = 12) and after (emicizumab group [emi group], n = 7) emicizumab approval in Japan. The median age, FVIII coagulation activity, and FVIII inhibitor titer were 81 vs 76 years, 1.0% vs 1.0%, and 43.75 vs 622 Bethesda units per mL in the non-emi and emi groups, respectively. Severe bleeding occurred in 14% of patients in the emi group, compared with 58% of patients in the non-emi group. Additionally, the doses of bypassing agents per patient were 43.4 vs 7, and the units of red blood cell transfusion per patient were 26.7 vs 4 in the non-emi and emi groups, respectively. Their hospital stays were median 73.5 days and 44 days, respectively. All patients treated with emicizumab maintained their activities of daily living (ADLs) and experienced no side effects. This study suggests that emicizumab effectively prevents bleeding in patients with AHA. Moreover, emicizumab may lead to shorter hospital stays, maintained ADLs, reduced costs, and improved prognosis in patients with AHA.</div></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"1 4","pages":"Article 100027"},"PeriodicalIF":0.0,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142535293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01DOI: 10.1016/j.bvth.2024.100017
Margot DeBot , Christopher Erickson , Terry Schaid , Ian LaCroix , Ernest E. Moore , Christopher Silliman , Mitchell J. Cohen , Angelo D’Alessandro , Kirk C. Hansen
Abstract
Trauma patients who sustain severe tissue injury and hemorrhage often receive fibrinogen repletion to avert coagulopathy and achieve hemostasis. However, fibrinogen supplementation has not shown a benefit in trauma patients with coagulopathy. The von Clauss functional fibrinogen assay is the primary indication for fibrinogen transfusion. This assay, however, infers fibrinogen levels optically via in vitro clot formation time and does not directly measure the quantity or quality of plasma fibrinogen. We hypothesized that the Clauss fibrinogen activity assay does not accurately reflect true fibrinogen levels in severely injured patients. Here, we demonstrate normal baseline plasma fibrinogen levels as measured by mass spectrometry despite coagulopathic Clauss values in severely injured patients. This discrepancy is most significant in patients with coagulopathy (international normalized ratio of >1.3) or with high shock, and persists even after fibrinogen repletion. These data highlight the need to reevaluate clinical testing of fibrinogen activity and transfusion criteria for the critically injured, and indicate that correcting shock and the oxidative, inflammatory milieu of trauma may be more effective at improving fibrinogen activity. This trial was registered at www.ClinicalTrials.gov as #NCT01838863.
{"title":"Trauma-induced dysfibrinogenemia: the von Clauss assay does not accurately measure fibrinogen levels after injury","authors":"Margot DeBot , Christopher Erickson , Terry Schaid , Ian LaCroix , Ernest E. Moore , Christopher Silliman , Mitchell J. Cohen , Angelo D’Alessandro , Kirk C. Hansen","doi":"10.1016/j.bvth.2024.100017","DOIUrl":"10.1016/j.bvth.2024.100017","url":null,"abstract":"<div><h3>Abstract</h3><p>Trauma patients who sustain severe tissue injury and hemorrhage often receive fibrinogen repletion to avert coagulopathy and achieve hemostasis. However, fibrinogen supplementation has not shown a benefit in trauma patients with coagulopathy. The von Clauss functional fibrinogen assay is the primary indication for fibrinogen transfusion. This assay, however, infers fibrinogen levels optically via in vitro clot formation time and does not directly measure the quantity or quality of plasma fibrinogen. We hypothesized that the Clauss fibrinogen activity assay does not accurately reflect true fibrinogen levels in severely injured patients. Here, we demonstrate normal baseline plasma fibrinogen levels as measured by mass spectrometry despite coagulopathic Clauss values in severely injured patients. This discrepancy is most significant in patients with coagulopathy (international normalized ratio of >1.3) or with high shock, and persists even after fibrinogen repletion. These data highlight the need to reevaluate clinical testing of fibrinogen activity and transfusion criteria for the critically injured, and indicate that correcting shock and the oxidative, inflammatory milieu of trauma may be more effective at improving fibrinogen activity. This trial was registered at <span><span>www.ClinicalTrials.gov</span><svg><path></path></svg></span> as #NCT01838863.</p></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"1 3","pages":"Article 100017"},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2950327224000172/pdfft?md5=5880916926772cd8bc0dccf15d720b5a&pid=1-s2.0-S2950327224000172-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141706753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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